Therapeutic drug management of linezolid: a missed opportunity for clinicians?

Science.gov (United States)

Cattaneo, Dario; Gervasoni, Cristina; Cozzi, Valeria; Castoldi, Simone; Baldelli, Sara; Clementi, Emilio

2016-12-01

Some studies have shown that adjustments to the linezolid dose guided by therapeutic drug monitoring (TDM) can reduce interindividual variability in drug exposure and improve linezolid tolerability. In this study, 6 years of linezolid TDM, a diagnostic service for our hospital and others in the Milan (Italy) area, is described. Samples were collected immediately before the morning dose intake (trough concentrations) in steady-state conditions. Linezolid concentrations were quantified by a validated high-performance liquid chromatography (HPLC) method. Four hundred linezolid trough concentrations from 220 patients were collected. A 20-fold variability in linezolid levels was observed. Positive and significant correlations between linezolid trough concentrations and patient age (r = 0.325, P linezolid concentrations with time was observed in a subgroup of patients with more than one TDM assessment. Elderly patients, especially those aged >80 years and with impaired renal function, are at a higher risk of overexposure to linezolid. Despite the observed progressive increase in linezolid concentrations over time, most physicians did not change the drug dose according to the TDM results, even in the presence of frank overexposure to linezolid. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Detection of linezolid resistance due to the optrA gene in Enterococcus faecalis from poultry meat from the American continent (Colombia)

DEFF Research Database (Denmark)

Cavaco, Lina; Bernal, J F; Zankari, Ea

2017-01-01

Three Enterococcus isolates obtained from retail chicken collected in 2010-11 as part of the Colombian Integrated Program for Antimicrobial Resistance Surveillance (COIPARS) showed reduced susceptibility towards linezolid (MIC 8 mg/L). This study aimed at characterizing the isolates resistant......A gene encoding resistance to linezolid and phenicols. Additional screening of 37 enterococci strains from the same study did not detect any further positives. Typing showed that two of the isolates belong to ST59, while the last belongs to ST489. All isolates carry genes encoding resistance to macrolide...

Multicenter assessment of the linezolid spectrum and activity using the disk diffusion and Etest methods: report of the Zyvox® Antimicrobial Potency Study in Latin America (LA-ZAPS

Directory of Open Access Journals (Sweden)

Ballow Charles H.

2002-01-01

Full Text Available Linezolid was the first clinically applied member of the new antimicrobial class called the "oxazolidinones". These agents have a powerful spectrum of activity focussed against Gram-positive organisms including strains with documented resistances to other antimicrobial classes. We conducted a multicenter surveillance (Zyvox Antimicrobial Potency Study; ZAPS trial of qualifying Gram-positive isolates from 24 medical centers in eight countries in Latin America. The activity and spectrum of linezolid was compared to numerous agents including glycopeptides, quinupristin/dalfopristin, b-lactams and fluoroquinolones when testing 2,640 strains by the standardized disk diffusion method or Etest (AB BIODISK, Solna, Sweden. The linezolid spectrum was complete against staphylococci (median zone diameter, 29 - 32 mm, as was the spectrum of vancomycin and quinupristin/dalfopristin. Among the enterococci, no linezolid resistance was detected, and the susceptibility rate was 93.1 - 96.4%. Only the vancomycin-susceptible Enterococcus faecium strains remained susceptible (92.8% to quinupristin/dalfopristin. Marked differences in the glycopeptide resistance patterns (van A versus van B were noted for the 22 isolates of VRE, thus requiring local susceptibility testing to direct therapy. Streptococcus pneumoniae and other species were very susceptible (100.0% to linezolid, MIC90 at 0.75 mug/ml. Penicillin non-susceptible rate was 27.7% and erythromycin resistance was at 17.4%. Other streptococci were also completely susceptible to linezolid (MIC90, 1 mug/ml. These results provide the initial benchmark of potency and spectrum for linezolid in Latin American medical centers. Future comparisons should recognize that the oxazolidinones possess essentially a complete spectrum coverage of the monitored staphylococci, enterococci and streptococcal isolates in 2000-2001. This positions linezolid as the widest spectrum empiric choice against multi-resistant Gram

Multicenter assessment of the linezolid spectrum and activity using the disk diffusion and Etest methods: report of the Zyvox® Antimicrobial Potency Study in Latin America (LA-ZAPS

Directory of Open Access Journals (Sweden)

Charles H. Ballow

Full Text Available Linezolid was the first clinically applied member of the new antimicrobial class called the "oxazolidinones". These agents have a powerful spectrum of activity focussed against Gram-positive organisms including strains with documented resistances to other antimicrobial classes. We conducted a multicenter surveillance (Zyvox Antimicrobial Potency Study; ZAPS trial of qualifying Gram-positive isolates from 24 medical centers in eight countries in Latin America. The activity and spectrum of linezolid was compared to numerous agents including glycopeptides, quinupristin/dalfopristin, b-lactams and fluoroquinolones when testing 2,640 strains by the standardized disk diffusion method or Etest (AB BIODISK, Solna, Sweden. The linezolid spectrum was complete against staphylococci (median zone diameter, 29 - 32 mm, as was the spectrum of vancomycin and quinupristin/dalfopristin. Among the enterococci, no linezolid resistance was detected, and the susceptibility rate was 93.1 - 96.4%. Only the vancomycin-susceptible Enterococcus faecium strains remained susceptible (92.8% to quinupristin/dalfopristin. Marked differences in the glycopeptide resistance patterns (van A versus van B were noted for the 22 isolates of VRE, thus requiring local susceptibility testing to direct therapy. Streptococcus pneumoniae and other species were very susceptible (100.0% to linezolid, MIC90 at 0.75 mug/ml. Penicillin non-susceptible rate was 27.7% and erythromycin resistance was at 17.4%. Other streptococci were also completely susceptible to linezolid (MIC90, 1 mug/ml. These results provide the initial benchmark of potency and spectrum for linezolid in Latin American medical centers. Future comparisons should recognize that the oxazolidinones possess essentially a complete spectrum coverage of the monitored staphylococci, enterococci and streptococcal isolates in 2000-2001. This positions linezolid as the widest spectrum empiric choice against multi-resistant Gram

Linezolid-Dependent Function and Structure Adaptation of Ribosomes in a Staphylococcus epidermidis Strain Exhibiting Linezolid Dependence

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Kokkori, Sofia; Apostolidi, Maria; Tsakris, Athanassios; Pournaras, Spyros

2014-01-01

Linezolid-dependent growth was recently reported in Staphylococcus epidermidis clinical strains carrying mutations associated with linezolid resistance. To investigate this unexpected behavior at the molecular level, we isolated active ribosomes from one of the linezolid-dependent strains and we compared them with ribosomes isolated from a wild-type strain. Both strains were grown in the absence and presence of linezolid. Detailed biochemical and structural analyses revealed essential differences in the function and structure of isolated ribosomes which were assembled in the presence of linezolid. The catalytic activity of peptidyltransferase was found to be significantly higher in the ribosomes derived from the linezolid-dependent strain. Interestingly, the same ribosomes exhibited an abnormal ribosomal subunit dissociation profile on a sucrose gradient in the absence of linezolid, but the profile was restored after treatment of the ribosomes with an excess of the antibiotic. Our study suggests that linezolid most likely modified the ribosomal assembly procedure, leading to a new functional ribosomal population active only in the presence of linezolid. Therefore, the higher growth rate of the partially linezolid-dependent strains could be attributed to the functional and structural adaptations of ribosomes to linezolid. PMID:24890589

Linezolid induced retinopathy.

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Park, Dae Hyun; Park, Tae Kwann; Ohn, Young-Hoon; Park, Jong Sook; Chang, Jee Ho

2015-12-01

While optic neuropathy is a well-known cause of visual disturbances in linezolid-treated patients, the possibility of linezolid-related retinopathy has not been investigated. Here, we report a case of retinopathy demonstrated by multifocal electroretinogram (mfERG) in a linezolid-treated patient. A 61-year-old man with extensively drug-resistant pulmonary tuberculosis treated with linezolid for 5 months presented with painless loss of vision in both eyes. The patient's best corrected visual acuity was 20/50 in the right eye and 20/100 in the left eye. Fundus examination revealed mild disc edema, and color vision was defective in both eyes. Humphrey visual field tests showed a superotemporal field defect in the right eye and central and pericentral field defect in the left eye. Optical coherence tomography (OCT) revealed only mild optic disc swelling. In mfERG, central amplitudes were depressed in both eyes. Four months after the cessation of linezolid, visual acuity was restored to 20/20 right eye and 20/25 left eye. The color vision and visual field had improved. The OCT and mfEFG findings improved as well. Although the clinical features were similar to linezolid-induced optic neuropathy, the mfERG findings suggest the possibility of a retinopathy through cone dysfunction.

Wide dissemination of linezolid-resistant Staphylococcus epidermidis in Greece is associated with a linezolid-dependent ST22 clone.

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Karavasilis, Vasilios; Zarkotou, Olympia; Panopoulou, Maria; Kachrimanidou, Melina; Themeli-Digalaki, Katerina; Stylianakis, Antonios; Gennimata, Vassiliki; Ntokou, Eleni; Stathopoulos, Constantinos; Tsakris, Athanasios; Pournaras, Spyros

2015-01-01

Dependence on linezolid was recently described as significant growth acceleration of linezolid-resistant Staphylococcus epidermidis (LRSE) isolates upon linezolid exposure. We investigated the possible contribution of linezolid dependence to LRSE dissemination in Greece. Linezolid resistance rates were estimated in six tertiary hospitals located throughout Greece between 2011 and 2013. Sixty-three randomly selected LRSE recovered in these hospitals during this period were studied. Growth curve analysis was conducted with and without linezolid. Clonality of the isolates was investigated by PFGE and MLST. During the study period, the LRSE rate in the participating hospitals rose significantly from 6.9% to 9% (P = 0.006); the increase was more prominent in ICUs (from 15.1% to 20.9%; P = 0.005). Forty-seven (74.6%) of the 63 LRSE, derived from all study hospitals, clearly exhibited linezolid dependence, growing significantly faster in the presence of 16 and 32 mg/L linezolid. Of note, 61 (96.8%) LRSE exhibited a single macrorestriction pattern and belonged to ST22, which included all linezolid-dependent LRSE. The remaining two LRSE belonged to unique STs. Five of six linezolid-dependent isolates tested also exhibited linezolid dependence upon exposure to 8 mg/L linezolid. Interestingly, five of six ST22 linezolid-non-dependent isolates tested developed linezolid dependence when linezolid exposure preceded growth analysis. The rapid LRSE dissemination in Greek hospitals threatens linezolid activity. The observation that most LRSE belonged to ST22 and expressed dependence on linezolid clearly implies that the spread of linezolid resistance should have been driven by this trait, which provided the LRSE with a selective advantage under linezolid pressure. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Linezolid Decreases Susceptibility to Secondary Bacterial Pneumonia Post-Influenza Infection in Mice Through its Effects on Interferon-γ

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Breslow-Deckman, Jessica M.; Mattingly, Cynthia M.; Birket, Susan E.; Hoskins, Samantha N.; Ho, Tam N.; Garvy, Beth A.; Feola, David J.

2013-01-01

Influenza infection predisposes patients to secondary bacterial pneumonia that contributes significantly to morbidity and mortality. While this association is well documented, the mechanisms that govern this synergism are poorly understood. A window of hyporesponsiveness following influenza infection has been associated with a substantial increase in local and systemic IFNγ concentrations. Recent data suggests that the oxazolidinone antibiotic linezolid decreases IFNγ and TNFα production in vitro from stimulated peripheral blood mononuclear cells. We therefore sought to determine whether linezolid would reverse immune hyporesponsiveness after influenza infection in mice through its effects on IFNγ. In vivo dose response studies demonstrated that oral linezolid administration sufficiently decreased bronchoalveolar lavage fluid levels of IFNγ at day 7 post-influenza infection in a dose-dependent manner. The drug also decreased morbidity as measured by weight loss compared to vehicle-treated controls. When mice were challenged intranasally with S. pneumoniae 7 days after infection with influenza, linezolid pre-treatment led to decreased IFNγ and TNFα production, decreased weight loss, and lower bacterial burdens at 24 hours post bacterial infection in comparison to vehicle-treated controls. To determine whether these effects were due to suppression of IFNγ, linezolid-treated animals were given intranasal instillations of recombinant IFNγ before challenge with S. pneumoniae. This partially reversed the protective effects observed in the linezolid-treated mice, suggesting that the modulatory effects of linezolid are mediated partially by its ability to blunt IFNγ production. These results suggest that IFNγ, and potentially TNFα, may be useful drug targets for prophylaxis against secondary bacterial pneumonia following influenza infection. PMID:23833238

Linezolid-resistant clinical isolates of enterococci and Staphylococcus cohnii from a multicentre study in China: molecular epidemiology and resistance mechanisms.

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Chen, Hongbin; Wu, Weiyuan; Ni, Ming; Liu, Yingmei; Zhang, Jixia; Xia, Fei; He, Wenqiang; Wang, Qi; Wang, Zhanwei; Cao, Bin; Wang, Hui

2013-10-01

Genetic characterisation of linezolid-resistant Gram-positive cocci in a multicentre study in China has not been reported previously. To study the mechanism underlying the resistance of linezolid-resistant isolates, nine Enterococcus faecalis, one Enterococcus faecium and three Staphylococcus cohnii isolates with various levels of resistance were collected from five hospitals across China in 2009-2012. The nine E. faecalis isolates were classified into seven sequence types, indicating that these linezolid-resistant E. faecalis isolates were polyclonal. Enterococci isolates had reduced susceptibility to linezolid (MICs of 4-8 mg/L) and had mutation of ribosomal protein L3, with three also having mutation of L4, but without the multidrug resistance gene cfr or the 23S rRNA mutation G2576T. The three S. cohnii isolates were highly resistant to linezolid (MICs of 64 mg/L to >256 mg/L), harboured the cfr gene and had the 23S rRNA mutation G2576T. Southern blotting indicated that the cfr gene of these three isolates resided on different plasmids (pHK01, pRM01 and pRA01). In plasmid pHK01, IS21-558 and the cfr gene were integrated into transposon Tn558. In plasmids pRM01 and pRA01, the cfr gene was flanked by two copies of an IS256-like insertion sequence, indicating that the transferable form of linezolid resistance is conferred by the cfr gene. In conclusion, the emergence of linezolid-resistant Gram-positive cocci in different regions of China is of concern. The cfr gene and the 23S rRNA mutation contribute to high-level linezolid resistance in S. cohnii, and the L3 and L4 mutations are associated with low-level linezolid resistance in enterococci. Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Intrapulmonary penetration of linezolid.

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Honeybourne, David; Tobin, Caroline; Jevons, Gail; Andrews, Jenny; Wise, Richard

2003-06-01

This study was designed to measure the concentrations of linezolid in bronchial mucosa, pulmonary macrophages and epithelial lining fluid and to compare them with simultaneous blood levels. Ten adult patients undergoing bronchoscopy for diagnostic purposes were given oral linezolid at a dosage of 600 mg twice a day for a total of six doses. Patients with active lung infection were excluded from the study. Flexible bronchoscopy was carried out between 2 and 8 h after the last dose of linezolid. Bronchial biopsies and bronchoalveolar lavage were carried out and a simultaneous blood sample obtained. Linezolid levels were measured using high-performance liquid chromatography (HPLC). Mean concentrations of linezolid were 13.4 mg/L in serum, 10.7 mg/kg in mucosa, 8.1 mg/L in alveolar macrophages and 25.1 mg/L in epithelial lining fluid. The mean site/serum concentration ratios were 0.79 for bronchial mucosa, 0.71 for macrophages and 8.35 for epithelial lining fluid. The MIC90 (< or =4 mg/L) of linezolid for Staphylococcus aureus and Streptococcus pneumoniae was exceeded in serum and bronchial mucosa in all subjects, in epithelial lining fluid in nine subjects and in macrophages in six subjects.

Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis.

Science.gov (United States)

Srivastava, Shashikant; Magombedze, Gesham; Koeuth, Thearith; Sherman, Carleton; Pasipanodya, Jotam G; Raj, Prithvi; Wakeland, Edward; Deshpande, Devyani; Gumbo, Tawanda

2017-08-01

Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect and dose-scheduling studies in the hollow fiber system model of tuberculosis (HFS-TB) for sterilizing effect. HFS-TB units were treated with several doses to mimic human-like linezolid intrapulmonary pharmacokinetics and repetitively sampled for drug concentration, total bacterial burden, linezolid-resistant subpopulations, and RNA sequencing over 2 months. Linezolid-resistant isolates underwent whole-genome sequencing. The expression of genes encoding efflux pumps in the first 1 to 2 weeks revealed the same exposure-response patterns as the linezolid-resistant subpopulation. Linezolid-resistant isolates from the 2nd month of therapy revealed mutations in several efflux pump/transporter genes and a LuxR-family transcriptional regulator. Linezolid sterilizing effect was linked to the ratio of unbound 0- to 24-h area under the concentration-time curve (AUC 0-24 ) to MIC. Optimal microbial kill was achieved at an AUC 0-24 /MIC ratio of 119. The optimal sterilizing effect dose for clinical use was identified using Monte Carlo simulations. Clinical doses of 300 and 600 mg/day (or double the dose every other day) achieved this target in 87% and >99% of 10,000 patients, respectively. The susceptibility breakpoint identified was 2 mg/liter. The simulations identified that a 300-mg/day dose did not achieve AUC 0-24 s associated with linezolid toxicity, while 600 mg/day achieved those AUC 0-24 s in linezolid dose of 300 mg/day performed well and should be compared to 600 mg/day or 1,200 mg every other day in clinical trials. Copyright © 2017 Srivastava et al.

Increasing Incidence of Linezolid-Intermediate or -Resistant, Vancomycin-Resistant Enterococcus faecium Strains Parallels Increasing Linezolid Consumption▿

OpenAIRE

Scheetz, Marc H.; Knechtel, Stephanie A.; Malczynski, Michael; Postelnick, Michael J.; Qi, Chao

2008-01-01

Clinical enterococcal resistance to linezolid is defined by the presence of the G2576T mutation. We evaluated the incidence of genetically proven linezolid resistance among vancomycin-resistant Enterococcus faecium strains and linezolid consumption for a possible association. A relationship was found (r2 = 0.73, P = 0.03) and predicts increasing resistance with current trends of linezolid use.

Linezolid-Dependent Function and Structure Adaptation of Ribosomes in a Staphylococcus epidermidis Strain Exhibiting Linezolid Dependence

OpenAIRE

Kokkori, Sofia; Apostolidi, Maria; Tsakris, Athanassios; Pournaras, Spyros; Stathopoulos, Constantinos; Dinos, George

2014-01-01

Linezolid-dependent growth was recently reported in Staphylococcus epidermidis clinical strains carrying mutations associated with linezolid resistance. To investigate this unexpected behavior at the molecular level, we isolated active ribosomes from one of the linezolid-dependent strains and we compared them with ribosomes isolated from a wild-type strain. Both strains were grown in the absence and presence of linezolid. Detailed biochemical and structural analyses revealed essential differe...

Clinical Population Pharmacokinetics and Toxicodynamics of Linezolid

Science.gov (United States)

Boak, Lauren M.; Rayner, Craig R.; Grayson, M. Lindsay; Paterson, David L.; Spelman, Denis; Khumra, Sharmila; Capitano, Blair; Forrest, Alan; Li, Jian

2014-01-01

Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h. PMID:24514086

In vitro evaluation of the effect of linezolid and levofloxacin on Bacillus anthracis toxin production, spore formation and cell growth.

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Head, Breanne M; Alfa, Michelle; Sitar, Daniel S; Rubinstein, Ethan; Meyers, Adrienne F A

2017-02-01

Owing to its ability to form spores and toxins, Bacillus anthracis is considered a bioterror agent. Although current therapeutic strategies can be effective, treatment does not prevent sporulation and toxin production. To quantify the combined effect of a protein synthesis inhibitor and a bactericidal agent on B. anthracis toxin production, sporulation and cell growth. Susceptibility and synergy titrations were conducted on B. anthracis Sterne and 03-0191 strains using linezolid and levofloxacin. The effect of antibiotic exposure on cell viability was evaluated using a continuous medium replacement model. In vitro static models were used to study the effect of linezolid and levofloxacin on sporulation and toxin production. Spores were quantified using the heat shock method. Toxin was quantified via commercial ELISA. Synergy titrations indicated that the combination was synergistic or indifferent; however, in all models antagonism was observed. In the spore model, linezolid resulted in the lowest sporulation rates, while combination therapy resulted in the highest. In the toxin model, linezolid prevented toxin production altogether. This study advances our understanding of the effects of combination therapy on B. anthracis infection. Used alone, linezolid therapy abolishes toxin production and reduces sporulation. These results suggest that studies using a step-wise approach using linezolid initially to stop sporulation and toxin production followed by levofloxacin to rapidly kill vegetative B. anthracis can be recommended. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Population pharmacokinetics and pharmacodynamics of linezolid-induced thrombocytopenia in hospitalized patients.

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Tsuji, Yasuhiro; Holford, Nicholas H G; Kasai, Hidefumi; Ogami, Chika; Heo, Young-A; Higashi, Yoshitsugu; Mizoguchi, Akiko; To, Hideto; Yamamoto, Yoshihiro

2017-08-01

Thrombocytopenia is among the most important adverse effects of linezolid treatment. Linezolid-induced thrombocytopenia incidence varies considerably but has been associated with impaired renal function. We investigated the pharmacodynamic mechanism (myelosuppression or enhanced platelet destruction) and the role of impaired renal function (RF) in the development of thrombocytopenia. The pharmacokinetics of linezolid were described with a two-compartment distribution model with first-order absorption and elimination. RF was calculated using the expected creatinine clearance. The decrease platelets by linezolid exposure was assumed to occur by one of two mechanisms: inhibition of the formation of platelets (PDI) or stimulation of the elimination (PDS) of platelets. About 50% of elimination was found to be explained by renal clearance (normal RF). The population mean estimated plasma protein binding of linezolid was 18% [95% confidence interval (CI) 16%, 20%] and was independent of the observed concentrations. The estimated mixture model fraction of patients with a platelet count decreased due to PDI was 0.97 (95% CI 0.87, 1.00), so the fraction due to PDS was 0.03. RF had no influence on linezolid pharmacodynamics. We have described the influence of weight, renal function, age and plasma protein binding on the pharmacokinetics of linezolid. This combined pharmacokinetic, pharmacodynamic and turnover model identified that the most common mechanism of thrombocytopenia associated with linezolid is PDI. Impaired RF increases thrombocytopenia by a pharmacokinetic mechanism. The linezolid dose should be reduced in RF. © 2017 The British Pharmacological Society.

Resistance to Linezolid

DEFF Research Database (Denmark)

Vester, Birte; Ntokou, Eleni

2017-01-01

Linezolid is an antimicrobial agent that binds to the bacterial ribosome and thereby inhibits protein synthesis. Soon after its release as a clinical drug, it became clear that bacteria could become resistant to linezolid. The resistance mechanisms are mainly causing alteration of the drug target...... site, but probably efflux might also play a role. The resistance is still rare in surveillance studies, but outbreaks of resistant clones from hospitals have been observed. So far the main mechanisms of resistance are occurrence of mutations in ribosomal genes or obtaining plasmids with a gene coding...... for a methyltransferase providing resistance. The most obvious way to avoid resistance may be development of derivatives of linezolid overcoming the known resistance mechanisms....

Five-Year Summary of In Vitro Activity and Resistance Mechanisms of Linezolid against Clinically Important Gram-Positive Cocci in the United States from the LEADER Surveillance Program (2011 to 2015).

Science.gov (United States)

Pfaller, Michael A; Mendes, Rodrigo E; Streit, Jennifer M; Hogan, Patricia A; Flamm, Robert K

2017-07-01

This report describes linezolid susceptibility testing results for 6,741 Gram-positive pathogens from 60 U.S. sites collected during 2015 for the LEADER Program. In addition, the report summarizes linezolid in vitro activity, resistance mechanisms, and molecular typing obtained for 2011 to 2015. During 2015, linezolid showed potent activity in testing against Staphylococcus aureus , inhibiting >99.9% of 3,031 isolates at ≤2 µg/ml. Similarly, linezolid showed coverage against 99.2% of coagulase-negative staphylococci, 99.7% of enterococci, and 100.0% of Streptococcus pneumoniae , virdans group, and beta-hemolytic streptococcus isolates tested. The overall linezolid resistance rate remained a modest linezolid resistance mechanisms. Increased annual trends for the presence of cfr among Staphylococcus aureus isolates were not observed, but 64.3% (9/14) of the isolates with decreased susceptibility (MIC, ≥4 µg/ml) to linezolid carried this transferrable gene (2011 to 2015). The cfr gene was detected in 21.9% (7/32) of linezolid-resistant staphylococci other than S. aureus from 2011 to 2015. The optrA gene was noted in half (2/4) of the population of linezolid-nonsusceptible Enterococcus faecalis isolates from 2011 to 2015, while linezolid-nonsusceptible Enterococcus faecium isolates showed alterations predominantly (16/16) in the 23S rRNA gene (G2576T). This report confirms a long record of linezolid activity against Gram-positive isolates in the United States since regulatory approval in 2000 and reports the oxazolidinones evolving resistance mechanisms. Copyright © 2017 American Society for Microbiology.

Pharmacokinetics of linezolid in critically ill patients.

Science.gov (United States)

Sazdanovic, Predrag; Jankovic, Slobodan M; Kostic, Marina; Dimitrijevic, Aleksandra; Stefanovic, Srdjan

2016-06-01

Linezolid is an oxazolidinone antibiotic active against Gram-positive bacteria, and is most commonly used to treat life-threatening infections in critically ill patients. The pharmacokinetics of linezolid are profoundly altered in critically ill patients, partly due to decreased function of vital organs, and partly because life-sustaining drugs and devices may change the extent of its excretion. This article is summarizes key changes in the pharmacokinetics of linezolid in critically ill patients. The changes summarized are clinically relevant and may serve as rationale for dosing recommendations in this particular population. While absorption and penetration of linezolid to tissues are not significantly changed in critically ill patients, protein binding of linezolid is decreased, volume of distribution increased, and metabolism may be inhibited leading to non-linear kinetics of elimination; these changes are responsible for high inter-individual variability of linezolid plasma concentrations, which requires therapeutic plasma monitoring and choice of continuous venous infusion as the administration method. Acute renal or liver failure decrease clearance of linezolid, but renal replacement therapy is capable of restoring clearance back to normal, obviating the need for dosage adjustment. More population pharmacokinetic studies are necessary which will identify and quantify the influence of various factors on clearance and plasma concentrations of linezolid in critically ill patients.

Assessment of linezolid prescriptions in three French hospitals.

Science.gov (United States)

Dentan, C; Forestier, E; Roustit, M; Boisset, S; Chanoine, S; Epaulard, O; Pavese, P

2017-07-01

The use of linezolid to treat gram-positive cocci infections is increasing in France. Linezolid is approved in pneumonia and complicated skin and soft tissue infections. Overuse and misuse of linezolid can favor the emergence and spreading of linezolid-resistant strains. We aimed to assess the appropriateness of linezolid use in French hospitals. This is a multicenter, retrospective study conducted in three tertiary care hospitals. Appropriateness of linezolid indications and adequacy (composite score concerning dosage, route of administration and blood monitoring) were assessed. Over a three-month period, all prescriptions of linezolid were extracted and analyzed by two independent infectious disease experts. Among the 81 initial prescriptions that were evaluated, indication was appropriate in 48% of cases. Among those, 51% complied with international guidelines. Fifty-seven percent of the prescriptions were adequate regarding dosage, route of administration and blood monitoring. Overall, 23% of prescriptions combined both appropriateness and adequacy. The most frequent reasons for inappropriateness were the possibility of choosing narrower-spectrum antibiotics and the empirical use of linezolid in severe sepsis or septic shock. Initial treatment was the most frequently appropriate in bone and joint infection cases (p = 0.001). Our study shows that even if modalities of use were mostly correct, appropriateness of linezolid indications is low. Educational programs are mandatory to improve practices, as well as clinical studies to better assess the efficacy and safety of linezolid in clinical situations other than pneumonia or complicated skin and soft tissue infections.

Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy

Science.gov (United States)

Drusano, George L.; Adams, Jonathan R.; Rodriquez, Jaime L.; Jambunathan, Kalyani; Baluya, Dodge L.; Brown, David L.; Kwara, Awewura; Mirsalis, Jon C.; Hafner, Richard; Louie, Arnold

2015-01-01

ABSTRACT Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis. Clinically relevant linezolid regimens were simulated in the in vitro hollow-fiber infection model (HFIM) system to identify the linezolid therapies that minimize toxicity, maximize antibacterial activity, and prevent drug resistance. Linezolid inhibited mitochondrial proteins in an exposure-dependent manner, with toxicity being driven by trough concentrations. Once-daily linezolid killed M. tuberculosis in an exposure-dependent manner. Further, 300 mg linezolid given every 12 hours generated more bacterial kill but more toxicity than 600 mg linezolid given once daily. None of the regimens prevented linezolid resistance. These findings show that with linezolid monotherapy, a clear tradeoff exists between antibacterial activity and toxicity. By identifying the pharmacokinetic parameters linked with toxicity and antibacterial activity, these data can provide guidance for clinical trials evaluating linezolid in multidrug antituberculosis regimens. PMID:26530386

Retrospective study of tolerability and efficacy of linezolid in patients with multidrug-resistant tuberculosis (1998-2014).

Science.gov (United States)

Ramírez-Lapausa, Marta; Pascual Pareja, José Francisco; Carrillo Gómez, Raquel; Martínez-Prieto, Mónica; González-Ruano Pérez, Patricia; Noguerado Asensio, Arturo

2016-02-01

Although linezolid is known to be effective when used as an adjunct therapy in the treatment of patients with multidrug-resistant tuberculosis (MDR-TB), the clinical experience is limited. In this study the efficacy and adverse effects of linezolid treatment were evaluated. A retrospective study of tolerability and efficacy of linezolid in MDR-TB patients was performed in Madrid, Spain. Demographic characteristics, microbiological and clinical features and data on treatment tolerability were collected. Regimens were constructed with a target of prescribing, at least, five anti-tuberculosis agents likely to be effective. Linezolid, at a dosage of 1200 or 600 mg daily, was included to complete the treatment if no other sensitive drugs were available. Vitamin B6 was used to reduce toxicity. Treatment outcome and clinical status at last contact were compared between patients with linezolid-containing regimens and with those without linezolid-containing regimens. During the period 1998-2014, 55 patients with MDR-TB received treatment. In 21 of these patients, linezolid was added. The median of linezolid administration was 23.9 months (IQT 13.1-24.7). Patients using linezolid showed a greater resistance to drugs, with a median of 6 (IQR 5-7) compared with those who did not use it, with a median of 4 drugs (IQR 3-5) (plinezolid group (73.5 days) did not differ significantly from those in the non-linezolid group (61 days) (p=0.29). There were no significant differences in the outcomes of the two patient groups. There were no reported adverse events in 81% of patients assigned to linezolid therapy. Only four patients developed toxicity attributed to linezolid. The most serious adverse event in these patients was anemia observed in the two patients treated with 1200 mg per day. One of them also developed moderate paresthesia. In both cases the dosage was reduced to 600 mg per day, with improvement of the anemia and paresthesias. No patients stopped linezolid therapy. A daily

Possible serotonin syndrome with carbidopa-levodopa and linezolid.

Science.gov (United States)

Pettit, N N; Alonso, V; Wojcik, E; Anyanwu, E C; Ebara, L; Benoit, J-L

2016-02-01

Serotonin syndrome (SS) can occur when linezolid is combined with other serotonergic agents. We report a case of possible SS in an elderly patient receiving linezolid in combination with carbidopa-levodopa (CL). Although certain classes of agents are commonly reported as causing SS among patients receiving linezolid, there are no specific case reports detailing this reaction with CL. Linezolid combined with CL should generally be avoided; however, if linezolid must be used, discontinuation of other agents with serotonergic activity is recommended with careful monitoring for signs and symptoms of SS. © 2016 John Wiley & Sons Ltd.

Global analysis of the impact of linezolid onto virulence factor production in S. aureus USA300.

Science.gov (United States)

Bonn, Florian; Pané-Farré, Jan; Schlüter, Rabea; Schaffer, Marc; Fuchs, Stephan; Bernhardt, Jörg; Riedel, Katharina; Otto, Andreas; Völker, Uwe; van Dijl, Jan Maarten; Hecker, Michael; Mäder, Ulrike; Becher, Dörte

2016-05-01

The translation inhibitor linezolid is an antibiotic of last resort against Gram-positive pathogens including methicillin resistant strains of the nosocomial pathogen Staphylococcus aureus. Linezolid is reported to inhibit production of extracellular virulence factors, but the molecular cause is unknown. To elucidate the physiological response of S. aureus to linezolid in general and the inhibition of virulence factor synthesis in particular a holistic study was performed. Linezolid was added to exponentially growing S. aureus cells and the linezolid stress response was analyzed with transcriptomics and quantitative proteomics methods. In addition, scanning and transmission electron microscopy experiments as well as fluorescence microscopy analyses of the cellular DNA and membrane were performed. As previously observed in studies on other translation inhibitors, S. aureus adapts its protein biosynthesis machinery to the reduced translation efficiency. For example the synthesis of ribosomal proteins was induced. Also unexpected results like a decline in the amount of extracellular and membrane proteins were obtained. In addition, cell shape and size changed after linezolid stress and cell division was diminished. Finally, the chromosome was condensed after linezolid stress and lost contact to the membrane. These morphological changes cannot be explained by established theories. A new hypothesis is discussed, which suggests that the reduced amount of membrane and extracellular proteins and observed defects in cell division are due to the disintegration of transertion complexes by linezolid. Copyright © 2016 Elsevier GmbH. All rights reserved.

Optimal Clinical Doses of Faropenem, Linezolid, and Moxifloxacin in Children With Disseminated Tuberculosis: Goldilocks.

Science.gov (United States)

Srivastava, Shashikant; Deshpande, Devyani; Pasipanodya, Jotam; Nuermberger, Eric; Swaminathan, Soumya; Gumbo, Tawanda

2016-11-01

 When treated with the same antibiotic dose, children achieve different 0- to 24-hour area under the concentration-time curves (AUC 0-24 ) because of maturation and between-child physiological variability on drug clearance. Children are also infected by Mycobacterium tuberculosis isolates with different antibiotic minimum inhibitory concentrations (MICs). Thus, each child will achieve different AUC 0-24 /MIC ratios when treated with the same dose.  We used 10 000-subject Monte Carlo experiments to identify the oral doses of linezolid, moxifloxacin, and faropenem that would achieve optimal target exposures associated with optimal efficacy in children with disseminated tuberculosis. The linezolid and moxifloxacin exposure targets were AUC 0-24 /MIC ratios of 62 and 122, and a faropenem percentage of time above MIC >60%, in combination therapy. A linezolid AUC 0-24 of 93.4 mg × hour/L was target for toxicity. Population pharmacokinetic parameters of each drug and between-child variability, as well as MIC distribution, were used, and the cumulative fraction of response (CFR) was calculated. We also considered drug penetration indices into meninges, bone, and peritoneum.  The linezolid dose of 15 mg/kg in full-term neonates and infants aged up to 3 months and 10 mg/kg in toddlers, administered once daily, achieved CFR ≥ 90%, with linezolid AUC 0-24 associated with toxicity. The moxifloxacin dose of 25 mg/kg/day achieved a CFR > 90% in infants, but the optimal dose was 20 mg/kg/day in older children. The faropenem medoxomil optimal dosage was 30 mg/kg 3-4 times daily.  The regimen and doses of linezolid, moxifloxacin, and faropenem identified are proposed to be adequate for all disseminated tuberculosis syndromes, whether drug-resistant or -susceptible. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Emergence of methicillin-resistant coagulase-negative staphylococci resistant to linezolid with rRNA gene C2190T and G2603T mutations.

Science.gov (United States)

Cidral, Thiago André; Carvalho, Maria Cícera; Figueiredo, Agnes Marie Sá; de Melo, Maria Celeste Nunes

2015-10-01

The aim of this article were to determinate the mechanism of linezolid resistance in coagulase-negative methicillin-resistant staphylococci from hospitals in the northeast of Brazil. We identified the isolates using VITEK(®) 2 and MALDI-TOF. Susceptibility to antibiotics was measured by the disk-diffusion method and by Etest(®) . Extraction of the whole genome DNA was performed, followed by screening of all the strains for the presence of mecA and cfr genes. The domain V region of 23S rRNA gene was sequenced and then aligned with a linezolid-susceptible reference strain. Pulsed-field gel electrophoresis (PFGE) macro-restriction analysis was performed. Three linezolid-resistant Staphylococcus hominis and two linezolid-resistant Staphylococcus epidermidis strains were analyzed. The isolates showed two point mutations in the V region of the 23S rRNA gene (C2190T and G2603T). We did not detect the cfr gene in any isolate by PCR. The S. hominis showed the same pulsotype, while the S. epidermidis did not present any genetic relation to each other. In conclusion, this study revealed three S. hominis and two S. epidermidis strains with resistance to linezolid due to a double mutation (C2190T and G2603T) in the domain V of the 23S rRNA gene. For the first time, the mutation of C2190T in S. epidermidis is described. This study also revealed the clonal spread of a S. hominis pulsotype between three public hospitals in the city of Natal, Brazil. These findings highlight the importance of continued vigilance of linezolid resistance in staphylococci. © 2015 APMIS. Published by John Wiley & Sons Ltd.

Identification and Characterization of Linezolid-Resistant cfr-Positive Staphylococcus aureus USA300 Isolates from a New York City Medical Center

Science.gov (United States)

Zuill, Douglas E.; Scharn, Caitlyn R.; Deane, Jennifer; Sahm, Daniel F.; Goering, Richard V.; Jenkins, Stephen G.; Shaw, Karen J.

2014-01-01

The cfr gene was identified in three linezolid-resistant USA300 methicillin-resistant Staphylococcus aureus (MRSA) isolates collected over a 3-day period at a New York City medical center in 2011 as part of a routine surveillance program. Each isolate possessed a plasmid containing a pSCFS3-like cfr gene environment. Transformation of the cfr-bearing plasmids into the S. aureus ATCC 29213 background recapitulated the expected Cfr antibiogram, including resistance to linezolid, tiamulin, clindamycin, and florfenicol and susceptibility to tedizolid. PMID:25136008

Successful treatment of methicillin-resistant Staphylococcus aureus osteomyelitis with combination therapy using linezolid and rifampicin under therapeutic drug monitoring.

Science.gov (United States)

Ashizawa, Nobuyuki; Tsuji, Yasuhiro; Kawago, Koyomi; Higashi, Yoshitsugu; Tashiro, Masato; Nogami, Makiko; Gejo, Ryuichi; Narukawa, Munetoshi; Kimura, Tomoatsu; Yamamoto, Yoshihiro

2016-05-01

Linezolid is an effective antibiotic against most gram-positive bacteria including drug-resistant strains such as methicillin-resistant Staphylococcus aureus. Although linezolid therapy is known to result in thrombocytopenia, dosage adjustment or therapeutic drug monitoring of linezolid is not generally necessary. In this report, however, we describe the case of a 79-year-old woman with recurrent methicillin-resistant S. aureus osteomyelitis that was successfully treated via surgery and combination therapy using linezolid and rifampicin under therapeutic drug monitoring for maintaining an appropriate serum linezolid concentration. The patient underwent surgery for the removal of the artificial left knee joint and placement of vancomycin-impregnated bone cement beads against methicillin-resistant S. aureus after total left knee implant arthroplasty for osteoarthritis. We also initiated linezolid administration at a conventional dose of 600 mg/h at 12-h intervals, but reduced it to 300 mg/h at 12-h intervals on day 9 because of a decrease in platelet count and an increase in serum linezolid trough concentration. However, when the infection exacerbated, we again increased the linezolid dose to 600 mg/h at 12-h intervals and performed combination therapy with rifampicin, considering their synergistic effects and the control of serum linezolid trough concentration via drug interaction. Methicillin-resistant S. aureus infection improved without reducing the dose of or discontinuing linezolid. The findings in the present case suggest that therapeutic drug monitoring could be useful for ensuring the therapeutic efficacy and safety of combination therapy even in patients with osteomyelitis who require long-term antibiotic administration. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients

NARCIS (Netherlands)

Bolhuis, Mathieu S.; van Altena, Richard; van Soolingen, Dick; de Lange, Wiel C. M.; Uges, Donald R. A.; van der Werf, Tjip S.; Kosterink, Jos G. W.; Alffenaar, Jan-Willem C.

2013-01-01

The use of linezolid for the treatment of multidrug-resistant tuberculosis is limited by dose-and time-dependent toxicity. Recently, we reported a case of pharmacokinetic drug drug interaction between linezolid and clarithromycin that resulted in increased linezolid exposure. The aim of this

Applicability of a Single Time Point Strategy for the Prediction of Area Under the Concentration Curve of Linezolid in Patients

DEFF Research Database (Denmark)

Srinivas, Nuggehally R; Syed, Muzeeb

2016-01-01

Background and Objectives: Linezolid, a oxazolidinone, was the first in class to be approved for the treatment of bacterial infections arising from both susceptible and resistant strains of Gram-positive bacteria. Since overt exposure of linezolid may precipitate serious toxicity issues......, therapeutic drug monitoring (TDM) may be required in certain situations, especially in patients who are prescribed other co-medications. Methods: Using appropriate oral pharmacokinetic data (single dose and steady state) for linezolid, both maximum plasma drug concentration (Cmax) versus area under the plasma...... concentration–time curve (AUC) and minimum plasma drug concentration (Cmin) versus AUC relationship was established by linear regression models. The predictions of the AUC values were performed using published mean/median Cmax or Cmin data and appropriate regression lines. The quotient of observed and predicted...

Activities of Tedizolid and Linezolid Determined by the Reference Broth Microdilution Method against 3,032 Gram-Positive Bacterial Isolates Collected in Asia-Pacific, Eastern Europe, and Latin American Countries in 2014.

Science.gov (United States)

Pfaller, Michael A; Flamm, Robert K; Jones, Ronald N; Farrell, David J; Mendes, Rodrigo E

2016-09-01

Tedizolid and linezolid in vitro activities against 3,032 Gram-positive pathogens collected in Asia-Pacific, Eastern European, and Latin American medical centers during 2014 were assessed. The isolates were tested for susceptibility by the current reference broth microdilution methods. Due to concern over the effect of MIC endpoint criteria on the results of testing the oxazolidinones tedizolid and linezolid, MIC endpoint values were read by two methods: (i) reading the MIC at the first well where the trailing began without regard for pinpoint trailing, according to CLSI M07-A10 and M100-S26 document instructions for reading linezolid (i.e., 80% inhibition of growth; these reads were designated tedizolid 80 and linezolid 80), and (ii) at 100% inhibition of growth (designated tedizolid 100 and linezolid 100). All Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, and Enterococcus faecalis isolates were inhibited at tedizolid 80 and 100 MIC values of 0.25 and 0.5, 0.25 and 0.25, 0.25 and 0.5, 0.12 and 0.25, and 0.5 and 1 μg/ml, respectively. Generally, MIC50 and MIC90 results for tedizolid 80 and linezolid 80 were one doubling dilution lower than those read at 100% inhibition. Tedizolid was 4- to 8-fold more potent than linezolid against all the isolates tested regardless of the MIC endpoint criterion used. Despite the differences in potency, >99.9% of isolates tested in this survey were susceptible to both linezolid and tedizolid using CLSI and EUCAST interpretive criteria. In conclusion, tedizolid demonstrated greater in vitro potency than linezolid against Gram-positive pathogens isolated from patients in medical centers across the Asia-Pacific region, Eastern Europe, and Latin America. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

The Emergence of Linezolid Resistance among Enterococci in Intestinal Microbiota of Treated Patients Is Unrelated to Individual Pharmacokinetic Characteristics

Science.gov (United States)

Nguyen, T. T.; Defrance, G.; Massias, L.; Alavoine, L.; Lefort, A; Noel, V.; Senneville, E.; Doucet-Populaire, F.; Mentré, F.; Andremont, A.; Duval, X.

2014-01-01

Linezolid is an antimicrobial agent for the treatment of multiresistant Gram-positive infections. We assessed the impact of linezolid on the microbiota and the emergence of resistance and investigated its relationship with plasma pharmacokinetics of the antibiotic. Twenty-eight patients were treated for the first time with linezolid administered orally (n = 17) or parenterally (n = 11) at 600 mg twice a day. Linezolid plasma pharmacokinetic analysis was performed on day 7. Colonization by fecal enterococci, pharyngeal streptococci, and nasal staphylococci were assessed using selective media with or without supplemental linezolid. The resistance to linezolid was characterized. The treatment led to a decrease of enterococci, staphylococci, and streptococci in the fecal (P = 0.03), nasal, and pharyngeal (P linezolid resistance during treatment was observed only in the intestinal microbiota and unrelated to pharmacokinetic parameters. However, colonization by Gram-positive bacteria was reduced as a result of treatment in all microbiotas. PMID:24566182

Impact of the PROVAUR stewardship programme on linezolid resistance in a tertiary university hospital: a before-and-after interventional study.

Science.gov (United States)

García-Martínez, Lucrecia; Gracia-Ahulfinger, Irene; Machuca, Isabel; Cantisán, Sara; De La Fuente, Soraya; Natera, Clara; Pérez-Nadales, Elena; Vidal, Elisa; Rivero, Antonio; Rodríguez-Lopez, Fernando; Del Prado, José Ramón; Torre-Cisneros, Julián

2016-09-01

There is little evidence of the impact of antimicrobial stewardship programmes on antimicrobial resistance. To study the efficacy and safety of a package of educational and interventional measures to optimize linezolid use and its impact on bacterial resistance. A quasi-experimental study was designed and carried out before and after implementation of a stewardship programme in hospitalized patients with Gram-positive infections treated with linezolid. The intervention reduced linezolid consumption by 76%. The risk of linezolid-resistant CoNS isolates (OR = 0.37; 95% CI = 0.27-0.49; P linezolid use can contribute to reducing the resistance rate of CoNS and E. faecalis to this antibiotic. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Linezolid-associated optic neuropathy in a pediatric patient with Mycobacterium nonchromogenicum: A case report.

Science.gov (United States)

González Saldaña, Napoleón; Galvis Trujillo, Diego Mauricio; Borbolla Pertierra, Ana Maria; Mondragón Pineda, Ana Ivette; Juárez Olguín, Hugo

2017-12-01

Toxic optic neuropathies are alterations of the optic nerve and can be caused by environmental, pharmacological, or nutritional agents. It is about a 7-year-old male patient, a native of the State of Mexico, Mexico who was diagnosed with cervical mycobacterial lymphadenitis that required management with linezolid. After 7 months of treatment, visual acuity of the left eye decreased and was accompanied by headache. Neuroinfection and other central nervous system affections were discarded. An adverse effect related to treatment with linezolid was suspected, and linezolid was suspended. The symptoms subsided after discontinuation; however, the patient continued to show decreased visual acuity of the left eye, assessed by his ability to count 2 fingers. The right eye remained unaffected. Neurotoxicity can be decreased by reducing the total dose of linezolid or by administrating it in an intermittent form. To avoid progression and loss of vision, we suggest frequent periodic ophthalmological evaluation in patients treated with linezolid. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Ribosomal protein L3 mutations are associated with cfr-mediated linezolid resistance in clinical isolates of Staphylococcus cohnii.

Science.gov (United States)

Xu, Hongtao; Tian, Rui; Li, Yanming; Chen, Dongke; Liu, Yalin; Hu, Yunjian; Xiao, Fei

2015-06-01

From June, 2012 to November, 2013 five linezolid-resistant Staphylococcus cohnii isolates were identified in our hospital in Beijing, China. The investigation of the resistance mechanisms confirmed that the cfr-carrying plasmids were the main cause of linezolid resistance in those clinical isolates. Moreover, all the five isolates had ribosomal protein L3 mutations, which had different coordinate effect on cfr-mediated linezolid resistance directly through the substitution of serine 158 by phenylalanine or tyrosine in L3 protein. In this study, two types of plasmids (p432, p438) (Accession No. KM114207) were found, which share high sequence identity with previously reported cfr-carrying pRM01 and pMHZ plasmids originated from northern and southern China, showing wide regional dissemination in China. The stability of linezolid resistance was studied by passaging single colonies serially on antibiotic-free blood medium, which showed that the susceptible derivatives emerged until the passages 39-42 with the elimination of cfr-carrying plasmid. Thus the high stability of this plasmid may pose a risk for the transmission among patients or even cause an outbreak in clinical settings.

Sepsis due to linezolid resistant Staphylococcus cohnii and Staphylococcus kloosii: first reports of linezolid resistance in coagulase negative staphylococci from India.

Science.gov (United States)

Peer, M A; Nasir, R A; Kakru, D K; Fomda, B A; Bashir, G; Sheikh, I A

2011-01-01

Linezolid, a viable alternative to vancomycin against methicillin resistant staphylococcal isolates, has been in use for a decade around the globe. However, resistance against staphylococci remains extremely rare and unreported from most of the Asian countries. Herein, we report two cases of linezolid resistant, coagulase negative staphylococcal sepsis for the first time from India. The first case was an 18-year-old burn patient, who, after a major graft surgery, landed in sepsis, and linezolid resistant Staphylococcus cohnii with an minimum inhibitory concentration (MIC) of >256 μg/ml by both broth microdilution and Etest, was isolated from multiple blood cultures. The second patient was a 60-year-old male with an intracranial bleed and sepsis, from whose blood cultures, linezolid resistant Staphylococcus kloosii was repeatedly isolated. Linezolid MIC was >32 μg/ml by broth microdilution and >16 μg/ml by Etest.

Sepsis due to linezolid resistant Staphylococcus cohnii and Staphylococcus kloosii: First reports of linezolid resistance in coagulase negative staphylococci from India

Directory of Open Access Journals (Sweden)

M A Peer

2011-01-01

Full Text Available Linezolid, a viable alternative to vancomycin against methicillin resistant staphylococcal isolates, has been in use for a decade around the globe. However, resistance against staphylococci remains extremely rare and unreported from most of the Asian countries. Herein, we report two cases of linezolid resistant, coagulase negative staphylococcal sepsis for the first time from India. The first case was an 18-year-old burn patient, who, after a major graft surgery, landed in sepsis, and linezolid resistant Staphylococcus cohnii with an minimum inhibitory concentration (MIC of >256 μg/ml by both broth microdilution and Etest, was isolated from multiple blood cultures. The second patient was a 60-year-old male with an intracranial bleed and sepsis, from whose blood cultures, linezolid resistant Staphylococcus kloosii was repeatedly isolated. Linezolid MIC was >32 μg/ml by broth microdilution and >16 μg/ml by Etest.

Linezolid-induced thrombocytopenia in two patients with renal dysfunction

Directory of Open Access Journals (Sweden)

Engin Melek

2016-12-01

Full Text Available Linezolid is an oxazolidinone antibiotic, active against gram positive bacteria that are resistant to other antibiotics including glycopeptides. Thrombocytopenia is an adverse effect of linezolid. Although various risk factors have been suggested, the mechanisms behind this side effect are largely unknown. Here, we report two adolescents with the diagnosis of chronic kidney disease who developed thrombocytopenia following treatment with linezolid. Our purpose in highlighting these cases is to increase the clinical awareness concerning this side effect of linezolid. While it is well known that thrombocytopenia may develop during linezolid treatment, it is relatively unknown that patients with renal dysfunction have an increased risk for the development of thrombocytopenia compared to patients without renal dysfunction. [Cukurova Med J 2016; 41(4.000: 808-810

Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps.

Science.gov (United States)

Deshpande, Devyani; Srivastava, Shashikant; Pasipanodya, Jotam G; Bush, Stephen J; Nuermberger, Eric; Swaminathan, Soumya; Gumbo, Tawanda

2016-11-01

 Infants and toddlers often present with disseminated and lymph node tuberculosis, in which Mycobacterium tuberculosis (Mtb) is predominantly intracellular. Linezolid, used to treat tuberculosis in adults, has not been formally studied in infants. Infants clear linezolid 5 times faster than adults and achieve lower 0- to 24-hour area under the concentration-time curves (AUC 0-24 ).  To mimic intracellular disease, we infected human-derived THP-1 macrophages with Mtb and inoculated hollow fiber systems. We performed dose-effect and dose-scheduling studies in which we recapitulated the linezolid half-life of 3 hours encountered in infants. Repetitive sampling for linezolid pharmacokinetics, Mtb intracellular burden, viable monocyte count, and RNA sequencing reads were performed up to 28 days.  The linezolid extracellular half-life was 2.64 ± 0.38 hours, whereas intracellular half-life was 8.93 ± 1.30 hours (r 2 = 0.89). Linezolid efficacy was linked to the AUC 0-24 to minimum inhibitory concentration (MIC) ratio (r 2 = 0.98). The exposure associated with maximal Mtb kill was an AUC 0-24 /MIC of 23.37 ± 1.16. We identified a 414-gene transcript on exposure to toxic linezolid doses. The largest number of genes mapped to ribosomal proteins, a signature hitherto not associated with linezolid toxicity. The second-largest number of differentially expressed genes mapped to mitochondrial enzyme inhibition. Linezolid AUC 0-24 best explained the mitochondrial gene inhibition, with 50% inhibition at 94 mg × hour/L (highest r 2 = 0.98).  We identified the linezolid AUC 0-24 /MIC target for optimal efficacy against pediatric intracellular tuberculosis, and an AUC 0-24 threshold associated with mitochondrial inhibition. These constitute a therapeutic window to be targeted for optimal linezolid doses in children with tuberculosis. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Antimicrobial susceptibility pattern of bacterial isolates from surgical ...

African Journals Online (AJOL)

S. aureus and Streptococcus spp. showed maximum susceptibility (100%) to linezolid and vancomycin. Maximum susceptibility of E. coli was observed to ciprofloxacin (75.7%), followed by gentamicin (54.5%); of Klebsiella spp. to ceftriaxone and gentamicin (66.6% each), of Proteus spp. to gentamicin (70%) followed by ...

A retrospective study of the risk factors for linezolid-induced thrombocytopenia and anemia.

Science.gov (United States)

Hanai, Yuki; Matsuo, Kazuhiro; Ogawa, Miki; Higashi, Ayaka; Kimura, Itsuki; Hirayama, Shinobu; Kosugi, Takayoshi; Nishizawa, Kenji; Yoshio, Takashi

2016-08-01

Myelosuppression is major treatment-related adverse events of linezolid therapy and result in treatment termination in some cases. We aimed to identify the risk factors for linezolid-induced thrombocytopenia and anemia. We retrospectively retrieved demographic and laboratory data from the medical records of 221 Japanese patients who were undergoing linezolid therapy. Thrombocytopenia and anemia were defined as an unexplained reduction of >30% in the patient's platelet count and hemoglobin level, respectively, from the baseline. Thrombocytopenia developed in 48.4% of patients, and anemia developed in 10.4% of patients during linezolid therapy. In multivariate analysis, creatinine clearance (adjusted odds ratio = 0.94 [0.92-0.95], P linezolid therapy (1.14 [1.07-1.21], P linezolid-induced thrombocytopenia. Patients with creatinine clearance rates of linezolid-induced thrombocytopenia. In addition, a high incidence of linezolid-induced thrombocytopenia was even detected among the patients that had received linezolid therapy for linezolid therapy (1.04 [1.01-1.07], P = 0.011) was shown to be a risk factor for anemia, and a high incidence of anemia was seen among the patients who received linezolid for >15 days. In conclusion, we recommend that among patients receiving linezolid therapy the platelet counts of those with risk factors for linezolid-induced thrombocytopenia should be monitored closely throughout treatment, and the hemoglobin levels of patients that receive linezolid for >15 days should be carefully monitored on a weekly basis to detect anemia. Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Emergence of linezolid-resistant coagulase-negative staphylococci in an intensive care unit.

Science.gov (United States)

Balandin, Bárbara; Lobo, Beatriz; Orden, Beatriz; Román, Federico; García, Elena; Martínez, Rocío; Valdivia, Miguel; Ortega, Alfonso; Fernández, Inmaculada; Galdos, Pedro

2016-01-01

The aim of this study was to report the emergence of linezolid-resistant coagulase-negative staphylococci (CoNS) in an intensive care unit. An observational study was conducted in critically ill patients with colonization or infection by linezolid-resistant CoNS between January 2010 and December 2014. We analyzed the epidemiological and clinical features, and the mechanism of resistance to linezolid. We also evaluated the association between the incidence of linezolid-resistant CoNS strains and the consumption of linezolid in the study period. During the study period 49 patients had a linezolid-resistant CoNS strain isolated from clinical samples (blood in 42 cases, urine in 6, peritoneal fluid in 1). Molecular study showed a combination of mechanisms of resistance. Most patients were critically ill (APACHE II score = 21.9 ± 8.3) and nearly all had undergone surgery and invasive procedures, and had prior exposure to antibiotics. Linezolid-resistant CoNS were considered to be contaminants in 42 patients and associated with infection in 7 patients, comprising bacteremia and septic shock in most of them. They were successfully treated with glycopeptides or daptomycin. A modest significant correlation was observed between the decrease in linezolid consumption and the lower incidence of resistant isolates. Linezolid-resistant CoNS had emerged in critically ill patients with severe underlying diseases and prior antibiotic exposure. Most isolates represented colonization; however, linezolid-resistant CoNS can produce serious infections in critically ill patients. Glycopeptides and daptomycin seem to provide useful alternatives for therapy of these infections. A relationship was found between linezolid consumption and the incidence of linezolid-resistant CoNS strains.

Linezolid is Associated with Improved Early Outcomes of Childhood Tuberculous Meningitis.

Science.gov (United States)

Li, Huimin; Lu, Jie; Liu, Jinrong; Zhao, Yuhong; Ni, Xin; Zhao, Shunying

2016-06-01

Linezolid serves as an important component for the treatment of drug-resistant tuberculosis although there is little published data about linezolid use in children, especially in childhood tuberculous meningitis (TBM). In this study, we retrospectively reviewed records of childhood TBM patients who started treatment between January 2012 and August 2014. A total of 86 childhood TBM patients younger than 15 years old were enrolled. Out of 86 children, 36 (41.9%) received the regimen containing linezolid. Thirty-two (88.9%) of 36 linezolid-treated cases had favorable outcomes, and 35 (70.0%) cases were successfully treated in the control group. The frequency of favorable outcome of linezolid group was significantly higher than that of control group (P = 0.037). In addition, compared with cases with fever clearance time of 4 weeks (P = 0.000) than linezolid group. Furthermore, there was no significant difference in the frequency of adverse events between the two regimens (P = 0.896). In addition, the patients with adverse events were more likely to have treatment failure, the P value of which was 0.008. Our data demonstrate that linezolid improves early outcome of childhood TBM. The low frequency of linezolid-associated adverse effects highlights the promising prospects of its use for treatment of childhood TBM.

Preparation and biodistribution of [131I]linezolid in animal model infection and inflammation

International Nuclear Information System (INIS)

Yurt Lambrecht, F.; Durkan, K.; Unak, P.; Bayrak, E.; Yilmaz, O.

2009-01-01

Linezolid is the first of new class of antibiotics, the oxazolidinones, and exhibits activity against many gram-positive organisms, including vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus, and penicillin-resistant Streptococcus pneumoniae. Aim of the study: Linezolid was to label with I-131 and potential of the radiolabeled antibiotic was to investigate in inflamed rats with S. aureus (S. aureus) and sterile inflamed rats with turpentine oil. Linezolid was labeled with I-131 by iodogen method. Biodistribution of [ 131 I]linezolid was carried out in bacterial inflamed and sterile inflamed rats. Radiolabeling yield of [ 131 I]linezolid was determined as 85 ± 1% at pH 2. After injecting of [ 131 I]linezolid into bacterial inflamed and sterile inflamed rats, radiolabeled linezolid was rapidly removed from the circulation via the kidneys. Binding of [ 131 I]linezolid to bacterial inflamed muscle (T/NT = 77.48 at 30 min) was five times higher than binding to sterile inflamed muscle (T/NT = 14.87 at 30 min) of rats. [ 131 I]linezolid showed good localization in bacterial inflamed tissue. It was demonstrated that [ 131 I]linezolid can be used to detect S. aureus inflammation in rats. (author)

Linezolid-resistant enterococci in Polish hospitals: species, clonality and determinants of linezolid resistance.

Science.gov (United States)

Gawryszewska, I; Żabicka, D; Hryniewicz, W; Sadowy, E

2017-07-01

The significant increase of the linezolid-resistant enterococci (LRE) has been observed in Polish hospitals since 2012 and our study aimed at elucidating the possible reasons for this phenomenon. Polish LRE isolates were analysed by multilocus-sequence typing (MLST) and multiple locus variable-number tandem repeat (VNTR) analysis (MLVA), polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) to establish clonal relatedness and mechanism of linezolid resistance, respectively. Fifty analysed LRE (2008-2015) included mostly Enterococcus faecium (82%) and Enterococcus faecalis (16%). Enterococcus faecium belonged to the hospital-adapted lineages 17/18 and 78, while E. faecalis isolates represented ST6, a hospital-associated type, and ST116, found in both humans and food-production animals. The G2576T 23S rRNA mutation was the most frequent (94%) mechanism of linezolid/tedizolid resistance of LRE. None of the isolates carried the plasmid-associated gene of Cfr methyltransferase, whereas optrA, encoding the ABC-type drug transporter, was identified in two E. faecalis isolates. In these isolates, optrA was located on a plasmid, transferable to both E. faecium and E. faecalis, whose partial (36.3 kb) sequence was 100% identical to the pE394 plasmid, identified previously in China in both clinical and farm animal isolates. The optrA-E. faecium transconjugant displayed a significant growth deficiency, in contrast to the optrA-E. faecalis. Our study indicates the role of mutation acquisition by hospital-adapted clones of enterococci as a major driver of increasing resistance to linezolid and tedizolid. Transferability and apparent lack of a biological cost of resistance suggest that E. faecalis may be a natural reservoir of optrA, an emerging mechanism of oxazolidinone resistance.

Linezolid desensitization for a patient with multiple medication hypersensitivity reactions.

Science.gov (United States)

Bagwell, Autumn D; Stollings, Joanna L; White, Katie D; Fadugba, Olajumoke O; Choi, Jane J

2013-01-01

To describe a case in which a linezolid desensitization protocol was successfully used for a polymicrobial surgical wound infection in a patient with multiple drug hypersensitivity reactions. A 24-year-old woman with vocal cord dysfunction requiring tracheostomy was admitted for a surgical wound infection following a tracheostomy fistula closure procedure. The patient reported multiple antibiotic allergies including penicillins (rash), sulfonamides (rash), vancomycin (anaphylaxis), azithromycin (rash), cephalosporins (anaphylaxis), levofloxacin (unspecified), clindamycin (unspecified), and carbapenems (unspecified). Gram stain of the purulent wound drainage demonstrated mixed gram-negative and gram-positive flora, and bacterial cultures were overgrown with Proteus mirabilis, which precluded identification of other pathogens. Following failed test doses of linezolid, tigecycline, and daptomycin, all of which resulted in hypersensitivity reactions, a 16-step linezolid desensitization protocol was developed and successfully implemented without adverse reactions. The patient completed a 2-week course of antibiotic therapy that included linezolid upon finishing the desensitization protocol. Linezolid is useful in treating complicated and uncomplicated skin and soft tissue infections caused by gram-positive bacteria. With precautions, including premedication, a monitored nursing unit, and immediate availability of an emergency anaphylaxis kit, drug desensitization allows patients the ability to safely use medications to which they may have an immediate hypersensitivity reaction. Minimal data exist on linezolid desensitization protocols. Linezolid desensitization can be a viable option in patients requiring antimicrobial therapy for complicated gram-positive skin infections.

Linezolid som behandling af infektiøs endokarditis

DEFF Research Database (Denmark)

Lauridsen, Trine Kiilerich; Arpi, Magnus; Bruun, Niels Eske

2010-01-01

In Denmark enterococci causes 15 to 20% of all endocarditis (IE) cases. The development of multi-resistant bacterial strains has increased the need for new antibiotics. Linezolid is an alternative to conventional treatment of infections with gram positive cocci. In this case report linezolid...

In Vitro Susceptibility Testing of Tedizolid against Isolates of Nocardia.

Science.gov (United States)

Brown-Elliott, Barbara A; Wallace, Richard J

2017-12-01

There is a paucity of efficacious antimicrobials (especially oral) against clinically relevant species of Nocardia To date, all species of Nocardia have been susceptible to linezolid, the first commercially available oxazolidinone. Tedizolid is a new oxazolidinone with previously reported improved in vitro and in vivo (intracellular) potency against multidrug-resistant strains of Mycobacterium sp. and Nocardia brasiliensis Using the current Clinical and Laboratory Standards Institute-recommended broth microdilution method, 101 isolates of Nocardia spp., including 29 Nocardia cyriacigeorgica , 17 Nocardia farcinica , 13 Nocardia nova complex, 21 Nocardia brasiliensis , 5 Nocardia pseudobrasiliensis , and 5 Nocardia wallacei isolates and 11 isolates of less common species, were tested for susceptibility to tedizolid and linezolid. For the most common clinically significant species of Nocardia , tedizolid MIC 50 values were 0.25 μg/ml for N. nova complex, N. brasiliensis , N. pseudobrasiliensis , and N. wallacei , compared to linezolid MIC 50 values of 1, 2, 0.5, and 1 μg/ml, respectively. Tedizolid and linezolid MIC 90 values were 2 μg/ml for N. nova complex and N. brasiliensis Tedizolid MIC 50 and MIC 90 values for both N. cyriacigeorgica and N. farcinica were 0.5 μg/ml and 1 μg/ml, respectively, compared to linezolid MIC 50 and MIC 90 values of 2 and 4 μg/ml, respectively. Based on MIC 90 values, this study showed that tedizolid was 2- to 3-fold more active than linezolid in vitro against most common species of Nocardia , with the exception of the N. nova complex and N. brasiliensis , for which values were the same. These results may warrant evaluation of tedizolid as a potential treatment option for Nocardia infections. Copyright © 2017 American Society for Microbiology.

Linezolid induced black hairy tongue: a rare side effect.

Science.gov (United States)

Aijazi, Ishma; Abdulla, Fadhil M

2014-01-01

Linezolid induced black hairy tongue is a rare benign reversible side effect of linezolid therapy. We report a case of a 61 year old diabetic lady who developed thrombocytopenia and black hairy discoloration of the tongue after being prescribed linezolid for foot osteomyelitis by the orthopaedic surgeon. Patient was encouraged to practice good oral dental hygiene, advised to use a soft tooth brush, regular mouth wash and baking soda containing tooth paste. The condition resolved four weeks after cessation of the antibiotic therapy.

Efficacy of Linezolid and Fosfomycin in Catheter-Related Biofilm Infection Caused by Methicillin-Resistant Staphylococcus aureus

Science.gov (United States)

Chai, Dong; Liu, Xu; Wang, Rui; Bai, Yan; Cai, Yun

2016-01-01

As long-standing clinical problems, catheter-related infections and other chronic biofilm infections are more difficult to treat due to the high antibiotic resistance of biofilm. Therefore, new treatments are needed for more effective bacteria clearance. In this study, we evaluated the antibacterial activities of several common antibiotics alone and their combinations against biofilm-embedded methicillin-resistant staphylococcus aureus (MRSA) infections, both in vitro and in vivo. In brief, fosfomycin, levofloxacin, and rifampin alone or in combination with linezolid were tested in vitro against planktonic and biofilm-embedded MRSA infection in three MRSA stains. The synergistic effects between linezolid and the other three antibiotics were assessed by fractional inhibitory concentration index (FICI) and time-kill curves, where the combination of linezolid plus fosfomycin showed the best synergistic effect in all strains. For further evaluation in vivo, we applied the combination of linezolid and fosfomycin in a catheter-related biofilm rat model and found that viable bacteria counts in biofilm were significantly reduced after treatment (P linezolid and fosfomycin treatment had improved therapeutic effects on biofilm-embedded MRSA infection both in vitro and in vivo, which provided important basis for new clinical therapy development. PMID:27366751

A severe infective endocarditis successfully treated with linezolid

Directory of Open Access Journals (Sweden)

Graziano Antonio Minafra

2010-03-01

Full Text Available Despite significant improvements in surgical and medical therapy, prosthetic valve endocarditis (PVE is a diagnostic and therapeutic challenge and is often associated with a severe prognosis. We report a case of a 59-year-old woman, with  PVE and bacterial endocarditis (Streptococcus bovis successfully treated with linezolid. Linezolid is a bacteriostatic oxazolidinone antibiotic that has been proven to be effective for the treatment of patients with pneumonia, skin and soft tissue infections, and infections due to Gram-positive cocci. Linezolid is not yet recognised as a standard therapy for infective endocarditis, but its use becomes a necessity when infection is due to multidrug-resistant microorganisms.

Bicytopenia, especially thrombocytopenia in hemodialysis and non-hemodialysis patients treated with linezolid therapy.

Science.gov (United States)

Kato, Hideo; Hamada, Yukihiro; Hagihara, Mao; Hirai, Jun; Yamagishi, Yuka; Matsuura, Katsuhiko; Mikamo, Hiroshige

2015-10-01

One of the major adverse events associated with linezolid treatment is pancytopenia. However, there are few reports about the tolerability of linezolid among patients undergoing hemodialysis. This study retrospectively investigated the frequency of bicytopenia (thrombocytopenia and erythropenia) secondary to linezolid treatment in patients undergoing and not-undergoing hemodialysis. In total, 181 patients treated with linezolid from January 2010 to July 2012 at Aichi Medical University Hospital were divided into three groups; patients undergoing hemodialysis (HD group), those with creatinine clearance (CLCR) of linezolid therapy were compared among three groups. Thrombocytopenia (linezolid therapy. In particular, the PLT nadir in HD group occurred earlier than that in non-HD groups (HD, 11.5 days [4-31 days]; CLCR linezolid treatment in patients undergoing hemodialysis. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Analysis of linezolid and tigecycline as candidates for local prophylaxis via antibiotic-loaded bone cement.

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Nichol, T; Smith, T J; Townsend, R; Stockley, I; Akid, R

2017-02-01

To assess the Gram-positive-specific antibiotic linezolid and the broad-spectrum antibiotic tigecycline for use in local antibiotic delivery via antibiotic-loaded bone cement. Linezolid and tigecycline were added to Biomet bone cement at varying concentrations. Antibiotic elution over 1 week was quantified by HPLC-MS. The effect of wear on elution over 51 h was determined using a modified TE-66 wear tester. Eluted antibiotics were used to determine the MICs for a panel of clinically relevant bacteria. The impact strength of antibiotic-loaded samples was determined using a Charpy-type impact testing apparatus. Cytotoxicity of eluted antibiotics against MG-63 cells was evaluated using an MTT assay. Linezolid and tigecycline eluted from bone cement to clinically relevant levels within 1 h and retained activity over 1 week. Mechanical wear significantly reduced elution of tigecycline, but had little effect on elution of linezolid. Linezolid showed low cytotoxicity towards MG-63 cells with ≤300 mg/mL resulting in >50% cell activity. Cytotoxicity of tigecycline was higher, with an IC 50 of 5-10 mg/L. Linezolid and tigecycline retain activity after elution from bone cement. The concentration of tigecycline may need to be carefully controlled due to cytotoxicity. The effect of wear on bone cement may need to be considered if tigecycline is to be used for local delivery. Up to 10% linezolid can be added without affecting the impact strength of the bone cement. These results are promising indications for future investigation of these antibiotics for use in local antibiotic delivery strategies. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Substitution of ethambutol with linezolid during the intensive phase of treatment of pulmonary tuberculosis: study protocol for a prospective, multicenter, randomized, open-label, phase II trial.

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Lee, Ji Yeon; Kim, Deog Kyeom; Lee, Jung-Kyu; Yoon, Ho Il; Jeong, Ina; Heo, Eunyoung; Park, Young Sik; Lee, Jae Ho; Park, Sung Soo; Lee, Sang-Min; Lee, Chang-Hoon; Lee, Jinwoo; Choi, Sun Mi; Park, Jong Sun; Joh, Joon-Sung; Cho, Young-Jae; Lee, Yeon Joo; Kim, Se Joong; Hwang, Young Ran; Kim, Hyeonjeong; Ki, Jongeun; Choi, Hyungsook; Han, Jiyeon; Ahn, Heejung; Hahn, Seokyung; Yim, Jae-Joon

2017-02-13

Linezolid, an oxazolidinone, substantially improves treatment outcomes of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. We started a trial to test whether the use of linezolid instead of ethambutol could increase the rate of sputum culture conversion as of 8 weeks of treatment in patients with drug-susceptible tuberculosis. This is a phase II, multicenter, randomized study with three arms. We are enrolling patients with pulmonary tuberculosis without rifampicin resistance screened by the Xpert MTB/RIF® assay. The standard treatment arm uses isoniazid (6 months), rifampicin (6 months), pyrazinamide (2 months), and ethambutol (2 months). Experimental arm 1 uses linezolid (600 mg/day) for 4 weeks instead of ethambutol. Experimental arm 2 uses linezolid (600 mg/day) for 2 weeks instead of ethambutol. The primary outcome is the sputum culture conversion rate on liquid media after 2 months of treatment. Secondary outcomes include the sputum culture conversion rate on solid media after 2 months of treatment, time to sputum culture conversion on liquid and solid media, cure rate, and treatment success rate. The frequencies of total adverse events (AEs) and serious AEs will be described and documented. Based on an α = 0.05 level of significance, a power of 85%, a 15% difference in the culture conversion rate after 2 months between the control arm and experimental arm 1 (75% vs. 90%), a 10% default (loss to follow-up) rate, and a 10% culture failure, the required number per arm was calculated to be 143 (429 in total). This trial will reveal the effectiveness and safety of 2 or 4 weeks of use of linezolid instead of ethambutol for patients with drug-susceptible pulmonary tuberculosis. If a new regimen including linezolid shows a higher culture conversion rate by week 8, and is safe, it could be tested as a 4-month antituberculosis treatment regimen in the future. ClincalTrials.gov, NCT01994460 . Registered on 13 November 2013.

cfr-mediated linezolid-resistant clinical isolates of methicillin-resistant coagulase-negative staphylococci from China.

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Song, Yunjia; Lv, Yuan; Cui, Lanqing; Li, Yun; Ke, Qian; Zhao, Yixuan

2017-03-01

Three linezolid-resistant coagulase-negative staphylococci (LR-CoNS), including two Staphylococcus cohnii and one Staphylococcus capitis, were isolated from 1104 clinical staphylococcal isolates across China in 2013-2014. Antibiotic susceptibilities of the bacteria were determined by the agar dilution method. PCR and DNA sequencing were performed to determine the potential molecular mechanism of linezolid resistance. The two linezolid-resistant S. cohnii isolates were subjected to pulsed-field gel electrophoresis (PFGE) to investigate their genetic relatedness. Primer walking, S1 nuclease PFGE and Southern blot hybridisation were conducted to ascertain the location and environment of the cfr gene. All three isolates were positive for the cfr gene. Amino acid mutations S158F and S158Y in the ribosomal protein L3 were identified in S. cohnii 13B289 and 13L105, respectively, both of which also had an additional substitution (D159Y) in L3. PFGE indicated that the two S. cohnii isolates belonged to diverse clonal strains. S1 nuclease PFGE and Southern blotting experiments indicated that the cfr gene of the three isolates resided on plasmids of similar size (ca. 35.4kb). The cfr-harbouring segments of S. capitis 13G350 and S. cohnii 13L105 were identical to plasmid pSS-01 reported previously. The cfr-carrying fragment of S. cohnii 13B289 was indistinguishable from the formerly described plasmid pSS-02. In conclusion, the presence of the cfr gene located on a plasmid was the main mechanism contributing to resistance to linezolid in the three staphylococcal isolates. Hence, timely detection and judicious use of antibiotics are essential to prevent further transmission of this resistance mechanism. Copyright © 2016 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

Toxicity to sensory neurons and Schwann cells in experimental linezolid-induced peripheral neuropathy.

Science.gov (United States)

Bobylev, Ilja; Maru, Helina; Joshi, Abhijeet R; Lehmann, Helmar C

2016-03-01

Peripheral neuropathy is a common side effect of prolonged treatment with linezolid. This study aimed to explore injurious effects of linezolid on cells of the peripheral nervous system and to establish in vivo and in vitro models of linezolid-induced peripheral neuropathy. C57BL/6 mice were treated with linezolid or vehicle over a total period of 4 weeks. Animals were monitored by weight, nerve conduction studies and behavioural tests. Neuropathic changes were assessed by morphometry on sciatic nerves and epidermal nerve fibre density in skin sections. Rodent sensory neuron and Schwann cell cultures were exposed to linezolid in vitro and assessed for mitochondrial dysfunction. Prolonged treatment with linezolid induced a mild, predominantly small sensory fibre neuropathy in vivo. Exposure of Schwann cells and sensory neurons to linezolid in vitro caused mitochondrial dysfunction primarily in neurons (and less prominently in Schwann cells). Sensory axonopathy could be partially prevented by co-administration of the Na(+)/Ca(2+) exchanger blocker KB-R7943. Clinical and pathological features of linezolid-induced peripheral neuropathy can be replicated in in vivo and in vitro models. Mitochondrial dysfunction may contribute to the axonal damage to sensory neurons that occurs after linezolid exposure. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Efficacy of Linezolid and Fosfomycin in Catheter-Related Biofilm Infection Caused by Methicillin-Resistant Staphylococcus aureus

Directory of Open Access Journals (Sweden)

Dong Chai

2016-01-01

Full Text Available As long-standing clinical problems, catheter-related infections and other chronic biofilm infections are more difficult to treat due to the high antibiotic resistance of biofilm. Therefore, new treatments are needed for more effective bacteria clearance. In this study, we evaluated the antibacterial activities of several common antibiotics alone and their combinations against biofilm-embedded methicillin-resistant staphylococcus aureus (MRSA infections, both in vitro and in vivo. In brief, fosfomycin, levofloxacin, and rifampin alone or in combination with linezolid were tested in vitro against planktonic and biofilm-embedded MRSA infection in three MRSA stains. The synergistic effects between linezolid and the other three antibiotics were assessed by fractional inhibitory concentration index (FICI and time-kill curves, where the combination of linezolid plus fosfomycin showed the best synergistic effect in all strains. For further evaluation in vivo, we applied the combination of linezolid and fosfomycin in a catheter-related biofilm rat model and found that viable bacteria counts in biofilm were significantly reduced after treatment (P<0.05. In summary, we have shown here that the combination of linezolid and fosfomycin treatment had improved therapeutic effects on biofilm-embedded MRSA infection both in vitro and in vivo, which provided important basis for new clinical therapy development.

Changes in Whole-Body Oxygen Consumption and Skeletal Muscle Mitochondria During Linezolid-Induced Lactic Acidosis.

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Protti, Alessandro; Ronchi, Dario; Bassi, Gabriele; Fortunato, Francesco; Bordoni, Andreina; Rizzuti, Tommaso; Fumagalli, Roberto

2016-07-01

To better clarify the pathogenesis of linezolid-induced lactic acidosis. Case report. ICU. A 64-year-old man who died with linezolid-induced lactic acidosis. Skeletal muscle was sampled at autopsy to study mitochondrial function. Lactic acidosis developed during continuous infusion of linezolid while oxygen consumption and oxygen extraction were diminishing from 172 to 52 mL/min/m and from 0.27 to 0.10, respectively. Activities of skeletal muscle respiratory chain complexes I, III, and IV, encoded by nuclear and mitochondrial DNA, were abnormally low, whereas activity of complex II, entirely encoded by nuclear DNA, was not. Protein studies confirmed stoichiometric imbalance between mitochondrial (cytochrome c oxidase subunits 1 and 2) and nuclear (succinate dehydrogenase A) DNA-encoded respiratory chain subunits. These findings were not explained by defects in mitochondrial DNA or transcription. There were no compensatory mitochondrial biogenesis (no induction of nuclear respiratory factor 1 and mitochondrial transcript factor A) or adaptive unfolded protein response (reduced concentration of heat shock proteins 60 and 70). Linezolid-induced lactic acidosis is associated with diminished global oxygen consumption and extraction. These changes reflect selective inhibition of mitochondrial protein synthesis (probably translation) with secondary mitonuclear imbalance. One novel aspect of linezolid toxicity that needs to be confirmed is blunting of reactive mitochondrial biogenesis and unfolded protein response.

Group B streptococcal carriage, antimicrobial susceptibility, and ...

African Journals Online (AJOL)

None of the carriers had rectal colonization alone. All isolates (100%) were susceptible to penicillin, ampicillin, ceftriaxone, cefotaxime, cefepime, vancomycin, and linezolid. On the other hand, 43.4%, 28.3%, 22.6%, and 15% of isolates were resistant to levofloxacin, azithromycin, erythromycin, and clindamycin respectively.

Carriage, antimicrobial susceptibility profiles and genetic diversity of ...

African Journals Online (AJOL)

All isolates were susceptible to nitrofurantoin and linezolid and resistant in high numbers (194, 81.9%) to ampicillin. Resistances to amoxicillin-clavulanic acid, erythromycin, chloramphenicol, gentamicin, ciprofloxacin, norfloxacin and trimethoprimsulfamethoxazole were below 20%. The overall prevalence of MRSA among ...

Anti-inflammatory effects of linezolid on carrageenan-induced paw edema in rats.

Science.gov (United States)

Matsumoto, Kazuaki; Obara, Shigeaki; Kuroda, Yuko; Kizu, Junko

2015-12-01

The immunomodulatory activity of linezolid has recently been reported using in vitro experimental models. However, the anti-inflammatory activity of linezolid has not yet been demonstrated using in vivo experimental models. Therefore, the aim of the present study was to demonstrate the anti-inflammatory activity of linezolid and other anti-MRSA agents using the carrageenan-induced rat paw edema model. The pretreatment with 50 mg/kg linezolid significantly suppressed edema rates, compared with control (5% glucose), with edema rates at 0.5 and 3 h after the administration of carrageenan being 17.3 ± 3.5 and 30.8 ± 3.0%, respectively. On the other hand, edema rates were not suppressed by the pretreatments with 50 mg/kg vancomycin, teicoplanin, arbekacin, and daptomycin. Furthermore, we demonstrated that linezolid exhibited anti-inflammatory activity in a concentration-dependent manner. These effects were observed at linezolid concentrations that are achievable in human serum with conventional dosing. In conclusion, the results of the present study suggest that the anti-inflammatory activities of linezolid, in addition to its antimicrobial effects, have a protective effect against destructive inflammatory responses in areas of inflammation. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Linezolid-induced lactic acidosis: the thin line between bacterial and mitochondrial ribosomes.

Science.gov (United States)

Santini, Alessandro; Ronchi, Dario; Garbellini, Manuela; Piga, Daniela; Protti, Alessandro

2017-07-01

Linezolid inhibits bacterial growth by targeting bacterial ribosomes and by interfering with bacterial protein synthesis. Lactic acidosis is a rare, but potentially lethal, side effect of linezolid. Areas covered: The pathogenesis of linezolid-induced lactic acidosis is reviewed with special emphasis on aspects relevant to the recognition, prevention and treatment of the syndrome. Expert opinion: Linezolid-induced lactic acidosis reflects the untoward interaction between the drug and mitochondrial ribosomes. The inhibition of mitochondrial protein synthesis diminishes the respiratory chain enzyme content and thus limits aerobic energy production. As a result, anaerobic glycolysis and lactate generation accelerate independently from tissue hypoxia. In the absence of any confirmatory test, linezolid-induced lactic acidosis should be suspected only after exclusion of other, more common, causes of lactic acidosis such as hypoxemia, anemia or low cardiac output. Normal-to-high whole-body oxygen delivery, high venous oxygen saturation and lack of response to interventions that effectively increase tissue oxygen provision all suggest a primary defect in oxygen use at the mitochondrial level. During prolonged therapy with linezolid, blood drug and lactate levels should be regularly monitored. The current standard-of-care treatment of linezolid-induced lactic acidosis consists of drug withdrawal to reverse mitochondrial intoxication and intercurrent life support.

Sequential antimicrobial treatment with linezolid for neurosurgical infections: efficacy, safety and cost study.

Science.gov (United States)

Martín-Gandul, Cecilia; Mayorga-Buiza, M J; Castillo-Ojeda, E; Gómez-Gómez, M J; Rivero-Garvía, M; Gil-Navarro, M V; Márquez-Rivas, F J; Jiménez-Mejías, M E

2016-10-01

Evidence for the effectiveness of linezolid in neurosurgical infections (NSIs) is growing. The comfortable oral dosage and tolerance of linezolid opens the possibility for sequential antimicrobial treatment (SAT) in stable patients after a period of intravenous treatment. To evaluate the efficacy and safety of SAT with oral linezolid in patients with NSI and to analyse the cost implications, an observational, non-comparative, prospective cohort study was conducted on clinically stable consecutive adult patients at the Neurosurgical Service. Following intravenous treatment, patients were discharged with SAT with oral linezolid. A total of 77 patients were included. The most common NSIs were: 41 surgical wound infections, 20 subdural empyemas, 18 epidural abscesses, and 16 brain abscesses. Forty-four percent of patients presented two or more concomitant NSIs. Aetiological agents commonly isolated were: Propionibacterium acnes (36 %), Staphylococcus aureus (23 %), Staphylococcus epidermidis (21 %) and Streptococcus spp. (13 %). The median duration of the SAT was 15 days (range, 3-42). The SAT was interrupted in five cases due to adverse events. The remainder of the patients were cured at the end of the SAT. A total of 1,163 days of hospitalisation were saved. An overall cost reduction of €516,188 was attributed to the SAT. Eight patients with device infections did not require removal of the device, with an additional cost reduction of €190,595. The mean cost saving per patient was €9,179. SAT with linezolid was safe and effective for the treatment of NSI. SAT reduces hospitalisation times, which means significant savings of health and economic resources.

Linezolid as treatment for pulmonary Mycobacterium avium disease.

Science.gov (United States)

Deshpande, Devyani; Srivastava, Shashikant; Pasipanodya, Jotam G; Gumbo, Tawanda

2017-09-01

To identify the pharmacokinetic/pharmacodynamic parameters and exposures of linezolid in the treatment of pulmonary Mycobacterium avium complex (MAC) disease. Human-derived monocytes infected with MAC were inoculated into hollow-fibre systems for dose-effect and dose-scheduling studies. We mimicked linezolid concentration-time profiles achieved in adult human lungs treated for 28 days. Sampling to confirm that the intended linezolid pharmacokinetics had been achieved, and for enumeration of MAC colony-forming units, was performed based on repetitive sampling from each system over the 28 days. We then performed 10 000 patient Monte Carlo simulations to identify doses associated with optimal effect in the clinic. Linezolid achieved a hitherto unprecedented feat of at least 1.0 log10 cfu/mL reduction. Efficacy was most closely linked to the AUC0-24/MIC ratio. The AUC0-24/MIC ratio associated with no change in bacterial burden or bacteriostasis was 7.82, while that associated with 1.0 log10 cfu/mL kill was 42.06. The clinical dose of 600 mg/day achieved or exceeded the bacteriostasis exposure in 98.73% of patients. The proportion of 10 000 patients treated with the standard 1200 mg/day who achieved the exposure for 1.0 log10 cfu/mL kill was 70.64%, but was 90% for 1800 mg/day. The proposed MIC breakpoint for linezolid is 16 mg/L, with which 49%-80% of clinical isolates would be considered resistant. Linezolid is associated with a bactericidal effect in pulmonary MAC that is greater than that seen with other recommended drugs. However, because of the MIC distribution, doses that would optimize the bactericidal effect would be associated with a high adverse event rate. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

In vitro antimicrobial activity of linezolid tested against vancomycin-resistant enterococci isolated in Brazilian hospitals

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Reis Adriana O.

2001-01-01

Full Text Available The emergence of vancomycin-resistant enterococci (VRE has been described recently in Brazil. This is in contrast to the USA and Europe, where the VRE appeared in the late 1980s. The progressive increase in VRE isolation poses important problems in the antimicrobial therapy of nosocomial infections. Treatment options and effective antimicrobial agents for VRE are often limited and the possibility of transfer of vancomycin genes to other Gram-positive microorganisms continues. In the search for antimicrobial agents for multiresistant Gram-positive cocci, compounds such as linezolid and quinupristin/dalfopristin have been evaluated. The present study was conducted to evaluate the in vitro activity of the oxazolidinone linezolid and 10 other antimicrobial agents, including quinupristin-dalfopristin, against multiresistant enterococci isolated in Brazilian hospitals. Thirty-three vancomycin resistant isolates (17 Enterococcus faecium and 16 E. faecalis, were analyzed. Strains were isolated from patients at São Paulo Hospital, Oswaldo Cruz Hospital, Hospital do Servidor Público Estadual, Santa Marcelina Hospital, Santa Casa de Misericórdia de São Paulo, and Hospital de Clínicas do Paraná. The samples were tested by a broth microdilution method following the National Committee for Clinical Laboratory Standards (NCCLS recommendations. All isolates were molecular typed using pulsed-field gel electrophoresis (PFGE. Linezolid was the most active compound against these multiresistant enterococci, showing 100% inhibition at the susceptible breakpoints. Quinupristin/dalfopristin and teicoplanin showed poor activity against both species. The molecular typing results suggest that there has been interhospital spread of vancomycin resistant E. faecium and E. faecalis among Brazilian hospitals. The results of this study indicate that linezolid is an appropriate therapeutic option for the treatment of vancomycin-resistant enterococci infections in Brazil.

Characterization of Vancomycin Reactions and Linezolid Utilization in the Pediatric Population.

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Lin, Samantha K; Mulieri, Kevin M; Ishmael, Faoud T

Red man syndrome (RMS) occurs because of non-IgE-mediated histamine release. Unlike vancomycin allergy, which necessitates the use of an alternative drug (often linezolid), RMS does not typically preclude further vancomycin use. Care should be taken to differentiate these reaction types from one another to prevent unnecessary vancomycin avoidance. To characterize vancomycin reaction types in our population, and to determine whether having a reaction consistent with RMS is associated with otherwise unexplained vancomycin avoidance and linezolid use. We retrospectively reviewed charts for children with documented vancomycin reactions. We classified the in-hospital reactions via an objective analysis and estimated the prevalence of different reaction types. We then identified children who received linezolid over 3 years, and investigated reasons for linezolid use instead of vancomycin. Of the 78 in-hospital reactions we characterized, 72 (92%) were objectively consistent with RMS, 5 we could not objectively classify (2 most likely RMS, 3 more suspicious for possible IgE-mediated allergy), and 1 was a non-RMS/non-IgE reaction. Of 60 children who received linezolid, 19 had previous reactions consistent with RMS, which should not preclude further vancomycin. Nevertheless, only 7 of 19 (37%) had a clear explanation for receiving linezolid instead of vancomycin compared with 32 of 39 (82%) children without previous vancomycin reactions (P linezolid utilization. We propose that this may be related to how reactions appear in the electronic medical record. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

A cfr-positive clinical staphylococcal isolate from India with multiple mechanisms of linezolid-resistance

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Vineeth Rajan

2014-01-01

Full Text Available Background & objectives: Linezolid, a member of the oxazolidinone class of antibiotics, has been an effective therapeutic option to treat severe infections caused by multidrug resistant Gram positive bacteria. Emergence of linezolid resistant clinical strains is a serious issue in the healthcare settings worldwide. We report here the molecular characterization of a linezolid resistant clinical isolate of Staphylococcus haemolyticus from India. Methods: The species of the clinical isolate was identified by 16S rRNA gene sequencing. The minimum inhibitory concentrations (MICs of linezolid, clindamycin, chloramphenicol and oxacillin were determined by E-test method. To elucidate the mechanism of linezolid-resistance, presence of cfr gene (chloramphenicol florfenicol resistance and mutations in 23S rRNA and ribosomal proteins (L3, L4 and L22 were investigated. Staphylococcal Cassette Chromosome mec (SCCmec typing was performed by multiplex PCR. Results: The study documented a rare clinical S. haemolyticus strain with three independent mechanisms of linezolid-resistance. The strain carried cfr gene, the only known transmissible mechanism of linezolid-resistance. The strain also possessed resistance-conferring mutations such as G 2576 T in domain V of 23S rRNA gene and Met 156 Thr in L3 ribosomal protein. The other ribosomal proteins (L4 and L22 did not exhibit mutations accountable for linezolid-resistance. Restriction digestion by NheI revealed that all the alleles of 23S rRNA gene were mutated. The isolate showed elevated MIC values (>256 ΅g ml -[1] of linezolid, clindamycin, chloramphenicol and oxacillin. Methicillin resistance was conferred by type I SCCmec element. The strain also harboured lsa(B gene which encodes an ABC transporter that can efflux clindamycin. Interpretation & conclusions: The present study reports the first clinical strain from India with transmissible and multiple mechanisms of linezolid-resistance. Judicious use of

[A study of population pharmacokinetics of linezolid in Chinese].

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Zhang, L; Bai, N; Liu, Y N; Wang, R

2016-12-12

Objective: To study the population pharmacokinetic (PPK) profiles of linezolid in Chinese healthy volunteers and infected patients. Methods: Linezolid 600 mg was administered to 31 Chinese healthy volunteers with a single dose and to 57 infected patients every 12 h for at least 5 doses. High performance liquid chromatography was applied to determine the plasma concentration of linezolid. Nonlinear mixed-effects modeling method was applied to analyze the PPK profiles. Results: For healthy volunteers with single dose of linezolid, 2-compartment with linear elimination model was the most appropriate structural pharmacokinetic model. The population typical value of apparent volume of central compartment was 26.99 L, volume of peripheral compartment was 22.22 L, apparent clearance of central compartment was 7.99 L/h, and clearance of peripheral compartment was 101.28 L/h. For each 1 kg deviation of weight from the mean value, 0.62 L of volume of peripheral compartment was correlated. For Chinese infected patients with multiple doses of linezolid, 1-compartment with linear elimination model was the most appropriate structural pharmacokinetic model. The population typical value of apparent volume was 38.85 L, and apparent clearance was 4.70 L/h. For each 1 kg deviation of weight from the mean value, 0.79 L of volume, as well as 0.04 L/h of clearance were correlated. For each 1 year deviation of age from the mean value, -0.045 L/h of clearance was correlated. Conclusions: The pharmacokinetic profiles of linezolid in Chinese simulate a 2-compartment with linear elimination model when single dose is administrated, and the weight is linearly positive-correlated to volume. While a 1-compartment with linear elimination model is appropriate when multiple doses are administrated, and the weight is linearly positive-correlated to volume and clearance, but the age is linearly negative-correlated to clearance.

Two cases of serious rhabdomyolysis during linezolid treatment.

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Lechner, Arno M; Past, Eva; Porsche, Ulla; Kern, Jan M; Hoppe, Uta; Pretsch, Ingrid

2017-08-01

Linezolid is an oxazolidinone antibiotic with activity against gram-positive organisms, particularly methicillin-resistant Staphylococcus aureus (MRSA). To the best of our knowledge, there are only two case reports on rhabdomyolysis in patients treated with linezolid. Here, we describe two cases of serious rhabdomyolysis: one in a patient with septic community-acquired (CA)-MRSA pneumonia and a second case in a patient with suspected catheter-related blood stream infection.

Emergence of linezolid resistant Staphylococcus aureus in Bastar tribal region, India

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Mohammad Fareed Khan

2012-09-01

Full Text Available Methicillin resistant Staphylococcus aureus(MRSA is a well-known threat to the healthcaresystems for its increasing global prevalence, intrinsicability of resistance to ß-lactam and cephalosporin,and for acquiring resistance to multipleclasses of other antibiotics, causing difficult-totreatinfections with significant increase in morbidity,mortality and treatment cost. Although forsevere MRSA infections vancomycin is describedas the first-line intravenous drug, vancomycinresistantand intermediate isolates of S. aureus(VRSA & VISA have been increasingly reportedthroughout the world. The therapeutic and lifesavingoption for VRSA and VISA infections remainlinezolid, first antimicrobial of oxazolidinonegroup available since 2000. The first case of linezolid-resistant staphylococci appeared within 1year after linezolid was approved for therapeuticuse.1 Although linezolid resistance in S. aureusis uncommon, emergence has been shown fromsome parts of the world.2 From India, first casereport of linezolid resistance was published in2011 from Kashmir.3 This is the first report fromthe Chattisgarh state in Central India where wefound two linezolid-resistant Staphylococcus aureusisolates which were cultured in March 2011from pus samples collected from the male surgicalward of Maharani Hospital, Jagdalpur, Bastar.

Variability of linezolid concentrations after standard dosing in critically ill patients: a prospective observational study

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2014-01-01

Introduction Severe infections in intensive care patients show high morbidity and mortality rates. Linezolid is an antimicrobial drug frequently used in critically ill patients. Recent data indicates that there might be high variability of linezolid serum concentrations in intensive care patients receiving standard doses. This study was aimed to evaluate whether standard dosing of linezolid leads to therapeutic serum concentrations in critically ill patients. Methods In this prospective observational study, 30 critically ill adult patients with suspected infections received standard dosing of 600 mg linezolid intravenously twice a day. Over 4 days, multiple serum samples were obtained from each patient, in order to determine the linezolid concentrations by liquid chromatography tandem mass spectrometry. Results A high variability of serum linezolid concentrations was observed (range of area under the linezolid concentration time curve over 24 hours (AUC24) 50.1 to 453.9 mg/L, median 143.3 mg*h/L; range of trough concentrations (Cmin) linezolid concentrations over 24 hours and at single time points (defined according to the literature as AUC24  400 mg*h/L and Cmin > 10 mg/L) were observed for 7 of the patients. Conclusions A high variability of linezolid serum concentrations with a substantial percentage of potentially subtherapeutic levels was observed in intensive care patients. The findings suggest that therapeutic drug monitoring of linezolid might be helpful for adequate dosing of linezolid in critically ill patients. Trial registration Clinicaltrials.gov NCT01793012. Registered 24 January 2013. PMID:25011656

Linezolid-Associated Optic Neuropathy in Drug-Resistant Tuberculosis Patients in Mumbai, India.

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Mehta, Salil; Das, Mrinalini; Laxmeshwar, Chinmay; Jonckheere, Sylvie; Thi, Sein Sein; Isaakidis, Petros

2016-01-01

Patients on linezolid-containing drug-resistant TB (DR-TB) regimen often develop adverse-events, particularly peripheral and optic neuropathy. Programmatic data and experiences of linezolid-associated optic neuropathy from high DR-TB burden settings are lacking. The study aimed to determine the frequency of and risk-factors associated with linezolid-associated optic neuropathy and document the experiences related to treatment/care of DR-TB patients on linezolid-containing regimens. This was a retrospective cohort study using routine clinical and laboratory data in Médecins Sans Frontières (MSF) HIV/DR-TB clinic in collaboration with Lilavati Hospital & Research Center, Mumbai, India. All DR-TB patients on linezolid-containing treatment regimens were included in the study and underwent routine evaluations for systemic and/or ocular complaints. Ophthalmological evaluation by a consultant ophthalmologist included visual-acuity screening, slit-lamp examination and dilated fundus examination. During January 2013-April 2016, 86 of 136 patients (with/without HIV co-infection) initiated linezolid-containing DR-TB treatment. The median age of these 86 patients was 25 (20-35) years and 47% were males. 20 percent of them had HIV co-infection. Of 86, 24 (27.9%) had at least one episode of ocular complaints (the majority blurred-vision) and among them, five (5.8%) had optic neuropathy. Patients received appropriate treatment and improvements were observed. None of the demographic/clinical factors were associated with optic neuropathy in Poissons or multivariate binary logistic-regression models. This is the first report focusing on optic neuropathy in a cohort of complex DR-TB patients, including patients co-infected with HIV, receiving linezolid-containing regimens. In our study, one out of four patients on linezolid had at least one episode of ocular complaints; therefore, systematic monitoring of patients by primary physicians/nurses, and access to specialized diagnostic

Linezolid-Associated Optic Neuropathy in Drug-Resistant Tuberculosis Patients in Mumbai, India

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Mehta, Salil; Das, Mrinalini; Laxmeshwar, Chinmay; Jonckheere, Sylvie; Thi, Sein Sein; Isaakidis, Petros

2016-01-01

Background Patients on linezolid-containing drug-resistant TB (DR-TB) regimen often develop adverse-events, particularly peripheral and optic neuropathy. Programmatic data and experiences of linezolid-associated optic neuropathy from high DR-TB burden settings are lacking. The study aimed to determine the frequency of and risk-factors associated with linezolid-associated optic neuropathy and document the experiences related to treatment/care of DR-TB patients on linezolid-containing regimens. Methods This was a retrospective cohort study using routine clinical and laboratory data in Médecins Sans Frontières (MSF) HIV/DR-TB clinic in collaboration with Lilavati Hospital & Research Center, Mumbai, India. All DR-TB patients on linezolid-containing treatment regimens were included in the study and underwent routine evaluations for systemic and/or ocular complaints. Ophthalmological evaluation by a consultant ophthalmologist included visual-acuity screening, slit-lamp examination and dilated fundus examination. Results During January 2013-April 2016, 86 of 136 patients (with/without HIV co-infection) initiated linezolid-containing DR-TB treatment. The median age of these 86 patients was 25 (20–35) years and 47% were males. 20 percent of them had HIV co-infection. Of 86, 24 (27.9%) had at least one episode of ocular complaints (the majority blurred-vision) and among them, five (5.8%) had optic neuropathy. Patients received appropriate treatment and improvements were observed. None of the demographic/clinical factors were associated with optic neuropathy in Poissons or multivariate binary logistic-regression models. Discussion This is the first report focusing on optic neuropathy in a cohort of complex DR-TB patients, including patients co-infected with HIV, receiving linezolid-containing regimens. In our study, one out of four patients on linezolid had at least one episode of ocular complaints; therefore, systematic monitoring of patients by primary physicians

In Vitro Evaluation of Linezolid and Meropenem Against Clinical Isolates of Multi Drug Resistant Tuberculosis By Mycobacterial Growth Indicator Tube (MGIT) 960

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Mirza, I. A.; Satti, L.; Khan, F. A.; Khan, K. A.

2015-01-01

Objective: To evaluate the in vitro effectiveness of multiple breakpoint concentrations of newer antituberculosis agents (Linezolid and Meropenem) against Multi Drug-Resistant Tuberculosis (MDR-TB) isolates. Study Design: Adescriptive cross-sectional study. Place and Duration of Study: Microbiology Department, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from September 2011 to August 2013. Methodology: Atotal of 100 MDR-TB isolates recovered during the study period were subjected to susceptibility testing against multiple breakpoint concentrations of Linezolid (LZD) and Meropenem (MER). The breakpoint concentration used for LZD were 0.5, 1.0 and 2.0 micro g/ml, while for MER were 4.0, 8.0 and 16 micro g/ml. Mycobacterial Growth Indicator Tube (MGIT) 960 system was used to carry out drug susceptibility testing as per recommended protocol. Results: At break point concentration of 0.5 micro g/ml, 80 out of 100 (80%) MDR-TB isolates were susceptible to LZD while at breakpoint concentration of 1.0 micro g/ml and 2.0 micro g/ml, 96/100, (96%) of MDR-TB isolates were susceptible. For MER, at breakpoint concentrations of 4.0 micro g/ml no MDR-TB isolate was susceptible, while at 8.0 micro g/ml 3/100, (3%) and at 16.0 micro g/ml 11/100, (11%) of MDR-TB isolates were susceptible. Conclusion: LZD was found to have excellent in vitroefficacy as 96% of MDR-TB isolates were susceptible at breakpoint concentration of 1.0 micro g/ml or more. In case of MER it was found that in vitrosusceptibility improved as the break point concentrations were increased. (author)

Linezolid in the treatment of drug-resistant tuberculosis: the challenge of its narrow therapeutic index.

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Wasserman, Sean; Meintjes, Graeme; Maartens, Gary

2016-10-01

Linezolid is an oxazolidinone with potent activity against M tuberculosis, and improves culture conversion and cure rates when added to treatment regimens for drug resistant tuberculosis. However, linezolid has a narrow therapeutic window, and the optimal dosing strategy that minimizes the substantial toxicity associated with linezolid's prolonged use in tuberculosis treatment has not been determined, limiting the potential impact of this anti-mycobacterial agent. This paper aims to review and summarize the current knowledge on linezolid for the treatment of drug-resistant tuberculosis. The focus is on the pharmacokinetic-pharmacodynamic determinants of linezolid's efficacy and toxicity in tuberculosis, and how this relates to defining an optimal dose. Mechanisms of linezolid toxicity and resistance, and the potential role of therapeutic drug monitoring are also covered. Expert commentary: Prospective pharmacokinetic-pharmacodynamic studies are required to define optimal therapeutic targets and to inform improved linezolid dosing strategies for drug-resistant tuberculosis.

Mechanisms of Linezolid Resistance among Coagulase-Negative Staphylococci Determined by Whole-Genome Sequencing

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Tewhey, Ryan; Gu, Bing; Kelesidis, Theodoros; Charlton, Carmen; Bobenchik, April; Hindler, Janet; Schork, Nicholas J.

2014-01-01

ABSTRACT Linezolid resistance is uncommon among staphylococci, but approximately 2% of clinical isolates of coagulase-negative staphylococci (CoNS) may exhibit resistance to linezolid (MIC, ≥8 µg/ml). We performed whole-genome sequencing (WGS) to characterize the resistance mechanisms and genetic backgrounds of 28 linezolid-resistant CoNS (21 Staphylococcus epidermidis isolates and 7 Staphylococcus haemolyticus isolates) obtained from blood cultures at a large teaching health system in California between 2007 and 2012. The following well-characterized mutations associated with linezolid resistance were identified in the 23S rRNA: G2576U, G2447U, and U2504A, along with the mutation C2534U. Mutations in the L3 and L4 riboproteins, at sites previously associated with linezolid resistance, were also identified in 20 isolates. The majority of isolates harbored more than one mutation in the 23S rRNA and L3 and L4 genes. In addition, the cfr methylase gene was found in almost half (48%) of S. epidermidis isolates. cfr had been only rarely identified in staphylococci in the United States prior to this study. Isolates of the same sequence type were identified with unique mutations associated with linezolid resistance, suggesting independent acquisition of linezolid resistance in each isolate. PMID:24915435

Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome

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Long, Katherine S.

2012-01-01

Linezolid is an oxazolidinone antibiotic in clinical use for the treatment of serious infections of resistant Gram-positive bacteria. It inhibits protein synthesis by binding to the peptidyl transferase center on the ribosome. Almost all known resistance mechanisms involve small alterations to the linezolid binding site, so this review will therefore focus on the various changes that can adversely affect drug binding and confer resistance. High-resolution structures of linezolid bound to the 50S ribosomal subunit show that it binds in a deep cleft that is surrounded by 23S rRNA nucleotides. Mutation of 23S rRNA has for some time been established as a linezolid resistance mechanism. Although ribosomal proteins L3 and L4 are located further away from the bound drug, mutations in specific regions of these proteins are increasingly being associated with linezolid resistance. However, very little evidence has been presented to confirm this. Furthermore, recent findings on the Cfr methyltransferase underscore the modification of 23S rRNA as a highly effective and transferable form of linezolid resistance. On a positive note, detailed knowledge of the linezolid binding site has facilitated the design of a new generation of oxazolidinones that show improved properties against the known resistance mechanisms. PMID:22143525

Linezolid and dexamethasone experience in a serious case of listeria rhombencephalitis.

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Yılmaz, Pakize Ö; Mutlu, Nevzat M; Sertçelik, Ahmet; Baştuğ, Aliye; Doğu, Cihangir; Kışlak, Sümeyye

2016-01-01

Listeria rhombencephalitis is a rare cause of brain stem encephalitis. We report a case with a history of immunosupressive therapy due to Takayasu's arteritis that was treated with corticosteroids and linezolid for Listeria rhombencephalitis. A 63-year-old woman was admitted to the hospital with fever, headache, nausea, and vomiting. The patient's body temperature was 38°C, and she had a stiff neck. Listeria monocytogenes was isolated from the cerebrospinal fluid (CSF), and penicillin G and gentamicin treatment was initiated. Linezolid and dexamethasone were added. Due to hematuria and thrombocytopenia, the linezolid was discontinued. In immunocompromised patients with CNS infections, Listeria rhombencephalitis should be suspected. Linezolid can be used in combination with dexamethasone. Copyright © 2016 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

Evaluation of the stability of linezolid in aqueous solution and commonly used intravenous fluids

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Taylor R

2017-07-01

Full Text Available Rachel Taylor, Bruce Sunderland, Giuseppe Luna, Petra Czarniak School of Pharmacy, Faculty of Health Sciences, Curtin University, Bentley, WA, Australia Purpose: The aim was to evaluate the stability of linezolid in commonly used intravenous fluids and in aqueous solution to determine the kinetics of degradation and shelf-life values at alkaline pH values. Methods: Forced degradation studies were performed on linezolid in solution to develop a validated high-performance liquid chromatography analysis. Sodium chloride 0.9%, sodium lactate, and glucose 5% and glucose 10% solution containing 2.0 mg/mL linezolid were stored at 25.0°C (±0.1°C for 34 days. The effect of temperature on the stability of linezolid in 0.1 M sodium hydroxide solution was investigated to determine the activation energy. The degradation rates of linezolid at selected pH values at 70.0°C and the influence of ionic strength were also examined. Activation energy data were applied to determine the shelf-life values at selected pH values, and a pH rate profile was constructed over the pH range of 8.7–11.4. The stability of intravenous linezolid (Zyvox® solution was evaluated by storing at 70.0°C for 72 hours. Results: Linezolid was found to maintain >95.0% of its initial concentration after storage at 25.0°C for 34 days in sodium lactate, 0.9% in sodium chloride, and 5% and 10% in glucose solutions. Linezolid was degraded at alkaline pH values by first-order kinetics. Activation energy data showed that temperature, but not ionic strength, influenced the degradation rate significantly. An activation energy of 58.22 kJ/mol was determined for linezolid in 0.1 M sodium hydroxide solution. Linezolid was least stable at high pH values and at elevated temperatures. It was determined that linezolid has adequate stability for the preparation of intravenous fluids for clinical administration. Conclusion: Linezolid was found to have a shelf life of 34 days at 25°C when added to

Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients.

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Taubert, Max; Zoller, Michael; Maier, Barbara; Frechen, Sebastian; Scharf, Christina; Holdt, Lesca-Miriam; Frey, Lorenz; Vogeser, Michael; Fuhr, Uwe; Zander, Johannes

2016-09-01

Adequate linezolid blood concentrations have been shown to be associated with an improved clinical outcome. Our goal was to assess new predictors of inadequate linezolid concentrations often observed in critically ill patients. Fifty-two critically ill patients with severe infections receiving standard dosing of linezolid participated in this prospective observational study. Serum samples (median, 32 per patient) were taken on four consecutive days, and total linezolid concentrations were quantified. Covariates influencing linezolid pharmacokinetics were identified by multivariate analysis and a population pharmacokinetic model. Target attainment (area under the concentration-time curve over 12 h [AUC12]/MIC ratio of >50; MIC = 2 mg/liter) was calculated for both the study patients and a simulated independent patient group (n = 67,000). Target attainment was observed for only 36% of the population on both days 1 and 4. Independent covariates related to significant decreases of linezolid concentrations included higher weight, creatinine clearance rates, and fibrinogen and antithrombin concentrations, lower concentrations of lactate, and the presence of acute respiratory distress syndrome (ARDS). Linezolid clearance was increased in ARDS patients (by 82%) and in patients with elevated fibrinogen or decreased lactate concentrations. In simulated patients, most covariates, including fibrinogen and lactate concentrations and weight, showed quantitatively minor effects on target attainment (difference of ≤9% between the first and fourth quartiles of the respective parameters). In contrast, the presence of ARDS had the strongest influence, with only ≤6% of simulated patients reaching this target. In conclusion, the presence of ARDS was identified as a new and strong predictor of insufficient linezolid concentrations, which might cause treatment failure. Insufficient concentrations might also be a major problem in patients with combined alterations of other covariate

Structural Basis for Linezolid Binding Site Rearrangement in the Staphylococcus aureus Ribosome.

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Belousoff, Matthew J; Eyal, Zohar; Radjainia, Mazdak; Ahmed, Tofayel; Bamert, Rebecca S; Matzov, Donna; Bashan, Anat; Zimmerman, Ella; Mishra, Satabdi; Cameron, David; Elmlund, Hans; Peleg, Anton Y; Bhushan, Shashi; Lithgow, Trevor; Yonath, Ada

2017-05-09

An unorthodox, surprising mechanism of resistance to the antibiotic linezolid was revealed by cryo-electron microscopy (cryo-EM) in the 70S ribosomes from a clinical isolate of Staphylococcus aureus This high-resolution structural information demonstrated that a single amino acid deletion in ribosomal protein uL3 confers linezolid resistance despite being located 24 Å away from the linezolid binding pocket in the peptidyl-transferase center. The mutation induces a cascade of allosteric structural rearrangements of the rRNA that ultimately results in the alteration of the antibiotic binding site. IMPORTANCE The growing burden on human health caused by various antibiotic resistance mutations now includes prevalent Staphylococcus aureus resistance to last-line antimicrobial drugs such as linezolid and daptomycin. Structure-informed drug modification represents a frontier with respect to designing advanced clinical therapies, but success in this strategy requires rapid, facile means to shed light on the structural basis for drug resistance (D. Brown, Nat Rev Drug Discov 14:821-832, 2015, https://doi.org/10.1038/nrd4675). Here, detailed structural information demonstrates that a common mechanism is at play in linezolid resistance and provides a step toward the redesign of oxazolidinone antibiotics, a strategy that could thwart known mechanisms of linezolid resistance. Copyright © 2017 Belousoff et al.

Accumulation of multiple mutations in linezolid-resistant Staphylococcus epidermidis causing bloodstream infections; in silico analysis of L3 amino acid substitutions that might confer high-level linezolid resistance.

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Ikonomidis, Alexandros; Grapsa, Anastasia; Pavlioglou, Charikleia; Demiri, Antonia; Batarli, Alexandra; Panopoulou, Maria

2016-12-01

Fifty-six Staphylococcus epidermidis clinical isolates, showing high-level linezolid resistance and causing bacteremia in critically ill patients, were studied. All isolates belonged to ST22 clone and carried the T2504A and C2534T mutations in gene coding for 23SrRNA as well as the C189A, G208A, C209T and G384C missense mutations in L3 protein which resulted in Asp159Tyr, Gly152Asp and Leu94Val substitutions. Other silent mutations were also detected in genes coding for ribosomal proteins L3 and L22. In silico analysis of missense mutations showed that although L3 protein retained the sequence of secondary motifs, the tertiary structure was influenced. The observed alteration in L3 protein folding provides an indication on the putative role of L3-coding gene mutations in high-level linezolid resistance. Furthermore, linezolid pressure in health care settings where linezolid consumption is of high rates might lead to the selection of resistant mutants possessing L3 mutations that might confer high-level linezolid resistance.

Ethambutol/Linezolid Toxic Optic Neuropathy.

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Libershteyn, Yevgeniya

2016-02-01

To report a rare toxic optic neuropathy after long-term use of two medications: ethambutol and linezolid. A 65-year-old man presented to the Miami Veterans Affairs Medical Center in December 2014 for evaluation of progressive vision decrease in both eyes. The patient presented with best-corrected visual acuities of 20/400 in the right eye and counting fingers at 5 feet in the left eye. Color vision was significantly reduced in both eyes. Visual fields revealed a cecocentral defect in both eyes. His fundus and optic nerve examination was unremarkable. Because vision continued to decline after discontinuation of ethambutol, linezolid was also discontinued, after which vision, color vision, and visual fields improved. Because of these findings, the final diagnosis was toxic optic neuropathy. Final visual outcome was 20/30 in the right eye and 20/40 in the left eye. Drug-associated toxic optic neuropathy is a rare but vision-threatening condition. Diagnosis is made based on an extensive case history and careful clinical examination. The examination findings include varying decrease in vision, normal pupils and extraocular muscles, and unremarkable fundoscopy, with the possibility of swollen optic discs in the acute stage of the optic neuropathy. Other important findings descriptive of toxic optic neuropathy include decreased color vision and cecocentral visual field defects. This case illustrates the importance of knowledge of all medications and/or substances a patient consumes that may cause a toxic reaction and discontinuing them immediately if the visual functions are worsening or not improving.

Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome

DEFF Research Database (Denmark)

Long, Katherine S.; Vester, Birte

2012-01-01

Linezolid is an oxazolidinone antibiotic in clinical use for the treatment of serious infections of resistant Gram-positive bacteria. It inhibits protein synthesis by binding to the peptidyl transferase center on the ribosome. Almost all known resistance mechanisms involve small alterations...... to the linezolid binding site, so this review will therefore focus on the various changes that can adversely affect drug binding and confer resistance. High-resolution structures of linezolid bound to the 50S ribosomal subunit show that it binds in a deep cleft that is surrounded by 23S rRNA nucleotides. Mutation...... of 23S rRNA has for some time been established as a linezolid resistance mechanism. Although ribosomal proteins L3 and L4 are located further away from the bound drug, mutations in specific regions of these proteins are increasingly being associated with linezolid resistance. However, very little...

Linezolid-induced optic neuropathy with a rare pathological change in the inner retina.

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Ishii, Nobuhito; Kinouchi, Reiko; Inoue, Masatomo; Yoshida, Akitoshi

2016-12-01

We report a case of linezolid-induced optic neuropathy with transient microcystic spaces in the inner retina. We observed the retina using Fourier-domain optical coherence tomography (FD-OCT) in a patient with linezolid-induced optic neuropathy. A 49-year-old woman presented to our department with a 1-week history of bilateral photophobia. At the first visit, her best-corrected visual acuity (VA) was 0.6 in the right eye and 0.5 in the left eye. She had moderate optic disk edema and central scotomas bilaterally. FD-OCT showed bilateral microcystic spaces in the retina. Microcystic spaces were seen in the retinal nerve fiber layer (RNFL) and at the border of the RNFL and the retinal ganglion cell layer. Magnetic resonance imaging and laboratory tests showed no positive findings except for an elevated lactic acid level. One week after the first visit, the VA levels decreased to 0.06 and 0.07 in the right and left eyes, respectively. Because the patient had a 7-month history of linezolid treatment for persistent pyogenic arthritis, we suspected linezolid-induced optic neuropathy and immediately terminated treatment with this drug. The optic disk edema and the microcystic spaces in the retina resolved, and the VA improved to 1.2 at 6 weeks after linezolid withdrawal. Microcystic spaces, which resolved with linezolid withdrawal, were observed in linezolid-induced optic neuropathy. The microcystic spaces in the inner retina can be the first retinal sign of some optic neuropathies.

Comparing the ocular surface effects of topical vancomycin and linezolid for treating bacterial keratitis.

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Akova Budak, Berna; Baykara, Mehmet; Kıvanç, Sertaç Argun; Yilmaz, Hakan; Cicek, Serhat

2016-01-01

Vancomycin is the gold standard in combination therapy for severe and resistant gram-positive keratitis and in particular for Methicillin-resistant Staphylococcus aureus (MRSA) infections. The aim of this study was to report the ocular surface toxicity and scoring in patients whose treatment shifted to topical linezolid/ceftazidime from topical vancomycin/ceftazidime due to their vancomycin intolerance. A retrospective, interventional case series of bacterial keratitis was treated with topical linezolid (one drop of 0.2% solution per eye), administered hourly until epithelization and then gradually decreased. The number and extent of punctate epithelial erosions were noted across the entire surface of the cornea. Ocular discomfort was assessed by means of (a) patient-reported pain upon instillation of the medication (vancomycin/linezolid), (b) reported burning sensation between doses and (c) reported foreign-body sensation. No ocular surface toxicity related to linezolid use was noted. Patients were followed for at least 2 months after treatment between April and December 2013. Of the seven patients included in the study (age range: 2-88 years; five females, two males), complete epithelization and resolution was achieved in five patients. One patient was treated with linezolid after penetrating keratoplasty. The second culture of another patient with impending perforation despite linezolid/ceftazidime therapy yielded Fusarium spp., so he underwent tectonic keratoplasty. The mean ocular surface score was 9.4 ± 1.6 during vancomycin treatment and 5.9 ± 1.3 during linezolid treatment after discontinuation of vancomycin. The topical linezolid score was significantly lower (p = 0.027). Topical linezolid may be better tolerated, according to the mean ocular surface score, than topical vancomycin by some patients and can be considered an alternative for patients who do not well tolerate vancomycin.

Clinical Outcome with Oral Linezolid and Rifampin Following Recurrent Methicillin-Resistant Staphylococcus aureus Bacteremia Despite Prolonged Vancomycin Treatment

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Jon-David Schwalm

2004-01-01

Full Text Available Drug-resistant Gram-positive bacteria, especially Staphylococcus aureus, are emerging as the predominant organisms involved in both nosocomial and community-acquired infections. Since the 1980s, vancomycin has been the first-line antibiotic used to treat methicillin-resistant S aureus. However, allergy and intolerance to vancomycin, the increasing number of vancomycin clinical failures and the existence of vancomycin intermediate-susceptible isolates of S aureus suggest that new antibiotics are needed. This paper reports the only known case of a successful clinical outcome with long term oral linezolid and rifampin therapy in the management of recurrent and persistent methicillin-resistant S aureus bacteremia with metastatic infections despite prolonged vancomycin use. More than two years since the initiation of linezolid and rifampin, the study patient has been clinically well with no evidence of adverse drug reactions including cytopenia and hepatic toxicities. Physicians must be aware of the novel developments in antibiotic therapy to treat drug-resistant bacterial infections.

EFFECT OF LINEZOLID ALONE AND IN COMBINATION WITH OTHER ANTIBIOTICS, ON METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS.

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Yehia, Hoda; El Said, Manal; Azmy, Magda; Badawy, Moushira; Mansy, Soheir; Gohar, Hamida; Madany, Nadia

2016-04-01

The prevalence of methicillin-resistant Staphyloccoccus aureus (MRSA) strains has presented a new challenge in antimicrobial medication. Linezolid is a new drug with potent activity on Gram-positive pathogens such as MRSA. The aim of the study was to investigate the in vitro activity of linezolid alone and in combination with imipenem, vancomycin or rifampicin to determine the most active therapy against MRSA strains. Twenty clinical MRSA strains were isolated from patients admitted to inpatient departments and outpatient clinics of Theodor Bilharz Research Institute. Standard strain MRSA ATCC 43300 was included as a control. The MICs of MRSA strains to linezolid, vancomycin, imipenem and rifampicin were evaluated using E test. Time-kill curve were used to assess the in vitro activity of linezolid (at 8x MIC) alone and in combination with imipenem (at 32x MIC), vancomycin or rifampicin (at 8x MIC). Scanning and transmission electron microscopy were performed to compare bacterial morphological alterations owing to the different combi- nations. Time-kill studies showed synergistic effect when linezolid combined with imipenem was tested against all the MRSA strains. Linezolid plus vancomycin or rifampicin combinations did not display any synergism or antagonism. Scanning and transmission electron microscopy observations confirmed the interactions observed in time kill experiments. Linezolid in combination with subinhibitory concentrations of imipenem can be bactericidal against MRSA strains and appears to be a promising combination for the treatment of MRSA infections. No synergistic activity was seen when the linezolid and vancomycin or rifampicin were combined. Linezolid could prevent the emergence of mutants resistant to rifampicin

A 1 year retrospective audit of quality indicators of clinical pharmacological advice for personalized linezolid dosing: one stone for two birds?

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Pea, Federico; Cojutti, Piergiorgio; Dose, Lucia; Baraldo, Massimo

2016-02-01

This study explored the clinical and economic impact of clinical pharmacological advice (CPA) (based on therapeutic drug monitoring [TDM] results, and on patients' characteristics and co-medications) on personalized linezolid therapy in a tertiary care hospital. A 1 year retrospective analysis of quality indicators of CPA (clinicians' adherence rate to CPA, pre-post rate of linezolid trough concentrations within the desired range and cost balance analysis) was conducted. Five hundred and forty-four CPAs were provided to clinicians during 2014 for personalizing linezolid therapy in 168 patients. Clinicians' adherence to CPAs was very high (94.7%). The pre-post rate of linezolid Cmin distribution showed a favourable impact of CPA on patient care (pre-post ratio of Cmin within the desired range + 23.4%, pre, 51.2% vs. post, 74.6%). Overall, linezolid dosage was mainly reduced (56.9% of cases), whereas dose augmentation was needed only in a minority of cases (7.7%). Cost balance analysis showed that overall 1258 standard doses of linezolid (unitary dose 600 mg) were spared for treating 168 patients with a personalized dosage for a median duration of 11 days (range 3-128 days) with a cost saving of 60038.05 €. Active computerized advice elaborated by the clinical pharmacologist on the basis of TDM results and of patient's pathophysiological data and co-medications may be cost-effective for personalizing linezolid treatment. © 2015 The British Pharmacological Society.

Linezolid extracorporeal removal during haemodialysis with high cut-off membrane in critically ill patients.

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Villa, Gianluca; Cassetta, Maria Iris; Tofani, Lorenzo; Valente, Serafina; Chelazzi, Cosimo; Falsini, Silvia; De Gaudio, Angelo Raffaele; Novelli, Andrea; Ronco, Claudio; Adembri, Chiara

2015-10-01

Continuous venovenous haemodialysis with high cut-off membrane (HCO-CVVHD) is often used in critically ill septic patients with acute kidney injury (AKI) to sustain renal function and to remove circulating inflammatory mediators. The aim of this study was to analyse the extracorporeal removal of linezolid and related alterations in pharmacokinetic/pharmacodynamic (PK/PD) parameters during HCO-CVVHD. Three critically ill septic patients with AKI, treated with linezolid and HCO-CVVHD, were prospectively observed. To calculate the extracorporeal clearance of linezolid and the PK parameters, effluent, pre-filter and post-filter samples were contemporaneously collected before linezolid infusion, just after 1-h infusion (maximum serum concentration; C(max)), at 3 h and 6 h after dosing, and before the next dose (trough serum concentration; C(min)). Linezolid C(max) and C(min) (pre-filter) ranged from 10.4-23.5 mg/L and from 2.9-10.3 mg/L. The dialysate saturation coefficient was 0.66-0.85 and the extracorporeal clearance with a diffusive dose of 35 m L/kg/h ranged from 2.1-2.5 L/h. Total linezolid clearance was between 1.7 L/h and 6.3 L/h. The total area under the plasma concentration-time curve (AUC0-∞) ranged from 95.1 mgh/L to 352.9 mgh/L, in accordance with the different clinical conditions. AUCfree/MIC ratios were always linezolid total clearance, the clinical features of critically ill septic patients appear to be mainly responsible for the high variability of linezolid serum concentrations. Copyright © 2015. Published by Elsevier B.V.

In vitro antibacterial activity of tigecycline against clinical isolates of Linezolid-Intermediate (LIE and Linezolid-Resistant Enterococci (LRE by time-kill assay

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Gustavo Enck Sambrano

2014-08-01

Full Text Available Introduction: Enterococci have become the third major leading cause of nosocomial bacteraemia, an infection which is significantly associated with the risk of developing infective endocarditis. Linezolid provides high rates of clinical cure and microbiologic success in complicated infections due to Enterococcus spp. However, several instances of emergence of resistance during linezolid treatment have been reported. The aim of this study was evaluate the activity of tigecycline against Linezolid-Intermediate (LIE and Linezolid-Resistant Enterococcus faecalis (LRE by the time-kill assay. Methods: Five isolates of LRE and two isolates of LIE were used in this study. MICs were determined by broth dilution following the CLSI (2014 guidelines. Time-kill assay was employed to access the in vitro response profile of tigecycline. Results: All seven of the isolates presented MIC of 0.125μg/mL. Tigecycline activity was individually evaluated and in three of the five isolates of LRE it presented bactericidal. Against the other isolates, tigecycline showed bacteriostatic activity. The tigecycline activity was measured according to CLSI criteria. Conclusions: Tigecycline presented both bacteriostatic and bactericidal activity against tested isolates, result not yet described in previous studies. Time and concentrations above MIC were key factors to achieving bactericidal effect. MIC and the tested concentration below it resulted in bacteriostatical effect to enterococci, corroborating previous data.

Lack of an Effect of Standard and Supratherapeutic Doses of Linezolid on QTc Interval Prolongation▿†

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Damle, Bharat; LaBadie, Robert R.; Cuozzo, Cheryl; Alvey, Christine; Choo, Heng Wee; Riley, Steve; Kirby, Deborah

2011-01-01

A double-blind, placebo-controlled, four-way crossover study was conducted in 40 subjects to assess the effect of linezolid on corrected QT (QTc) interval prolongation. Time-matched, placebo-corrected QT intervals were determined predose and at 0.5, 1 (end of infusion), 2, 4, 8, 12, and 24 h after intravenous dosing of linezolid 600 and 1,200 mg. Oral moxifloxacin at 400 mg was used as an active control. The pharmacokinetic profile of linezolid was also evaluated. At each time point, the upper bound of the 90% confidence interval (CI) for placebo-corrected QTcF values (i.e., QTc values adjusted for ventricular rate using the correction methods of Fridericia) for linezolid 600 and 1,200-mg doses were 5 ms, indicating that the study was adequately sensitive to assess QTc prolongation. The pharmacokinetic profile of linezolid at 600 mg was consistent with previous observations. Systemic exposure to linezolid increased in a slightly more than dose-proportional manner at supratherapeutic doses, but the degree of nonlinearity was small. At a supratherapeutic single dose of 1,200 mg of linezolid, no treatment-related increase in adverse events was seen compared to 600 mg of linezolid, and no clinically meaningful effects on vital signs and safety laboratory evaluations were noted. PMID:21709083

Antibacterial susceptibility patterns and cross-resistance of methicillin resistant and sensitive Staphyloccus aureus isolated from the hospitalized patients in Shiraz, Iran

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Aziz Japoni

2010-10-01

Full Text Available Nosocomial infections caused by methicillin-resistant staphylococci (MRSA pose a serious problem in many countries. This study aimed to determine the antibacterial susceptibility patterns of methicillin sensitive and resistant Staphylococcus aureus isolates from the hospitalized patients. Totally 356 isolates of Staphylococcus aureus (S. aureus including 200, 137 and 19 corresponding to MSSA, MRSA, and intermediate MRSA strains, respectively were isolated. Antibacterial susceptibility patterns of the isolates to 14 antibiotics were examined using Kirby-Bauer method. MICs of 15 antibiotics to 156 MRSA isolates were determined by E test method. Cross-resistances of MRSA isolates (137+19 to the other tested antibiotics were also determined. S.aureus with high frequencies were isolated from the blood, sputum and deep wound samples. All of 200 MSSA isolates were sensitive to oxacillin, vancomycin, tecoplanin, rifampin, linezolid, quinupristin/dalfopristin, mupirocin and fusidic acid. A gradient of reduced susceptibility of MSSA to cephalexin, co-trimoxazole, ciprofloxacin, clindamycin, tetracycline, erythromycin and gentamicin were evident. MRSA isolates were sensitive to vancomycin, tecoplanin, linezolid, quinupristin/dalfopristin, mupirocin and fusidic acid, while reduced susceptibility of them to rifampin, co-trimoxazole, clindamycin, cephalexin, tetracycline, ciprofloxacin, erythromycin and gentamicin were observed. MRSA isolates exhibited a high range of cross-resistance to the eight tested antibiotics. Overall, co-trimoxazole, ciprofloxacin, clindamycin, tetracycline, erythromycin and gentamicin showed low activity against MSSA and MRSA isolates which may indicate they are not suitable to be used in clinical practices. To preserve the effectiveness of antibiotics, rational prescription and concomitant application of preventive measures against the spread of MRSA are recommended.

Resistance mechanisms of linezolid-nonsusceptible enterococci in Korea: low rate of 23S rRNA mutations in Enterococcus faecium.

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Lee, Sae-Mi; Huh, Hee Jae; Song, Dong Joon; Shim, Hyang Jin; Park, Kyung Sun; Kang, Cheol-In; Ki, Chang-Seok; Lee, Nam Yong

2017-12-01

To investigate linezolid-resistance mechanisms in linezolid-nonsusceptible enterococci (LNSE) isolated from a tertiary hospital in Korea. Enterococcal isolates exhibiting linezolid MICs ≥4 mg l -1 that were isolated between December 2011 and May 2016 were investigated by PCR and sequencing for mutations in 23S rRNA or ribosomal proteins (L3, L4 and L22) and for the presence of cfr, cfr(B) and optrA genes.Results/Key findings. Among 135 LNSE (87 Enterococcus faecium and 48 Enterococcus faecalis isolates), 39.1 % (34/87) of E. faecium and 18.8 % (9/48) of E. faecalis isolates were linezolid-resistant. The optrA carriage was the dominant mechanism in E. faecalis: 13 isolates, including 10 E. faecalis [70 % (7/10) linezolid-resistant and 30 % (3/10) linezolid-intermediate] and three E. faecium [33.3 % (1/3) linezolid-resistant and 66.7 % (2/3) linezolid-intermediate], contained the optrA gene. G2576T mutations in the 23S rRNA gene were detected only in E. faecium [14 isolates; 71.4 % (10/14) linezolid-resistant and 28.6 % (4/14) linezolid-intermediate]. One linezolid-intermediate E. faecium harboured a L22 protein alteration (Ser77Thr). No isolates contained cfr or cfr(B) genes and any L3 or L4 protein alterations. No genetic mechanism of resistance was identified for 67.6 % (23/34) of linezolid-resistant E. faecium. A low rate of 23S rRNA mutations and the absence of known linezolid-resistance mechanisms in the majority of E. faecium isolates suggest regional differences in the mechanisms of linezolid resistance and the possibility of additional mechanisms.

Antimicrobial Susceptibility Pattern of Enterococci Isolated From Patients in Tehran

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Horieh Saderi

2015-11-01

Full Text Available Background: Enterococci are one of the most common nosocomial pathogens and the emergence of multidrug-resistant strains has been increasing. Objectives: We studied the antimicrobial susceptibility of enterococci isolated from different clinical specimens of patients in Tehran. Materials and Methods: From the beginning of April 2013 to the end of June 2013, a total of 146 enterococci were isolated from the Pars General Hospital in Tehran. The antimicrobial susceptibility pattern of the isolates against ampicillin, clindamaycin, ciprofloxacin, erythromycin, levofloxacin, linezolid, nitrofurantoin, tetracycline, and vancomycin was determined using the disk diffusion method according to the guidelines of clinical laboratory standards institute (CLSI. Results: The rates of resistance were high to clindamycin, tetracycline, and erythromycin (97.2%, 89%, and 74.5%, respectively; moderate to ciprofloxacilin and levofloxacilin (40.6% and 36.4%, respectively; and low to ampicillin and nitrofurantoin (13.8% and 3.5%, respectively. All isolates were linezolid sensitive. Vancomycin-resistant enterococci (VRE accounted for 9.6% of the isolates. Conclusions: VRE and a high rate of resistance to some of antimicrobial agents were found among the enterococci isolated from patients in Tehran. These findings highlight the importance of regular supervision of antimicrobial susceptibilities.

[Linezolid-induced Apoptosis through Mitochondrial Damage and Role of Superoxide Dismutase-1 in Human Monocytic Cell Line U937].

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Fujii, Satoshi; Muraoka, Sanae; Miyamoto, Atsushi; Sakurai, Koichi

2018-01-01

 Cytopenia is a major adverse event associated with linezolid therapy. The objective of this study was to examine whether the cytotoxicity of linezolid to eukaryotic cells was associated with mitochondrial dysfunction and apoptosis-like cell death in human leukemic monocyte lymphoma cell line U937. Apoptosis-like cell death was clearly observed when cells were incubated with linezolid, depending on the duration and linezolid concentration. Mitochondrial membrane potential of cells treated with linezolid collapsed in a short period of time, but the number of mitochondria did not decrease. Cytotoxicity of linezolid was relieved by the knockdown of superoxide dismutase-1 in U937 cells. On the other hand, no autophagy was observed in cells treated with linezolid. These results suggest that mitochondrial damages would be linked to the induction of apoptosis in U937 cells treated with linezolid and that its mechanism does not involve autophagy.

Comparison of M.I.C.E. and Etest with CLSI agar dilution for antimicrobial susceptibility testing against oxacillin-resistant Staphylococcus spp.

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Eloiza H Campana

Full Text Available OBJECTIVE: The main objective of this study was to comparatively evaluate the performance of M.I.C.E. and Etest methodologies to that of agar dilution for determining the antimicrobial susceptibility profile of oxacillin-resistant Staphylococcus spp. METHODS: A total of 100 oxacillin-resistant Staphylococcus spp. isolates were collected from hospitalized patients at a teaching hospital. Antimicrobial susceptibility testing for vancomycin, teicoplanin and linezolid was performed using the reference CLSI agar dilution method (2009, Etest and M.I.C.E. methodologies. The MIC values were interpreted according to CLSI susceptibility breakpoints and compared by regression analysis. RESULTS: In general, the essential agreement (±1-log2 between M.I.C.E. and CLSI agar dilution was 93.0%, 84.0% and 77.0% for linezolid, teicoplanin and vancomycin, respectively. Essential agreement rates between M.I.C.E. and Etest were excellent (>90.0% for all antibiotics tested. Both strips (M.I.C.E. and Etest yielded two very major errors for linezolid. Unacceptable minor rates were observed for teicoplanin against CoNS and for vancomycin against S. aureus. CONCLUSIONS: According to our results, linezolid and teicoplanin MICs against all staphylococci and S. aureus, respectively, were more accurately predicted by M.I.C.E. strips. However, the Etest showed better performance than M.I.C.E. for predicting vancomycin MICs against all staphylococci. Thus, microbiologists must be aware of the different performance of commercially available gradient strips against staphylococci.

Oral-Only Linezolid-Rifampin Is Highly Effective Compared with Other Antibiotics for Periprosthetic Joint Infection: Study of a Mouse Model.

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Thompson, John M; Saini, Vikram; Ashbaugh, Alyssa G; Miller, Robert J; Ordonez, Alvaro A; Ortines, Roger V; Wang, Yu; Sterling, Robert S; Jain, Sanjay K; Miller, Lloyd S

2017-04-19

The medical treatment of periprosthetic joint infection (PJI) involves prolonged systemic antibiotic courses, often with suboptimal clinical outcomes including increased morbidity and health-care costs. Oral and intravenous monotherapies and combination antibiotic regimens were evaluated in a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) PJI. Oral linezolid with or without oral rifampin, intravenous vancomycin with oral rifampin, intravenous daptomycin or ceftaroline with or without oral rifampin, oral doxycycline, or sham treatment were administered at human-exposure doses for 6 weeks in a mouse model of PJI. Bacterial burden was assessed by in vivo bioluminescent imaging and ex vivo counting of colony-forming units (CFUs), and reactive bone changes were evaluated with radiographs and micro-computed tomography (μCT) imaging. Oral-only linezolid-rifampin and all intravenous antibiotic-rifampin combinations resulted in no recoverable bacteria and minimized reactive bone changes. Although oral linezolid was the most effective monotherapy, all oral and intravenous antibiotic monotherapies failed to clear infection or prevent reactive bone changes. Combination antibiotic-rifampin regimens, including oral-only linezolid-rifampin and the newer ceftaroline-rifampin combinations, were highly effective and more efficacious than monotherapies when used against a preclinical MRSA PJI. This study provides important preclinical evidence to better optimize future antibiotic therapy against PJIs. In particular, the oral-only linezolid-rifampin option might reduce venous access complications and health-care costs.

In Vitro Activity of PNU-100766 (Linezolid), a New Oxazolidinone Antimicrobial, against Nocardia brasiliensis

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Vera-Cabrera, Lucio; Gómez-Flores, Alejandra; Escalante-Fuentes, Wendy G.; Welsh, Oliverio

2001-01-01

The in vitro activity of a novel oxazolidinone, linezolid, was studied by comparing the activity of linezolid with those of amikacin, trimethoprim-sulfamethoxazole, and amoxicillin-clavulanic acid against 25 strains of Nocardia brasiliensis isolated from patients with mycetoma. All N. brasiliensis strains tested were sensitive to linezolid (MIC at which 90% of strains are inhibited [MIC90], 2 μg/ml; MIC50, 1 μg/ml). This antimicrobial might constitute a good alternative for treatment of actinomycetoma. PMID:11709356

Risk factors associated with high linezolid trough plasma concentrations.

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Morata, L; De la Calle, C; Gómez-Cerquera, J M; Manzanedo, L; Casals, G; Brunet, M; Cobos-Trigueros, N; Martínez, J A; Mensa, J; Soriano, A

2016-06-01

The major concern of linezolid is the adverse events. High linezolid trough serum concentration (Cmin) has been associated with toxicity. The aim of this study was to analyze factors associated with high Cmin. Main clinical characteristics of 104 patients treated with 600 mg/12 hours of linezolid were retrospectively reviewed. Samples were obtained just before the next dose after at least three doses and within the first 8 days of treatment. High Cmin was considered when it was >8 mg/L. Univariate and multivariate analysis were performed. 34.6% patients had a Cmin >8 mg/L, and they were older and had more frequently an estimated glomerular filtration by MDRD 8 was the renal function. Patients with an eGF 80 mL/min (OR: 4.273) and there was a trend towards a high Cmin in patients with eGF between 40-80 mL/min (OR: 2.109). High Cmin were frequent, especially in patients with MDRD <40 mL/min. Therapeutic drug monitoring could be useful to avoid toxicity in patients with renal dysfunction.

The efficacy and safety of linezolid and glycopeptides in the treatment of Staphylococcus aureus infections.

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Jinjian Fu

Full Text Available To assess the effectiveness and safety of linezolid in comparison with glycopeptides (vancomycin and teicoplanin for the treatment of Staphylococcus aureus infections, we conducted a meta-analysis of relevant randomized controlled trials. A thorough search of Pubmed and other databases was performed. Thirteen trials on 3863 clinically assessed patients were included. Linezolid was slightly more effective than glycopeptides in the intent-to-treat population (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.10, was more effective in clinically assessed patients (OR 95% CI: 1.38, 1.17-1.64 and in all microbiologically assessed patients (OR 95% CI: 1.38, 1.15-1.65. Linezolid was associated with better treatment in skin and soft-tissue infections (SSTIs patients (OR 95% CI: 1.61, 1.22-2.12, but not in bacteraemia (OR 95% CI: 1.24, 0.78-1.97 or pneumonia (OR 95% CI: 1.25, 0.97-1.60 patients. No difference of mortality between linezolid and glycopeptides was seen in the pooled trials (OR 95% CI: 0.98, 0.83-1.15. While linezolid was associated with more haematological (OR 95% CI: 2.23, 1.07-4.65 and gastrointestinal events (OR 95% CI: 2.34, 1.53-3.59, a significantly fewer events of skin adverse effects (OR 95% CI: 0.27, 0.16-0.46 and nephrotoxicity (OR 95% CI: 0.45, 0.28-0.72 were recorded in linezolid. Based on the analysis of the pooled data of randomized control trials, linezolid should be a better choice for treatment of patients with S. aureus infections, especially in SSTIs patients than glycopeptides. However, when physicians choose to use linezolid, risk of haematological and gastrointestinal events should be taken into account according to the characteristics of the specific patient populations.

Daptomycin versus linezolid for the treatment of vancomycin-resistant enterococcal bacteraemia: implications of daptomycin dose.

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Chuang, Y-C; Lin, H-Y; Chen, P-Y; Lin, C-Y; Wang, J-T; Chang, S-C

2016-10-01

Treatment options for vancomycin-resistant enterococci (VRE) bloodstream infection are limited. Studies comparing daptomycin or linezolid in treating VRE bloodstream infection have conflicting results and suggest daptomycin underdosing. The responses to different daptomycin doses have not been studied. We conducted a multicentre prospective cohort study to compare linezolid and daptomycin (≥6 mg/kg) for the treatment of VRE bloodstream infection. The primary outcome was 14-day mortality. We used multivariate logistic regression analysis for outcome analysis and a generalized additive model for dose-dependent response estimation. Two hundred twelve patients were included (daptomycin, n = 141; linezolid, n = 71). All-cause 14-day mortality was higher in the daptomycin group (36.9% vs. 21.1%; p 0.03). After adjusting for confounders in logistic regression, mortality was lower in the linezolid group (adjusted odds ratio (aOR), 0.45; 95% confidence interval (CI), 0.21-0.96; p 0.04). The generalized additive model showed that higher-dose daptomycin (≥9 mg/kg) was associated with better survival than lower-dose daptomycin (6-9 mg/kg). Logistic regression showed that linezolid (aOR, 0.36; 95% CI, 0.17-0.79; p 0.01) and higher-dose daptomycin (aOR, 0.26; 95% CI, 0.09-0.74; p 0.01) independently predicted lower mortality compared to lower-dose daptomycin. Linezolid was not superior to higher-dose daptomycin in terms of mortality (aOR, 1.40; 95% CI, 0.45-4.37; p 0.57). Higher-dose daptomycin had lower mortality than lower-dose daptomycin. Despite higher mortality for lower-dose daptomycin than linezolid, linezolid conferred no survival benefit compared to higher-dose daptomycin. Our findings suggest that the recommended daptomycin dose is suboptimal for treating VRE bacteraemia. Copyright © 2016. Published by Elsevier Ltd.

Investigation of mechanisms and molecular epidemiology of linezolid nonsusceptible Enterococcus faecalis isolated from a teaching hospital in China.

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Li, Bin; Ma, Chuan-Ling; Yu, Xiao; Sun, Yao; Li, Mei-Mei; Ye, Jian-Zhong; Zhang, Ya-Pei; Wu, Qing; Zhou, Tie-Li

2016-08-01

The epidemiological and molecular characteristics of eight linezolid nonsusceptible Enterococcus faecalis isolated from a teaching hospital in China (January to July 2014) were investigated. The target site modifications and cfr gene associated with linezolid resistance were not found. Results of the epidemiological investigation indicated that linezolid resistance possibly occurred on several independent occasions and was often not related to linezolid administration. Copyright © 2015. Published by Elsevier B.V.

Effects of continuous renal replacement therapy on linezolid pharmacokinetic/pharmacodynamics: a systematic review.

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Villa, Gianluca; Di Maggio, Paola; De Gaudio, A Raffaele; Novelli, Andrea; Antoniotti, Riccardo; Fiaccadori, Enrico; Adembri, Chiara

2016-11-19

Major alterations in linezolid pharmacokinetic/pharmacodynamic (PK/PD) parameters might be expected in critically ill septic patients with acute kidney injury (AKI) who are undergoing continuous renal replacement therapy (CRRT). The present review is aimed at describing extracorporeal removal of linezolid and the main PK-PD parameter changes observed in critically ill septic patients with AKI, who are on CRRT. Citations published on PubMed up to January 2016 were systematically reviewed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. All authors assessed the methodological quality of the studies and consensus was used to ensure studies met inclusion criteria. In-vivo studies in adult patients with AKI treated with linezolid and on CRRT were considered eligible for the analysis only if operational settings of the CRRT machine, membrane type, linezolid blood concentrations and main PK-PD parameters were all clearly reported. Among 68 potentially relevant articles, only 9 were considered eligible for the analysis. Across these, 53 treatments were identified among the 49 patients included (46 treated with high-flux and 3 with high cut-off membranes). Continuous veno-venous hemofiltration (CVVH) was the most frequent treatment performed amongst the studies. The extracorporeal clearance values of linezolid across the different modalities were 1.2-2.3 L/h for CVVH, 0.9-2.2 L/h for hemodiafiltration and 2.3 L/h for hemodialysis, and large variability in PK/PD parameters was reported. The optimal area under the curve/minimum inhibitory concentration (AUC/MIC) ratio was reached for pathogens with an MIC of 4 mg/L in one study only. Wide variability in linezolid PK/PD parameters has been observed across critically ill septic patients with AKI treated with CRRT. Particular attention should be paid to linezolid therapy in order to avoid antibiotic failure in these patients. Strategies to improve the effectiveness of

A simple high-performance liquid chromatography for the determination of linezolid in human plasma and saliva.

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Hara, Shuuji; Uchiyama, Masanobu; Yoshinari, Masami; Matsumoto, Taichi; Jimi, Shiro; Togawa, Atsushi; Takata, Tohru; Takamatsu, Yasushi

2015-09-01

Linezolid is an antimicrobial agent for the treatment of multiresistant Gram-positive infections. A practical high-performance liquid chromatography method was developed for the determination of linezolid in human plasma and saliva. Linezolid and an internal standard (o-ethoxybenzamide) were extracted from plasma and saliva with ethyl acetate and analyzed on a Capcell Pak C18 MG column with UV detection at 254 nm. The calibration curve was linear through the range 0.5-50 µg/mL using a 200 μL sample volume. The intra- and interday precisions were all plasma and 5.60% for saliva. The accuracies ranged from 98.8 to 110% for both matrices. The mean recoveries of linezolid were 80.8% for plasma and 79.0% for saliva. This method was used to determine the plasma and saliva concentrations of linezolid in healthy volunteers who were orally administered a 600 mg dose of linezolid. Our liquid-liquid extraction procedure is easy and requires a small volume of plasma or saliva (200 μL). This small volume can be advantageous in clinical pharmacokinetic studies, especially if children participate. Copyright © 2015 John Wiley & Sons, Ltd.

Treatment of MRSA pneumonia: Clinical and economic comparison of linezolid vs. vancomycin – a retrospective analysis of medical charts and re-imbursement data of real-life patient populations

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Wilke, Michael H.

2017-01-01

Full Text Available Objectives: To supplement the data collected in randomized clinical trials, the present study in patients with methicillin resistant (MRSA pneumonia was conducted to explore the clinical effectiveness of linezolid and vancomycin in a routine clinical setting. Further, the overall costs of the patients' stay in the intensive care unit (ICU were compared.Methods: This was a retrospective analysis of medical and reimbursement data of adult patients who were treated for MRSA pneumonia with linezolid or vancomycin. Since the subjects were not randomly assigned to treatments, propensity score adjustment was applied to reduce a potential selection bias.Results: In total, 226 patients were included; 95 received linezolid and 131 received vancomycin as initial therapy for MRSA pneumonia. Switches to another antibiotic were observed in 4 patients (4.2% receiving linezolid and in 23 patients (17.6% receiving vancomycin (logistic regression analysis; odds ratio linezolid/vancomycin: 0.183; 95% confidence interval [CI]: 0.052–0.647; p<0.01. All-cause in-hospital mortality was also lower in patients receiving linezolid (22 patients [23.2%] vs. 54 patients [41.2%] (logistic regression analysis; odds ratio linezolid/vancomycin: 0.351; 95% CI: 0.184–0.671; p<0.01. The analysis of the total costs of stay in ICU did not reveal any major differences between the two treatment groups (cost ratio linezolid/vancomycin: 1.29; 95% CI: 0.84–1.98; p=0.24.Conclusions: These findings confirm in a routine clinical setting that linezolid is a valuable therapeutic alternative to vancomycin for the treatment of MRSA pneumonia. However, prospective studies in real-life patient populations are warranted.

Rapid Acquisition of Linezolid Resistance in Methicillin-Resistant Staphylococcus aureus: Role of Hypermutation and Homologous Recombination.

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Iguchi, Shigekazu; Mizutani, Tomonori; Hiramatsu, Keiichi; Kikuchi, Ken

2016-01-01

We previously reported the case of a 64-year-old man with mediastinitis caused by Staphylococcus aureus in which the infecting bacterium acquired linezolid resistance after only 14 days treatment with linezolid. We therefore investigated relevant clinical isolates for possible mechanisms of this rapid acquisition of linezolid resistance. Using clinical S. aureus isolates, we assessed the in vitro mutation rate and performed stepwise selection for linezolid resistance. To investigate homologous recombination, sequences were determined for each of the 23S ribosomal RNA (23S rRNA) loci; analyzed sequences spanned the entirety of each 23S rRNA gene, including domain V, as well as the 16S-23S intergenic spacer regions. We additionally performed next-generation sequencing on clinical strains to identify single-nucleotide polymorphisms compared to the N315 genome. Strains isolated from the patient prior to linezolid exposure (M5-M7) showed higher-level linezolid resistance than N315, and the pre-exposure strain (M2) exhibited more rapid acquisition of linezolid resistance than did N315. However, the mutation rates of these and contemporaneous clinical isolates were similar to those of N315, and the isolates did not exhibit any mutations in hypermutation-related genes. Sequences of the 23S rRNA genes and 16S-23S intergenic spacer regions were identical among the pre- and post-exposure clinical strains. Notably, all of the pre-exposure isolates harbored a recQ missense mutation (Glu69Asp) with respect to N315; such a lesion may have affected short sequence recombination (facilitating, for example, recombination among rrn loci). We hypothesize that this mechanism contributed to rapid acquisition of linezolid resistance. Hypermutation and homologous recombination of the ribosomal RNA genes, including 23S rRNA genes, appear not to have been sources of the accelerated acquisition of linezolid resistance observed in our clinical case. Increased frequency of short sequence

Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis.

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Song, Taeksun; Lee, Myungsun; Jeon, Han-Seung; Park, Yumi; Dodd, Lori E; Dartois, Véronique; Follman, Dean; Wang, Jing; Cai, Ying; Goldfeder, Lisa C; Olivier, Kenneth N; Xie, Yingda; Via, Laura E; Cho, Sang Nae; Barry, Clifton E; Chen, Ray Y

2015-11-01

Long-term linezolid use is limited by mitochondrial toxicity-associated adverse events (AEs). Within a prospective, randomized controlled trial of linezolid to treat chronic extensively drug-resistant tuberculosis, we serially monitored the translational competence of mitochondria isolated from peripheral blood of participants by determining the cytochrome c oxidase/citrate synthase activity ratio. We compared this ratio with AEs associated with mitochondrial dysfunction. Linezolid trough concentrations were determined for 38 participants at both 600 mg and 300 mg doses. Those on 600 mg had a significantly higher risk of AE than those on 300 mg (HR 3·10, 95% CI 1·23-7 · 86). Mean mitochondrial function levels were significantly higher in patients before starting linezolid compared to their concentrations on 300 mg (P = 0·004) or 600 mg (P linezolid trough concentrations were associated with lower mitochondrial function levels (Spearman's ρ = - 0.48; P = 0.005). Mitochondrial toxicity risk increased with increasing linezolid trough concentrations, with all patients with mean linezolid trough > 2 μg/ml developing an AE related to mitochondrial toxicity, whether on 300 mg or 600 mg. Therapeutic drug monitoring may be useful to prevent the development of mitochondrial toxicity associated with long-term linezolid use.

Estimating the cost-effectiveness of linezolid for the treatment of methicillin-resistant Staphylococcus aureus nosocomial pneumonia in Taiwan.

Science.gov (United States)

Lin, Po-Chang; Wang, Bruce C M; Kim, Richard; Magyar, Andrew; Lai, Chung-Chih; Yang, Ya-Wen; Huang, Yhu-Chering

2016-02-01

Methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia (NP) is associated with higher resource utilization, increased hospital stays, and mortality. We present a health economics model to understand the impact of using linezolid as the first-line treatment of MRSA NP in Taiwan. We developed a cost-effectiveness model to estimate the costs and clinical outcomes of using linezolid 600 mg b.i.d. versus vancomycin 15 mg/kg b.i.d. as the first-line treatment of MRSA NP in Taiwan. The model is a decision-analytic analysis in which a MRSA-confirmed patient is simulated to utilize one of the treatments, using data from a clinical trial. Within each treatment arm, the patient can or cannot achieve clinical cure. Regardless of whether the clinical cure was achieved or not, the patient may or may not have experienced an adverse event. The per-protocol results for clinical cure were 57.6% and 46.6% for linezolid and vancomycin, respectively. The total cost of linezolid was $376 more per patient than that of vancomycin. Drug costs were higher for linezolid than for vancomycin ($1108 vs. $233), and hospitalization costs were lower ($4998 vs. $5496). With higher cost and higher cure rates for linezolid, the incremental cost per cure was $3421. This study projects linezolid to have higher drug costs, lower hospital costs, and higher overall costs compared with vancomycin. This is balanced against the higher clinical cure rate for linezolid. Depending on the willingness to pay for clinical cure, linezolid could be cost effective as the first-line treatment of NP in Taiwan. Copyright © 2015. Published by Elsevier B.V.

Comparison of Linezolid and Vancomycin for Methicillin-Resistant Staphylococcus aureus Pneumonia: Institutional Implications.

Science.gov (United States)

Tong, ManShan C; Wisniewski, Christopher S; Wolf, Bethany; Bosso, John A

2016-07-01

Recent studies suggesting clinical superiority of linezolid over vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia led to a change in our institution's clinical pathway/order form for hospital-acquired pneumonia, positioning linezolid as the preferred agent. Our objective was to assess the impact of this change within our institution. Retrospective electronic medical records review. The analysis for this observational study included eligible patients admitted to our medical center between May 1, 2011, and August 31, 2014, with ICD-9 codes for MRSA and pneumonia. Included patients were at least 18 years of age and had vancomycin or linezolid initiated at least 2 days after admission and continued for at least 2 consecutive days. The primary end points were extent of antibiotic use before and after order form change and length of stay (LOS) and hospital charges in the two treatment groups. A secondary aim was to detect any gross discrepancies in patient outcomes such as treatment duration, mechanical ventilation duration, all-cause mortality rate, nephrotoxicity, and 30-day readmission between the two treatment groups. Outcomes in 227 patients were assessed. Linezolid use increased 16.2% subsequent to the change in the order form. Although not statistically significant, the median hospital admission charge was $6200 lower in patients treated with linezolid compared with those treated with vancomycin ($25,900 vs $32,100). Hospital LOS was significantly associated with Charlson Comorbidity Index score (plinezolid treatment, and these patients were more likely to be discharged (shorter LOS). Although linezolid use increased markedly with this pathway/order form change, no negative institutional consequences or unfavorable patient outcomes were detected, justifying the change in policy from these perspectives. © 2016 Pharmacotherapy Publications, Inc.

Activity of Daptomycin or Linezolid in Combination with Rifampin or Gentamicin against Biofilm-Forming Enterococcus faecalis or E. faecium in an In Vitro Pharmacodynamic Model Using Simulated Endocardial Vegetations and an In Vivo Survival Assay Using Galleria mellonella Larvae

Science.gov (United States)

Luther, Megan K.; Arvanitis, Marios; Mylonakis, Eleftherios

2014-01-01

Enterococci are the third most frequent cause of infective endocarditis. A high-inoculum stationary-phase in vitro pharmacodynamic model with simulated endocardial vegetations was used to simulate the human pharmacokinetics of daptomycin at 6 or 10 mg/kg of body weight/day or linezolid at 600 mg every 12 h (q12h), alone or in combination with gentamicin at 1.3 mg/kg q12h or rifampin at 300 mg q8h or 900 mg q24h. Biofilm-forming, vancomycin-susceptible Enterococcus faecalis and vancomycin-resistant Enterococcus faecium (vancomycin-resistant enterococcus [VRE]) strains were tested. At 24, 48, and 72 h, all daptomycin-containing regimens demonstrated significantly more activity (decline in CFU/g) than any linezolid-containing regimen against biofilm-forming E. faecalis. The addition of gentamicin to daptomycin (at 6 or 10 mg/kg) in the first 24 h significantly improved bactericidal activity. In contrast, the addition of rifampin delayed the bactericidal activity of daptomycin against E. faecalis, and the addition of rifampin antagonized the activities of all regimens against VRE at 24 h. Also, against VRE, the addition of gentamicin to linezolid at 72 h improved activity and was bactericidal. Rifampin significantly antagonized the activity of linezolid against VRE at 72 h. In in vivo Galleria mellonella survival assays, linezolid and daptomycin improved survival. Daptomycin at 10 mg/kg improved survival significantly over that with linezolid against E. faecalis. The addition of gentamicin improved the efficacy of daptomycin against E. faecalis and those of linezolid and daptomycin against VRE. We conclude that in enterococcal infection models, daptomycin has more activity than linezolid alone. Against biofilm-forming E. faecalis, the addition of gentamicin in the first 24 h causes the most rapid decline in CFU/g. Of interest, the addition of rifampin decreased the activity of daptomycin against both E. faecalis and VRE. PMID:24867993

Optimization of linezolid treatment regimens for Gram-positive bacterial infections based on pharmacokinetic/pharmacodynamic analysis.

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Yang, Minjie; Zhang, Jing; Chen, Yuancheng; Liang, Xiaoyu; Guo, Yan; Yu, Jicheng; Zhu, Demei; Zhang, Yingyuan

2017-01-01

To optimize linezolid treatment regimens for Gram-positive bacterial infections based on pharmacokinetic/pharmacodynamic analysis. The minimum inhibitory concentration (MIC) distribution of 572 Gram-positive strains from patients with clinically confirmed infections was analyzed. Using the Monte Carlo simulation method, the cumulative fraction of response and probability of target attainment were determined for linezolid regimens of 600 mg q.12h and q.8h Results: Linezolid dosage of 600 mg q.12h yielded >90% cumulative fraction of response and probability of target attainment for staphylococcal infections with an MIC of ≤1 mg/l, enterococcal infections with higher MIC values required 600 mg q.8h. Linezolid 600 mg q.12h is still the clinically recommended empirical dosage for Gram-positive bacterial infections. However, as bacterial MICs increase, 600 mg q.8h may be required to achieve better efficacy.

Applicability of a Single Time Point Strategy for the Prediction of Area Under the Concentration Curve of Linezolid in Patients: Superiority of Ctrough- over Cmax-Derived Linear Regression Models.

Science.gov (United States)

Srinivas, Nuggehally R; Syed, Muzeeb

2016-03-01

Linezolid, a oxazolidinone, was the first in class to be approved for the treatment of bacterial infections arising from both susceptible and resistant strains of Gram-positive bacteria. Since overt exposure of linezolid may precipitate serious toxicity issues, therapeutic drug monitoring (TDM) may be required in certain situations, especially in patients who are prescribed other co-medications. Using appropriate oral pharmacokinetic data (single dose and steady state) for linezolid, both maximum plasma drug concentration (Cmax) versus area under the plasma concentration-time curve (AUC) and minimum plasma drug concentration (Cmin) versus AUC relationship was established by linear regression models. The predictions of the AUC values were performed using published mean/median Cmax or Cmin data and appropriate regression lines. The quotient of observed and predicted values rendered fold difference calculation. The mean absolute error (MAE), root mean square error (RMSE), correlation coefficient (r), and the goodness of the AUC fold prediction were used to evaluate the two models. The Cmax versus AUC and trough plasma concentration (Ctrough) versus AUC models displayed excellent correlation, with r values of >0.9760. However, linezolid AUC values were predicted to be within the narrower boundary of 0.76 to 1.5-fold by a higher percentage by the Ctrough (78.3%) versus Cmax model (48.2%). The Ctrough model showed superior correlation of predicted versus observed values and RMSE (r = 0.9031; 28.54%, respectively) compared with the Cmax model (r = 0.5824; 61.34%, respectively). A single time point strategy of using Ctrough level is possible as a prospective tool to measure the AUC of linezolid in the patient population.

Clinical update on linezolid in the treatment of Gram-positive bacterial infections

Science.gov (United States)

Ager, Sally; Gould, Kate

2012-01-01

Gram-positive pathogens are a significant cause of morbidity and mortality in both community and health care settings. Glycopeptides have traditionally been the antibiotics of choice for multiresistant Gram-positive pathogens but there are problems with their use, including the emergence of glycopeptide-resistant strains, tissue penetration, and achieving and monitoring adequate serum levels. Newer antibiotics such as linezolid, a synthetic oxazolidinone, are available for the treatment of resistant Gram-positive bacteria. Linezolid is active against a wide range of Gram-positive bacteria and has been generally available for the treatment of Gram-positive infections since 2000. There are potential problems with linezolid use, including its bacteriostatic action and the relatively high incidence of reported adverse effects, particularly with long-term use. Long-term use may also be complicated by the development of resistance. However, linezolid has been shown to be clinically useful in the treatment of several serious infections where traditionally bacteriocidal agents have been required and many of its adverse effects are reversible on cessation. It has also been shown to be a cost-effective treatment option in several studies, with its high oral bioavailability allowing an early change from intravenous to oral formulations with consequent earlier patient discharge and lower inpatient costs. PMID:22787406

Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis.

Science.gov (United States)

Kamp, Jasper; Bolhuis, Mathieu S; Tiberi, Simon; Akkerman, Onno W; Centis, Rosella; de Lange, Wiel C; Kosterink, Jos G; van der Werf, Tjip S; Migliori, Giovanni B; Alffenaar, Jan-Willem C

2017-06-01

Linezolid is used increasingly for the treatment of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis (TB). However, linezolid can cause severe adverse events, such as peripheral and optical neuropathy or thrombocytopenia related to higher drug exposure. This study aimed to develop a population pharmacokinetic model to predict the area under the concentration curve (AUC) for linezolid using a limited number of blood samples. Data from patients with MDR-/XDR-TB who received linezolid and therapeutic drug monitoring as part of their TB treatment were used. Mw\\Pharm 3.82 (Mediware, Zuidhorn, The Netherlands) was used to develop a population pharmacokinetic model and limited sampling strategy (LSS) for linezolid. LSS was evaluated over a time span of 6 h. Blood sampling directly before linezolid administration and 2 h after linezolid administration were considered to be the most clinically relevant sampling points. The model and LSS were evaluated by analysing the correlation between AUC 12h,observed and AUC 12h,estimated . In addition, LSS was validated with an external group of patients with MDR-/XDR-TB from Sondalo, Italy. Fifty-two pharmacokinetic profiles were used to develop the model. Thirty-three profiles with a 300 mg dosing regimen and 19 profiles with a 600 mg dosing regimen were obtained. Model validation showed prediction bias of 0.1% and r 2 of 0.99. Evaluation of the most clinically relevant LSS showed prediction bias of 4.8% and r 2 of 0.97. The root mean square error corresponding to the most relevant LSS was 6.07%. The developed LSS could be used to enable concentration-guided dosing of linezolid. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Linezolid induced black hairy tongue

OpenAIRE

Govindan Balaji; B Maharani; Velappan Ravichandran; Thiyagarajan Parthasarathi

2014-01-01

Black hairy tongue (BHT) also called as lingua villosa nigra, is a self limiting benign condition characterized by hypertrophy and elongation of filiform papillae of tongue with brown or black discoloration. Smoking, poor oral hygiene, xerostomia, using peroxide containing mouth washes, substance abuse and drugs (steroids, methyldopa, olanzapine, etc) are the predisposing factors. However its occurrence in relation to linezolid ingestion among south Indians has not been reported in PubMed dat...

Limited Sampling Strategies for Therapeutic Drug Monitoring of Linezolid in Patients With Multidrug-Resistant Tuberculosis

NARCIS (Netherlands)

Alffenaar, Jan-Willem C.; Kosterink, Jos G. W.; van Altena, Richard; van der Werf, Tjip S.; Uges, Donald R. A.; Proost, Johannes H.

Introduction: Linezolid is a potential drug for the treatment of multidrug-resistant tuberculosis but its use is limited because of severe adverse effects such as anemia, thrombocytopenia, and peripheral neuropathy. This study aimed to develop a model for the prediction of linezolid area. under the

Effect of Linezolid on Hematologic Recovery in Newly Diagnosed Acute Myeloid Leukemia Patients Following Induction Chemotherapy.

Science.gov (United States)

Nedved, Adrienne N; DeFrates, Sean R; Hladnik, Lindsay M; Stockerl-Goldstein, Keith E

2016-10-01

Assess the effects of linezolid on hematologic outcomes in newly diagnosed patients with acute myeloid leukemia (AML) following induction chemotherapy. Single-center, retrospective, observational, cohort study. Large, tertiary care academic medical center. A total of 225 patients ≥ 18 years admitted between December 2010 and 2013 with newly diagnosed AML were assessed for inclusion. Patients were identified through the use of ICD-9 codes and chemotherapy ordered via the computerized physician order entry system. Sixty-eight patients met inclusion criteria and were grouped into two arms based on antimicrobial treatment: LZD group (linezolid plus gram-negative antimicrobial, n=21) or control group (vancomycin or daptomycin plus gram-negative antimicrobial, n=47). The LZD group received linezolid ≥ 72 hours. The control group received vancomycin or daptomycin ≥ 72 hours. If patients switched extended gram-positive therapy, they were included in the LZD group as long as they had received ≥ 72 hours of linezolid. The primary end point of time to neutrophil recovery was not statistically different (28 days for LZD group vs 26 days for control group; p=0.675). The preplanned subgroup analysis of patients who received ≥ 14 days of linezolid demonstrated statistically similar median times to neutrophil recovery (29 days for LZD group vs 26 days for control group; p=0.487). Total duration of extended gram-positive antimicrobial therapy was significantly longer in the LZD group (27 days vs 16 days; plinezolid for extended gram-positive antimicrobial coverage following induction chemotherapy. This study provides new insight with a primary focus on the effects of hematologic outcomes when using linezolid in a well-defined acute leukemia population. Further study is warranted with larger populations to assess the potential adverse effects linezolid may have in patients with acute leukemia. © 2016 Pharmacotherapy Publications, Inc.

Global analysis of the impact of linezolid onto virulence factor production in S. aureus USA300

NARCIS (Netherlands)

Bonn, Florian; Pane-Farre, Jan; Schlueter, Rabea; Schaffer, Marc; Fuchs, Stephan; Bernhardt, Joerg; Riedel, Katharina; Otto, Andreas; Voelker, Uwe; van Dijl, Jan Maarten; Hecker, Michael; Maeder, Ulrike; Becher, Doerte

The translation inhibitor linezolid is an antibiotic of last resort against Gram-positive pathogens including methicillin resistant strains of the nosocomial pathogen Staphylococcus aureus. Linezolid is reported to inhibit production of extracellular virulence factors, but the molecular cause is

Modeling the economic impact of linezolid versus vancomycin in confirmed nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus.

Science.gov (United States)

Patel, Dipen A; Shorr, Andrew F; Chastre, Jean; Niederman, Michael; Simor, Andrew; Stephens, Jennifer M; Charbonneau, Claudie; Gao, Xin; Nathwani, Dilip

2014-07-22

We compared the economic impacts of linezolid and vancomycin for the treatment of hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA)-confirmed nosocomial pneumonia. We used a 4-week decision tree model incorporating published data and expert opinion on clinical parameters, resource use and costs (in 2012 US dollars), such as efficacy, mortality, serious adverse events, treatment duration and length of hospital stay. The results presented are from a US payer perspective. The base case first-line treatment duration for patients with MRSA-confirmed nosocomial pneumonia was 10 days. Clinical treatment success (used for the cost-effectiveness ratio) and failure due to lack of efficacy, serious adverse events or mortality were possible clinical outcomes that could impact costs. Cost of treatment and incremental cost-effectiveness per successfully treated patient were calculated for linezolid versus vancomycin. Univariate (one-way) and probabilistic sensitivity analyses were conducted. The model allowed us to calculate the total base case inpatient costs as $46,168 (linezolid) and $46,992 (vancomycin). The incremental cost-effectiveness ratio favored linezolid (versus vancomycin), with lower costs ($824 less) and greater efficacy (+2.7% absolute difference in the proportion of patients successfully treated for MRSA nosocomial pneumonia). Approximately 80% of the total treatment costs were attributed to hospital stay (primarily in the intensive care unit). The results of our probabilistic sensitivity analysis indicated that linezolid is the cost-effective alternative under varying willingness to pay thresholds. These model results show that linezolid has a favorable incremental cost-effectiveness ratio compared to vancomycin for MRSA-confirmed nosocomial pneumonia, largely attributable to the higher clinical trial response rate of patients treated with linezolid. The higher drug acquisition cost of linezolid was offset by lower treatment failure

Comparative Evaluation of Serotonin Toxicity among Veterans Affairs Patients Receiving Linezolid and Vancomycin

Science.gov (United States)

Patel, N.; Rivera, A.; Tristani, L.; Lazariu, V.; Vandewall, H.; McNutt, L. A.

2013-01-01

Despite the theoretical risk of serotonin toxicity (ST) with linezolid, “real-world” clinical evaluations of the risk of ST in patients receiving linezolid have been limited to case reports and noncomparator studies. An observational, matched-cohort study was conducted to evaluate the risk of ST among hospitalized patients who received linezolid or vancomycin at the Upstate New York Veterans Affairs Healthcare Network (Veterans Integrated Service Network 2 [VISN-2]). Matching criteria included VISN-2 hospital, hospital ward, prior hospital length of stay, age, and baseline platelet counts. The patients' electronic medical records were evaluated for symptoms consistent with ST and the Hunter serotonin toxicity criteria (HSTC) using an intensive, natural word search algorithm. The study included 251 matched pairs. Demographics and comorbidities were similar between groups. Over half of the study population received at least one concurrent medication with serotonergic activity. Receipt of agents with serotonergic activity was more pronounced in the vancomycin group, and the higher frequency was due to concomitant antihistamine and antiemetic use. Antidepressant use, including selective serotonin reuptake inhibitors (SSRIs), was similar between groups. No patients in either group were found to meet the criteria using the word search algorithm for ST. Fewer linezolid patients than vancomycin patients met the HSTC overall (3.2% versus 8.8%) and when stratified by receipt of a concurrent serotonergic agent (4.3% versus 12.4%). Of the patients meeting the HSTC, most had past or present comorbidities that may have contributed to or overlapped the HSTC. This study of hospitalized patients revealed comparably low frequencies of adverse events potentially related to ST among patients who received linezolid or vancomycin. PMID:24041888

Pharmacokinetic/pharmacodynamic evaluation of linezolid for the treatment of staphylococcal infections in critically ill patients.

Science.gov (United States)

Dong, Haiyan; Xie, Jiao; Wang, Taotao; Chen, Lihong; Zeng, Xiaoyan; Sun, Jinyao; Wang, Xue; Dong, Yalin

2016-09-01

Several studies have demonstrated that the ideal therapeutic effect of linezolid cannot be achieved in critically ill patients with the recommended standard dosing regimen of 600 mg every 12 h (q12h). Moreover, the optimal strategy for successful treatment is still lacking. This study analysed factors influencing the efficacy of linezolid treatment and determined the target for successful treatment by logistic regression in 27 critically ill patients with staphylococcal infection who received linezolid 600 mg q12h. The results showed that only the 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) ratio was significantly associated with staphylococcal eradication. Reaching 80% bacterial eradication required an AUC24/MIC of 120.5, defining the therapeutic target. Different dosing regimens were evaluated using Monte Carlo simulation to determine the optimal dosage strategy for linezolid. Although the probability of target attainment (PTA) was high (>99.9%) for the standard dosing regimen at MIC ≤ 1 mg/L, the PTA was almost 0 at MIC = 2 mg/L, thus the dosing regimen required adjustment. In addition, if the dosing regimen was adjusted to 600 mg every 8 h or 600 mg every 6 h, the major staphylococci (except for MRSA and MSSA) exhibited a cumulative fraction of response of >80%, showing a higher treatment success. These findings indicate that a strategy of high linezolid dosage may be needed to increase the probability of successful treatment at MIC > 1 mg/L. The role of therapeutic drug monitoring should be encouraged for optimising linezolid exposure in critically ill patients. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Comparative Efficacy of Ceftaroline with Linezolid against Staphylococcus Aureus and Methicillin Resistant Staphylococcus Aureus

International Nuclear Information System (INIS)

Hafeez, A.; Munir, T.; Rehman, S.; Najeeb, S.; Gilani, M.; Latif, M.; Ansari, M.; Saad, N.

2015-01-01

Objective:To compare the in vitro antimicrobial efficacy of ceftaroline with linezolid against Staphylococcus aureus and methicillin resistant Staphylococcus aureus. Study Design: Quasi-experimental study. Place and Duration of Study: Microbiology Department, Army Medical College, Rawalpindi, from January to December 2013. Methodology: Clinical samples from respiratory tract, blood, pus and various catheter tips routinely received in the Department of Microbiology, Army Medical College, Rawalpindi were innoculated on blood and MacConkey agar. Staphylococcus aureus was identified by colony morphology, Gram reaction, catalase test and coagulase test. Methicillin resistant Staphylococcus aureus detection was done by modified Kirby Bauer disc diffusion method using cefoxitin disc (30g) and the isolates were considered methicillin resistant if the zone of inhibition around cefoxitin disc was /sup 2/ 21 mm. Bacterial suspensions of 56 Staphylococcus aureus isolates and 50 MRSA isolates were prepared, which were standardized equal to 0.5 McFarland's turbidity standard and inoculated on Mueller-Hinton agar plates followed by application of ceftaroline and linezolid disc (Oxoid, UK), according to manufacturer's instructions. The plates were then incubated at 37 Degree C aerobically for 18 - 24 hours. Diameters of inhibition zone were measured and interpretated as per Clinical and Laboratory Standards Institute (CLSI) guidelines. Results: Out of 106 isolates all of the 56 Staphylococcus aureus (100%) were sensitive to ceftaroline and linezolid. However, out of 50 methicillin resistant Staphylococcus aureus, 48 (96%) were sensitive to ceftaroline whereas, 49 (98%) were sensitive to linezolid. Conclusion: Ceftaroline is equally effective as linezolid against Staphylococcus aureus and methicillin resistant Staphylococcus aureus. (author)

Polymorphic solidification of Linezolid confined in electrospun PCL fibers for controlled release in topical applications.

Science.gov (United States)

Tammaro, Loredana; Saturnino, Carmela; D'Aniello, Sharon; Vigliotta, Giovanni; Vittoria, Vittoria

2015-07-25

Poly(ϵ-caprolactone) (PCL) membranes loaded with Linezolid, chemically N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (empirical formula C16H20FN3O4) have been prepared by electrospinning technique, at different Linezolid concentrations (0.5, 1, 2.5 and 5%, w/w). Structural characterization, morphological analysis and the study of the mechanical properties have been performed on loaded membranes and compared with neat PCL membranes. Linezolid embedded in the membranes is prevalently amorphous, with a low crystallinity showing a different polymorphic form respect to the usual Form I and Form II. The release kinetics of the drug were studied by spectrophotometric analysis (UV-vis). It allowed to discriminate between Linezolid molecules on the surface and encapsulated into the fibers. The antibacterial activity of the electrospun membranes was effective to inhibit Staphylococcus aureus. The properties of the loaded membranes and their capability for local delivery of the antibiotic make them good candidates as drug release devices for topical use. Copyright © 2015 Elsevier B.V. All rights reserved.

Synthesis of Linezolid Metabolites PNU-142300 and PNU-142586 toward the Exploration of Metabolite-Related Events.

Science.gov (United States)

Hanaya, Kengo; Matsumoto, Kazuaki; Yokoyama, Yuta; Kizu, Junko; Shoji, Mitsuru; Sugai, Takeshi

2017-01-01

Linezolid (1) is an oxazolidinone antibiotic that is partially metabolized in vivo via ring cleavage of its morpholine moiety to mainly form two metabolites, PNU-142300 (2) and PNU-142586 (3). It is supposed that accumulation of 2 and 3 in patients with renal insufficiency may cause thrombocytopenia, one of the adverse effects of linezolid. However, the poor availability of 2 and 3 has hindered further investigation of the clinical significance of the accumulation of these metabolites. In this paper, we synthesized metabolites 2 and 3 via a common synthetic intermediate, 4; this will encourage further exploration of events related to these metabolites and lead to improved clinical use of linezolid.

Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis

NARCIS (Netherlands)

Kamp, Jasper; Bolhuis, Mathieu S.; Tiberi, Simon; Akkerman, Onno W.; Centis, Rosella; de lange, Wiel C.; Kosterink, Jos G.; van der Werf, Tjip S.; Migliori, Giovanni B.; Alffenaar, Jan-Willem C.

Linezolid is used increasingly for the treatment of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis (TB). However, linezolid can cause severe adverse events, such as peripheral and optical neuropathy or thrombocytopenia related to higher drug exposure. This study aimed

Linezolid and atorvastatin impact on pneumonia caused by Staphyloccocus aureus in rabbits with or without mechanical ventilation

Science.gov (United States)

Pauchard, Laure-Anne; Blot, Mathieu; Bruyere, Rémi; Barbar, Saber-Davide; Croisier, Delphine; Piroth, Lionel

2017-01-01

Pneumonia may involve methicillin-resistant Staphylococcus aureus (MRSA), with elevated rates of antibiotics failure. The present study aimed to assess the effect of statins given prior to pneumonia development. Spontaneously breathing (SB) or mechanically ventilated (MV) rabbits with pneumonia received atorvastatin alone, linezolid (LNZ) alone, or a combination of both (n = 5 in each group). Spontaneously breathing and MV untreated infected animals (n = 11 in each group), as well as uninfected animals (n = 5 in each group) were used as controls. Microbiological features and inflammation were evaluated. Data are presented as medians (interquartile range). Linezolid alone tended to reduce pulmonary MRSA load in both SB and MV rabbits, but failed to prevent bacteremia (59%) in the latter. Linezolid alone dampened TNF-α lung production in both SB and MV rabbits (e.g., 2226 [789] vs. 11478 [10251] pg/g; p = 0.022). Statins alone did the same in both SB and MV animals (e.g., 2040 [133]; p = 0.016), and dampened systemic inflammation in the latter, possibly through TLR2 down-regulation within the lung. However, the combination of LNZ and statin led to an increased rate of bacteremia in MV animals up to 75%. Statins provide an anti-inflammatory effect in rabbits with MRSA pneumonia, especially in MV ones. However, dampening the systemic inflammatory response with statins could impede blood defenses against MRSA. PMID:29149185

Linezolid Versus Vancomycin in the Empiric Treatment of Nosocomial Pneumonia: A Cost-Utility Analysis Incorporating Results from the ZEPHyR Trial.

Science.gov (United States)

Collins, Curtis D; Schwemm, Ann K

2015-07-01

To examine the cost-effectiveness of vancomycin versus linezolid in the empiric treatment of nosocomial pneumonias incorporating results from a recent prospective, double-blind, multicenter, controlled trial in adults with suspected methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. A decision-analytic model examining the cost-effectiveness of linezolid versus vancomycin for the empiric treatment of nosocomial pneumonia was created. Publicly available cost, efficacy, and utility data populated relevant model variables. A probabilistic sensitivity analysis varied parameters in 10,000 Monte-Carlo simulations, and univariate sensitivity analyses assessed the impact of model uncertainties and the robustness of our conclusions. Results indicated that the cost per quality-adjusted life-year (QALY) increased 6% ($22,594 vs. $23,860) by using linezolid versus vancomycin for nosocomial pneumonia. The incremental cost per QALY gained by using linezolid over vancomycin was $6,089, and the incremental cost per life saved was $68,615 with the use of linezolid. Vancomycin dominated linezolid in the subset of patients with documented MRSA. The incremental cost per QALY gained using linezolid if no mortality benefit exists between agents or a 60-day time horizon was analyzed was $19,608,688 and $443,662, respectively. Linezolid may be a cost-effective alternative to vancomycin in the empiric treatment of patients with suspected MRSA nosocomial pneumonia; however, results of our model were highly variable on a number of important variables and assumptions including mortality differences and time frame analyzed. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Concentration-Dependent Synergy and Antagonism of Linezolid and Moxifloxacin in the Treatment of Childhood Tuberculosis: The Dynamic Duo.

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Deshpande, Devyani; Srivastava, Shashikant; Nuermberger, Eric; Pasipanodya, Jotam G; Swaminathan, Soumya; Gumbo, Tawanda

2016-11-01

 No treatment regimens have been specifically designed for children, in whom tuberculosis is predominantly intracellular. Given their activity as monotherapy and their ability to penetrate many diseased anatomic sites that characterize disseminated tuberculosis, linezolid and moxifloxacin could be combined to form a regimen for this need.  We examined microbial kill of intracellular Mycobacterium tuberculosis (Mtb) by the combination of linezolid and moxifloxacin multiple exposures in a 7-by-7 mathematical matrix. We then used the hollow fiber system (HFS) model of intracellular tuberculosis to identify optimal dose schedules and exposures of moxifloxacin and linezolid in combination. We mimicked pediatric half-lives and concentrations achieved by each drug. We sampled the peripheral compartment on days 0, 7, 14, 21, and 28 for Mtb quantification, and compared the slope of microbial kill of Mtb by these regimens to the standard regimen of isoniazid, rifampin, and pyrazinamide, based on exponential decline regression.  The full exposure-response surface identified linezolid-moxifloxacin zones of synergy, antagonism, and additivity. A regimen based on each of these zones was then used in the HFS model, with observed half-lives of 4.08 ± 0.66 for linezolid and 3.80 ± 1.34 hours for moxifloxacin. The kill rate constant was 0.060 ± 0.012 per day with the moxifloxacin-linezolid regimen in the additivity zone vs 0.083 ± 0.011 per day with standard therapy, translating to a bacterial burden half-life of 11.52 days vs 8.53 days, respectively.  We identified doses and dose schedules of a linezolid and moxifloxacin backbone regimen that could be highly efficacious in disseminated tuberculosis in children. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Activity of moxifloxacin and linezolid against Mycobacterium tuberculosis in combination with potentiator drugs verapamil, timcodar, colistin and SQ109.

Science.gov (United States)

de Knegt, Gerjo J; van der Meijden, Aart; de Vogel, Corné P; Aarnoutse, Rob E; de Steenwinkel, Jurriaan E M

2017-03-01

Current treatment for tuberculosis (TB) is complicated by the emergence of multidrug resistant TB (MDR-TB). As a result, there is an urgent need for new powerful anti-TB regimens and novel strategies. In this study, we aimed to potentiate a moxifloxacin + linezolid backbone as treatment for MDR-TB with the efflux pump inhibitors verapamil and timcodar as well as with drugs that act on mycobacterial cell wall stability such as colistin and SQ109. Using a time-kill kinetics assay, the activities of moxifloxacin, linezolid, verapamil, timcodar, colistin and SQ109 as single drugs against Mycobacterium tuberculosis were evaluated. In addition, the activity of the moxifloxacin + linezolid backbone in combination with one of the potentiator drugs was assessed. As little as 0.125 mg/L moxifloxacin achieved 99% killing of M. tuberculosis after 6 days of exposure. Linezolid showed moderate killing but 99% killing was not achieved. Verapamil, timcodar and colistin only resulted in killing with the highest concentrations tested but 99% killing was not achieved. SQ109 resulted in complete elimination after 1 day of exposure to 256 mg/L and in 99% elimination after 6 days of exposure to 1 mg/L. Furthermore, colistin added to the moxifloxacin + linezolid backbone resulted in increased elimination, whereas verapamil, timcodar and SQ109 showed no added value to the backbone. This finding that colistin potentiates the activity of the moxifloxacin + linezolid backbone against M. tuberculosis suggests its potential role in further studies on the applicability of a moxifloxacin + linezolid treatment of MDR-TB. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Successful Treatment of Necrotizing Fasciitis and Streptococcal Toxic Shock Syndrome with the Addition of Linezolid

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Hana Rac

2017-01-01

Full Text Available Necrotizing fasciitis is a deep-seated subcutaneous tissue infection that is commonly associated with streptococcal toxic shock syndrome (TSS. Surgical debridement plus penicillin and clindamycin are the current standard of care. We report a case of necrotizing fasciitis and streptococcal TSS where linezolid was added after a failure to improve with standard therapy. Briefly after isolation of Streptococcus pyogenes from tissue cultures, the patient underwent two surgical debridement procedures and was changed to standard of care therapy. While the patient was hemodynamically stable, the patient’s wounds, leukocytosis, and thrombocytopenia all progressively worsened. After initiation of linezolid, the patient slowly improved clinically. The present report is the first to highlight the role of linezolid in streptococcal necrotizing fasciitis and TSS not improving with standard therapy.

Crystal Structure of the Oxazolidinone Antibiotic Linezolid Bound to the 50S Ribosomal Subunit

Energy Technology Data Exchange (ETDEWEB)

Ippolito,J.; Kanyo, Z.; Wang, D.; Franceschi, F.; Moore, P.; Steitz, T.; Duffy, E.

2008-01-01

The oxazolidinone antibacterials target the 50S subunit of prokaryotic ribosomes. To gain insight into their mechanism of action, the crystal structure of the canonical oxazolidinone, linezolid, has been determined bound to the Haloarcula marismortui 50S subunit. Linezolid binds the 50S A-site, near the catalytic center, which suggests that inhibition involves competition with incoming A-site substrates. These results provide a structural basis for the discovery of improved oxazolidinones active against emerging drug-resistant clinical strains.

Linezolid and tiamulin cross-resistance in Staphylococcus aureus mediated by point mutations in the peptidyl transferase center.

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Miller, Keith; Dunsmore, Colin J; Fishwick, Colin W G; Chopra, Ian

2008-05-01

Oxazolidinone and pleuromutilin antibiotics are currently used in the treatment of staphylococcal infections. Although both antibiotics inhibit protein synthesis and have overlapping binding regions on 23S rRNA, the potential for cross-resistance between the two classes through target site mutations has not been thoroughly examined. Mutants of Staphylococcus aureus resistant to linezolid were selected and found to exhibit cross-resistance to tiamulin, a member of the pleuromutilin class of antibiotics. However, resistance was unidirectional because mutants of S. aureus selected for resistance to tiamulin did not exhibit cross-resistance to linezolid. This contrasts with the recently described PhLOPS(A) phenotype, which confers resistance to both oxazolidinones and pleuromutilins. The genotypes responsible for the phenotypes we observed were examined. Selection with tiamulin resulted in recovery of mutants with changes in the single-copy rplC gene (Gly155Arg, Ser158Leu, or Arg149Ser), whereas selection with linezolid led to recovery of mutants with changes (G2576U in 23S rRNA) in all five copies of the multicopy operon rrn. In contrast, cross-resistance to linezolid was exhibited by tiamulin-resistant mutants generated in a single-copy rrn knockout strains of Escherichia coli, illustrating that the copy number of 23S rRNA is the limiting factor in the selection of 23S rRNA tiamulin-resistant mutants. The interactions of linezolid and tiamulin with the ribosome were modeled to seek explanations for resistance to both classes in the 23S rRNA mutants and the lack of cross-resistance between tiamulin and linezolid following mutation in rplC.

Neisseria gonorrhoeae strain with reduced susceptibilities to extended-spectrum cephalosporins.

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Nguyen, Duylinh; Gose, Severin; Castro, Lina; Chung, Kathleen; Bernstein, Kyle; Samuel, Micheal; Bauer, Heidi; Pandori, Mark

2014-07-01

The spread of Neisseria gonorrhoeae strains with reduced susceptibility to extended-spectrum cephalosporins is an increasing public health threat. Using Etest and multiantigen sequence typing, we detected sequence type 1407, which is associated with reduced susceptibilities to extended-spectrum cephalosporins, in 4 major populated regions in California, USA, in 2012.

Variable Linezolid Exposure in Intensive Care Unit Patients-Possible Role of Drug-Drug Interactions.

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Töpper, Christoph; Steinbach, Cathérine L; Dorn, Christoph; Kratzer, Alexander; Wicha, Sebastian G; Schleibinger, Michael; Liebchen, Uwe; Kees, Frieder; Salzberger, Bernd; Kees, Martin G

2016-10-01

Standard doses of linezolid may not be suitable for all patient groups. Intensive care unit (ICU) patients in particular may be at risk of inadequate concentrations. This study investigated variability of drug exposure and its potential sources in this population. Plasma concentrations of linezolid were determined by high-performance liquid chromatography in a convenience sample of 20 ICU patients treated with intravenous linezolid 600 mg twice daily. Ultrafiltration applying physiological conditions (pH 7.4/37°C) was used to determine the unbound fraction. Individual pharmacokinetic (PK) parameters were estimated by population PK modeling. As measures of exposure to linezolid, area under the concentration-time curve (AUC) and trough concentrations (Cmin) were calculated and compared with published therapeutic ranges (AUC 200-400 mg*h/L, Cmin 2-10 mg/L). Coadministered inhibitors or inducers of cytochrome P450 and/or P-glycoprotein were noted. Data from 18 patients were included into the PK evaluation. Drug exposure was highly variable (median, range: AUC 185, 48-618 mg*h/L, calculated Cmin 2.92, 0.0062-18.9 mg/L), and only a minority of patients had values within the target ranges (6 and 7, respectively). AUC and Cmin were linearly correlated (R = 0.98), and classification of patients (underexposed/within therapeutic range/overexposed) according to AUC or Cmin was concordant in 15 cases. Coadministration of inhibitors was associated with a trend to higher drug exposure, whereas 3 patients treated with levothyroxine showed exceedingly low drug exposure (AUC ∼60 mg*h/L, Cmin linezolid is highly variable and difficult to predict in ICU patients, and therapeutic drug monitoring seems advisable. PK drug-drug interactions might partly be responsible and should be further investigated; protein binding appears to be stable and irrelevant.

Linezolid as rescue treatment for left-sided infective endocarditis

DEFF Research Database (Denmark)

Lauridsen, Trine Kiilerich; Bruun, Louise E; Rasmussen, R V

2012-01-01

The increasing number of resistant bacterial strains in infective endocarditis (IE) emphasizes the need for a constant development of antimicrobials. Linezolid is an oxazolidinone with an effect on Gram-positive cocci. Only a few casuistic reports describe its utilization in the treatment of IE...

Outpatient treatment of acute bacterial skin and skin structure infections (ABSSSI) with tedizolid phosphate and linezolid in patients in the United States: Subgroup analysis of 2 randomized phase 3 trials.

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De Anda, Carisa; Anuskiewicz, Steven; Prokocimer, Philippe; Vazquez, Jose

2017-12-01

Acute bacterial skin and skin structure infections (ABSSSI) are a frequent cause of hospital admissions in the United States. Safe and effective outpatient treatments may lower ABSSSI-associated health care costs by reducing unnecessary hospital admissions. Using data from 2 phase 3 trials (ESTABLISH-1, NCT01170221; ESTABLISH-2, NCT01421511), this post-hoc analysis explored the efficacy and safety of tedizolid in an outpatient setting. Subgroup analysis was performed on US outpatients (defined as patients who were not in hospital at the time of treatment initiation) with ABSSSI caused by presumed or proven gram-positive pathogens. Patients were randomly assigned to receive tedizolid phosphate 200 mg once daily for 6 days (n = 403) or linezolid 600 mg twice daily for 10 days (n = 410). The primary end point was early clinical response (48-72 hours after the start of treatment). Secondary end points included investigator-assessed clinical response at end of therapy (EOT) and post-therapy evaluation (PTE; 7-14 days after therapy). Additional assessments included the patient-reported level of pain using a visual analog scale (VAS) and the per-pathogen favorable microbiological response rate at the PTE visit. Compliance with treatment and safety outcomes was also recorded. Early clinical response was similar between treatment groups (tedizolid, 82.4%; linezolid, 79.0%), as was investigator-assessed clinical response at EOT (tedizolid, 87.1%; linezolid, 86.1%) and PTE (tedizolid, 83.1%; linezolid, 83.7%). Mean changes from baseline to days 10 to 13 in VAS scores were identical between treatment groups (tedizolid, -51.9 mm; linezolid, -51.9 mm). Microbiological eradication rates were generally similar in both treatment groups for all key pathogens. Patients in both groups had favorable response at PTE. More tedizolid-treated patients (89.3%) than linezolid-treated patients (77.3%) were compliant with treatment. The most frequently reported drug

Complex long-distance effects of mutations that confer linezolid resistance in the large ribosomal subunit

Science.gov (United States)

Fulle, Simone; Saini, Jagmohan S.; Homeyer, Nadine; Gohlke, Holger

2015-01-01

The emergence of multidrug-resistant pathogens will make current antibiotics ineffective. For linezolid, a member of the novel oxazolidinone class of antibiotics, 10 nucleotide mutations in the ribosome have been described conferring resistance. Hypotheses for how these mutations affect antibiotics binding have been derived based on comparative crystallographic studies. However, a detailed description at the atomistic level of how remote mutations exert long-distance effects has remained elusive. Here, we show that the G2032A-C2499A double mutation, located > 10 Å away from the antibiotic, confers linezolid resistance by a complex set of effects that percolate to the binding site. By molecular dynamics simulations and free energy calculations, we identify U2504 and C2452 as spearheads among binding site nucleotides that exert the most immediate effect on linezolid binding. Structural reorganizations within the ribosomal subunit due to the mutations are likely associated with mutually compensating changes in the effective energy. Furthermore, we suggest two main routes of information transfer from the mutation sites to U2504 and C2452. Between these, we observe cross-talk, which suggests that synergistic effects observed for the two mutations arise in an indirect manner. These results should be relevant for the development of oxazolidinone derivatives that are active against linezolid-resistant strains. PMID:26202966

Activity of vancomycin, linezolid, and daptomycin against staphylococci and enterococci isolated in 5 Greek hospitals during a 5-year period (2008-2012).

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Papadimitriou-Olivgeris, Matthaios; Kolonitsiou, Fevronia; Zerva, Loukia; Lebessi, Evangelia; Koutsia, Chryssa; Drougka, Eleanna; Sarrou, Styliani; Giormezis, Nikolaos; Vourli, Sofia; Doudoulakakis, Anastassios; Konsolakis, Christos; Marangos, Markos; Anastassiou, Evangelos D; Petinaki, Efthimia; Spiliopoulou, Iris

2015-12-01

The tendency of vancomycin, linezolid, and daptomycin MICs was investigated among 6920 staphylococci and enterococci during a 5-year period. Antimicrobial consumption was determined. Decrease of vancomycin MIC was detected associated with reduction in consumption. Linezolid and daptomycin remained active. An upward trend of linezolid MIC for methicillin-resistant staphylococci was observed. Copyright © 2015 Elsevier Inc. All rights reserved.

Reducing Susceptibility to Courtesy Stigma.

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Bachleda, Catherine L; El Menzhi, Leila

2018-06-01

In light of the chronic shortage of health professionals willing to care for HIV/AIDS patients, and rising epidemics in many Muslim countries, this qualitative study examined susceptibility and resistance to courtesy stigma as experienced by nurses, doctors, and social workers in Morocco. Forty-nine in-depth interviews provided rich insights into the process of courtesy stigma and how it is managed, within the context of interactions with Islam, interactions within the workplace (patients, other health professionals), and interactions outside the workplace (the general public, friends, and family). Theoretically, the findings extend understanding of courtesy stigma and the dirty work literature. The findings also offer practical suggestions for the development of culturally appropriate strategies to reduce susceptibility to courtesy stigmatization. This study represents the first to explore courtesy stigma as a process experienced by health professionals providing HIV/AIDS care in an Islamic country.

Assessing outcomes of adult oncology patients treated with linezolid versus daptomycin for bacteremia due to vancomycin-resistant Enterococcus.

Science.gov (United States)

Patel, Khilna; Kabir, Rubiya; Ahmad, Samrah; Allen, Steven L

2016-04-01

The incidence and severity of vancomycin-resistant Enterococcus blood stream infections continue to rise and is a significant burden in the healthcare setting. Literature thus far is minimal regarding treatment outcomes in patients with malignancy and vancomycin-resistant Enterococcus bacteremia. Appropriate antibiotic selection is vital to treatment success due to high rates of resistance, limited antimicrobials and mortality in this patient population. We conducted this study to determine whether treatment outcomes differed between cancer patients treated with linezolid and those treated with daptomycin for vancomycin-resistant Enterococcus bacteremia. This single-center, retrospective study included adult patients hospitalized on the oncology service with documented vancomycin-resistant Enterococcus faecium or Enterococcus faecalis bacteremia who received at least 48 h of either linezolid or daptomycin as primary treatment. A total of 65 patients were included in the analysis. Thirty-two patients received daptomycin as primary treatment, and 33 patients received linezolid as primary treatment. Twenty-six (76.5%) patients in the linezolid cohort versus 22 (71%) patients in the daptomycin cohort achieved microbiological cure (p = 0.6141). Median length of stay in days (30 vs. 42, p = 0.0714) and mortality (7/32 (20.6%) vs. 8/33 (25.8%), p = 0.6180) were also similar between the linezolid and daptomycin treated patients, respectively. No differences in microbiological cure, length of stay or mortality were identified between the groups. This study suggests that linezolid and daptomycin are each reasonable options for treating vancomycin-resistant Enterococcus bacteremia in oncology patients. Further prospective, randomized controlled trials are needed to assess the optimal treatment for vancomycin-resistant Enterococcus bacteremia in this patient population. © The Author(s) 2014.

Linezolid and Tiamulin Cross-Resistance in Staphylococcus aureus Mediated by Point Mutations in the Peptidyl Transferase Center ▿

Science.gov (United States)

Miller, Keith; Dunsmore, Colin J.; Fishwick, Colin W. G.; Chopra, Ian

2008-01-01

Oxazolidinone and pleuromutilin antibiotics are currently used in the treatment of staphylococcal infections. Although both antibiotics inhibit protein synthesis and have overlapping binding regions on 23S rRNA, the potential for cross-resistance between the two classes through target site mutations has not been thoroughly examined. Mutants of Staphylococcus aureus resistant to linezolid were selected and found to exhibit cross-resistance to tiamulin, a member of the pleuromutilin class of antibiotics. However, resistance was unidirectional because mutants of S. aureus selected for resistance to tiamulin did not exhibit cross-resistance to linezolid. This contrasts with the recently described PhLOPSA phenotype, which confers resistance to both oxazolidinones and pleuromutilins. The genotypes responsible for the phenotypes we observed were examined. Selection with tiamulin resulted in recovery of mutants with changes in the single-copy rplC gene (Gly155Arg, Ser158Leu, or Arg149Ser), whereas selection with linezolid led to recovery of mutants with changes (G2576U in 23S rRNA) in all five copies of the multicopy operon rrn. In contrast, cross-resistance to linezolid was exhibited by tiamulin-resistant mutants generated in a single-copy rrn knockout strains of Escherichia coli, illustrating that the copy number of 23S rRNA is the limiting factor in the selection of 23S rRNA tiamulin-resistant mutants. The interactions of linezolid and tiamulin with the ribosome were modeled to seek explanations for resistance to both classes in the 23S rRNA mutants and the lack of cross-resistance between tiamulin and linezolid following mutation in rplC. PMID:18180348

Whole genome analysis of linezolid resistance in Streptococcus pneumoniae reveals resistance and compensatory mutations

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Légaré Danielle

2011-10-01

Full Text Available Abstract Background Several mutations were present in the genome of Streptococcus pneumoniae linezolid-resistant strains but the role of several of these mutations had not been experimentally tested. To analyze the role of these mutations, we reconstituted resistance by serial whole genome transformation of a novel resistant isolate into two strains with sensitive background. We sequenced the parent mutant and two independent transformants exhibiting similar minimum inhibitory concentration to linezolid. Results Comparative genomic analyses revealed that transformants acquired G2576T transversions in every gene copy of 23S rRNA and that the number of altered copies correlated with the level of linezolid resistance and cross-resistance to florfenicol and chloramphenicol. One of the transformants also acquired a mutation present in the parent mutant leading to the overexpression of an ABC transporter (spr1021. The acquisition of these mutations conferred a fitness cost however, which was further enhanced by the acquisition of a mutation in a RNA methyltransferase implicated in resistance. Interestingly, the fitness of the transformants could be restored in part by the acquisition of altered copies of the L3 and L16 ribosomal proteins and by mutations leading to the overexpression of the spr1887 ABC transporter that were present in the original linezolid-resistant mutant. Conclusions Our results demonstrate the usefulness of whole genome approaches at detecting major determinants of resistance as well as compensatory mutations that alleviate the fitness cost associated with resistance.

Bacteriophage Mediated Killing of Staphylococcus aureus In Vitro on Orthopaedic K Wires in Presence of Linezolid Prevents Implant Colonization

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Kaur, Sandeep; Harjai, Kusum; Chhibber, Sanjay

2014-01-01

Background Infections of bone and joint tissues following arthroplasty surgeries remain a major challenge in orthopaedic settings. Methicillin resistant Staphylococcus aureus (MRSA) is recognised as an established pathogen in such infections. Combination therapy using linezolid and bacteriophage impregnated in biopolymer was investigated in the present study as an alternative strategy to prevent MRSA colonisation on the orthopaedic implant surface. Methodology Coating of stainless steel orthopaedic grade K-wires was achieved using hydroxypropylmethlycellulose (HPMC) mixed with phage alone, linezolid alone and phage and linezolid together. The potential of these agents to inhibit adhesion of S.aureus (MRSA) 43300 on K-wires was assessed. Coated and naked wires were analysed by scanning electron microscopy (SEM) and fluorescent staining. Result Significant reduction in bacterial adhesion was achieved on phage/linezolid wires in comparison to naked as well as HPMC coated wires. However, maximum reduction in bacterial adherence (∼4 log cycles) was observed on the wires coated with phage-linezolid combination. The frequency of emergence of resistant mutants was also negligible in presence of both the agents. Conclusion This study provides evidence to confirm that local delivery system employing linezolid (a potent protein synthesis inhibitor) along with a broad spectrum lytic bacteriophage (capable of self-multiplication) is able to attack the adhered as well as surrounding bacteria present near the implant site. Unlike other antibiotic based therapies, this combination has the potential to significantly restrict the emergence of resistant mutants, thus paving the way for effective treatment of MRSA associated infection of medical implants. PMID:24594764

Effectiveness and safety of imipenem/clavulanate and linezolid to treat multidrug and extensively drug-resistant tuberculosis at a referral hospital in Brazil

Directory of Open Access Journals (Sweden)

M.A. Arbex

2016-11-01

Full Text Available Evidence on effectiveness, safety, and tolerability of imipenem/clavulanate (IC and linezolid containing regimens to treat multidrug-resistant (MDR- and extensively drug-resistant tuberculosis (XDR-TB is scarce. The aim of this observational study is to evaluate the therapeutic contribution of IC and linezolid to manage MDR/XDR-TB cases at the reference centre of São Paulo state, Brazil. Twelve patients (9 males, 1 HIV positive in antiretroviral treatment, 4 MDR, 8 XDR were treated with IC, 11 of them within linezolid-containing regimens. They all were previously treated with treatment failure, for a median (IQR, interquartile range of 4.5 (2–6.5 times, having a severe resistance pattern (median number of resistances: 7 (5–8 and being sputum smear and culture positive. IC and linezolid were prescribed at the dose of 1000 mg/day and 600 mg/day, respectively. The overall exposure was (median (IQR 419 (375.5–658 days for IC and 678 (392–720 days for linezolid. All of them converted their sputum (time to sputum conversion; 60 (37.5–90 days and culture (75 (60–135 days, and 7 were cured while 5 are still on treatment with a gradually improving clinical picture.While no adverse events were reported for IC, 2 minor side effects, only, were attributed to linezolid (17%; in both cases the drug was re-started without further problems. Our study suggests that IC and linezolid-containing regimens can be used safely and with satisfactory outcomes in reference centres to treat MDR/XDR-TB patients. Keywords: MDR-TB, XDR-TB, Imipenem, Linezolid, Effectiveness, Safety, Tolerability

Novel Inhibitors of Staphyloxanthin Virulence Factor in Comparison with Linezolid and Vancomycin versus Methicillin-Resistant, Linezolid-Resistant, and Vancomycin-Intermediate Staphylococcus aureus Infections in Vivo.

Science.gov (United States)

Ni, Shuaishuai; Wei, Hanwen; Li, Baoli; Chen, Feifei; Liu, Yifu; Chen, Wenhua; Xu, Yixiang; Qiu, Xiaoxia; Li, Xiaokang; Lu, Yanli; Liu, Wenwen; Hu, Linhao; Lin, Dazheng; Wang, Manjiong; Zheng, Xinyu; Mao, Fei; Zhu, Jin; Lan, Lefu; Li, Jian

2017-10-12

Our previous work ( Wang et al. J. Med. Chem. 2016 , 59 , 4831 - 4848 ) revealed that effective benzocycloalkane-derived staphyloxanthin inhibitors against methicillin-resistant Staphylococcus aureus (S. aureus) infections were accompanied by poor water solubility and high hERG inhibition and dosages (preadministration). In this study, 92 chroman and coumaran derivatives as novel inhibitors have been addressed for overcoming deficiencies above. Derivatives 69 and 105 displayed excellent pigment inhibitory activities and low hERG inhibition, along with improvement of solubility by salt type selection. The broad and significantly potent antibacterial spectra of 69 and 105 were displayed first with normal administration in the livers and hearts in mice against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate S. aureus), and NRS271 (linezolid-resistant S. aureus), compared with linezolid and vancomycin. In summary, both 69 and 105 have the potential to be developed as good antibacterial candidates targeting virulence factors.

Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB : systematic review and meta-analysis

NARCIS (Netherlands)

Sotgiu, Giovanni; Centis, Rosella; D'Ambrosio, Lia; Alffenaar, Jan-William C.; Anger, Holly A.; Caminero, Jose A.; Castiglia, Paolo; De Lorenzo, Saverio; Ferrara, Giovanni; Koh, Won-Jung; Schecter, Giesela F.; Shim, Tae S.; Singla, Rupak; Skrahina, Alena; Spanevello, Antonio; Udwadia, Zarir F.; Villar, Miquel; Zampogna, Elisabetta; Zellweger, Jean-Pierre; Zumla, Alimuddin; Migliori, Giovanni Battista

2012-01-01

Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis. 12 studies (11 countries from

Nonclinical and Pharmacokinetic Assessments To Evaluate the Potential of Tedizolid and Linezolid To Affect Mitochondrial Function

Science.gov (United States)

McKee, Edward E.; Das, Debaditya; Hosako, Hiromi; Fiedler-Kelly, Jill; Passarell, Julie; Radovsky, Ann; Prokocimer, Philippe

2014-01-01

Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [± standard error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 ± 0.02 μM versus 6.4 ± 1.2 μM). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC50 in 84% of tedizolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies. PMID:25331703

Drug Susceptibility Testing of 31 Antimicrobial Agents on Rapidly Growing Mycobacteria Isolates from China.

Science.gov (United States)

Pang, Hui; Li, Guilian; Zhao, Xiuqin; Liu, Haican; Wan, Kanglin; Yu, Ping

2015-01-01

Several species of rapidly growing mycobacteria (RGM) are now recognized as human pathogens. However, limited data on effective drug treatments against these organisms exists. Here, we describe the species distribution and drug susceptibility profiles of RGM clinical isolates collected from four southern Chinese provinces from January 2005 to December 2012. Clinical isolates (73) were subjected to in vitro testing with 31 antimicrobial agents using the cation-adjusted Mueller-Hinton broth microdilution method. The isolates included 55 M. abscessus, 11 M. fortuitum, 3 M. chelonae, 2 M. neoaurum, and 2 M. septicum isolates. M. abscessus (75.34%) and M. fortuitum (15.07%), the most common species, exhibited greater antibiotic resistance than the other three species. The isolates had low resistance to amikacin, linezolid, and tigecycline, and high resistance to first-line antituberculous agents, amoxicillin-clavulanic acid, rifapentine, dapsone, thioacetazone, and pasiniazid. M. abscessus and M. fortuitum were highly resistant to ofloxacin and rifabutin, respectively. The isolates showed moderate resistance to the other antimicrobial agents. Our results suggest that tigecycline, linezolid, clofazimine, and cefmetazole are appropriate choices for M. abscessus infections. Capreomycin, sulfamethoxazole, tigecycline, clofazimine, and cefmetazole are potentially good choices for M. fortuitum infections. Our drug susceptibility data should be useful to clinicians.

Drug Susceptibility Testing of 31 Antimicrobial Agents on Rapidly Growing Mycobacteria Isolates from China

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Hui Pang

2015-01-01

Full Text Available Objectives. Several species of rapidly growing mycobacteria (RGM are now recognized as human pathogens. However, limited data on effective drug treatments against these organisms exists. Here, we describe the species distribution and drug susceptibility profiles of RGM clinical isolates collected from four southern Chinese provinces from January 2005 to December 2012. Methods. Clinical isolates (73 were subjected to in vitro testing with 31 antimicrobial agents using the cation-adjusted Mueller-Hinton broth microdilution method. The isolates included 55 M. abscessus, 11 M. fortuitum, 3 M. chelonae, 2 M. neoaurum, and 2 M. septicum isolates. Results. M. abscessus (75.34% and M. fortuitum (15.07%, the most common species, exhibited greater antibiotic resistance than the other three species. The isolates had low resistance to amikacin, linezolid, and tigecycline, and high resistance to first-line antituberculous agents, amoxicillin-clavulanic acid, rifapentine, dapsone, thioacetazone, and pasiniazid. M. abscessus and M. fortuitum were highly resistant to ofloxacin and rifabutin, respectively. The isolates showed moderate resistance to the other antimicrobial agents. Conclusions. Our results suggest that tigecycline, linezolid, clofazimine, and cefmetazole are appropriate choices for M. abscessus infections. Capreomycin, sulfamethoxazole, tigecycline, clofazimine, and cefmetazole are potentially good choices for M. fortuitum infections. Our drug susceptibility data should be useful to clinicians.

Effectiveness and safety of imipenem/clavulanate and linezolid to treat multidrug and extensively drug-resistant tuberculosis at a referral hospital in Brazil.

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Arbex, M A; Bonini, E H; Kawakame Pirolla, G; D'Ambrosio, L; Centis, R; Migliori, G B

Evidence on effectiveness, safety, and tolerability of imipenem/clavulanate (IC) and linezolid containing regimens to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) is scarce. The aim of this observational study is to evaluate the therapeutic contribution of IC and linezolid to manage MDR/XDR-TB cases at the reference centre of São Paulo state, Brazil. Twelve patients (9 males, 1 HIV positive in antiretroviral treatment, 4 MDR, 8 XDR) were treated with IC, 11 of them within linezolid-containing regimens. They all were previously treated with treatment failure, for a median (IQR, interquartile range) of 4.5 (2-6.5) times, having a severe resistance pattern (median number of resistances: 7 (5-8)) and being sputum smear and culture positive. IC and linezolid were prescribed at the dose of 1000mg/day and 600mg/day, respectively. The overall exposure was (median (IQR)) 419 (375.5-658) days for IC and 678 (392-720) days for linezolid. All of them converted their sputum (time to sputum conversion; 60 (37.5-90) days) and culture (75 (60-135) days), and 7 were cured while 5 are still on treatment with a gradually improving clinical picture. While no adverse events were reported for IC, 2 minor side effects, only, were attributed to linezolid (17%); in both cases the drug was re-started without further problems. Our study suggests that IC and linezolid-containing regimens can be used safely and with satisfactory outcomes in reference centres to treat MDR/XDR-TB patients. Copyright © 2016 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.

Peripheral neuropathy in a diabetic child treated with linezolid for multidrug-resistant tuberculosis: a case report and review of the literature.

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Swaminathan, Aravind; du Cros, Philipp; Seddon, James A; Mirgayosieva, Shamsiya; Asladdin, Rajabov; Dusmatova, Zulfiya

2017-06-12

Extensively drug-resistant (XDR) tuberculosis (TB) and multidrug resistant (MDR)-TB with additional resistance to injectable agents or fluoroquinolones are challenging to treat due to lack of available, effective drugs. Linezolid is one of the few drugs that has shown promise in treating these conditions. Long-term linezolid use is associated with toxicities such as peripheral and optic neuropathies. Diabetes mellitus (DM), especially when uncontrolled, can also result in peripheral neuropathy. The global burden of DM is increasing, and DM has been associated with a three-fold increased risk of developing TB disease. TB and DM can be a challenging combination to treat. DM can inhibit the host immune response to tuberculosis infection; and TB and some anti-TB drugs can worsen glycaemic control. A child experiencing neuropathy that is a possible complication of both DM and linezolid used to treat TB has not been reported previously. We report peripheral neuropathy in a 15-year-old boy with type 1 DM, diagnosed with MDR-TB and additional resistance to injectable TB medications. The boy was treated with a linezolid-based regimen, but after 8 months developed peripheral neuropathy. It was unclear whether the neuropathy was caused by the DM or the linezolid therapy. He had clinical improvement following cessation of linezolid and was declared cured following 21 months of treatment. Following completion of treatment, nerve conduction studies demonstrated significant improvement in neuropathy. To the best of our knowledge, this is the first case of peripheral neuropathy reported in a diabetic child on long-term linezolid therapy for tuberculosis. This case study underlines the importance of stringent follow-up for side effects of linezolid, especially when associated with co-morbidity such as DM that increases the chances of adverse effects. The presence of both DM and TB should alert a physician to strive for optimal glycaemic control to minimize the risk of

A validated stability-indicating LC method for the separation of enantiomer and potential impurities of Linezolid using polar organic mode

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T. Satyanarayana Raju

2012-08-01

Full Text Available Although a number of methods are available for evaluating Linezolid and its possible impurities, a common method for separation if its potential impurities, degradants and enantiomer in a single method with good efficiency remain unavailable. With the objective of developing an advanced method with shorter runtimes, a simple, precise, accurate stability-indicating LC method was developed for the determination of purity of Linezolid drug substance and drug products in bulk samples and pharmaceutical dosage forms in the presence of its impurities and degradation products. This method is capable of separating all the related substances of Linezolid along with the chiral impurity. This method can also be used for the estimation of assay of Linezolid in drug substance as well as in drug product. The method was developed using Chiralpak IA (250 mm×4.6 mm, 5 μm column. A mixture of acetonitrile, ethanol, n-butyl amine and trifluoro acetic acid in 96:4:0.10:0.16 (v/v/v/v ratio was used as a mobile phase. The eluted compounds were monitored at 254 nm. Linezolid was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. The degradation products were well resolved from main peak and its impurities, proving the stability-indicating power of the method. The developed method was validated as per International Conference on Harmonization (ICH guidelines with respect to specificity, limit of detection, limit of quantification, precision, linearity, accuracy, robustness and system suitability. Keywords: HPLC, Linezolid, Validation, Polar organic mode, Stability-indicating

Comparison of the Effectiveness and Safety of Linezolid and Daptomycin in Vancomycin-Resistant Enterococcal Bloodstream Infection: A National Cohort Study of Veterans Affairs Patients.

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Britt, Nicholas S; Potter, Emily M; Patel, Nimish; Steed, Molly E

2015-09-15

Vancomycin-resistant Enterococcus bloodstream infections (VRE-BSIs) are becoming increasingly common. Linezolid and daptomycin are the primary treatment options for VRE-BSI, but optimal treatment is unclear. This was a national retrospective cohort study comparing linezolid and daptomycin for the treatment of VRE-BSI among Veterans Affairs Medical Center patients admitted during 2004-2013. The primary outcome was treatment failure, defined as a composite of (1) 30-day all-cause mortality; (2) microbiologic failure; and (3) 60-day VRE-BSI recurrence. Poisson regression was conducted to determine if antimicrobial treatment was independently associated with clinical outcomes. A total of 644 patients were included (linezolid, n = 319; daptomycin, n = 325). Overall, treatment failure was 60.9% (n = 392/644), and 30-day all-cause mortality was 38.2% (n = 246/644). Linezolid was associated with a significantly higher risk of treatment failure compared with daptomycin (risk ratio [RR], 1.37; 95% confidence interval [CI], 1.13-1.67; P = .001). After adjusting for confounding factors in Poisson regression, the relationship between linezolid use and treatment failure persisted (adjusted RR, 1.15; 95% CI, 1.02-1.30; P = .026). Linezolid was also associated with higher 30-day mortality (42.9% vs 33.5%; RR, 1.17; 95% CI, 1.04-1.32; P = .014) and microbiologic failure rates (RR, 1.10; 95% CI, 1.02-1.18; P = .011). No difference in 60-day VRE-BSI recurrence was observed between treatment groups. Treatment with linezolid for VRE-BSI resulted in significantly higher treatment failure in comparison to daptomycin. Linezolid treatment was also associated with greater 30-day all-cause mortality and microbiologic failure in this cohort. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Susceptibility profiles of Nocardia isolates based on current taxonomy.

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Schlaberg, Robert; Fisher, Mark A; Hanson, Kimberley E

2014-01-01

The genus Nocardia has undergone rapid taxonomic expansion in recent years, and an increasing number of species are recognized as human pathogens. Many established species have predictable antimicrobial susceptibility profiles, but sufficient information is often not available for recently described organisms. Additionally, the effectiveness of sulfonamides as first-line drugs for Nocardia has recently been questioned. This led us to review antimicrobial susceptibility patterns for a large number of molecularly identified clinical isolates. Susceptibility results were available for 1,299 isolates representing 39 different species or complexes, including 11 that were newly described, during a 6-year study period. All tested isolates were susceptible to linezolid. Resistance to trimethoprim-sulfamethoxazole (TMP-SMX) was rare (2%) except among Nocardia pseudobrasiliensis (31%) strains and strains of the N. transvalensis complex (19%). Imipenem susceptibility varied for N. cyriacigeorgica and N. farcinica, as did ceftriaxone susceptibility of the N. nova complex. Resistance to more than one of the most commonly used drugs (amikacin, ceftriaxone, TMP-SMX, and imipenem) was highest for N. pseudobrasiliensis (100%), N. transvalensis complex (83%), N. farcinica (68%), N. puris (57%), N. brasiliensis (51%), N. aobensis (50%), and N. amikacinitolerans (43%). Thus, while antimicrobial resistance can often be predicted, susceptibility testing should still be considered when combination therapy is warranted, for less well characterized species or those with variable susceptibility profiles, and for patients with TMP-SMX intolerance.

Observed Antagonistic Effect of Linezolid on Daptomycin or Vancomycin Activity against Biofilm-Forming Methicillin-Resistant Staphylococcus aureus in an In Vitro Pharmacodynamic Model

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Luther, Megan K.

2015-01-01

Pharmacodynamic activity in antibiotic combinations of daptomycin, vancomycin, and linezolid was investigated in a 48-h in vitro pharmacodynamic model. Using human-simulated free drug concentrations, activity against clinical biofilm-forming methicillin-resistant Staphylococcus aureus isolates was evaluated. Linezolid antagonized vancomycin activity at 24 and 48 h. Linezolid antagonized daptomycin at 24 and 48 h depending on dose and strain. Adding daptomycin increased vancomycin activity at 48 h (P < 0.03). These results may be strain dependent and require further clinical investigation. PMID:26369963

Front-Loaded Linezolid Regimens Result in Increased Killing and Suppression of the Accessory Gene Regulator System of Staphylococcus aureus

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Brown, Tanya; Parasrampuria, Ridhi; Brazeau, Daniel A.; Forrest, Alan; Kelchlin, Pamela A.; Holden, Patricia N.; Peloquin, Charles A.; Hanna, Debra; Bulitta, Jurgen B.

2012-01-01

Front loading is a strategy used to optimize the pharmacodynamic profile of an antibiotic through the administration of high doses early in therapy for a short duration. Our aims were to evaluate the impact of front loading of linezolid regimens on bacterial killing and suppression of resistance and on RNAIII, the effector molecule of the accessory gene regulator system (encoded by agr) in methicillin-resistant Staphylococcus aureus (MRSA). Time-killing experiments over 48 h were utilized for linezolid against four strains of MRSA: USA100, USA300, USA400, and ATCC 29213. A hollow-fiber infection model simulated traditional and front-loaded human therapeutic regimens of linezolid versus USA300 at 106 CFU/ml over 240 h. Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity, with reductions of >1 log10 CFU/ml for all strains. Front-loaded regimens that were administered over 5 days, 1,200 mg every 12 h (q12h) (total, 10 doses) and 2,400 mg q12h (total, 10 doses) followed by 300 mg q12h thereafter, resulted in sustained bactericidal activity, with reductions of the area under the CFU curve of −6.15 and −6.03, respectively, reaching undetectable limits at the 10-day study endpoint. All regimens displayed a reduction in RNAIII relative expression at 24 h and 240 h compared with that of the growth control. Monte Carlo simulations predicted a linezolid are promising and may be of utility in severe MRSA infections, where early aggressive therapy is necessary. PMID:22526313

Resistance to linezolid in Staphylococcus spp. clinical isolates associated with ribosomal binding site modifications: novel mutation in domain V of 23S rRNA.

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Musumeci, Rosario; Calaresu, Enrico; Gerosa, Jolanda; Oggioni, Davide; Bramati, Simone; Morelli, Patrizia; Mura, Ida; Piana, Andrea; Are, Bianca Maria; Cocuzza, Clementina Elvezia

2016-10-01

Linezolid is the main representative of the oxazolidinones, introduced in 2000 in clinical practice to treat severe Gram-positive infections. This compound inhibits protein synthesis by binding to the peptidyl transferase centre of the 50S bacterial ribosomal subunit. The aim of this study was to characterize 12 clinical strains of linezolid-resistant Staphylococcus spp. isolated in Northern Italy. All isolates of Staphylococcus spp. studied showed a multi-antibiotic resistance phenotype. In particular, all isolates showed the presence of the mecA gene associated with SSCmec types IVa, V or I. Mutations in domain V of 23S rRNA were shown to be the most prevalent mechanism of linezolid resistance: among these a new C2551T mutation was found in S. aureus, whilst the G2576T mutation was shown to be the most prevalent overall. Moreover, three S. epidermidis isolates were shown to have linezolid resistance associated only with alterations in both L3 and L4 ribosomal proteins. No strain was shown to harbor the previously described cfr gene. These results have shown how the clinical use of linezolid in Northern Italy has resulted in the selection of multiple antibiotic-resistant clinical isolates of Staphylococcus spp., with linezolid resistance in these strains being associated with mutations in 23S rRNA or ribosomal proteins L3 and L4.

Linezolid-resistant clinical isolates of meticillin-resistant coagulase-negative staphylococci and Enterococcus faecium from China.

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Cai, Jia Chang; Hu, Yan Yan; Zhang, Rong; Zhou, Hong Wei; Chen, Gong-Xiang

2012-11-01

Seventeen meticillin-resistant coagulase-negative staphylococci (MRCoNS), including ten Staphylococcus capitis, four Staphylococcus cohnii, two Staphylococcus haemolyticus and one Staphylococcus sciuri, and an Enterococcus faecium isolate with various levels of linezolid resistance were isolated from intensive care units in a Chinese hospital. PFGE indicated that the four S. cohnii isolates belonged to a clonal strain, and that nine of the S. capitis isolates were indistinguishable (clone A1) and the other one was closely related (clone A2). A G2576T mutation was identified in domain V of the 23S rRNA gene in the E. faecium isolate. Besides the G2576T mutation, a novel C2104T mutation was detected in the nine clone A1 S. capitis isolates. The cfr gene was detected in all the staphylococci except an S. sciuri isolate, whose 23S rRNA gene contained the G2576T mutation. There was a clonal dissemination of linezolid-resistant MRCoNS in intensive care units of our hospital, and this is the first report, to our knowledge, of linezolid-resistant staphylococci and enterococci in China.

Antistaphylococcal activity of DX-619 alone and in combination with vancomycin, teicoplanin, and linezolid assessed by time-kill synergy testing.

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Credito, Kim; Lin, Genrong; Appelbaum, Peter C

2007-04-01

Time-kill synergy studies testing in vitro activity of DX-619 alone and with added vancomycin, teicoplanin, or linezolid against 101 Staphylococcus aureus strains showed synergy between DX-619 and teicoplanin at 12 to 24 h in 72 strains and between DX-619 and vancomycin in 28 strains. No synergy was found with linezolid, and no antagonism was observed with any combination.

Aerococcus urinae and Aerococcus sanguinicola

DEFF Research Database (Denmark)

Carkaci, Derya; Nielsen, Xiaohui C.; Fuursted, Kurt

2017-01-01

, cefotaxime, meropenem, vancomycin, linezolid, and rifampicin. Methods: Three susceptibility testing methods were used; disk diffusion according to The European Committee on Antimicrobial Susceptibility Testing (EUCAST) standardized disk diffusion methodology and MIC determination with Etest and broth...... were found susceptible to all six antimicrobial agents: penicillin, cefotaxime, meropenem, vancomycin, linezolid, and rifampicin....

Antimicrobial Disk Susceptibility Testing of Leptospira spp. Using Leptospira Vanaporn Wuthiekanun (LVW) Agar.

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Wuthiekanun, Vanaporn; Amornchai, Premjit; Langla, Sayan; White, Nicholas J; Day, Nicholas P J; Limmathurotsakul, Direk; Peacock, Sharon J

2015-08-01

Leptospira Vanaporn Wuthiekanun (LVW) agar was used to develop a disk diffusion assay for Leptospira spp. Ten pathogenic Leptospira isolates were tested, all of which were susceptible to 17 antimicrobial agents (amoxicillin/clavulanic acid, amoxicillin, azithromycin, cefoxitin, ceftazidime, ceftriaxone, chloramphenicol, ciprofloxacin, clindamycin, doripenem, doxycycline, gentamicin, linezolid, nitrofurantoin, penicillin, piperacillin/tazobactam, and tetracycline). All 10 isolates had no zone of growth inhibition for four antimicrobials (fosfomycin, nalidixic acid, rifampicin, and trimethoprim/sulfamethoxazole). Of the ten Leptospira, seven had a growth inhibition zone of ≤ 21 mm for aztreonam, the zone diameter susceptibility break point for Enterobacteriaceae. This assay could find utility as a simple screening method during the epidemiological surveillance of antimicrobial resistance in Leptospira spp. © The American Society of Tropical Medicine and Hygiene.

A validated stability-indicating LC method for the separation of enantiomer and potential impurities of Linezolid using polar organic mode.

Science.gov (United States)

Satyanarayana Raju, T; Vishweshwari Kutty, O; Ganesh, V; Yadagiri Swamy, P

2012-08-01

Although a number of methods are available for evaluating Linezolid and its possible impurities, a common method for separation if its potential impurities, degradants and enantiomer in a single method with good efficiency remain unavailable. With the objective of developing an advanced method with shorter runtimes, a simple, precise, accurate stability-indicating LC method was developed for the determination of purity of Linezolid drug substance and drug products in bulk samples and pharmaceutical dosage forms in the presence of its impurities and degradation products. This method is capable of separating all the related substances of Linezolid along with the chiral impurity. This method can also be used for the estimation of assay of Linezolid in drug substance as well as in drug product. The method was developed using Chiralpak IA (250 mm×4.6 mm, 5 μm) column. A mixture of acetonitrile, ethanol, n-butyl amine and trifluoro acetic acid in 96:4:0.10:0.16 (v/v/v/v) ratio was used as a mobile phase. The eluted compounds were monitored at 254 nm. Linezolid was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. The degradation products were well resolved from main peak and its impurities, proving the stability-indicating power of the method. The developed method was validated as per International Conference on Harmonization (ICH) guidelines with respect to specificity, limit of detection, limit of quantification, precision, linearity, accuracy, robustness and system suitability.

Success of linezolid therapy for postneurosurgical ventriculitis due to vancomycin-resistant Enterococcus faecium: case report and literature review

Institute of Scientific and Technical Information of China (English)

JiaJi Qiu; Jie Tang; DeLing Li

2016-01-01

Background:Vancomycin-resistant Enterococcus faecium ventriculitis is one of the most severe events in postneurosurgical intracranial infections.There are no guidelines recommending an appropriate treatment before.Case presentation:This case presents a successful linezolid treatment for post-neurosurgical vancomycin-resistant Enterococcus faecium ventriculitis of a 24-year-old man in the department of neurosurgery,Beijing Tiantan Hospital.Conclusions:Linezolid should be considered as one of the important methods for the treatment of postneurosurgical intracranial infections caused by vancomycin-resistant Enterococcus.

Linezolid has unique immunomodulatory effects in post-influenza community acquired MRSA pneumonia.

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Urvashi Bhan

Full Text Available Post influenza pneumonia is a leading cause of mortality and morbidity, with mortality rates approaching 60% when bacterial infections are secondary to multi-drug resistant (MDR pathogens. Staphylococcus aureus, in particular community acquired MRSA (cMRSA, has emerged as a leading cause of post influenza pneumonia.Linezolid (LZD prevents acute lung injury in murine model of post influenza bacterial pneumonia.Mice were infected with HINI strain of influenza and then challenged with cMRSA at day 7, treated with antibiotics (LZD or Vanco or vehicle 6 hours post bacterial challenge and lungs and bronchoalveolar lavage fluid (BAL harvested at 24 hours for bacterial clearance, inflammatory cell influx, cytokine/chemokine analysis and assessment of lung injury.Mice treated with LZD or Vanco had lower bacterial burden in the lung and no systemic dissemination, as compared to the control (no antibiotic group at 24 hours post bacterial challenge. As compared to animals receiving Vanco, LZD group had significantly lower numbers of neutrophils in the BAL (9×10(3 vs. 2.3×10(4, p < 0.01, which was associated with reduced levels of chemotactic chemokines and inflammatory cytokines KC, MIP-2, IFN-γ, TNF-α and IL-1β in the BAL. Interestingly, LZD treatment also protected mice from lung injury, as assessed by albumin concentration in the BAL post treatment with H1N1 and cMRSA when compared to vanco treatment. Moreover, treatment with LZD was associated with significantly lower levels of PVL toxin in lungs.Linezolid has unique immunomodulatory effects on host inflammatory response and lung injury in a murine model of post-viral cMRSA pneumonia.

Nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus treated with linezolid or vancomycin: A secondary economic analysis of resource use from a Spanish perspective.

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Rello, J; Nieto, M; Solé-Violán, J; Wan, Y; Gao, X; Solem, C T; De Salas-Cansado, M; Mesa, F; Charbonneau, C; Chastre, J

2016-11-01

Adopting a unique Spanish perspective, this study aims to assess healthcare resource utilization (HCRU) and the costs of treating nosocomial pneumonia (NP) produced by methicillin-resistant Staphylococcus aureus (MRSA) in hospitalized adults using linezolid or vancomycin. An evaluation is also made of the renal failure rate and related economic outcomes between study groups. An economic post hoc evaluation of a randomized, double-blind, multicenter phase 4 study was carried out. Nosocomial pneumonia due to MRSA in hospitalized adults. The modified intent to treat (mITT) population comprised 224 linezolid- and 224 vancomycin-treated patients. Costs and HCRU were evaluated between patients administered either linezolid or vancomycin, and between patients who developed renal failure and those who did not. Analysis of HCRU outcomes and costs. Total costs were similar between the linezolid- (€17,782±€9,615) and vancomycin-treated patients (€17,423±€9,460) (P=.69). The renal failure rate was significantly lower in the linezolid-treated patients (4% vs. 15%; Prenal failure (€19,626±€10,840 vs. €17,388±€9,369; P=.14). Among the patients who developed renal failure, HCRU (days on mechanical ventilation: 13.2±10.7 vs. 7.6±3.6 days; P=.21; ICU stay: 14.4±10.5 vs. 9.9±6.6 days; P=.30; hospital stay: 19.5±9.5 vs. 16.1±11.0 days; P=.26) and cost (€17,219±€8,792 vs. €20,263±€11,350; P=.51) tended to be lower in the linezolid- vs. vancomycin-treated patients. There were no statistically significant differences in costs per patient-day between cohorts after correcting for mortality (€1000 vs. €1,010; P=.98). From a Spanish perspective, there were no statistically significant differences in total costs between the linezolid and vancomycin pneumonia cohorts. The drug cost corresponding to linezolid was partially offset by fewer renal failure adverse events. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

Similar efficacy and safety of daptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bloodstream infections: a meta-analysis.

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Zhao, Ming; Liang, Liang; Ji, Liwei; Chen, Di; Zhang, Yatong; Zhu, Yuanchao; Patel, Khilna

2016-09-01

Daptomycin and linezolid are the most commonly used antibiotics for bloodstream infection caused by vancomycin-resistant enterococci (VRE-BSI). However, the best therapeutic agent to treat VRE-BSI remains to be established. In order to provide evidence for an optimal treatment decision, a systematic review and meta-analysis was performed comparing the efficacy and safety of daptomycin and linezolid for the treatment of VRE-BSI. After thorough searching of relevant studies from MEDLINE, EMBASE, Clinicaltrials.gov and international meetings up to November 2015, 11 retrospective cohort studies were finally included with a sample size of 1339 patients. Among these 11 included studies, all patients in the daptomycin group received standard or high-dose daptomycin treatment (≥6 mg/kg/day). Data were extracted and pooled risk ratios (RRs) and 95% confidence intervals (95% CIs) were calculated using a random-effects model. The meta-analysis indicated similar crude overall mortality between patients receiving daptomycin and those treated with linezolid (RR = 1.07, 95% CI 0.83-1.37). Moreover, no difference regarding clinical cure (RR = 1.11, 95% CI 0.88-1.42), microbiological cure (RR = 0.99, 95% CI 0.90-1.09) or relapse rate of VRE-BSI (RR = 1.08, 95% CI 0.76-1.52) was found between daptomycin and linezolid. Adverse event rates were not significantly different between the two groups. Currently available evidence indicates similar efficacy and safety of daptomycin and linezolid for the treatment of VRE-BSI. However, the findings in the meta-analysis are limited by heterogeneity between relatively small-scale retrospective studies and should be interpreted cautiously. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Proper use of antibiotics: situation of linezolid at the intensive care unit of the Tunisian Military Hospital.

Science.gov (United States)

Safa, Louhichi; Afif, Neffati; Zied, Hajjej; Mehdi, Dridi; Ali, Yousfi Mohamed

2016-01-01

Linezolid was introduced in clinical practice in the early 2000s. It was considered to be an ideal reserve drug for treatment of vancomycin-resistant Enterococcus spp. (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA). The aim of our study was to describe and evaluate the use of linezolid in clinical practice at the intensive care unit (ICU) of the Tunisian military hospital. This is a thirty-month retrospective study including patients treated with linezolid at the ICU of the Tunisian military hospital. Data collection was realized using the patients' medical files and prescriptions. A pharmacist conducted an extended medication history and checked if an advice from an infectious disease-physician and a microbiological documentation were requested. A total of 80 patients were included. Forty-one per cent of indications were outside the Marketing Authorization (MA) criteria, and were mainly sepsis and postoperative mediastinitis (32% and 4% of total prescriptions, respectively). This antibiotic was used as a first-line therapy in 58% of cases. The advice from an infectious-disease physician was requested for 33% of prescriptions. Only 20% of infections were documented microbiologically, of which 35% were caused by methicillin resistant coagulase-negative Staphylococcus. Linezolid is an interesting therapeutic alternative in case of infections due to multi-resistant bacteria and/or complex clinical situations. Therefore, its prescription must be rationalized in order to slow down the emergence of resistance to this antibiotic. The high frequency of its use outside the MA criteria shows the importance of carrying out more clinical trials to evaluate its effectiveness and safety for new indications.

Nocardia asteroides peritoneal dialysis-related peritonitis: First case in pediatrics, treated with protracted linezolid.

Science.gov (United States)

El-Naggari, Mohamed; El Nour, Ibtisam; Al-Nabhani, Dana; Al Muharrmi, Zakaria; Gaafar, Heba; Abdelmogheth, Anas A W

2016-01-01

Nocardia asteroides is a rare pathogen in peritoneal dialysis-related peritonitis. We report on a 13-year-old female with Nocardia asteroides peritonitis complicated by an intra-abdominal abscess. Linezolid was administered intravenously for 3 months and followed by oral therapy for an additional 5 months with close monitoring for adverse effects. The patient was discharged after 3 months of hospitalization on hemodialysis. The diagnosis and management of such cases can be problematic due to the slow growth and difficulty of identifying Nocardia species. The optimal duration of treatment for Nocardia peritonitis is not known. Linezolid can be used for prolonged periods in cases of trimethoprim/sulfamethoxazole-resistant cases with close monitoring for adverse effects. Copyright © 2015 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

Successful Treatment of Disseminated Bacillus Calmette-Guérin Disease in an HIV-Infected Child with a Linezolid-Containing Regimen

Directory of Open Access Journals (Sweden)

Srđan Roglić

2016-01-01

Full Text Available Upon HIV infection diagnosis, an 8-month-old boy was transferred for evaluation of worsening respiratory distress requiring mechanical ventilation. Pneumocystis jirovecii pneumonia (PCP was diagnosed; the boy also had a nonhealing ulcer at the site of vaccination with Statens Serum Institut (Danish strain Bacillus Calmette-Guérin (BCG vaccine and associated axillary lymphadenopathy. PCP treatment resulted in weaning from mechanical ventilation. Antimycobacterial treatment was immediately attempted but was discontinued because of hepatotoxicity. Over several months, he developed splenic lesions and then disseminated skin and cystic bone lesions. M. bovis was repeatedly cultured from both skin and bone lesions despite various multidrug antimycobacterial regimens which included linezolid. Eventually, treatment with a regimen of rifabutin, isoniazid, ethambutol, and linezolid led to definitive cure. Clinicians should consider a linezolid-containing regimen for treatment of severe disseminated BCG infection, especially if other drug regimens have failed. Although drug toxicity is a particular concern for young children, this patient received linezolid for 13 months without serious toxicity. This case also highlights the need for universal screening among pregnant women to prevent vertical transmission of HIV. Finally, routine immunization with BCG vaccine at birth should be questioned in countries with low and declining burden of tuberculosis.

Antistaphylococcal Activity of DX-619 Alone and in Combination with Vancomycin, Teicoplanin, and Linezolid Assessed by Time-Kill Synergy Testing▿ †

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Credito, Kim; Lin, Genrong; Appelbaum, Peter C.

2007-01-01

Time-kill synergy studies testing in vitro activity of DX-619 alone and with added vancomycin, teicoplanin, or linezolid against 101 Staphylococcus aureus strains showed synergy between DX-619 and teicoplanin at 12 to 24 h in 72 strains and between DX-619 and vancomycin in 28 strains. No synergy was found with linezolid, and no antagonism was observed with any combination. PMID:17261625

A 10-Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital-wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

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Pea, Federico; Cojutti, Pier Giorgio; Baraldo, Massimo

2017-10-01

A retrospective study was conducted to assess our 10-year experience of therapeutic drug monitoring (TDM) of linezolid in a large patient population to establish whether conventional dosing may result in adequate drug exposure in the majority of patients. Patients included in this study underwent TDM of linezolid trough concentration (C min ) during treatment with conventional doses of 600 mg every 12 hr in the period between January 2007 and June 2016. The desired range of C min was set between 2 and 7 mg/L (underexposure, C min   7 mg/L). Multivariate logistic regression analysis investigated variables potentially correlated with linezolid C min . One thousand and forty-nine patients had 2484 linezolid C min assessed during treatment with conventional doses. Median (IQR) linezolid C min was 5.08 mg/L (2.78-8.52 mg/L). Linezolid C min was within the desired range in 50.8% of cases (1262/2484). Overexposure (n = 821; 33%) occurred much more frequently than underexposure (n = 401; 16.2%) and was severe (>20 mg/L) in 3.9% of cases (98/2484). Linezolid overexposure was significantly associated with CrCL C -G estimates ≤40 mL/min. (OR 1.463; 95% CI 1.124-1.904, p = 0.005). Linezolid underexposure was significantly associated with CrCL C -G estimates >100 mL/min. (OR 3.046; 95% CI 2.234-4.152, p Linezolid C min was not correlated linearly with CrCL C -G (R 2  = 0.061). Variability in renal function explained only partially the very wide interindividual linezolid C min variability. Our study suggests that TDM could represent a valuable approach in optimizing linezolid exposure in the majority of patients. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Antimicrobial susceptibility pattern of bacterial isolates from surgical wound infections in Tertiary Care Hospital in Allahabad, India

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A K Kapoor

2012-01-01

Full Text Available The aim of present study to analyze the occurrence and in-vitro antimicrobial susceptibility of bacterial pathogens isolated from surgical wound infections. Specimens from a total of 129 patients undergoing either emergency or elective surgery were collected from infected sites or stitch lines and inoculated onto appropriate media. The bacterial cultures were identified utilizing standard microbiological and biochemical methods. Isolates were tested for susceptibility to antimicrobials using the Kirby Bauer disk diffusion method. Statistical analysis was performed using the chi-square test. Of 129 patients investigated (62 emergency and 67 elective surgery cases, bacterial isolates were isolated with almost equal frequency both from emergency and elective surgery cases. Of 108 (83.72% culture positive samples, 62 (57.41% were Gram negative, 39 (36.11% Gram positive, and 7 (6.48% showed multiple organisms. Of total 115 bacteria isolated (101 single and 7 double organisms culture positive, 33 (28.69% were Escherichia coli and were also the commonest; followed by Staphylococcus aureus, 30 (26.09% cases. S. aureus and Streptococcus spp. showed maximum susceptibility (100% to linezolid and vancomycin. Maximum susceptibility of E. coli was observed to ciprofloxacin (75.7%, followed by gentamicin (54.5%; of Klebsiella spp. to ceftriaxone and gentamicin (66.6% each, of Proteus spp. to gentamicin (70% followed by ciprofloxacin (60%, and of Pseudomonas aeruginosa to piperacillin (100% and tobramycin (71.4%. E. coli and S. aureus were the most common and Salmonella spp. and Acinetobacter spp. were the least common organism causing surgical site infections. The definitive therapy included ciprofloxacin and gentamicin for E. coli; linezolid and vancomycin for S. aureus and Streptococcus spp; ceftriaxone and ciprofloxacin for Klebsiella spp., Citrobacter spp., acinetobacter spp and Salmonella spp.

Antibacterial susceptibility patterns of methicillin resistant staphylococcus spp. from a tertiary reference hospital

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Çiğdem Karabıçak

2012-03-01

Full Text Available Objectives: Methicillin resistant Staphylococcus strainsstill remain as an important reason of hospital acquiredinfections. The aim of this study to see the antimicrobialsensitivity patterns of these strains for effective empiricaltherapyMaterial and methods: Antibiotic susceptibility resultsof staphylococcus strains were investigated retrospectivelyfrom tertiary reference hospital. 276 methicillin resistantstaphylococcus species, which were isolated fromKırıkkale University Faculty of Medicine Department of InfectiousDisease and Clinical Microbiology laboratory betweenNovember 2009-2010 were enrolled in this study.Identification and antibiotic susceptibilities of the strainswere evaluated by using Vitek automated systems (bioMerieux.Results: Most of these strains were isolated from blood(49% and wound (40 % samples. There was no glycopeptideresistance established from 276 strains. Susceptibilitypercents of these strains to linezolid and erythromycinwere 97% and 16% respectively.Conclusions: we believe that, informing physiciansabout antibiotic susceptibility patterns of methicillin resistantstaphylococcus species will be helpful for effectivetreatment and control the spread of these infections. JClin Exp Invest 2012; 3(1: 71-74

MICROBIAL PROFILE AND ANTIBIOTIC SUSCEPTIBILITY PATTERNS OF PATHOGENS CAUSING VENTILATOR- ASSOCIATED PNEUMONIA AT INTENSIVE CARE UNIT, SESTRE MILOSRDNICE UNIVERSITY HOSPITAL CENTER, ZAGREB, CROATIA.

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Turković, Tihana Magdić; Grginić, Ana Gverić; Cucujić, Branka Đuras; Gašpar, Božena; Širanović, Mladen; Perić, Mladen

2015-06-01

Ventilator-associated pneumonia (VAP) is very common in many intensive care Units, but there are still many uncertainties about VAP, especially about the choice of initial empiric antibiotics. The incidence of specific pathogens with different susceptibility patterns causing VAP varies from hospital to hospital. This is the reason why empiric initial antibiotic treatment for VAP should be based not only on general guidelines (that recommend therapy according to the presence of risk factors for multidrug-resistant bacteria), but also on up-to-date information on local epidemiology. The aim of this study was to determine the microbial profile of pathogens causing VAP and their antibiotic susceptibility patterns. The study was conducted in the 15-bed surgical and neurosurgical Intensive Care Unit, Department of Anesthesiology and Intensive Care, Sestre milosrdnice University Hospital Center, Zagreb, Croatia. Retrospective data were collected from September 2009 to March 2013. All patients that developed VAP during the study period were eligible for the study. According to study results, the incidence of VAP was 29.4%. The most commonly isolated bacterium was Staphylococcus aureus (21.1%), followed by Pseudomonas aeruginosa (19.0%) and Acinetobacter species (13.6%). All Staphylococcus aureus isolates were susceptible to vancomycin and linezolid. Pseudomonas aeruginosa showed 100% susceptibility to cefepime and very high susceptibility to pip'eracillin-tazobactam (96%), ceftazidime (93%) and ciprofloxacin (89%). Ampicillin-sulbactam was highly effective for Acinetobacter species, showing resistance in only 8% of isolates. In conclusion, according to study data, appropriate empiric antibiotic therapy for patients with VAP without risk factors for multidrug-resistant bacteria is ceftriaxone and for patients with risk factors for multidrug-resistant bacteria ampicillin-sulbactam plus cefepime plus vancomycin or linezolid.

Comparing the cost-effectiveness of linezolid to trimethoprim/sulfamethoxazole plus rifampicin for the treatment of methicillin-resistant Staphylococcus aureus infection: a healthcare system perspective.

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von Dach, E; Morel, C M; Murthy, A; Pagani, L; Macedo-Vinas, M; Olearo, F; Harbarth, S

2017-09-01

Few industry-independent studies have been conducted to compare the relative costs and benefits of drugs to treat methicillin-resistant Staphylococcus aureus (MRSA) infection. We performed a stochastic cost-effectiveness analysis comparing two treatment strategies-linezolid versus trimethoprim-sulfamethoxazole plus rifampicin-for the treatment of MRSA infection. We used cost and effectiveness data from a previously conducted clinical trial, complementing with other data from published literature, to compare the two regimens from a healthcare system perspective. Effectiveness was expressed in terms of quality-adjusted life-years (QALYs). Several sensitivity analyses were performed using Monte Carlo simulation, to measure the effect of potential parameter changes on the base-case model results, including potential differences related to type of infection and drug toxicity. Treatment of MRSA infection with trimethoprim-sulfamethoxazole plus rifampicin and linezolid were found to cost on average €146 and €2536, and lead to a gain of 0.916 and 0.881 QALYs, respectively. Treatment with trimethoprim-sulfamethoxazole plus rifampicin was found to be more cost-effective than linezolid in the base case and remained dominant over linezolid in most alternative scenarios, including different types of MRSA infection and potential disadvantages in terms of toxicity. With a willingness-to-pay threshold of €0, €50 000 and €200 000 per QALY gained, trimethoprim-sulfamethoxazole plus rifampicin was dominant in 100%, 96% and 85% of model iterations. A 95% discount on the current purchasing price of linezolid would be needed when it goes off-patent for it to represent better value for money compared with trimethoprim-sulfamethoxazole plus rifampicin. Combined treatment of trimethoprim-sulfamethoxazole plus rifampicin is more cost-effective than linezolid in the treatment of MRSA infection. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

An economic model to compare linezolid and vancomycin for the treatment of confirmed methicillin-resistant Staphylococcus aureus nosocomial pneumonia in Germany

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Patel DA

2014-10-01

Full Text Available Dipen A Patel,1 Andre Michel,2 Jennifer Stephens,1 Bertram Weber,3 Christian Petrik,4 Claudie Charbonneau5 1Health Economic and Outcomes Research, Pharmerit International, Bethesda, MD, USA; 2Klinikum Hanau GmbH, Hanau, Germany; 3Health Technology Assessment and Outcomes Research, 4Anti-infectives, Pfizer, Berlin, Germany; 5Pfizer International Operations, Pfizer France, Paris, France Background: Across Europe, methicillin-resistant Staphylococcus aureus (MRSA is considered to be the primary cause of nosocomial pneumonia (NP. In Germany alone, approximately 14,000 cases of MRSA-associated NP occur annually, which may have a significant impact on health care resource use and associated economic costs. The objective of this study was to investigate the economic impact of linezolid compared with that of vancomycin in the treatment of hospitalized patients with MRSA-confirmed NP in the German health care system. Methods: A 4-week decision tree model incorporated published data and expert opinion on clinical parameters, resource use, and costs (2012 euros was constructed. The base case first-line treatment duration for patients with MRSA-confirmed NP was 10 days. Treatment success (survival, failure due to lack of efficacy, serious adverse events, and mortality were possible outcomes that could impact costs. Alternate scenarios were analyzed, such as varying treatment duration (7 or 14 days or treatment switch due to a serious adverse event/treatment failure (at day 5 or 10. Results: The model calculated total base case inpatient costs of €15,116 for linezolid and €15,239 for vancomycin. The incremental cost-effectiveness ratio favored linezolid (versus vancomycin, with marginally lower costs (by €123 and greater efficacy (+2.7% absolute difference in the proportion of patients successfully treated for MRSA NP. Approximately 85%–87% of the total treatment costs were attributed to hospital stay (primarily in the intensive care unit

Rifapentine-linezolid-loaded PLGA microspheres for interventional therapy of cavitary pulmonary tuberculosis: preparation and in vitro characterization.

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Huang, Jieyun; Chen, Zhi; Li, Ying; Li, Li; Zhang, Guangyu

2017-01-01

In this study, we aimed to design controlled-release microspheres for the treatment of cavitary pulmonary tuberculosis (TB) for solving the issues of poor drug delivery and short duration maintained at effective drug concentration during bronchoscopic interventional therapy. We fabricated rifapentine-linezolid-loaded poly(lactic acid-co-glycolic acid) microspheres (RLPMs) using the oil-in-water emulsion solvent evaporation method and assessed their in vitro release as well as the bronchial mucosal retention characteristics. The microspheres are spherical in shape with a circular concave on the surface. The particle size of RLPMs was 27.38±1.28 μm. The drug loading of rifapentine and linezolid was 18.51±0.26 and 8.42%±0.24%, respectively, while the encapsulation efficiencies were 55.53±0.78 and 16.87%±0.47%, respectively (n=3). During the burst release phase of the in vitro release test, 21.37%±0.68% rifapentine was released in 3 days and 43.56%±2.54% linezolid was released in 1 day. Then, both the drugs entered the sustained release phase. Finally, the cumulative percentage release of rifapentine and linezolid in 14 days was 27.61±1.52 and 51.01%±3.31%, respectively (n=3). Bronchoscopic observation revealed that the controlled-release microspheres could slowly release the drugs and retain them on the surface of bronchial mucosa of canines for 20 days. These results indicated that the fabricated microspheres exhibited a significant sustained release effect and could effectively retain the drugs on the surface of bronchial mucosa. Therefore, this study provides a theoretical and practical foundation for the development of fabricated microspheres loaded with multiple anti-TB drugs in the bronchoscopic interventional therapy of cavity pulmonary TB.

Unbound fraction of fluconazole and linezolid in human plasma as determined by ultrafiltration: Impact of membrane type.

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Kratzer, Alexander; Kees, Frieder; Dorn, Christoph

2016-12-15

Ultrafiltration is a rapid and convenient method to determine the free concentrations of drugs in plasma. Several ultrafiltration devices based on Eppendorf cups are commercially available, but are not validated for such use by the manufacturer. Plasma pH, temperature and relative centrifugal force as well as membrane type can influence the results. In the present work, we developed an ultrafiltration method in order to determine the free concentrations of linezolid or fluconazole, both neutral and moderately lipophilic antiinfective drugs for parenteral as well as oral administration, in plasma of patients. Whereas both substances behaved relatively insensitive in human plasma regarding variations in pH (7.0-8.5), temperature (5-37°C) or relative centrifugal force (1000-10.000xg), losses of linezolid were observed with the Nanosep Omega device due to adsorption onto the polyethersulfone membrane (unbound fraction 75% at 100mg/L and 45% at 0.1mg/L, respectively). No losses were observed with Vivacon which is equipped with a membrane of regenerated cellulose. With fluconazole no differences between Nanosep and Vivacon were observed. Applying standard conditions (pH 7.4/37°C/1000xg/20min), the mean unbound fraction of linezolid in pooled plasma from healthy volunteers was 81.5±2.8% using Vivacon, that of fluconazole was 87.9±3.5% using Nanosep or 89.4±3.3% using Vivacon. The unbound fraction of linezolid was 85.4±3.7% in plasma samples from surgical patients and 92.1±6.2% in ICU patients, respectively. The unbound fraction of fluconazole was 93.9±3.3% in plasma samples from ICU patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Costo-efectividad de linezolid comparado con vancomicina en el manejo de la neumonía asociada a ventilación mecánica en Colombia

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Fabio Varón

2014-12-01

Full Text Available Objetivo: Estimar la costo-efectividad de linezolid versus vancomicina en el manejo de neumonía asociada a ventilación mecánica (NAV causada por Staphylococcus aureus resistente a meticilina (SARM en Colombia. Materiales y métodos: Se construyó un árbol de decisión para determinar la razón de costo-efectividad incremental de linezolid (600 mg iv/12 h comparado con vancomicina (15 mg/kg iv/12 h en el tratamiento de NAV por SARM. La perspectiva fue la del sistema de salud incluyendo solo costos directos. Todas las unidades monetarias se expresan en pesos colombianos del 2013 sin descuento (1 USD =$ 1.876,22. Se empleó un horizonte temporal de 30 días. Los resultados se midieron en proporción de pacientes curados. Los datos de eficacia y seguridad se tomaron de la literatura. Los costos de los procedimientos se obtuvieron del manual tarifario ISS del 2001, para medicamentos se utilizó el SISMED y la regulación de precios vigente. Se realizaron análisis de sensibilidad univariados y probabilísticos. Resultados: Los costos totales esperados por paciente curado fueron: $ 2.600.094 para linezolid y $ 1.992.753 para vancomicina. La proporción de pacientes curados fue: 53% con linezolid y 41%.con vancomicina. La razón de costo-efectividad de linezolid comparado con vancomicina fue $ 5.061.173 por paciente curado. Para cada alternativa, los resultados fueron sensibles a la probabilidad de éxito del tratamiento, a la probabilidad de presentar eventos adversos y al costo del tratamiento. Conclusión: En Colombia, linezolid sería una alternativa costo-efectiva en el tratamiento de NAV por SARM, para disponibilidades a pagar superiores a $ 5.061.173 por paciente curado.

Rifapentine-linezolid-loaded PLGA microspheres for interventional therapy of cavitary pulmonary tuberculosis: preparation and in vitro characterization

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Huang J

2017-03-01

Full Text Available Jieyun Huang,1,* Zhi Chen,2,* Ying Li,3 Li Li,2 Guangyu Zhang2 1The Second Clinical Medical College, Shanxi Medical University, Taiyuan, People’s Republic of China; 2Institute for Tuberculosis Research, The 309th Hospital of Chinese PLA, Beijing, People’s Republic of China; 3Department of Drug Delivery Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: In this study, we aimed to design controlled-release microspheres for the treatment of cavitary pulmonary tuberculosis (TB for solving the issues of poor drug delivery and short duration maintained at effective drug concentration during bronchoscopic interventional therapy. We fabricated rifapentine-linezolid-loaded poly(lactic acid-co-glycolic acid microspheres (RLPMs using the oil-in-water emulsion solvent evaporation method and assessed their in vitro release as well as the bronchial mucosal retention characteristics. The microspheres are spherical in shape with a circular concave on the surface. The particle size of RLPMs was 27.38±1.28 µm. The drug loading of rifapentine and linezolid was 18.51±0.26 and 8.42%±0.24%, respectively, while the encapsulation efficiencies were 55.53±0.78 and 16.87%±0.47%, respectively (n=3. During the burst release phase of the in vitro release test, 21.37%±0.68% rifapentine was released in 3 days and 43.56%±2.54% linezolid was released in 1 day. Then, both the drugs entered the sustained release phase. Finally, the cumulative percentage release of rifapentine and linezolid in 14 days was 27.61±1.52 and 51.01%±3.31%, respectively (n=3. Bronchoscopic observation revealed that the controlled-release microspheres could slowly release the drugs and retain them on the surface of bronchial mucosa of canines for 20 days. These results indicated that the fabricated microspheres exhibited

Efficacy and safety profile of linezolid in the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis: a systematic review and meta-analysis.

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Agyeman, Akosua Adom; Ofori-Asenso, Richard

2016-06-22

Treatment options for drug-resistant tuberculosis are still limited. Linezolid has been recommended for treatment of patients with multidrug-resistant (MDR) or extensively-drug-resistant (XDR) tuberculosis, although uncertainties remain regarding its safety and tolerability in these circumstances. To systematically evaluate the existing evidence regarding the efficacy and tolerability of linezolid in the treatment of MDR or XDR tuberculosis. We conducted a systematic review and meta-analysis in accordance with the PRISMA guidelines. Searches were conducted in PubMed, Web of Science and EMBASE followed by direct search of abstracts in the International Journal of Tuberculosis and Lung Disease to retrieve primary studies published between January 2000 and January 2016 assessing linezolid efficacy and safety in the treatment of drug-resistant TB. We evaluated the occurrence of outcomes including culture conversion, treatment success and incidence of adverse events such as myelosuppression and neuropathy. Twenty-three (23) studies conducted in fourteen (14) countries and involving 507 patients were retrieved. Only 1 randomized controlled trial was identified and none of the identified studies involved participants from Africa. The pooled proportion for treatment success was 77.36 % (95 % CI = 71.38-82.83 %, I(2) = 37.6 %) with culture conversion rate determined as 88.45 % (95 % CI = 83.82-92.38 %, I(2) = 45.4 %). There was no strong evidence for both culture conversion (p = 0.0948) and treatment success (p = 0.0695) between linezolid daily doses ≤ 600 and > 600 mg. Only myelosuppression showed a strong statistical significance (p linezolid also showed no significance upon dose comparisons (p = 0.3213, p = 0.9050 respectively). Available evidence presents Linezolid as a viable option in the treatment of MDR/XDR TB although patients ought to be monitored closely for the incidence of major adverse events such as myelosuppression and

Simultaneous determination of tedizolid and linezolid in rat plasma by ultra performance liquid chromatography tandem mass spectrometry and its application to a pharmacokinetic study.

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Yu, Hua-chen; Pan, Chen-wei; Xie, Qi-peng; Zheng, Yi; Hu, Yue-zheng; Lin, Yi-mu

2016-02-01

A sensitive and rapid ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed to determine tedizolid and linezolid in rat plasma simultaneously. Chromatographic separation was carried out on an Acquity UPLC BEH C18 column and mass spectrometric analysis was performed using a XEVO TQD triple quadruple mass spectrometer coupled with an electrospray ionization (ESI) source in the positive ion mode. Multiple reaction monitoring (MRM) mode was used for quantification using target fragment ions m/z 371.4→343.2 for tedizolid, and m/z 338.3→56.1 for linezolid. This assay method has been fully validated in terms of selectivity, linearity, recovery and matrix effect, accuracy, precision and stability. The linearity of this method was found to be within the concentration range of 5-5000ng/mL for tedizolid, and 10-10,000ng/mL for linezolid in rat plasma, respectively. Only 3.0min was needed for an analytical run. This assay was used to support a preclinical study where multiple oral doses were administered to rats to investigate the pharmacokinetics of tedizolid and linezolid. Copyright © 2015 Elsevier B.V. All rights reserved.

Antimicrobial susceptibility among clinical Nocardia species identified by multilocus sequence analysis.

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McTaggart, Lisa R; Doucet, Jennifer; Witkowska, Maria; Richardson, Susan E

2015-01-01

Antimicrobial susceptibility patterns of 112 clinical isolates, 28 type strains, and 9 reference strains of Nocardia were determined using the Sensititre Rapmyco microdilution panel (Thermo Fisher, Inc.). Isolates were identified by highly discriminatory multilocus sequence analysis and were chosen to represent the diversity of species recovered from clinical specimens in Ontario, Canada. Susceptibility to the most commonly used drug, trimethoprim-sulfamethoxazole, was observed in 97% of isolates. Linezolid and amikacin were also highly effective; 100% and 99% of all isolates demonstrated a susceptible phenotype. For the remaining antimicrobials, resistance was species specific with isolates of Nocardia otitidiscaviarum, N. brasiliensis, N. abscessus complex, N. nova complex, N. transvalensis complex, N. farcinica, and N. cyriacigeorgica displaying the traditional characteristic drug pattern types. In addition, the antimicrobial susceptibility profiles of a variety of rarely encountered species isolated from clinical specimens are reported for the first time and were categorized into four additional drug pattern types. Finally, MICs for the control strains N. nova ATCC BAA-2227, N. asteroides ATCC 19247(T), and N. farcinica ATCC 23826 were robustly determined to demonstrate method reproducibility and suitability of the commercial Sensititre Rapmyco panel for antimicrobial susceptibility testing of Nocardia spp. isolated from clinical specimens. The reported values will facilitate quality control and standardization among laboratories. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Reduced susceptibility to praziquantel among naturally occurring Kenyan isolates of Schistosoma mansoni.

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Sandra D Melman

2009-08-01

Full Text Available The near exclusive use of praziquantel (PZQ for treatment of human schistosomiasis has raised concerns about the possible emergence of drug-resistant schistosomes.We measured susceptibility to PZQ of isolates of Schistosoma mansoni obtained from patients from Kisumu, Kenya continuously exposed to infection as a consequence of their occupations as car washers or sand harvesters. We used a an in vitro assay with miracidia, b an in vivo assay targeting adult worms in mice and c an in vitro assay targeting adult schistosomes perfused from mice. In the miracidia assay, in which miracidia from human patients were exposed to PZQ in vitro, reduced susceptibility was associated with previous treatment of the patient with PZQ. One isolate ("KCW" that was less susceptible to PZQ and had been derived from a patient who had never fully cured despite multiple treatments was studied further. In an in vivo assay of adult worms, the KCW isolate was significantly less susceptible to PZQ than two other isolates from natural infections in Kenya and two lab-reared strains of S. mansoni. The in vitro adult assay, based on measuring length changes of adults following exposure to and recovery from PZQ, confirmed that the KCW isolate was less susceptible to PZQ than the other isolates tested. A sub-isolate of KCW maintained separately and tested after three years was susceptible to PZQ, indicative that the trait of reduced sensitivity could be lost if selection was not maintained.Isolates of S. mansoni from some patients in Kisumu have lower susceptibility to PZQ, including one from a patient who was never fully cured after repeated rounds of treatment administered over several years. As use of PZQ continues, continued selection for worms with diminished susceptibility is possible, and the probability of emergence of resistance will increase as large reservoirs of untreated worms diminish. The potential for rapid emergence of resistance should be an important

Reduced Slc6a15 in Nucleus Accumbens D2-Neurons Underlies Stress Susceptibility.

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Chandra, Ramesh; Francis, T Chase; Nam, Hyungwoo; Riggs, Lace M; Engeln, Michel; Rudzinskas, Sarah; Konkalmatt, Prasad; Russo, Scott J; Turecki, Gustavo; Iniguez, Sergio D; Lobo, Mary Kay

2017-07-05

Previous research demonstrates that Slc6a15, a neutral amino acid transporter, is associated with depression susceptibility. However, no study examined Slc6a15 in the ventral striatum [nucleus accumbens (NAc)] in depression. Given our previous characterization of Slc6a15 as a striatal dopamine receptor 2 (D2)-neuron-enriched gene, we examined the role of Slc6a15 in NAc D2-neurons in mediating susceptibility to stress in male mice. First, we showed that Slc6a15 mRNA was reduced in NAc of mice susceptible to chronic social defeat stress (CSDS), a paradigm that produces behavioral and molecular adaptations that resemble clinical depression. Consistent with our preclinical data, we observed Slc6a15 mRNA reduction in NAc of individuals with major depressive disorder (MDD). The Slc6a15 reduction in NAc occurred selectively in D2-neurons. Next, we used Cre-inducible viruses combined with D2-Cre mice to reduce or overexpress Slc6a15 in NAc D2-neurons. Slc6a15 reduction in D2-neurons caused enhanced susceptibility to a subthreshold social defeat stress (SSDS) as observed by reduced social interaction, while a reduction in social interaction following CSDS was not observed when Slc6a15 expression in D2-neurons was restored. Finally, since both D2-medium spiny neurons (MSNs) and D2-expressing choline acetyltransferase (ChAT) interneurons express Slc6a15, we examined Slc6a15 protein in these interneurons after CSDS. Slc6a15 protein was unaltered in ChAT interneurons. Consistent with this, reducing Slc5a15 selectively in NAc D2-MSNs, using A2A-Cre mice that express Cre selectively in D2-MSNs, caused enhanced susceptibility to SSDS. Collectively, our data demonstrate that reduced Slc6a15 in NAc occurs in MDD individuals and that Slc6a15 reduction in NAc D2-neurons underlies stress susceptibility. SIGNIFICANCE STATEMENT Our study demonstrates a role for reduced Slc6a15, a neutral amino acid transporter, in nucleus accumbens (NAc) in depression and stress susceptibility. The

Moellerella wisconsensis: identification, natural antibiotic susceptibility and its dependency on the medium applied.

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Stock, Ingo; Falsen, Enevold; Wiedemann, Bernd

2003-01-01

The present study establishes a data compilation on biochemical features and natural antibiotic susceptibilities of Moellerella wisconsensis strains. 17 moellerellae isolated from humans (n = 11), food (n = 5) and water (n = 1) were tested. Identification was carried out using two commercially available systems and conventional tests. MIC determinations of 74 antibiotics were performed applying a microdilution procedure in Cation-adjusted Mueller Hinton broth and IsoSensitest broth. M. wisconsensis was naturally sensitive to doxycycline, minocycline, all tested aminoglycosides, numerous beta-lactams, all fluoroquinolones, folate-pathway inhibitors, chloramphenicol and nitrofurantoin. Natural resistance was found with oxacillin, penicillin G, all tested macrolides, lincomycin, streptogramins, ketolides, glycopeptides, fusidic acid, linezolid and rifampicin. Medium-dependent differences in susceptibility affecting clinical assessment criteria were seen with tetracycline, clindamycin and fosfomycin. From the data of the present study it is possible that some moellerellae are misidentified as Klebsiella pneumoniae subsp. ozaenae.

Endocarditis due to vancomycin-resistant Enterococcus raffinosus successfully treated with linezolid: case report and review of literature Endocarditis por Enterococcus raffinosus resistente a vancomicina exitosamente tratada con linezolid: caso clínico y revisión de la literatura

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A. Jasovich

2008-12-01

Full Text Available Enterococcus raffinosus is scarcely found in clinical samples and even less frequently as etiologic agent of endocarditis. We are herein presenting one case of mitral prosthetic-valve endocarditis in a 77-y-o male due to a vancomycinresistant Enterococcus raffinosus isolate, successfully treated with 6 weeks of linezolid, and a two-year follow up.Enterococcus raffinosus es una especie poco frecuente en materiales clínicos y menos aún como agente etiológico de endocarditis. En este trabajo se presenta un caso de endocarditis de válvula mitral protésica en un paciente de 77 años debida a Enterococcus raffinosus resistente a vancomicina y que fue exitosamente tratada con linezolid durante 6 semanas, con un seguimiento de 2 años.

Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis

NARCIS (Netherlands)

Vu, D H; Bolhuis, M S; Koster, R A; Greijdanus, B; de Lange, W C M; van Altena, R; Brouwers, J R B J; Uges, D R A; Alffenaar, J W C

2012-01-01

Linezolid is a promising antimicrobial agent for the treatment of multidrug-resistant tuberculosis (MDR-TB), but its use is limited by toxicity. Therapeutic drug monitoring (TDM) may help to minimize toxicity while adequate drug exposure is maintained. Conventional plasma sampling and monitoring

Endophthalmitis caused by gram-positive bacteria resistant to vancomycin: Clinical settings, causative organisms, antimicrobial susceptibilities, and treatment outcomes

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Hegde Sharat Shivaramaiah

2018-06-01

Full Text Available Purpose: To report the clinical settings, causative organisms, antimicrobial susceptibilities, and treatment outcomes of patients with endophthalmitis caused by gram-positive bacteria resistant to vancomycin. Methods: Retrospective case series of all patients with culture-proven endophthalmitis caused by gram-positive bacteria resistant to vancomycin between January 2010 and December 2016 in LV Prasad Eye Institute, Visakhapatnam, India. Results: The current study included 14 patients. The clinical settings were post-cataract surgery in 8/14 (57.1% and open globe injury in 6/14 (42.8%. Primary intervention for all patients included tap and intravitreal antibiotic injection. During subsequent follow-up, pars plana vitrectomy was performed in 6 patients and one patient underwent penetrating keratoplasty. Mean number of intravitreal antibiotic injections performed were 3.4 per patient. The most common organisms isolated were coagulase-negative Staphylococci in 6/14 (42.8%, Staphylococcus aureus in 5/14 (35.7%, Streptococcus sp in 2/14 (14.2% and Bacillus sp in 1/14 (7.14%. In addition to vancomycin, resistance to multiple drugs (three or more groups of antibiotics was found in all 14 cases. Antimicrobial susceptibility results showed susceptibility to amikacin in 7/14 (50.0%, gatifloxacin in 6/14 (42.8%, moxifloxacin in 3/13 (23.0%, cefazoline in 5/14 (35.7%, cefuroxime in 3/14 (21.4%, ciprofloxacin in 2/14 (14.2% and linezolid in 5/5 (100%. The mean duration of follow-up was 30.7 weeks (6 weeks–90 weeks. At last follow-up, visual acuity (VA of 20/200 or better was recorded in 7/14 (50% and VA < 5/200 occurred in 7/14 (50%. Conclusion and importance: Antimicrobial susceptibility testing may help in selection of suitable antimicrobial agents for repeat intravitreal injection. Inspite of retreatment with intravitreal antibiotics, these patients generally had poor VA outcomes. Keywords: Coagulase-negative Staphylococci, Endophthalmitis

Serotonin syndrome in an orthopaedic patient secondary to linezolid therapy for MRSA infection.

LENUS (Irish Health Repository)

McClean, M

2012-01-31

A 67-year-old patient was admitted for incision and drainage of a recurrent methicillin-resistant Staphylococcus aureus (MRSA) hip abscess. Linezolid therapy was initiated postoperatively. Within 48 h the patient developed confusion, agitation, hypertension and acute renal failure. Citalopram was stopped and resolution of symptoms occurred within 48 h of discontinuing the offending agent. The symptoms observed in our patient were consistent with the Sternbach criteria for serotonin syndrome.

Working memory in schizophrenia: behavioral and neural evidence for reduced susceptibility to item-specific proactive interference.

Science.gov (United States)

Kaller, Christoph P; Loosli, Sandra V; Rahm, Benjamin; Gössel, Astrid; Schieting, Stephan; Hornig, Tobias; Hennig, Jürgen; Tebartz van Elst, Ludger; Weiller, Cornelius; Katzev, Michael

2014-09-15

Susceptibility to item-specific proactive interference (PI) contributes to interindividual differences in working memory (WM) capacity and complex cognition relying on WM. Although WM deficits are a well-recognized impairment in schizophrenia, the underlying pathophysiological effects on specific WM control functions, such as the ability to resist item-specific PI, remain unknown. Moreover, opposing hypotheses on increased versus reduced PI susceptibility in schizophrenia are both justifiable by the extant literature. To provide first insights into the behavioral and neural correlates of PI-related WM control in schizophrenia, a functional magnetic resonance imaging experiment was conducted in a sample of 20 patients and 20 well-matched control subjects. Demands on item-specific PI were experimentally manipulated in a recent-probes task (three runs, 64 trials each) requiring subjects to encode and maintain a set of four target items per trial. Compared with healthy control subjects, schizophrenia patients showed a significantly reduced PI susceptibility in both accuracy and latency measures. Notably, reduced PI susceptibility in schizophrenia was not associated with overall WM impairments and thus constituted an independent phenomenon. In addition, PI-related activations in inferior frontal gyrus and anterior insula, typically assumed to support PI resistance, were reduced in schizophrenia, thus ruling out increased neural efforts as a potential cause of the patients' reduced PI susceptibility. The present study provides first evidence for a diminished vulnerability of schizophrenia patients to item-specific PI, which is presumably a consequence of the patients' more efficient clearing of previously relevant WM traces and the accordingly reduced likelihood for item-specific PI to occur. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

A validated UPLC-MS/MS method for the analysis of linezolid and a novel oxazolidinone derivative (PH027) in plasma and its application to tissue distribution study in rabbits.

Science.gov (United States)

Hedaya, Mohsen A; Thomas, Vidhya; Abdel-Hamid, Mohamed E; Kehinde, Elijah O; Phillips, Oludotun A

2017-01-01

Linezolid is the first approved oxazolidinone antibacterial agent, whereas PH027 is a novel compound of the same class that exhibits good in vitro antibacterial activity. The objective of this study was to develop an UPLC-MS/MS assay for the analysis of linezolid and PH027 in plasma and to apply the method for comparative pharmacokinetic and tissue distribution studies of both compounds. Plasma samples and calibrators were extracted with diethyl ether after addition of the internal standard solution. After evaporation of the ether layer, the residue was reconstituted in mobile phase and injected into UPLC-MS/MS. The mobile phase consisted of 2mM ammonium acetate buffer solution and acetonitrile (70:30) at a flow rate of 0.2ml/min. Separation was achieved using UPLC BEH C 18 column, and quantitative determination of the analytes was performed using multiple-reaction monitoring (MRM) scanning mode. The method was validated by analyzing quality control tissue homogenate samples, and was applied to analyze tissue homogenate samples obtained following IV injections of linezolid and PH027 in rabbits. The developed UPLC-MS/MS method was linear in the concentration range of 50-5000ng/ml. Validation of the method proved that the method's precision, selectivity and stability were all within the acceptable limits. Linezolid and PH027 concentrations were accurately determined in the quality control tissue homogenate samples, and analysis of samples obtained following IV administration of the two compounds showed that the tissue to plasma concentration ratio of PH027 was higher than that of linezolid probably due to its higher lipophilicity. The developed UPLC-MS/MS method for the analysis of linezolid and PH027 in rabbit's plasma can accurately determine the concentrations of these compounds in different tissues. Copyright © 2016 Elsevier B.V. All rights reserved.

Multiple paths towards reduced membrane potential and concomitant reduction in aminoglycoside susceptibility in staphylococcus aureus

DEFF Research Database (Denmark)

Vestergaard, Martin; Nøhr-Meldgaard, Katrine; Ingmer, Hanne

2018-01-01

susceptibility to gentamicin. 9 mutants were confirmed by E-test to display between 2 and 16-fold reduced susceptibility to this antibiotic. All of the identified genes were associated with the electron transport chain and energy metabolism. Four mutant strains (menD, hemB, aroC and SAUSA300_0355) conferred...

In Vivo Assessment of Phage and Linezolid Based Implant Coatings for Treatment of Methicillin Resistant S. aureus (MRSA Mediated Orthopaedic Device Related Infections.

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Sandeep Kaur

Full Text Available Staphylococcus comprises up to two-thirds of all pathogens in orthopaedic implant infections with two species respectively Staphylococcus aureus and Staphylococcus epidermidis, being the predominate etiological agents isolated. Further, with the emergence of methicillin-resistant S. aureus (MRSA, treatment of S. aureus implant infections has become more difficult, thus representing a devastating complication. Use of local delivery system consisting of S.aureus specific phage along with linezolid (incorporated in biopolymer allowing gradual release of the two agents at the implant site represents a new, still unexplored treatment option (against orthopaedic implant infections that has been studied in an animal model of prosthetic joint infection. Naked wire, hydroxypropyl methylcellulose (HPMC coated wire and phage and /or linezolid coated K-wire were surgically implanted into the intra-medullary canal of mouse femur bone of respective groups followed by inoculation of S.aureus ATCC 43300(MRSA. Mice implanted with K-wire coated with both the agents i.e phage as well as linezolid (dual coated wires showed maximum reduction in bacterial adherence, associated inflammation of the joint as well as faster resumption of locomotion and motor function of the limb. Also, all the coating treatments showed no emergence of resistant mutants. Use of dual coated implants incorporating lytic phage (capable of self-multiplication as well as linezolid presents an attractive and aggressive early approach in preventing as well as treating implant associated infections caused by methicillin resistant S. aureus strains as assessed in a murine model of experimental joint infection.

Molecular Characterization of Reduced Susceptibility to Biocides in Clinical Isolates of Acinetobacter baumannii

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Fei Lin

2017-09-01

Full Text Available Active efflux is regarded as a common mechanism for antibiotic and biocide resistance. However, the role of many drug efflux pumps in biocide resistance in Acinetobacter baumannii remains unknown. Using biocide-resistant A. baumannii clinical isolates, we investigated the incidence of 11 known/putative antimicrobial resistance efflux pump genes (adeB, adeG, adeJ, adeT1, adeT2, amvA, abeD, abeM, qacE, qacEΔ1, and aceI and triclosan target gene fabI through PCR and DNA sequencing. Reverse transcriptase quantitative PCR was conducted to assess the correlation between the efflux pump gene expression and the reduced susceptibility to triclosan or chlorhexidine. The A. baumannii isolates displayed high levels of reduced susceptibility to triclosan, chlorhexidine, benzalkonium, hydrogen peroxide, and ethanol. Most tested isolates were resistant to multiple antibiotics. Efflux resistance genes were widely distributed and generally expressed in A. baumannii. Although no clear relation was established between efflux pump gene expression and antibiotic resistance or reduced biocide susceptibility, triclosan non-susceptible isolates displayed relatively increased expression of adeB and adeJ whereas chlorhexidine non-susceptible isolates had increased abeM and fabI gene expression. Increased expression of adeJ and abeM was also demonstrated in multiple antibiotic resistant isolates. Exposure of isolates to subinhibitory concentrations of triclosan or chlorhexidine induced gene expression of adeB, adeG, adeJ and fabI, and adeB, respectively. A point mutation in FabI, Gly95Ser, was observed in only one triclosan-resistant isolate. Multiple sequence types with the major clone complex, CC92, were identified in high level triclosan-resistant isolates. Overall, this study showed the high prevalence of antibiotic and biocide resistance as well as the complexity of intertwined resistance mechanisms in clinical isolates of A. baumannii, which highlights the

Clinical Validation of the Analysis of Linezolid and Clarithromycin in Oral Fluid of Patients with Multidrug-Resistant Tuberculosis

NARCIS (Netherlands)

Bolhuis, M. S.; van Altena, R.; van Hateren, K.; de Lange, W. C. M.; Greijdanus, B.; Uges, D. R. A.; Kosterink, J. G. W.; van der Werf, T. S.; Alffenaar, J. W. C.

Linezolid plays an increasingly important role in the treatment of multidrug-resistant tuberculosis (MDR-TB). However, patients should be carefully monitored due to time-and dose-dependent toxicity. Clarithromycin plays a more modest role. Therapeutic drug monitoring may contribute to assessment of

Comparison of vancomycin and linezolid in patients with peripheral vascular disease and/or diabetes in an observational European study of complicated skin and soft-tissue infections due to methicillin-resistant Staphylococcus aureus.

Science.gov (United States)

Eckmann, C; Nathwani, D; Lawson, W; Corman, S; Solem, C; Stephens, J; Macahilig, C; Li, J; Charbonneau, C; Baillon-Plot, N; Haider, S

2015-09-01

Suboptimal antibiotic penetration into soft tissues can occur in patients with poor circulation due to peripheral vascular disease (PVD) or diabetes. We conducted a real-world analysis of antibiotic treatment, hospital resource use and clinical outcomes in patients with PVD and/or diabetes receiving linezolid or vancomycin for the treatment of methicillin-resistant Staphylococcus aureus complicated skin and soft-tissue infections (MRSA cSSTIs) across Europe. This subgroup analysis evaluated data obtained from a retrospective, observational medical chart review study that captured patient data from 12 European countries. Data were obtained from the medical records of patients ≥ 18 years of age, hospitalized with an MRSA cSSTI between 1 July 2010 and 30 June 2011 and discharged alive by 31 July 2011. Hospital length of stay and length of treatment were compared between the treatment groups using inverse probability of treatment weights to adjust for clinical and demographic differences. A total of 485 patients had PVD or diabetes and received treatment with either vancomycin (n = 258) or linezolid (n = 227). After adjustment, patients treated with linezolid compared with vancomycin respectively had significantly shorter hospital stays (17.9 ± 13.6 vs. 22.6 ± 13.6 days; p linezolid and vancomycin groups, respectively (p linezolid compared with vancomycin. Copyright © 2015. Published by Elsevier Ltd.

Comparative effectiveness of linezolid versus vancomycin as definitive antibiotic therapy for heterogeneously resistant vancomycin-intermediate coagulase-negative staphylococcal central-line-associated bloodstream infections in a neonatal intensive care unit.

Science.gov (United States)

Blanchard, A C; Fortin, E; Laferrière, C; Goyer, I; Moussa, A; Autmizguine, J; Quach, C

2017-06-01

Heterogeneously resistant vancomycin-intermediate coagulase-negative staphylococci (hVICoNS) are emerging pathogens causing central-line-associated bloodstream infections (CLABSIs) in neonatal intensive care unit (NICU) patients. Given the burden of disease associated with CLABSI and the current lack of therapeutic guidelines, we aimed to compare the effectiveness of linezolid versus vancomycin used as the definitive antibiotic therapy for hVICoNS CLABSI. We performed a retrospective cohort study of infants with hVICoNS CLABSI from a single NICU between 2009 and 2014, treated with either linezolid or vancomycin as definitive antibiotic therapy. CLABSI duration, early and late recurrence and in-hospital mortality were compared using propensity score-adjusted proportional hazards and logistic regression models. Of 89 infants with hVICoNS CLABSI, 33 (37.1%) treated with linezolid were compared with 56 (62.9%) treated with vancomycin. The median duration of CLABSI was 5 (range 1-12) versus 4 days (range 0-14) ( P  =   0.11), early recurrences were 3.0% versus 7.1% ( P  =   0.42), late recurrences 0% versus 14.3% ( P  =   0.02) and mortality 27.3% versus 28.6% ( P  =   0.90), when treated with linezolid versus vancomycin, respectively. When adjusting using a continuous propensity score, linezolid had an HR of 0.78 (95% CI 0.48-1.27) for CLABSI duration, an OR of 0.23 (95% CI 0.02-2.56) for early recurrence and an OR of 0.9 (95% CI 0.3-2.67) for mortality, relative to vancomycin. There was no statistically significant difference between linezolid and vancomycin when used as definitive treatment for hVICoNS CLABSI in NICU patients, in terms of CLABSI duration, recurrence or all-cause mortality. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Optimization of nebulized delivery of linezolid, daptomycin, and vancomycin aerosol

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Zarogoulidis P

2014-08-01

Full Text Available Paul Zarogoulidis,1 Ioannis Kioumis,1 Sofia Lampaki,1 John Organtzis,1 Konstantinos Porpodis,1 Dionysios Spyratos,1 Georgia Pitsiou,1 Dimitris Petridis,2 Athanasia Pataka,1 Haidong Huang,3 Qiang Li,3 Lonny Yarmus,4 Wolfgang Hohenforst-Schmidt,5 Nikolaos Pezirkianidis,6 Konstantinos Zarogoulidis1 1Pulmonary Department-Oncology Unit, “G Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2Department of Food Technology, School of Food Technology and Nutrition, Alexander Technological Educational Institute, Thessaloniki, Greece; 3Department of Respiratory Diseases, Shanghai Hospital, II Military University Hospital, Shanghai, People’s Republic of China; 4Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA; 5II Medical Department, “Coburg” Regional Hospital, Coburg, Germany; 6Surgery Department, Private Cabinet, Serres, Greece Background: At this time, several antibiotics have been investigated as possibilities for aerosol administration, but local therapy has been found to be more efficient in several diseases. Materials and methods: The drugs linezolid (Zyvox, vancomycin (Voncon, and daptomycin (Cubicin were tested with three jet nebulizers with seven different residual cups and different loadings. Moreover, three ultrasound nebulizers were again tested with these drugs, with different loadings and mouthpiece attachments. Results: When drugs are combined with particular cup designs, they significantly lower the droplet size to 1.60 and 1.80 µm, which represents the best combination of Zyvox and cup G and Cubicin and cup D, respectively. Cup design D is suggested as the most effective cup for lowering the droplet size (2.30 µm when considering a higher loading level (8 mL. Conclusion: Modification of current drugs from dry powder to solution is possible, and the residual cup design plays the most important role in droplet size production when the

Virulence-suppressing effects of linezolid on methicillin-resistant Staphylococcus aureus: possible contribution to early defervescence.

Science.gov (United States)

Yoshizawa, Sadako; Tateda, Kazuhiro; Saga, Tomoo; Ishii, Yoshikazu; Yamaguchi, Keizo

2012-04-01

In the present study, immunomodulatory effects of linezolid (LZD) on methicillin-resistance Staphylococcus aureus (MRSA) infections were evaluated. We have retrospectively reviewed treatment effects of LZD on 52 patients with severe MRSA infections. Sixty-four percent of the febrile patients demonstrated significant defervescence within 3 days, despite the presence of positive culture results. We speculated that this finding might be due to early anti-inflammatory effects of LZD, and to investigate this further we initiated in vivo experiments using mice MRSA pneumonia models. Mice were treated with either LZD or vancomycin (VCM) immediately after intranasal administration of MRSA. Bacterial numbers and levels of inflammatory cytokines in the lungs were determined. Although the bacterial burden in the lungs was not apparently different between the two groups, LZD but not VCM treatment significantly reduced induction of inflammatory cytokines in the lungs (P endogenous pyrogens. These data may explain at least in part early defervescence observed in LZD-treated individuals.

The effect of diabetes mellitus on outcomes of patients with nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus: data from a prospective double-blind clinical trial comparing treatment with linezolid versus vancomycin.

Science.gov (United States)

Equils, Ozlem; da Costa, Christopher; Wible, Michele; Lipsky, Benjamin A

2016-09-06

The presence of diabetes mellitus increases the risk of several severe infections, but data on its effect on treatment outcomes in patients with nosocomial pneumonia (NP) caused by methicillin-resistant Staphylococcus aureus (MRSA) are limited. We retrospectively analyzed data from a double-blind, randomized, multi-center, international clinical trial of culture-confirmed MRSA NP that compared treatment with linezolid to vancomycin. Specifically, we evaluated the clinical and microbiologic outcomes of patients with and without diabetes in the modified intent to treat population at end-of-treatment (EOT) and end-of-study (EOS, 7-30 days post-EOT). Among 448 enrolled patients 183 (40.8 %) had diabetes mellitus, 87 (47.5 %) of whom received linezolid and 96 (52.5 %) vancomycin. Baseline demographic and clinical characteristics were similar for the two treatment groups. Clinical success rates at EOS were 57.6 % with linezolid and 39.3 % with vancomycin, while microbiological success rates were 58.9 % with linezolid and 41.1 % with vancomycin. Among diabetic patients, rates of mortality and study drug-related adverse effects were similar between the treatment groups. Overall day 28 mortality rates were higher among diabetic patients compared to non-diabetic patients (23.5 vs 14.7 %, respectively: RD = 8.8 %, 95 % CI [1.4, 16.3]). Among diabetic patients with MRSA NP, treatment with linezolid, compared to vancomycin, was associated with higher clinical and microbiologic success rates, and comparable adverse event rates. NCT00084266 .

Efficacy of linezolid compared to vancomycin in an experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus in ventilated pigs.

Science.gov (United States)

Martinez-Olondris, Pilar; Rigol, Montserrat; Soy, Dolors; Guerrero, Laura; Agusti, Carlos; Quera, Maria Angels; Li Bassi, Gianluigi; Esperatti, Mariano; Luque, Nestor; Liapikou, Manto; Filella, Xavier; Marco, Francesc; de la Bellacasa, Jordi Puig; Torres, Antoni

2012-01-01

To assess the efficacy of linezolid compared with vancomycin in an experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus (MRSA) in ventilated pigs. Forty pigs (30 kg) were intubated and challenged via bronchoscopy with a suspension of 106 colony forming units of MRSA into every lobe. Afterwards, pigs were ventilated up to 96 hours. Twelve hours after bacterial inoculation, the animals were randomized into 4 groups of treatment: group 1, control; group 2, vancomycin twice daily; group 3, continuous infusion of vancomycin; and group 4, linezolid. Clinical and laboratory parameters were monitored throughout the study. Bacterial cultures of bronchoalveolar lavage fluid and lung tissue samples were performed at the end of the study. Measurements of histopathology derangements of lung samples and studies of intrapulmonary drug penetration were performed. A total of 34 animals completed the study. No differences in clinical and laboratory parameters were observed. The percentage of bronchoalveolar lavage fluid and lung tissue samples with positive cultures for MRSA in controls and groups 2, 3, and 4 was respectively 75%, 11%, 11%, and 0% (p pneumonia in 95%, 69%, 58%, and 57% and signs of severe pneumonia in 48%, 29%, 22%, and 0% of controls and groups 2, 3, and 4, respectively (p treatments. In this animal model of MRSA pneumonia, linezolid showed a better efficacy than vancomycin showed because of a better pharmacokinetics/pharmacodynamics index.

Effect of Linezolid on the 50% Lethal Dose and 50% Protective Dose in Treatment of Infections by Gram-Negative Pathogens in Naive and Immunosuppressed Mice and on the Efficacy of Ciprofloxacin in an Acute Murine Model of Septicemia

Science.gov (United States)

Marra, Andrea; Lamb, Lucinda; Medina, Ivette; George, David; Gibson, Glenn; Hardink, Joel; Rugg, Jady; Van Deusen, Jeffrey

2012-01-01

Murine models of infection were used to study the effect of linezolid on the virulence of Gram-negative bacteria and to assess potential pharmacodynamic interactions with ciprofloxacin in the treatment of these infections, prompted by observations from a recent clinical trial. Naive and immunosuppressed mice were challenged with Klebsiella pneumoniae 53A1109, K. pneumoniae GC6658, and Pseudomonas aeruginosa UC12120 in acute sepsis and pulmonary infection models, using different serial dilutions of these pathogens (groups of 8 animals each). Linezolid (100 mg/kg/dose) was administered orally at 0.5 and 4.0 h postchallenge in the sepsis model and at 4 h postchallenge followed by 2 days of twice-daily treatment in the pulmonary model. Further, ciprofloxacin alone and in combination with oral linezolid was investigated in the sepsis model. Survival was assessed for 4 and 10 days postchallenge in the systemic and respiratory models, respectively. The data were fitted to a nonlinear regression analysis to determine 50% lethal doses (LD50s) and 50% protective doses (PD50s). A clinically relevant, high-dose regimen of linezolid had no significant effect on LD50 in these models. This lack of effect was independent of immune status. A combination of oral ciprofloxacin with linezolid yielded lower PD50s than oral ciprofloxacin alone (ciprofloxacin in combination, 8.4 to 32.7 mg/kg; oral ciprofloxacin, 39.4 to 88.3 mg/kg). Linezolid did not improve the efficacy of subcutaneous ciprofloxacin (ciprofloxacin in combination, 2.0 to 2.4 mg/kg; subcutaneous ciprofloxacin, 2.0 to 2.8 mg/kg). In conclusion, linezolid does not seem to potentiate infections caused by Gram-negative pathogens or to interact antagonistically with ciprofloxacin. PMID:22710118

Comparison of the pharmacokinetics of two dosage regimens of linezolid in multidrug-resistant and extensively drug-resistant tuberculosis patients.

NARCIS (Netherlands)

Alffenaar, J.W.C.; Altena, R. van; Harmelink, I.M.; Filguera, P.; Molenaar, E.; Wessels, A.M.; Soolingen, D. van; Kosterink, J.G.W.; Uges, D.R.A.; Werf, T.S. van der

2010-01-01

BACKGROUND AND OBJECTIVES: For the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), potent new drugs are urgently needed. Linezolid is a promising drug, but its use is limited by adverse effects with prolonged administration of 600 mg twice daily. In

Comparison of the Pharmacokinetics of Two Dosage Regimens of Linezolid in Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis Patients

NARCIS (Netherlands)

Alffenaar, Jan-Willem C.; van Altena, Richard; Harmelink, Ilse M.; Filguera, Patricia; Molenaar, Esther; Wessels, A. Mireille A.; van Soolingen, Dick; Kosterink, Jos G. W.; Uges, Donald R. A.; van der Werf, Tjip S.

2010-01-01

Background and Objectives: For the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), potent new drugs are urgently needed. Linezolid is a promising drug, but its use is limited by adverse effects with prolonged administration of 600 mg twice daily. In

Detection of Reduced Susceptibility to Chlorfenapyr- and Bifenthrin-Containing Products in Field Populations of the Bed Bug (Hemiptera: Cimicidae).

Science.gov (United States)

Ashbrook, Aaron R; Scharf, Michael E; Bennett, Gary W; Gondhalekar, Ameya D

2017-06-01

Insecticide resistance is a major impediment for effective control of Cimex lectularius L. Previous resistance detection studies with bed bugs have focused on certain pyrethroid, neonicotinoid, organochlorine, organophosphate, and carbamate insecticides. Within the pyrethroid class, resistance studies have mostly been limited to deltamethrin, lambda-cyhalothrin, and alpha- and beta-cyfluthrin. The goal of this study was to develop diagnostic concentration bioassays for assessing bed bug susceptibility levels to chlorfenapyr- and bifenthrin-containing products. First, glass vial and filter paper bioassay methods were compared for their utility in susceptibility monitoring. Statistical comparison of toxicity data between bioassays indicated that the vial assay was less confounded by assay susbtrate effects, required less insecticide, and was faster, especially for chlorfenapyr. Next, using vial diagnostic concentrations (LC99) for each insecticide, 10 laboratory-adapted field strains and the Harlan lab-susceptible strain were screened for susceptibility to chlorfenapyr and bifenthrin. The results of this study reveal recent bed bug susceptibility levels to certain chlorfenapyr- and bifenthrin-containing products. Reduced susceptibility was detected in three and five field strains to chlorfenapyr and bifenthrin, respectively. Detection of reduced susceptibility suggests that certain strains may be segregating toward greater chlorfenapyr and bifenthrin resistance. These results merit continuous resistance monitoring efforts to detect chlorfenapyr and bifenthrin susceptibility shifts. Additionally, to reduce insecticide selection pressures and delay resistance development, adoption of integrated bed bug control strategies that combine chemical and nonchemical methods is recommended. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Analysis of gyrA and parC mutations in enterococci from environmental samples with reduced susceptibility to ciprofloxacin

DEFF Research Database (Denmark)

Petersen, A.; Jensen, Lars Bogø

2004-01-01

The quinolone resistance determining regions of gyrA and parC in four species of enterococci from environmental samples with reduced susceptibility to ciprofloxacin were sequenced. The nucleotide sequence variations of parC could be related to the different enterococcal species. Mutations...... in Enterococcus faecalis and Enterococcus faecium related to reduced susceptibility were identical to mutations detected in E jaecalis and E. faecium of clinical origin. A minimal inhibitory concentration of 8 mug ml(-1) to ciprofloxacin was not associated with any mutations in the gyrA and parC gene...... of Enterococcus casseliflavus and Enterococcus gallinarum. These two species may be intrinsically less susceptible to ciprofloxacin....

Smart Methods for Linezolid Determination in the Presence of Alkaline and Oxidative Degradation Products Utilizing Their Overlapped Spectral Bands

Science.gov (United States)

Abd El-Monem Hegazy, M.; Shaaban Eissa, M.; Abd El-Sattar, O. I.; Abd El-Kawy, M. M.

2014-09-01

Linezolid (LIN) is considered the first available oxazolidinone antibacterial agent. It is susceptible to hydrolysis and oxidation. Five simple, accurate, sensitive and validated UV spectrophotometric methods were developed for LIN determination in the presence of its alkaline (ALK) and oxidative (OXD) degradation products in bulk powder and pharmaceutical formulation. Method A is a second derivative one (D2) in which LIN is determined at 240.9 nm. Method B is a pH-induced differential derivative one where LIN is determined using the fourth derivative (D4) of the difference spectra (ΔA) at 285.3 nm. Methods C, D, and E are manipulating ratio spectra, where C is the double divisor-ratio difference spectrophotometric one (DD-RD) in which LIN was determined by calculating the amplitude difference at 243.7 and 267.6 nm of the ratio spectra. Method D is the double divisor-first derivative of ratio spectra (DD-DD1) in which LIN was determined at 270.2 nm. Method E is a mean centering of ratio spectra one (MCR) in which LIN was determined at 318.0 nm. The developed methods have been validated according to ICH guidelines. The results were statistically compared to that of a reported HPLC method and there was no significant difference regarding both accuracy and precision.

Emergence and dissemination of a linezolid-resistant Staphylococcus capitis clone in Europe.

Science.gov (United States)

Butin, M; Martins-Simões, P; Pichon, B; Leyssene, D; Bordes-Couecou, S; Meugnier, H; Rouard, C; Lemaitre, N; Schramm, F; Kearns, A; Spiliopoulou, I; Hyyryläinen, H-L; Dumitrescu, O; Vandenesch, F; Dupieux, C; Laurent, F

2017-04-01

We investigated the epidemiological, clinical, microbiological and genetic characteristics of linezolid-resistant (LZR) Staphylococcus capitis isolates from French ICUs, and compared them with LZR S. capitis isolates from other European countries. All LZR isolates were subjected to antimicrobial susceptibility testing (AST) and the presence of cfr and optrA genes as well as mutations in the 23S rRNA and ribosomal proteins were investigated using specific PCR with sequencing. The genetic relationship between isolates was investigated using PFGE and WGS. Epidemiological data concerning LZR S. capitis were collected retrospectively in French microbiology laboratories. Twenty-one LZR isolates were studied: 9 from France, 11 from Greece and 1 from Finland. All were resistant to methicillin and aminoglycosides. In addition, this unusual AST profile was identified in S. capitis isolates from seven French hospitals, and represented up to 12% of the S. capitis isolates in one centre. A G2576T mutation in 23S rRNA was identified in all isolates; cfr and optrA genes were absent. All isolates belonged to the same clone on the basis of their PFGE profiles, whatever their geographical origin. WGS found at most 212 SNPs between core genomes of the LZR isolates. We identified and characterized an LZR S. capitis clone disseminated in three European countries, harbouring the same multiple resistance and a G2576T mutation in the 23S rRNA. The possible unrecognized wider distribution of this clone, belonging to a species classically regarded as a low-virulence skin colonizer, is of major concern not least because of the increasing use of oxazolidinones. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Aging increases the susceptibility to motor memory interference and reduces off-line gains in motor skill learning

DEFF Research Database (Denmark)

Roig, Marc; Ritterband-Rosenbaum, Anina; Jensen, Jesper Lundbye

2014-01-01

Declines in the ability to learn motor skills in older adults are commonly attributed to deficits in the encoding of sensorimotor information during motor practice. We investigated whether aging also impairs motor memory consolidation by assessing the susceptibility to memory interference and off...... greater susceptibility to memory interference and no off-line gains in motor skill learning. Performing B produced memory interference and reduced off-line gains only in the older group. However, older adults also showed deficits in memory consolidation independent of the interfering effects of B. Age......-related declines in motor skill learning are not produced exclusively by deficits in the encoding of sensorimotor information during practice. Aging also increases the susceptibility to memory interference and reduces off-line gains in motor skill learning after practice....

The Use of Linezolid in Children with Malignant Solid Tumors

Directory of Open Access Journals (Sweden)

H.I. Klymniuk

2015-09-01

Full Text Available In recent decades, in the treatment of cancer there has been achieved a significant success not only by the introduction of cancer treatment protocol, but mostly due to the planned combination concomitant treatment of infectious complications. The need for antimicrobial agents against resistant Gram-positive bacteria, such as methicillin-resistant staphylococci, penicillin-resistant pneumococci, vancomycin-resistant enterococci, has significantly increased. In the department of pediatric oncology of the National cancer institute (Kyiv, linezolid preparations were used in children with infection of soft tissues and bones, febrile neutropenia and for the treatment of severe cases of sepsis. Experience of Linelid® use in the department of pediatric oncology of the National cancer institute indicates its effectiveness, safety and good tolerance in children with malignant solid tumors.

Loading of atorvastatin and linezolid in β-cyclodextrin–conjugated cadmium selenide/silica nanoparticles: A spectroscopic study

Energy Technology Data Exchange (ETDEWEB)

Antony, Eva Janet; Shibu, Abhishek [Department of Nanosciences & Technology, Karunya University, Coimbatore 641114, Tamil Nadu (India); Ramasamy, Sivaraj; Paulraj, Mosae Selvakumar [Department of Chemistry, Karunya University, Coimbatore 641114, Tamil Nadu (India); Enoch, Israel V.M.V., E-mail: drisraelenoch@gmail.com [Department of Nanosciences & Technology, Karunya University, Coimbatore 641114, Tamil Nadu (India); Department of Chemistry, Karunya University, Coimbatore 641114, Tamil Nadu (India)

2016-08-01

The preparation of β–cyclodextrin–conjugated cadmium selenide–silica nanoparticles, the loading of two drugs viz., Atorvastatin and linezolid in the cyclodextrin cavity, and the fluorescence energy transfer between CdSe/SiO{sub 2} nanoparticles and the drugs encapsulated in the cyclodextrin cavity are reported in this paper. IR spectroscopy, X-ray diffractometry, transmission electron microscopy, and particle size analysis by light–scattering experiment were used as the tools of characterizing the size and the crystal system of the nanoparticles. The nanoparticles fall under hexagonal system. The silica–shell containing CdSe nanoparticles were functionalized by reaction with aminoethylamino–β–cyclodextrin. Fluorescence spectra of the nanoparticles in their free and drug–encapsulated forms were studied. The FÖrster distances between the encapsulated drugs and the CdSe nanoparticles are below 3 nm. The change in the FÖrster resonance energy parameters under physiological conditions may aid in tracking the release of drugs from the cavity of the cyclodextrin. - Highlights: • CdSe/SiO{sub 2} nanoparticles of crystallite size 15 nm are prepared. • β-Cyclodextrin is attached to the surface of the nanoparticles. • Atorvastatin and linezolid get encapsulated in the cyclodextrin cavity. • FRET efficiency between the nanoparticles and the loaded drugs are determined.

Loading of atorvastatin and linezolid in β-cyclodextrin–conjugated cadmium selenide/silica nanoparticles: A spectroscopic study

International Nuclear Information System (INIS)

Antony, Eva Janet; Shibu, Abhishek; Ramasamy, Sivaraj; Paulraj, Mosae Selvakumar; Enoch, Israel V.M.V.

2016-01-01

The preparation of β–cyclodextrin–conjugated cadmium selenide–silica nanoparticles, the loading of two drugs viz., Atorvastatin and linezolid in the cyclodextrin cavity, and the fluorescence energy transfer between CdSe/SiO_2 nanoparticles and the drugs encapsulated in the cyclodextrin cavity are reported in this paper. IR spectroscopy, X-ray diffractometry, transmission electron microscopy, and particle size analysis by light–scattering experiment were used as the tools of characterizing the size and the crystal system of the nanoparticles. The nanoparticles fall under hexagonal system. The silica–shell containing CdSe nanoparticles were functionalized by reaction with aminoethylamino–β–cyclodextrin. Fluorescence spectra of the nanoparticles in their free and drug–encapsulated forms were studied. The FÖrster distances between the encapsulated drugs and the CdSe nanoparticles are below 3 nm. The change in the FÖrster resonance energy parameters under physiological conditions may aid in tracking the release of drugs from the cavity of the cyclodextrin. - Highlights: • CdSe/SiO_2 nanoparticles of crystallite size 15 nm are prepared. • β-Cyclodextrin is attached to the surface of the nanoparticles. • Atorvastatin and linezolid get encapsulated in the cyclodextrin cavity. • FRET efficiency between the nanoparticles and the loaded drugs are determined.

Clinical Determinants of Target Non-Attainment of Linezolid in Plasma and Interstitial Space Fluid: A Pooled Population Pharmacokinetic Analysis with Focus on Critically Ill Patients.

Science.gov (United States)

Minichmayr, Iris K; Schaeftlein, André; Kuti, Joseph L; Zeitlinger, Markus; Kloft, Charlotte

2017-06-01

We aimed to assess linezolid pharmacokinetics in the plasma and interstitial space fluid (ISF) of patients with sepsis, diabetic foot infections or cystic fibrosis and healthy volunteers. The impacts of joint characteristics and disease on plasma and target-site exposure were to be identified together with the benefit of dose intensification in critically ill patients. Rich plasma (n = 1598) and ISF concentrations in subcutaneous adipose (n = 1430) and muscle tissue (n = 1089) measured by microdialysis were pooled from three clinical trials with 51 individuals receiving 600 mg of intravenous and oral linezolid. All data were analysed simultaneously by a population approach also considering methodological aspects of microdialysis. The impact of covariates on the attainment of the pharmacokinetic/pharmacodynamic targets, AUC/MIC = 100 (area under the concentration-time curve/minimum inhibitory concentration) and fT >MIC  = 99 % (time that unbound concentrations exceed the MIC), was assessed by deterministic and Monte Carlo simulations. A two-compartment pharmacokinetic model with nonlinear elimination and tissue distribution factors accounting for differences between plasma and ISF concentrations adequately predicted all measurements. Clearance (CL) was highest in septic patients (11.2 L/h vs. CL Healthy /CL Cystic fibrosis /CL Diabetic  = 7.67/6.87/6.35 L/h). Penetration into subcutaneous adipose ISF was lowest in diabetic patients (-34.9 % compared with healthy volunteers). Creatinine clearance and total body weight further impacted linezolid exposure. To achieve timely efficacious therapy, front-loaded dosing and continuous infusion seemed beneficial in septic patients. Our analysis suggests that after standard linezolid doses, particularly patients with sepsis and conserved renal function are at risk of not attaining pharmacokinetic/pharmacodynamic targets and would benefit from initial dose intensification.

Pathogens causing blood stream infections and their drug susceptibility profile in immunocompromised patients.

Science.gov (United States)

Fayyaz, Muhammad; Mirza, Irfan Ali; Ikram, Aamer; Hussain, Aamir; Ghafoor, Tahir; Shujat, Umer

2013-12-01

To determine the types of pathogens causing blood stream infections and their drug susceptibility profile in immunocompromised patients. Cross-sectional, observational study. Department of Microbiology, Armed Forces Institute of Pathology, Rawalpindi, from January to September 2012. Blood culture bottles received from immunocompromised patients were dealt by two methods, brain heart infusion (BHI) broth based manual method and automated BACTEC system. The samples yielding positive growth from either of two methods were further analyzed. The identification of isolates was done with the help of biochemical reactions and rapid tests. Antimicrobial susceptibility of the isolates was carried out as per recommendations of Clinical and Laboratory Standards Institute (CLSI). Out of the 938 blood culture specimens received from immunocompromised patients, 188 (20%) yielded positive growth. Out of these, 89 (47.3%) isolates were Gram positive and Gram negative each, while 10 (5.3%) isolates were fungi (Candida spp.). In case of Gram positive isolates, 75 (84.3%) were Staphylococcus spp. and 51 (67%) were Methicillin resistant. Amongst Gram negative group 49 (55.1%) isolates were of enterobacteriaceae family, while 40 (44.9%) were non-lactose fermenters (NLF). In vitro antimicrobial susceptibility of Staphylococci revealed 100% susceptibility to vancomycin and linezolid. The enterobacteriaceae isolates had better susceptibility against amikacin 85.7% compared to tigecycline 61.2% and imipenem 59.2%. For NLF, the in vitro efficacy of aminoglycosides was 72.5%. The frequency of Gram positive and Gram negative organisms causing blood stream infections in immunocompromised patients was equal. Vancomycin in case of Gram positive and amikacin for Gram negative organisms revealed better in vitro efficacy as compared to other antibiotics.

Pathogens Causing Blood Stream Infections and their Drug Susceptibility Profile in Immunocompromised Patients

International Nuclear Information System (INIS)

Fayyaz, M.; Mirza, I.A.; Ikram, A.; Hussain, A.; Ghafoor, T.; Shujat, U.

2013-01-01

Objective: To determine the types of pathogens causing blood stream infections and their drug susceptibility profile in immunocompromised patients. Study Design: Cross-sectional, observational study. Place and Duration of Study: Department of Microbiology, Armed Forces Institute of Pathology, Rawalpindi, from January to September 2012. Methodology: Blood culture bottles received from immunocompromised patients were dealt by two methods, brain heart infusion (BHI) broth based manual method and automated BACTEC system. The samples yielding positive growth from either of two methods were further analyzed. The identification of isolates was done with the help of biochemical reactions and rapid tests. Antimicrobial susceptibility of the isolates was carried out as per recommendations of Clinical and Laboratory Standards Institute (CLSI). Results: Out of the 938 blood culture specimens received from immunocompromised patients, 188 (20%) yielded positive growth. Out of these, 89 (47.3%) isolates were Gram positive and Gram negative each, while 10 (5.3%) isolates were fungi (Candida spp.). In case of Gram positive isolates, 75 (84.3%) were Staphylococcus spp. and 51 (67%) were Methicillin resistant. Amongst Gram negative group 49 (55.1%) isolates were of enterobacteriaceae family, while 40 (44.9%) were non-lactose fermenters (NLF). In vitro antimicrobial susceptibility of Staphylococci revealed 100% susceptibility to vancomycin and linezolid. The enterobacteriaceae isolates had better susceptibility against amikacin 85.7% compared to tigecycline 61.2% and imipenem 59.2%. For NLF, the in vitro efficacy of aminoglycosides was 72.5%. Conclusion: The frequency of Gram positive and Gram negative organisms causing blood stream infections in immunocompromised patients was equal. Vancomycin in case of Gram positive and amikacin for Gram negative organisms revealed better in vitro efficacy as compared to other antibiotics. (author)

Spatial Clustering of Escherichia coli with Reduced Susceptibility to Cefotaxime and Ciprofloxacin among Dairy Cattle Farms Relative to European Starling Night Roosts.

Science.gov (United States)

Medhanie, G A; Pearl, D L; McEwen, S A; Guerin, M T; Jardine, C M; Schrock, J; LeJeune, J T

2017-05-01

European starlings (Sturnus vulgaris) have been implicated in the dispersal of zoonotic enteric pathogens. However, their role in disseminating antimicrobial-resistant organisms through their home range has not been clearly established. The aim of this study was to determine whether starling night roosts served as foci for spreading organisms with reduced susceptibility to antimicrobials among dairy cattle farms. Bovine faecal pats were collected from 150 dairy farms in Ohio. Each farm was visited twice (in summer and fall) between 2007 and 2009. A total of 1490 samples (10 samples/farm over two visits) were tested for Escherichia coli with reduced susceptibility to cefotaxime and ciprofloxacin. Using a spatial scan statistic, focal scans were conducted to determine whether clusters of farms with a high prevalence of organisms with reduced susceptibility to cefotaxime and ciprofloxacin surrounded starling night roosts. Faecal pats 13.42% and 13.56% of samples carried Escherichia coli with reduced susceptibility to cefotaxime and ciprofloxacin, respectively. Statistically significant (P Escherichia coli showing reduced susceptibility to cefotaxime and ciprofloxacin were identified around these night roosts. This finding suggests that the risk of carriage of organisms with reduced susceptibility to antimicrobials in cattle closer to starling night roosts was higher compared to cattle located on farms further from these sites. Starlings might have an important role in spreading antimicrobial-resistant E. coli to livestock environments, thus posing a threat to animal and public health. © 2016 Blackwell Verlag GmbH.

Density functional theory, comparative vibrational spectroscopic studies, highest occupied molecular orbital and lowest unoccupied molecular orbital analysis of Linezolid

Science.gov (United States)

Rajalakshmi, K.; Gunasekaran, S.; Kumaresan, S.

2015-06-01

The Fourier transform infrared spectra and Fourier transform Raman spectra of Linezolid have been recorded in the regions 4,000-400 and 4,000-100 cm-1, respectively. Utilizing the observed Fourier transform infrared spectra and Fourier transform Raman spectra data, a complete vibrational assignment and analysis of the fundamental modes of the compound have been carried out. The optimum molecular geometry, harmonic vibrational frequencies, infrared intensities and Raman scattering activities, have been calculated by density functional theory with 6-31G(d,p), 6-311G(d,p) and M06-2X/6-31G(d,p) levels. The difference between the observed and scaled wavenumber values of most of the fundamentals is very small. A detailed interpretation of the infrared and Raman spectra of Linezolid is reported. Mulliken's net charges have also been calculated. Ultraviolet-visible spectrum of the title molecule has also been calculated using time-dependent density functional method. Besides, molecular electrostatic potential, highest occupied molecular orbital and lowest unoccupied molecular orbital analysis and several thermodynamic properties have been performed by the density functional theoretical method.

The inactivation of RNase G reduces the Stenotrophomonas maltophilia susceptibility to quinolones by triggering the heat shock response.

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Alejandra eBernardini

2015-10-01

Full Text Available Quinolone resistance is usually due to mutations in the genes encoding bacterial topoisomerases. However different reports have shown that neither clinical quinolone resistant isolates nor in vitro obtained S. maltophilia mutants present mutations in such genes. The mechanisms so far described consist on efflux pumps' overexpression. Our objective is to get information on novel mechanisms of S. maltophilia quinolone resistance. For this purpose, a transposon-insertion mutant library was obtained in S. maltophilia D457.. One mutant presenting reduced susceptibility to nalidixic acid was selected. Inverse PCR showed that the inactivated gene encodes RNase G. Complementation of the mutant with wild-type RNase G allele restored the susceptibility to quinolones. Transcriptomic and real-time RT-PCR analyses showed that several genes encoding heat-shock response proteins were expressed at higher levels in the RNase defective mutant than in the wild-type strain. In agreement with this situation, heat-shock reduces the S. maltophilia susceptibility to quinolone. We can then conclude that the inactivation of the RNase G reduces the susceptibility of S. maltophilia to quinolones, most likely by regulating the expression of heat-shock response genes. Heat-shock induces a transient phenotype of quinolone resistance in S. maltophilia.

Reduced intrinsic heart rate is associated with reduced arrhythmic susceptibility in guinea-pig heart.

Science.gov (United States)

Osadchii, Oleg E

2014-12-01

In the clinical setting, patients with slower resting heart rate are less prone to cardiovascular death compared with those with elevated heart rate. However, electrophysiological adaptations associated with reduced cardiac rhythm have not been thoroughly explored. In this study, relationships between intrinsic heart rate and arrhythmic susceptibility were examined by assessments of action potential duration (APD) rate adaptation and inducibility of repolarization alternans in sinoatrial node (SAN)-driven and atrioventricular (AV)-blocked guinea-pig hearts perfused with Langendorff apparatus. Electrocardiograms, epicardial monophasic action potentials, and effective refractory periods (ERP) were assessed in normokalemic and hypokalemic conditions. Slower basal heart rate in AV-blocked hearts was associated with prolonged ventricular repolarization during spontaneous beating, and with attenuated APD shortening at increased cardiac activation rates during dynamic pacing, when compared with SAN-driven hearts. During hypokalemic perfusion, the inducibility of repolarization alternans and tachyarrhythmia by rapid pacing was found to be lower in AV-blocked hearts. This difference was ascribed to prolonged ERP in the setting of reduced basal heart rate, which prevented ventricular capture at critically short pacing intervals required to induce arrhythmia. Reduced basal heart rate is associated with electrophysiological changes that prevent electrical instability upon an abrupt cardiac acceleration.

Recommendations to address the difficulties encountered when determining linezolid resistance from whole genome sequencing data.

Science.gov (United States)

Beukers, Alicia G; Hasman, Henrik; Hegstad, Kristin; van Hal, Sebastiaan J

2018-05-29

Mutations associated with linezolid resistance within the V domain of 23S rRNA are annotated using an Escherichia coli numbering system. The 23S rRNA gene varies in length, nucleotide sequence and copy number between bacterial species. Consequently, this numbering system is not intuitive and can lead to confusion when locating mutation sites using whole genome sequencing data. Using the mutation G2576T as an example, we demonstrate the difficulties associated with using the E. coli numbering system. © Crown copyright 2018.

Reduced Susceptibility to Rifampicin and Resistance to Multiple Antimicrobial Agents among Brucella abortus Isolates from Cattle in Brazil.

Science.gov (United States)

Barbosa Pauletti, Rebeca; Reinato Stynen, Ana Paula; Pinto da Silva Mol, Juliana; Seles Dorneles, Elaine Maria; Alves, Telma Maria; de Sousa Moura Souto, Monalisa; Minharro, Silvia; Heinemann, Marcos Bryan; Lage, Andrey Pereira

2015-01-01

This study aimed to determine the susceptibility profile of Brazilian Brucella abortus isolates from cattle to eight antimicrobial agents that are recommended for the treatment of human brucellosis and to correlate the susceptibility patterns with origin, biotype and MLVA16-genotype of the strains. Screening of 147 B. abortus strains showed 100% sensitivity to doxycycline and ofloxacin, one (0.68%) strain resistant to ciprofloxacin, two strains (1.36%) resistant to streptomycin, two strains (1.36%) resistant to trimethoprim-sulfamethoxazole and five strains (3.40%) resistant to gentamicin. For rifampicin, three strains (2.04%) were resistant and 54 strains (36.73%) showed reduced sensitivity. Two strains were considered multidrug resistant. In conclusion, the majority of B. abortus strains isolated from cattle in Brazil were sensitive to the antimicrobials commonly used for the treatment of human brucellosis; however, a considerable proportion of strains showed reduced susceptibility to rifampicin and two strains were considered multidrug resistant. Moreover, there was no correlation among the drug susceptibility pattern, origin, biotype and MLVA16-genotypes of these strains.

Combined Effect of the Cfr Methyltransferase and Ribosomal Protein L3 Mutations on Resistance to Ribosome-Targeting Antibiotics

DEFF Research Database (Denmark)

Pakula, Kevin K; Hansen, Lykke H; Vester, Birte

2017-01-01

. The presence of Cfr has a very minor influence on the growth rate. The resistance of the transformants to linezolid, tiamulin, florfenicol, and Synercid (a combination of quinupristin and dalfopristin [Q-D]) was measured by MIC assays. The resistance from Cfr was, in all cases, stronger than the effects...... of the L3 mutations, but various effects were obtained with the combinations of Cfr and L3 mutations ranging from a synergistic to an antagonistic effect. Linezolid and tiamulin susceptibility varied greatly among the L3 mutations, while no significant effects on florfenicol and Q-D susceptibility were...

Proteases in Escherichia coli and Staphylococcus aureus confer reduced susceptibility to lactoferricin B.

Science.gov (United States)

Ulvatne, Hilde; Haukland, Hanne Husom; Samuelsen, Ørjan; Krämer, Manuela; Vorland, Lars H

2002-10-01

Lactoferricin B is a cationic antimicrobial peptide derived from the N-terminal part of bovine lactoferrin. The effect of bacterial proteases on the antibacterial activity of lactoferricin B towards Escherichia coli and Staphylococcus aureus was investigated using various protease inhibitors and protease-deficient E. coli mutants. Sodium-EDTA, a metalloprotease inhibitor, was the most efficient inhibitors in both species, but combinations of sodium-EDTA with other types of protease inhibitor gave a synergic effect. The results indicate that several groups of proteases are involved in resistance to lactoferricin B in both E. coli and S. aureus. We also report that genetic inactivation of the heat shock-induced serine protease DegP increased the susceptibility to lactoferricin B in E. coli, suggesting that this protease, at least, is involved in reduced susceptibility to lactoferricin B.

Co-therapy using lytic bacteriophage and linezolid: effective treatment in eliminating methicillin resistant Staphylococcus aureus (MRSA from diabetic foot infections.

Directory of Open Access Journals (Sweden)

Sanjay Chhibber

Full Text Available BACKGROUND: Staphylococcus aureus remains the predominant pathogen in diabetic foot infections and prevalence of methicillin resistant S.aureus (MRSA strains further complicates the situation. The incidence of MRSA in infected foot ulcers is 15-30% and there is an alarming trend for its increase in many countries. Diabetes acts as an immunosuppressive state decreasing the overall immune functioning of body and to worsen the situation, wounds inflicted with drug resistant strains represent a morbid combination in diabetic patients. Foot infections caused by MRSA are associated with an increased risk of amputations, increased hospital stay, increased expenses and higher infection-related mortality. Hence, newer, safer and effective treatment strategies are required for treating MRSA mediated diabetic foot infections. The present study focuses on the use of lytic bacteriophage in combination with linezolid as an effective treatment strategy against foot infection in diabetic population. METHODOLOGY: Acute hindpaw infection with S.aureus ATCC 43300 was established in alloxan induced diabetic BALB/c mice. Therapeutic efficacy of a well characterized broad host range lytic bacteriophage, MR-10 was evaluated alone as well as in combination with linezolid in resolving the course of hindpaw foot infection in diabetic mice. The process of wound healing was also investigated. RESULTS AND CONCLUSIONS: A single administration of phage exhibited efficacy similar to linezolid in resolving the course of hindpaw infection in diabetic animals. However, combination therapy using both the agents was much more effective in arresting the entire infection process (bacterial load, lesion score, foot myeloperoxidase activity and histopathological analysis. The entire process of tissue healing was also hastened. Use of combined agents has been known to decrease the frequency of emergence of resistant mutants, hence this approach can serve as an effective strategy in

A randomized, double-blind, comparative study to assess the safety and efficacy of topical retapamulin ointment 1% versus oral linezolid in the treatment of secondarily infected traumatic lesions and impetigo due to methicillin-resistant Staphylococcus aureus.

Science.gov (United States)

Tanus, Tonny; Scangarella-Oman, Nicole E; Dalessandro, Marybeth; Li, Gang; Breton, John J; Tomayko, John F

2014-12-01

To evaluate the clinical and bacteriological efficacy of topical retapamulin ointment 1% versus oral linezolid in the treatment of patients with secondarily infected traumatic lesions (SITLs; excluding abscesses) or impetigo due to methicillin-resistant Staphylococcus aureus (MRSA). A randomized, double-blind, double-dummy, multicenter, comparative study (NCT00852540). Patients recruited from 36 study centers in the United States. Patients 2 months or older with SITL (including secondarily infected lacerations or sutured wounds) or impetigo (bullous and nonbullous) suitable for treatment with a topical antibiotic, with a total Skin Infection Rating Scale score of 8 or greater, including a pus/exudate score of 3 or greater. Patients received retapamulin ointment 1% (plus oral placebo), twice daily for 5 days or oral linezolid (plus placebo ointment) 2 or 3 times daily for 10 days. Primary end point: clinical response (success/failure) at follow-up in patients with MRSA at baseline (per-protocol population). Secondary efficacy end points: clinical and microbiologic response and outcome at follow-up and end of therapy; therapeutic response at follow-up. The majority of patients had SITL (70.4% [188/267] and 66.4% [91/137] in the retapamulin and linezolid groups, respectively; intent-to-treat clinical population). Clinical success rate at follow-up was significantly lower in the retapamulin versus the linezolid group (63.9% [39/61] vs 90.6% [29/32], respectively; difference in success rate -26.7%; 95% CI, -45.7 to -7.7). Clinical success rate at follow-up in the per-protocol MRSA population was significantly lower in the retapamulin versus the linezolid group. It could not be determined whether this was related to study design, bacterial virulence, or retapamulin activity.

Development, Optimization, and Validation of a Microplate Bioassay for Relative Potency Determination of Linezolid Using a Design Space Concept, and its Measurement Uncertainty.

Science.gov (United States)

Saviano, Alessandro Morais; Francisco, Fabiane Lacerda; Ostronoff, Celina Silva; Lourenço, Felipe Rebello

2015-01-01

The aim of this study was to develop, optimize, and validate a microplate bioassay for relative potency determination of linezolid in pharmaceutical samples using quality-by-design and design space approaches. In addition, a procedure is described for estimating relative potency uncertainty based on microbiological response variability. The influence of culture media composition was studied using a factorial design and a central composite design was adopted to study the influence of inoculum proportion and triphenyltetrazolium chloride in microbial growth. The microplate bioassay was optimized regarding the responses of low, medium, and high doses of linezolid, negative and positive controls, and the slope, intercept, and correlation coefficient of dose-response curves. According to optimization results, design space ranges were established using: (a) low (1.0 μg/mL), medium (2.0 μg/mL), and high (4.0 μg/mL) doses of pharmaceutical samples and linezolid chemical reference substance; (b) Staphylococcus aureus ATCC 653 in an inoculum proportion of 10%; (c) antibiotic No. 3 culture medium pH 7.0±0.1; (d) 6 h incubation at 37.0±0.1ºC; and (e) addition of 50 μL of 0.5% (w/v) triphenyltetrazolium chloride solution. The microplate bioassay was linear (r2=0.992), specific, precise (repeatability RSD=2.3% and intermediate precision RSD=4.3%), accurate (mean recovery=101.4%), and robust. The overall measurement uncertainty was reasonable considering the increased variability inherent in microbiological response. Final uncertainty was comparable with those obtained with other microbiological assays, as well as chemical methods.

Efficacy of linezolid, teicoplanin, and vancomycin in prevention of an experimental polytetrafluoroethylene graft infection model caused by methicillin-resistant Staphylococcus aureus.

Science.gov (United States)

Mese, Bulent; Bozoglan, Orhan; Elveren, Serdal; Eroglu, Erdinc; Gul, Mustafa; Celik, Ahmet; Ciralik, Harun; Yildirimdemir, Halil Ibrahim; Yasim, Alptekin

2015-03-27

The aim of this study was to evaluate the effectiveness of linezolid, teicoplanin, and vancomycin in prevention of prosthetic vascular graft infections in a vascular graft infection model. Fifty rats were divided into 5 groups. A polytetrafluoroethylene graft was implanted on the back of each rat. Methicillin-resistant Staphylococcus aureus (MRSA) strain was inoculated into all rats except Group 1. Group 2 was not given any treatment, Group 3 received linezolid, Group 4 received vancomycin, and Group 5 received teicoplanin. The grafts were removed for microbiological and histological examinations on the 7th day. In addition, C-reactive protein and prealbumin levels and leukocyte counts in obtained blood specimens were determined. Group 1 did not have infection. Group 2 had bacteria 5.7 × 10(4) CFU/cm(2). Group 3 and Group 4 had less bacterial growth. Group 5 had no bacterial growth. The number of bacteria was significantly higher in Group 2 than in the other experimental groups and the control group (pprevention of prosthetic vascular graft infections.

Linezolid and Tiamulin Cross-Resistance in Staphylococcus aureus Mediated by Point Mutations in the Peptidyl Transferase Center ▿

OpenAIRE

Miller, Keith; Dunsmore, Colin J.; Fishwick, Colin W. G.; Chopra, Ian

2008-01-01

Oxazolidinone and pleuromutilin antibiotics are currently used in the treatment of staphylococcal infections. Although both antibiotics inhibit protein synthesis and have overlapping binding regions on 23S rRNA, the potential for cross-resistance between the two classes through target site mutations has not been thoroughly examined. Mutants of Staphylococcus aureus resistant to linezolid were selected and found to exhibit cross-resistance to tiamulin, a member of the pleuromutilin class of an...

High rate of non-susceptibility to metronidazole and clindamycin in anaerobic isolates: Data from a clinical laboratory from Karachi, Pakistan.

Science.gov (United States)

Sheikh, Sadia Omer; Jabeen, Kauser; Qaiser, Saba; Ahsan, Syed Tanwir; Khan, Erum; Zafar, Afia

2015-06-01

Due to increasing resistance amongst anaerobic pathogens periodic surveillance of resistance has been recommended in regional/local settings. Anaerobic antimicrobial susceptibility testing is not routinely performed in many laboratories in Pakistan, hence absence of local data may lead to inappropriate empirical therapy in serious cases. 121 clinically significant anaerobic strains (26/121; 21% bacteremic isolates) were isolated and saved from 2010 to 2011. Susceptibility testing against metronidazole, clindamycin, co-amoxiclav, meropenem, piperacillin/tazobactam, linezolid and gatifloxacin was performed by determining minimum inhibitory concentrations (MICs). A high proportion of non-susceptible strains to metronidazole (10% of 121 isolates) and clindamycin (12% of 121 isolates) was seen, most noticeable in Bacteroides fragilis. Three Bacteroides species strains were non-susceptible to both metronidazole and clindamycin. One strain of Clostridium species was fully resistant to metronidazole and had intermediate resistance to clindamycin. No resistance to any of the other tested antibiotics was seen. Resistance to metronidazole was higher in bacteremic vs. non bacteremic isolates (p = value 0.07). In our setting where there is a high usage of empirical metronidazole and clindamycin for the treatment of serious anaerobic infections clinicians should be aware of increased resistance to these agents. Periodic surveillance of resistance to anti-anaerobic drugs especially metronidazole and clindamycin should be performed to generate antibiogram and guide appropriate empiric therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Reduced salinity increases susceptibility of zooxanthellate jellyfish to herbicide toxicity during a simulated rainfall event

International Nuclear Information System (INIS)

Klein, Shannon G.; Pitt, Kylie A.; Carroll, Anthony R.

2016-01-01

Accurately predicting how marine biota are likely to respond to changing ocean conditions requires accurate simulation of interacting stressors, exposure regimes and recovery periods. Jellyfish populations have increased in some parts of the world and, despite few direct empirical tests, are hypothesised to be increasing because they are robust to a range of environmental stressors. Here, we investigated the effects of contaminated runoff on a zooxanthellate jellyfish by exposing juvenile Cassiopea sp. medusae to a photosystem II (PSII) herbicide, atrazine and reduced salinity conditions that occur following rainfall. Four levels of atrazine (0ngL"−"1, 10ngL"−"1, 2μgL"−"1, 20μgL"−"1) and three levels of salinity (35 ppt, 25 ppt, 17 ppt) were varied, mimicking the timeline of light, moderate and heavy rainfall events. Normal conditions were then slowly re-established over four days to mimic the recovery of the ecosystem post-rain and the experiment continued for a further 7 days to observe potential recovery of the medusae. Pulse-amplitude modulated (PAM) chlorophyll fluorescence, growth and bell contraction rates of medusae were measured. Medusae exposed to the combination of high atrazine and lowest salinity died. After 3 days of exposure, bell contraction rates were reduced by 88% and medusae were 16% smaller in the lowest salinity treatments. By Day 5 of the experiment, all medusae that survived the initial pulse event began to recover quickly. Although atrazine decreased YII under normal salinity conditions, YII was further reduced when medusae were exposed to both low salinity and atrazine simultaneously. Atrazine breakdown products were more concentrated in jellyfish tissues than atrazine at the end of the experiment, suggesting that although bioaccumulation occurred, atrazine was metabolised. Our results suggest that reduced salinity may increase the susceptibility of medusae to herbicide exposure during heavy rainfall events. - Highlights: �

Pan-European monitoring of susceptibility to human-use antimicrobial agents in enteric bacteria isolated from healthy food-producing animals.

Science.gov (United States)

de Jong, Anno; Thomas, Valérie; Simjee, Shabbir; Godinho, Kevin; Schiessl, Brigitte; Klein, Ulrich; Butty, Pascal; Vallé, Michel; Marion, Hervé; Shryock, Thomas R

2012-03-01

To determine the antimicrobial susceptibility of Escherichia coli, Salmonella, Campylobacter and Enterococcus from cattle, pigs and chickens across the European Union (EU) using uniform methodology. Intestinal samples (1624) were taken at slaughter across five EU countries. Bacteria were isolated in national laboratories, whilst MICs were determined in a central laboratory for key antimicrobials used in human medicine. Clinical resistance was based on CLSI breakpoints and decreased susceptibility based on European Food Safety Authority (EFSA)/EUCAST epidemiological cut-off values. Isolation rates were high for E. coli (n=1540), low for Salmonella (n=201) and intermediate for Campylobacter (n=940) and Enterococcus (n=786). For E. coli and Salmonella, clinical resistance to newer compounds (cefepime, cefotaxime and ciprofloxacin) was absent or low, but decreased susceptibility was apparent, particularly in chicken strains. Resistance to older compounds (except gentamicin) was variable and higher. Colistin resistance was absent for E. coli, but apparent for Salmonella. For Campylobacter jejuni, ciprofloxacin resistance was markedly prevalent for chickens, whereas clinical resistance and decreased susceptibility to erythromycin was absent or very low. For Campylobacter coli, resistance was notably higher. None of the Enterococcus faecium strains was resistant to linezolid, but some were resistant to ampicillin or vancomycin. Resistance to quinupristin/dalfopristin was frequent. Resistance patterns varied widely depending on bacterial species, antibiotics, hosts and region. Resistance varied among countries, particularly for older antimicrobials, but clinical resistance to newer antibiotics used to treat foodborne disease in humans was generally very low. In the absence of resistance to newer compounds in E. coli and Salmonella, the apparent decreased susceptibility should be monitored.

Reducing Children's Susceptibility to Alcohol Use: Effects of a Home-Based Parenting Program.

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Jackson, Christine; Ennett, Susan T; Reyes, H Luz McNaughton; Hayes, Kim A; Dickinson, Denise M; Choi, Seulki; Bowling, J Michael

2016-07-01

This 4-year efficacy trial tested whether a home-based, self-administered parenting program could have a long-term effect on children's cognitive susceptibility to alcohol use, and it tested hypothesized moderators and mediators of any such program effect. Using a two-group randomized controlled design, 1076 children (540 treatment; 536 control; mean age of 9.2 years at baseline) completed telephone interviews prior to randomization and follow-up interviews 12, 24, 36, and 48 months post-baseline. Mothers of children randomized to treatment received a 5-month-long parenting program during year 1, followed by two 1-month-long boosters in years 2 and 3. Exposure to the program was significantly inversely associated with susceptibility to alcohol use 48 months post-baseline (b = -0.03, p = .04), with no variation in program effects by parental alcohol use or mother's race/ethnicity or education, suggesting broad public health relevance of the parenting program. Path analyses of simple indirect effects through each hypothesized mediator showed that program exposure positively influenced parental communication to counter pro-drinking influences in the family and media domains and parental rule setting 36 months post-baseline; these variables, in turn, predicted reduced susceptibility to alcohol use 48 months post-baseline. Parallel (multiple) mediation analysis showed that the program had a significant indirect effect on susceptibility through parental rule setting. Together, the findings indicate that internalization of protective alcohol-related expectancies and intentions is possible among children whose mothers provide early exposure to alcohol-specific socialization. Additional research is needed to link alcohol-specific socialization during childhood with adolescent drinking outcomes.

ANTIMICROBIAL SUSCEPTIBILITY PATTERN OF ORGANISMS CAUSING SURGICAL SITE INFECTIONS (SSI

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Rohini Murlidhar Gajbhiye

2017-02-01

Full Text Available BACKGROUND CDC defines surgical site infection as ‘Infections related to operative procedure that occurs at or near surgical incision within 30 days of operative procedure or within one year if the implant is left in situ’. Surgical site infection (SSI is 3 rd most frequently reported nosocomial infection (12%-16% as per National Nosocomial Infection Surveillance (NNIS. The aim of this study was to investigate the antimicrobial susceptibility pattern of organisms causing SSI. MATERIALS AND METHODS During a two year study period in a tertiary care hospital, 19,127 patients underwent surgeries in various surgical departments. Of these 517 (2.7% developed surgical site infection. The surgical wounds were classified by CDC & NNIS criteria into 4 classes. Two wound swabs were taken and processed by standard microbiological techniques. Antimicrobial susceptibility along with testing of ESBLs, MBLs, AmpCβ lactamases was done for all isolates causing SSI. RESULTS Among 19,127 patients, 517 (2.7% developed SSI. It was highest in patients of perforation peritonitis (11.99%.Among 517 specimens, 340 (65.76% showed growth and 177 (34.23% were culture negative. E.coli (23.33% was the commonest organism isolated followed by Acinetobacter spp. (16%, Klebsiella spp. (15.66%, Pseudomonas spp. (15.33%, S. aureus (10.33%, S. epidermidis(7.3%, Proteus spp. (6.00% and Citrobacter spp. (2.66%.Staphylococcus spp. were 100 % sensitive to Vancomycin & Linezolid. (27.5% S. aureus were MRSA and (17.5% were Inducible Clindamycin resistant (ICR. Enterobacteriaceae isolates showed maximum sensitivity towards Imipenem, Piperacillin-Tazobactam and Amikacin. Klebsiella spp. (40.62%, E.coli (35.89%, Citrobacter spp. (33.33%, Proteus spp. (26.08% were ESBL producers. Klebsiella spp. (17.18%, E.coli (10.25%, Proteus spp. (11.11% and Citrobacter spp. (8.69% were AmpC producers. Acinetobacter spp. (28.57% was commonest MBL producer followed by Klebsiella spp. (20

Seminational surveillance of fungemia in Denmark: notably high rates of fungemia and numbers of isolates with reduced azole susceptibility

DEFF Research Database (Denmark)

Arendrup, Maiken Cavling; Fuursted, Kurt; Gahrn-Hansen, Bente

2005-01-01

laboratory systems documented a continuous increase of candidemia cases since the early 1990s. For the 272 susceptibility-tested isolates, MICs of amphotericin B and caspofungin were within the limits expected for the species or genus. However, decreased azole susceptibility, defined as a fluconazole MIC...... of >8 microg/ml and/or itraconazole MIC of >0.125 microg/ml, was detected for 11 Candida isolates that were neither C. glabrata nor C. krusei. Including intrinsically resistant fungi, we detected decreased susceptibility to fluconazole and/or itraconazole in 87 (32%) current Danish bloodstream fungal...... isolates. We showed a continuous increase of fungemia in Denmark and an annual rate in 2003 to 2004 higher than in most other countries. The proportion of bloodstream fungal isolates with reduced susceptibility to fluconazole and/or itraconazole was also notably high....

Comparison of ViTEK 2, MALDI-TOF and Partial Sequencing of 16S ...

African Journals Online (AJOL)

All the strains were susceptible to Vancomycin, Linezolid and Rifampicin while they were all resistant to Penicillin, Fusidic acid, and Trimethoprim. Brevibacterium epidermidis were generally resistant to Erythromycin and Clindamycin while B. iodinum and B. oceani were susceptible. Conclusion - 16S rRNA identification is ...

In vitro activities of ramoplanin, teicoplanin, vancomycin, linezolid, bacitracin, and four other antimicrobials against intestinal anaerobic bacteria.

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Citron, D M; Merriam, C V; Tyrrell, K L; Warren, Y A; Fernandez, H; Goldstein, E J C

2003-07-01

By using an agar dilution method, the in vitro activities of ramoplanin, teicoplanin, vancomycin, linezolid, and five other agents were determined against 300 gram-positive and 54 gram-negative strains of intestinal anaerobes. Ramoplanin was active at Eubacterium, Actinomyces, Propionibacterium, and Peptostreptococcus spp. were inhibited by spp. were >or=256 microg/ml. Ramoplanin displays excellent activity against C. difficile and other gram-positive enteric anaerobes, including vancomycin-resistant strains; however, it has poor activity against most gram-negative anaerobes and thus potentially has a lesser effect on the ecological balance of normal fecal flora.

Multisite reproducibility of the broth microdilution method for susceptibility testing of Nocardia species.

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Conville, Patricia S; Brown-Elliott, Barbara A; Wallace, Richard J; Witebsky, Frank G; Koziol, Deloris; Hall, Geraldine S; Killian, Scott B; Knapp, Cindy C; Warshauer, David; Van, Tam; Wengenack, Nancy L; Deml, Sharon; Woods, Gail L

2012-04-01

Antimicrobial susceptibility testing (AST) of clinical isolates of Nocardia is recommended to detect resistance to commonly used antimicrobial agents; such testing is complicated by difficulties in inoculum preparation and test interpretation. In this study, six laboratories performed repetitive broth microdilution testing on single strains of Nocardia brasiliensis, Nocardia cyriacigeorgica, Nocardia farcinica, Nocardia nova, and Nocardia wallacei. For each isolate, a total of 30 microdilution panels from three different lots were tested at most sites. The goal of the study was to determine the inter- and intralaboratory reproducibility of susceptibility testing of this group of isolates. Acceptable agreement (>90% agreement at ±1 dilution of the MIC mode) was found for amikacin, ciprofloxacin, clarithromycin, and moxifloxacin. After eliminating MIC values from single laboratories whose results showed the greatest deviation from those of the remaining laboratories, acceptable agreement was also found for amoxicillin-clavulanic acid, linezolid, minocycline, and tobramycin. Results showed unsatisfactory reproducibility of broth microdilution testing of ceftriaxone with N. cyriacigeorgica and N. wallacei, tigecycline with N. brasiliensis and N. cyriacigeorgica, and sulfonamides with N. farcinica and N. wallacei. N. nova ATCC BAA-2227 is proposed as a quality control organism for AST of Nocardia sp., and the use of a disk diffusion test for sulfisoxazole is proposed as a check of the adequacy of the inoculum and to confirm sulfonamide MIC results.

Antibiotic Susceptibility Pattern of Aerobic and Anaerobic Bacteria Isolated From Surgical Site Infection of Hospitalized Patients.

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Akhi, Mohammad Taghi; Ghotaslou, Reza; Beheshtirouy, Samad; Asgharzadeh, Mohammad; Pirzadeh, Tahereh; Asghari, Babak; Alizadeh, Naser; Toloue Ostadgavahi, Ali; Sorayaei Somesaraei, Vida; Memar, Mohammad Yousef

2015-07-01

Surgical Site Infections (SSIs) are infections of incision or deep tissue at operation sites. These infections prolong hospitalization, delay wound healing, and increase the overall cost and morbidity. This study aimed to investigate anaerobic and aerobic bacteria prevalence in surgical site infections and determinate antibiotic susceptibility pattern in these isolates. One hundred SSIs specimens were obtained by needle aspiration from purulent material in depth of infected site. These specimens were cultured and incubated in both aerobic and anaerobic condition. For detection of antibiotic susceptibility pattern in aerobic and anaerobic bacteria, we used disk diffusion, agar dilution, and E-test methods. A total of 194 bacterial strains were isolated from 100 samples of surgical sites. Predominant aerobic and facultative anaerobic bacteria isolated from these specimens were the members of Enterobacteriaceae family (66, 34.03%) followed by Pseudomonas aeruginosa (26, 13.4%), Staphylococcus aureus (24, 12.37%), Acinetobacter spp. (18, 9.28%), Enterococcus spp. (16, 8.24%), coagulase negative Staphylococcus spp. (14, 7.22%) and nonhemolytic streptococci (2, 1.03%). Bacteroides fragilis (26, 13.4%), and Clostridium perfringens (2, 1.03%) were isolated as anaerobic bacteria. The most resistant bacteria among anaerobic isolates were B. fragilis. All Gram-positive isolates were susceptible to vancomycin and linezolid while most of Enterobacteriaceae showed sensitivity to imipenem. Most SSIs specimens were polymicrobial and predominant anaerobic isolate was B. fragilis. Isolated aerobic and anaerobic strains showed high level of resistance to antibiotics.

Clinical response and hospital costs associated with the empirical use of vancomycin and linezolid for hospital-acquired pneumonia in a Chinese tertiary care hospital: a retrospective cohort study

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Song Y

2014-10-01

Full Text Available Yuanlin Song,1,* Yicheng Yang,2,* Wendong Chen,3,4 Wei Liu,2 Kai Wang,2 Xuehai Li,5 Ke Wang,2 Manny Papadimitropoulos,3,6 William Montgomery7 1Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 2Lilly Suzhou Pharmaceutical Co, Ltd, Shanghai Branch, Shanghai, People's Republic of China; 3Division of Social and Administrative Pharmacy, Leslie Dan Faculty of Pharmacy, University of Toronto, 4Normin Health, Toronto, ON, Canada; 5VitalStrategic Research Institute, Shanghai, People's Republic of China; 6Global Health Outcomes Research, Eli Lilly, Indianapolis, IN, USA; 7Eli Lilly Australia Pty Ltd, West Ryde, NSW, Australia *These authors contributed equally to this work Aims: To evaluate clinical outcomes and allocation of hospital costs associated with empirical use of vancomycin or linezolid for hospital-acquired pneumonia (HAP in the People's Republic of China. Methods: Hospital episodes including HAP treated by vancomycin or linezolid between 2008 and 2012 in a Chinese tertiary care hospital were retrospectively identified from hospital administrative databases. Propensity score methods created best-matched pairs for the antibiotics. The matched pairs were used for adjusted comparisons on clinical response and allocation of hospital costs. Multiple regression analyses adjusting residual imbalance after matching were performed to confirm adjusted comparisons. Results: Sixty matched pairs were created. Adjusted comparisons between vancomycin and linezolid showed similar clinical response rates (clinical cure: 30.0% versus 31.7%, respectively; P=0.847; treatment failure: 55.0% versus 45.0%, respectively; P=0.289 but a significantly lower in-hospital mortality rate for vancomycin (3.3% versus 18.3%, respectively; P=0.013. After further adjusting for the imbalanced variables between matched treatment groups, the risks of treatment failure associated with the two antibiotics were comparable (odds ratio: 1.139; P=0.308 and there was

The role of cognitive and affective defense mechanisms in reducing children’s susceptibility to advertising effects

NARCIS (Netherlands)

Rozendaal, E.; Buijzen, M.; Valkenburg, P.

2011-01-01

The main aim of this study was to develop and test a model of children’s advertising defenses. In this model two paths to reduced advertising susceptibility (i.e., advertised brand attitude) were hypothesized: a cognitive and an affective path. The secondary aim was to compare these paths for two

Cost Comparison of Linezolid Versus Vancomycin for Treatment of Complicated Skin and Skin-Structure Infection Caused by Methicillin-Resistant Staphylococcus aureus in Quebec

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Martine Pettigrew

2012-01-01

Full Text Available BACKGROUND: In Canada, complicated skin and skin-structure infection (cSSSI caused by methicillin-resistant Staphylococcus aureus (MRSA is usually treated with antibiotics in hospital, with a follow-up course at home for stable patients. The cost implications of using intravenous and oral linezolid instead of intravenous vancomycin in Canadian clinical practice have not been examined.

[Identification and drug susceptibility testing of Mycobacterium thermoresistibile and Mycobacterium elephantis isolated from a cow with mastitis].

Science.gov (United States)

Li, W B; Ji, L Y; Xu, D L; Liu, H C; Zhao, X Q; Wu, Y M; Wan, K L

2018-05-10

Objective: To understand the etiological characteristics and drug susceptibility of Mycobacterium thermoresistibile and Mycobacterium elephantis isolated from a cow with mastitis and provide evidence for the prevention and control of infectious mastitis in cows. Methods: The milk sample was collected from a cow with mastitis, which was pretreated with 4 % NaOH and inoculated with L-J medium for Mycobacterium isolation. The positive cultures were initially identified by acid-fast staining and multi-loci PCR, then Mycobacterium species was identified by the multiple loci sequence analysis (MLSA) with 16S rRNA , hsp65 , ITS and SodA genes. The drug sensitivity of the isolates to 27 antibiotics was tested by alamar blue assay. Results: Two anti-acid stain positive strains were isolated from the milk of a cow with mastitis, which were identified as non- tuberculosis mycobacterium by multi-loci PCR, and multi-loci nucleic acid sequence analysis indicated that one strain was Mycobacterium thermoresistibile and another one was Mycobacterium elephantis . The results of the drug susceptibility test showed that the two strains were resistant to most antibiotics, including rifampicin and isoniazid, but they were sensitive to amikacin, moxifloxacin, levofloxacin, ethambutol, streptomycin, tobramycin, ciprofloxacin and linezolid. Conclusions: Mycobacterium thermoresistibile and Mycobacterium elephantis were isolated in a cow with mastitis and the drug susceptibility spectrum of the pathogens were unique. The results of the study can be used as reference for the prevention and control the infection in cows.

Linezolid Is Associated with Serotonin Syndrome in a Patient Receiving Amitriptyline, and Fentanyl: A Case Report and Review of the Literature

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Lampros Samartzis

2013-01-01

Full Text Available We report a unique case of an adverse interaction between the oxazolidinone antibiotic linezolid, the tricyclic antidepressant amitriptyline and the opioid analgesic fentanyl in a 68-year-old woman with advanced ischemic peripheral arterial disease and sepsis, under empirical antibiotic treatment. We also summarize the current relevant literature as identified via PubMed, EMBASE, and PsycINFO as well as reference sections of selected articles.

Extreme ocean acidification reduces the susceptibility of eastern oyster shells to a polydorid parasite.

Science.gov (United States)

Clements, J C; Bourque, D; McLaughlin, J; Stephenson, M; Comeau, L A

2017-11-01

Ocean acidification poses a threat to marine organisms. While the physiological and behavioural effects of ocean acidification have received much attention, the effects of acidification on the susceptibility of farmed shellfish to parasitic infections are poorly understood. Here we describe the effects of moderate (pH 7.5) and extreme (pH 7.0) ocean acidification on the susceptibility of Crassostrea virginica shells to infection by a parasitic polydorid, Polydora websteri. Under laboratory conditions, shells were exposed to three pH treatments (7.0, 7.5 and 8.0) for 3- and 5-week periods. Treated shells were subsequently transferred to an oyster aquaculture site (which had recently reported an outbreak of P. websteri) for 50 days to test for effects of pH and exposure time on P. websteri recruitment to oyster shells. Results indicated that pH and exposure time did not affect the length, width or weight of the shells. Interestingly, P. websteri counts were significantly lower under extreme (pH 7.0; ~50% reduction), but not moderate (pH 7.5; ~20% reduction) acidification levels; exposure time had no effect. This study suggests that extreme levels - but not current and projected near-future levels - of acidification (∆pH ~1 unit) can reduce the susceptibility of eastern oyster shells to P. websteri infections. © 2017 John Wiley & Sons Ltd.

Pharmacokinetics of linezolid during continuous hemodiafiltration: A case report.

Science.gov (United States)

Yamashina, Takuya; Tsuruyama, Moeko; Odawara, Miki; Tsuruta, Minako; Miyata, Hirochika; Kozono, Aki; Tsuji, Yasuhiro; Miyoshi, Takanori; Kawamata, Yosei; Hiraki, Yoichi

2017-10-01

The pharmacokinetics of linezolid clearance (CL LZD ) during continuous hemodiafiltration (CHDF) has not been comprehensively analyzed. Here, we examined CL LZD by CHDF in a patient with septic shock and disseminated intravascular coagulation due to methicillin-resistant Staphylococcus aureus. The extraction ratio of LZD by CHDF was 22.6%, and the protein-binding rate was 17.9% ± 7.7%. In addition, it was determined that the calculated total body clearance of LZD was 30.2 mL/min, plasma elimination half-life was 8.66 h, and the CL LZD by the dialyzer used for CHDF was 23.0 mL/min. From the obtained pharmacokinetics, the CL LZD of patients continuing CHDF was estimated to be approximately half of the reported CL LZD for healthy subjects. In addition, the LZD concentration of the sepsis patient who underwent CHDF remained higher than the minimum inhibitory concentration and was similar to the LZD concentrations reported in normal renal function patients. Although further studies are warranted, when LZD is administered to patients treated with CHDF, the present findings suggest that dose regulation is not required. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Antimicrobial susceptibility survey of pathogens isolated from selected patients in Northern Italy

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Elisabetta Maioli

2005-03-01

Full Text Available The Clinical Microbiology Laboratory of the University of Genoa participated, during the year 2003, in an international antimicrobial surveillance program.The collection of isolates was done according to the site of infection and/or type of patient. Four hundred twenty (420 clinical isolates were analyzed during this year and the frequencies of the different pathogens were investigated. A reference centre carried out susceptibility tests. Oxacillin-resistant Staphylococcus aureus represented 47.6% of all S. aureus isolates from blood stream infections and 33.3% of all S. aureus isolated from skin and soft tissue infections in hospitalised patients.These strains showed resistance to most of the antimicrobial agents evaluated, except vancomycin, teicoplanin, quinupristin/dalfopristin and linezolid which registered 100% of susceptibility. Some isolates from blood stream infections such as E. coli demonstrated resistance to ciprofloxacin (23.3%, levofloxacin (20%, and gatifloxacin (16.6%, and Klebsiella pneumoniae was resistant (18% to all fluoroquinolones tested. Pseudomonas aeruginosa manifested resistance to ciprofloxacin (16.6%, while 27.7% of these strains were resistant both to levofloxacin and gatifloxacin. All the Enterobacter cloacae isolated from blood were susceptible to ciprofloxacin, levofloxacin and gatifloxacin. Haemophilus influenzae and Moraxella catarrhalis collected from community-acquired respiratory tract infections were all inhibited by ciprofloxacin, levofloxacin and gatifloxacin. E. coli isolated from urinary tract infections in hospitalised patients were resistant to ciprofloxacin, levofloxacin and gatifloxacin (2.7%. All Salmonella spp. collected from samples of patients affected by infections of the gastro-intestinal tract were susceptible to all fluoroquinolones. Penicillin resistance in Streptococcus pneumoniae was found in 21.4% of isolates from patients with respiratory tract infections. Fluoroquinolone resistance was

Efficacy of Tigecycline Alone and in Combination with Gentamicin in the Treatment of Experimental Endocarditis Due to Linezolid-Resistant Enterococcus faecium

OpenAIRE

Pontikis, Konstantinos; Pefanis, Angelos; Tsaganos, Thomas; Tzepi, Ira-Maria; Carrer, Dionyssia-Pinelopi; Giamarellou, Helen

2013-01-01

We evaluated the efficacy of tigecycline in a rabbit model of experimental endocarditis caused by a linezolid-resistant clinical strain of Enterococcus faecium. Tigecycline-treated animals had a 2.8-log10-CFU/g reduction in microbial counts in excised vegetations compared with controls. Addition of gentamicin caused a further arithmetical reduction in colony counts. The therapeutic effect was sustained 5 days after completion of treatment, as shown by relapse studies performed in treatment gr...

Efficacy of tigecycline alone and in combination with gentamicin in the treatment of experimental endocarditis due to linezolid-resistant Enterococcus faecium.

Science.gov (United States)

Pontikis, Konstantinos; Pefanis, Angelos; Tsaganos, Thomas; Tzepi, Ira-Maria; Carrer, Dionyssia-Pinelopi; Giamarellou, Helen

2013-07-01

We evaluated the efficacy of tigecycline in a rabbit model of experimental endocarditis caused by a linezolid-resistant clinical strain of Enterococcus faecium. Tigecycline-treated animals had a 2.8-log10-CFU/g reduction in microbial counts in excised vegetations compared with controls. Addition of gentamicin caused a further arithmetical reduction in colony counts. The therapeutic effect was sustained 5 days after completion of treatment, as shown by relapse studies performed in treatment groups.

Antibiotic susceptibility pattern and the prevalence of Staphylococcus aureus isolated from skin and soft tissue in Tehran Razi skin hospital (2014-15

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Zeynab Fagheei-Aghmiyuni

2017-06-01

Full Text Available Background: Staphylococcus aureus (S. aureus is the most common cause of skin and soft tissue infections. This study aimed to determine the prevalence of S. aureus isolated from skin and soft tissue and antibiotic susceptibility pattern among the patient hospitalized in Razi skin hospital (Tehran-Iran. Materials and Methods: This cross-sectional study was conducted on patients (n=400 with skin and soft tissue infections in Razi skin hospital. Sterilized swabs were used to collect the skin infection samples. S. aureus isolates were confirmed using biochemical tests (gram staining, catalase, coagulase, DNase test and manitol fermentation tests. Result: 51.3 %( 205 out of 400 of isolates were S. aureus. Ninety six (46.8% of isolates were methicillin and penicillin-resistant S. aureus. All of the isolates showed sensitivity to vancomycin, linezolid. 98% of the isolates were susceptible to daptomycin. One-hundred sixteen (56.6% isolates were multi- drug resistant. Conclusion: More than half of the skin and soft tissue infections were caused by S.aureus. More than 46 percent of the isolates were methicillin resistant. The highest resistance to penicillin was observed.

Relaxin reduces susceptibility to post-infarct atrial fibrillation in mice due to anti-fibrotic and anti-inflammatory properties.

Science.gov (United States)

Beiert, Thomas; Tiyerili, Vedat; Knappe, Vincent; Effelsberg, Verena; Linhart, Markus; Stöckigt, Florian; Klein, Sabine; Schierwagen, Robert; Trebicka, Jonel; Nickenig, Georg; Schrickel, Jan W; Andrié, René P

2017-08-26

Relaxin-2 (RLX) is a peptide hormone that exerts beneficial anti-fibrotic and anti-inflammatory effects in diverse models of cardiovascular disease. The goal of this study was to determine the effects of RLX treatment on the susceptibility to atrial fibrillation (AF) after myocardial infarction (MI). Mice with cryoinfarction of the left anterior ventricular wall were treated for two weeks with either RLX (75 μg/kg/d) or vehicle (sodium acetate) delivered via subcutaneously implanted osmotic minipumps. RLX treatment significantly attenuated the increase in AF-inducibility following cryoinfarction and reduced the mean duration of AF episodes. Furthermore, epicardial mapping of both atria revealed an increase in conduction velocity. In addition to an attenuation of atrial hypertrophy, chronic application of RLX reduced atrial fibrosis, which was linked to a significant reduction in atrial mRNA expression of connective tissue growth factor. Transcript levels of the pro-inflammatory cytokines interleukin-6 and interleukin-1β were reduced in RLX treated mice, but macrophage infiltration into atrial myocardium was similar in the vehicle and RLX treated groups. Treatment with RLX in mice after MI reduces susceptibility to AF due to anti-inflammatory and anti-fibrotic properties. Because to these favorable actions, RLX may become a new therapeutic option in the treatment of AF, even when complicating MI. Copyright © 2017 Elsevier Inc. All rights reserved.

Antimicrobial drug resistance of Salmonella enterica serovar typhi in asia and molecular mechanism of reduced susceptibility to the fluoroquinolones

NARCIS (Netherlands)

Chau, Tran Thuy; Campbell, James Ian; Galindo, Claudia M.; van Minh Hoang, Nguyen; Diep, To Song; Nga, Tran Thu Thi; van Vinh Chau, Nguyen; Tuan, Phung Quoc; Page, Anne Laure; Ochiai, R. Leon; Schultsz, Constance; Wain, John; Bhutta, Zulfiqar A.; Parry, Christopher M.; Bhattacharya, Sujit K.; Dutta, Shanta; Agtini, Magdarina; Dong, Baiqing; Honghui, Yang; Anh, Dang Duc; Canh, Do Gia; Naheed, Aliya; Albert, M. John; Phetsouvanh, Rattanaphone; Newton, Paul N.; Basnyat, Buddha; Arjyal, Amit; La, Tran Thi Phi; Rang, Nguyen Ngoc; Phuong, Le Thi; van Be Bay, Phan; von Seidlein, Lorenz; Dougan, Gordon; Clemens, John D.; Vinh, Ha; Hien, Tran Tinh; Chinh, Nguyen Tran; Acosta, Camilo J.; Farrar, Jeremy; Dolecek, Christiane

2007-01-01

This study describes the pattern and extent of drug resistance in 1,774 strains of Salmonella enterica serovar Typhi isolated across Asia between 1993 and 2005 and characterizes the molecular mechanisms underlying the reduced susceptibilities to fluoroquinolones of these strains. For 1,393 serovar

Emergence in Asian Countries of Staphylococcus aureus with Reduced Susceptibility to Vancomycin

Science.gov (United States)

Song, Jae-Hoon; Hiramatsu, Keiichi; Suh, Ji Yoeun; Ko, Kwan Soo; Ito, Teruyo; Kapi, Maria; Kiem, Sungmin; Kim, Yeon-Sook; Oh, Won Sup; Peck, Kyong Ran; Lee, Nam Yong

2004-01-01

To investigate the prevalence of Staphylococcus aureus with reduced susceptibility to vancomycin among methicillin-resistant S. aureus (MRSA) strains in Asian countries, a total of 1,357 clinical isolates of MRSA collected from 12 Asian countries were screened by using brain heart infusion agar plates containing 4 mg of vancomycin per liter. The presence of strains that were heterointermediately resistant to vancomycin (hVISA) was confirmed by population analysis. Of 347 (25.6%) MRSA isolates that grew on the screening agar plates, 58 isolates (4.3%) were hVISA. hVISA strains were found in India, South Korea, Japan, the Philippines, Singapore, Thailand, and Vietnam. However, neither vancomycin-intermediate S. aureus nor vancomycin-resistant S. aureus isolates were found among MRSA isolates from Asian countries in this survey. PMID:15561884

Antimicrobial susceptibility of bacteria, isolated from patients treated at Jesenice General hospital in the period between 2004 and 2006

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Helena Ribič

2007-11-01

Full Text Available Background: Antimicrobial resistance of bacteria is still one of the mayor problems in medicine. In the year 2006, microbiologists of the Institute of Public Health Kranj together with clinicians and pharmacist of Jesenice General Hospital prepared the programm of antimicrobial resistance surveillance of patients treated in the hospital. Some of the results are presented in this article.Methods: In the retrospective study, bacterial strains, isolated from different samples were analysed. The strains were isolated and studied during the routine work of microbiology laboratory of IPH Kranj in the period between 2004 and 2006.Results: The most frequently isolated bacteria from haemocultures was Escherichia coli (35.4 %. In the years 2004 and 2006, susceptibility of strains for ciprofloxacin was 95.7 % and 97.2 %, for parenteral cefuroxime (95.7 % and 94.4 %, for cefotaxime and gentamicin in both years 100 %. Susceptibility of E. coli strains from urine samples in patients from the department for internal medicine was in 2004 and 2006 for co-amoxiclav 88.5 % and 70.1 %, for co-trimoxazole 60.3 % and 81.3 %, for cefaclor 94.9 % and 89.7 %, for ciprofloxacin 83.3 % and 82.2 %. Among strains of Staphylococcus aureus, 100 % were sensitive to vancomycin and 99.3 % to linezolid in 2006. Among methicillin susceptible strains, sensitivity to erythromycin, clindamycin and ciprofloxacin lowered slightely in the three years period; in 2006 it was 87.6 %, 90.6 % and 89.1 %. Susceptibility of strains Pseudomonas aeruginosa was in 2006 similar comparing to 2004; it was 92 % for ceftazidime, 75 % for gentamicin, 64.6 % for ciprofloxacin and 96 % for imipenem. Among strains of Acinetobacter spp., sensitivity rate to ciprofloxacin, ceftazidime, piperacillin with tazobactam and gentamicin significantly fell in the year 2005 and stayed low in 2006.Conclusions: The results of antimicrobial susceptibility surveillance and trends of susceptibility are intended to guide

Methicillin-resistant Staphylococcus aureus in North-east Croatia

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Tajana Pastuović

2015-05-01

Full Text Available Objective. The aim of this 5-year study was to determine the frequency and antibiotic susceptibility of methicillin-resistant Staphylococcus aureus (MRSA-related infections at Osijek Clinical Hospital. Materials and methods. A total of 1987 staphylococci-infected clinical isolates were collected and analysed at the Microbiology Department of the Public Health Institute of Osijek-Baranja County. Results. Between 2008 and 2012, the average rate of MRSA-related infections in staphylococci-infected patients was 27.4%. The proportion of MRSArelated infections on all Staphylococcus aureus (S. aureus isolates from clinical specimens showed a decreasing trend, from 32.6% in 2008 to 25.5% in 2012. MRSA-related infections were mostly detected in wound swabs (50.6% and aspirates (28.8% of patients hospitalized in the surgical (49.8% and intensive care units (27.9%. MRSA-related infection showed an increase compared to S. aureus-infections in samples of wounds and aspirates in 2011 and 2012 (57.9%/34.9% and 35.2%/16.3%, respectively. The majority of strains of MRSA-related infections were resistant to several antibiotics, including erythromycin and clindamycin, where susceptibility were less than 10%. All MRSA isolates were susceptible to vancomycin, teicoplanin and linezolid. Therefore, antibiotic therapies for MRSA infections include vancomycin, teicoplanin and linezolid, but microbiological diagnostics need to be performed in order to know when the use of glycopeptides and oxazolidinones is indicated. Conclusion. Our results suggest that appropriate prevention measures, combined with the more rational use of antibiotics are crucial to reduce the spread of MRSA-related infection in healthcare settings. Further monitoring is necessary of the incidence and antibiotic susceptibility of MRSA-related infections in our community.

Sequencing of FKS Hot Spot 1 from Saprochaete capitata To Search for a Relationship to Reduced Echinocandin Susceptibility.

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Arrieta-Aguirre, Inés; Menéndez-Manjón, Pilar; Cuétara, María Soledad; Fernández de Larrinoa, Iñigo; García-Ruiz, Juan Carlos; Moragues, María Dolores

2018-02-01

Saprochaete capitata , formerly known as Geotrichum capitatum , is an emerging fungal pathogen with low susceptibility to echinocandins. Here, we report the nucleotide sequence of the S. capitata hot spot 1 region of the FKS gene ( FKS HS1), which codifies for the catalytic subunit of β-1,3-d-glucan synthase, the target of echinocandins. For that purpose, we first designed degenerated oligonucleotide primers derived from conserved flanking regions of the FKS1 HS1 segment of 12 different fungal species. Interestingly, analysis of the translated FKS HS1 sequences of 12 isolates of S. capitata revealed that all of them exhibited the same F-to-L substitution in a position that is highly related to reduced echinocandin susceptibility. Copyright © 2018 American Society for Microbiology.

Global transcriptional response of methicillin-resistant Staphylococcus aureus to thioridazine

DEFF Research Database (Denmark)

Bonde, Mette; Jacobsen, Kirstine; Kolmos, Hans Jørn

Few drugs are available against methicillin-resistant S. aureus (MRSA), and decreased susceptibility among staphylococci to newly introduced agents such as linezolid, daptomycin, and tigecycline has been observed [1-3]. Consequently, new treatment strategies are urgently needed. Thioridazine...

Elevated Chitin Content Reduces the Susceptibility of Candida Species to Caspofungin

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Walker, Louise A.; Gow, Neil A. R.

2013-01-01

The echinocandin antifungal drugs inhibit synthesis of the major fungal cell wall polysaccharide β(1,3)-glucan. Echinocandins have good efficacy against Candida albicans but reduced activity against other Candida species, in particular Candida parapsilosis and Candida guilliermondii. Treatment of Candida albicans with a sub-MIC level of caspofungin has been reported to cause a compensatory increase in chitin content and to select for sporadic echinocandin-resistant FKS1 point mutants that also have elevated cell wall chitin. Here we show that elevated chitin in response to caspofungin is a common response in various Candida species. Activation of chitin synthesis was observed in isolates of C. albicans, Candida tropicalis, C. parapsilosis, and C. guilliermondii and in some isolates of Candida krusei in response to caspofungin treatment. However, Candida glabrata isolates demonstrated no exposure-induced change in chitin content. Furthermore, isolates of C. albicans, C. krusei, C. parapsilosis, and C. guilliermondii which were stimulated to have higher chitin levels via activation of the calcineurin and protein kinase C (PKC) signaling pathways had reduced susceptibility to caspofungin. Isolates containing point mutations in the FKS1 gene generally had higher chitin levels and did not demonstrate a further compensatory increase in chitin content in response to caspofungin treatment. These results highlight the potential of increased chitin synthesis as a potential mechanism of tolerance to caspofungin for the major pathogenic Candida species. PMID:23089748

Molecular characterization and drug susceptibility profile of a Mycobacterium avium subspecies avium isolate from a dog with disseminated infection.

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Armas, Federica; Furlanello, Tommaso; Camperio, Cristina; Trotta, Michele; Novari, Gianluca; Marianelli, Cinzia

2016-01-12

Mycobacterium avium complex (MAC) infections have been described in many mammalian species including humans and pets. We isolated and molecularly typed the causative agent of a rare case of disseminated mycobacteriosis in a dog. We identified the pathogen as a M. avium subspecies avium by sequencing the partial genes gyrB and rpsA. Considering the zoonotic potential of this infection, and in an attempt to ensure the most effective treatment for the animal, we also determined the drug susceptibility profile of the isolate to the most common drugs used to treat MAC disease in humans. The pathogen was tested in vitro against the macrolide clarithromycin, as well as against amikacin, ciprofloxacin, rifampicin, ethambutol and linezolid by the resazurin microdilution assay. It was found to be sensitive to all tested drugs save ethambutol. Despite the fact that the pathogen was sensitive to the therapies administered, the dog's overall clinical status worsened, and the animal died shortly after antimicrobial susceptibility results became available. Nucleotide sequencing of the embB gene, the target gene most commonly associated with ethambutol resistance, showed new missense mutations when compared to sequences available in public databases. In conclusion, we molecularly identified the MAC pathogen and determined its drug susceptibility profile in a relatively short period of time (seven days). We also characterized new genetic mutations likely to have been involved in the observed ethambutol resistance. Our results confirm the usefulness of both the gyrB and the rpsA genes as biomarkers for an accurate identification and differentiation of MAC pathogens.

Outdoor air pollution, genetic susceptibility, and asthma management: opportunities for intervention to reduce the burden of asthma.

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Gilliland, Frank D

2009-03-01

Outdoor air pollution at levels occurring in many urban areas around the world has substantial adverse effects on health. Children in general, and children with asthma in particular, are sensitive to the adverse effects of outdoor air pollutants, including ozone, nitrogen oxides, and respirable particulate matter. A growing number of studies also show that children living in environments near traffic have increased risks of new-onset asthma, asthma symptoms, exacerbations, school absences, and asthma-related hospitalizations. The large population of children exposed to high levels of outdoor air pollutants and the substantial risks for adverse health effects present unexploited opportunities to reduce the burden of asthma. Because the evidence indicates significant adverse effects of air pollution at current levels, there is clearly a need to reduce levels of regulated pollutants such as ozone, as well as unregulated pollutants in tailpipe emissions from motor vehicles. Achieving this long-term goal requires the active involvement of physicians and medical providers to ensure that the health of children is at the top of the list of competing priorities for regulatory policy decision-making. Clinical approaches include treatment to control asthma and patient education to reduce adverse effects of the disease. Reduction in exposures also can be approached at a policy level through changes in schools and school bus operations. Beyond clinical and public health approaches to reduce exposure, another strategy to be used before clean air goals are met is to decrease the susceptibility of children to air pollution. Emerging research indicates that dietary supplementation for individuals with low antioxidant levels is one promising approach to reducing susceptibility to air pollution. A second approach involves induction of enzymatic antioxidant defenses, especially for individuals with at-risk genetic variants of key antioxidant enzymes.

Antistaphylococcal activity of LBM415, a new peptide deformylase inhibitor, compared with those of other agents.

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Credito, Kim; Lin, Gengrong; Ednie, Lois M; Appelbaum, Peter C

2004-10-01

The MICs of LBM415, a new peptide diformylase inhibitor, were susceptible or resistant. All strains were also susceptible to vancomycin, linezolid, ranbezolid, daptomycin, oritavancin, and quinupristin-dalfopristin. LBM415 at the MIC was bacteriostatic after 24 h.

Reduced noise susceptibility in littermate offspring from heterozygous animals of the German waltzing guinea pig.

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Skjönsberg, Åsa; Mannström, Paula

2015-07-08

The German waltzing guinea pig is a spontaneously mutated strain with severe auditory and vestibular impairment caused by a so far unknown genetic mutation. The animals are born deaf and show a circling behavior. The heterozygote animals of this guinea pig strain have functionally normal hearing and balance. However, these animals have, in earlier studies, shown an increased resistance to noise compared with normal wild-type guinea pigs. In the present study, we explored the functional hearing with auditory brainstem response thresholds before and at different time points after noise exposure. Symptom-free littermates from heterozygote couples of the German waltzing guinea pigs were exclusively used for the study, which, after the hearing test, were sent back for breeding to confirm their genotype (i.e. heterozygote or normal). The aim of this paper was to ascertain that the previously shown reduced susceptibility to noise trauma in the heterozygote animals of the German waltzing guinea pig was also evident when littermates were used as control animals. The findings are important for further analysis of the heterozygote animals of this strain and for future investigations of the underlying mechanisms behind the diverse susceptibility to exposures of loud sound.

Education reduces the effects of genetic susceptibilities to poor physical health.

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Johnson, Wendy; Kyvik, Kirsten Ohm; Mortensen, Erik L; Skytthe, Axel; Batty, G David; Deary, Ian J

2010-04-01

Greater education is associated with better physical health. This has been of great concern to public health officials. Most demonstrations show that education influences mean levels of health. Little is known about the influence of education on variance in health status, or about how this influence may impact the underlying genetic and environmental sources of health problems. This study explored these influences. In a 2002 postal questionnaire, 21 522 members of same-sex pairs in the Danish Twin Registry born between 1931 and 1982 reported physical health in the 12-item Short Form Health Survey. We used quantitative genetic models to examine how genetic and environmental variance in physical health differed with level of education, adjusting for birth-year effects. and Conclusions As expected, greater education was associated with better physical health. Greater education was also associated with smaller variance in health status. In both sexes, 2 standard deviations (SDs) above mean educational level, variance in physical health was only about half that among those 2 SDs below. This was because fewer highly educated people reported poor health. There was less total variance in health primarily because there was less genetic variance. Education apparently reduced expression of genetic susceptibilities to poor health. The patterns of genetic and environmental correlations suggested that this might take place because more educated people manage their environments to protect their health. If so, fostering the personal charactieristics associated with educational attainment could be important in reducing the education-health gradient.

Reduced susceptibility to vancomycin and biofilm formation in methicillin-resistant Staphylococcus epidermidis isolated from blood cultures

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Luiza Pinheiro

2014-11-01

Full Text Available This study aimed to correlate the presence of ica genes, biofilm formation and antimicrobial resistance in 107 strains of Staphylococcus epidermidis isolated from blood cultures. The isolates were analysed to determine their methicillin resistance, staphylococcal cassette chromosome mec (SCCmec type, ica genes and biofilm formation and the vancomycin minimum inhibitory concentration (MIC was measured for isolates and subpopulations growing on vancomycin screen agar. The mecA gene was detected in 81.3% of the S. epidermidis isolated and 48.2% carried SCCmec type III. The complete icaADBC operon was observed in 38.3% of the isolates; of these, 58.5% produced a biofilm. Furthermore, 47.7% of the isolates grew on vancomycin screen agar, with an increase in the MIC in 75.9% of the isolates. Determination of the MIC of subpopulations revealed that 64.7% had an MIC ≥ 4 μg mL-1, including 15.7% with an MIC of 8 μg mL-1 and 2% with an MIC of 16 μg mL-1. The presence of the icaADBC operon, biofilm production and reduced susceptibility to vancomycin were associated with methicillin resistance. This study reveals a high level of methicillin resistance, biofilm formation and reduced susceptibility to vancomycin in subpopulations of S. epidermidis. These findings may explain the selection of multidrug-resistant isolates in hospital settings and the consequent failure of antimicrobial treatment.

Single- and Multiple-Dose Study To Determine the Safety, Tolerability, Pharmacokinetics, and Food Effect of Oral MRX-I versus Linezolid in Healthy Adult Subjects.

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Eckburg, Paul B; Ge, Yigong; Hafkin, Barry

2017-04-01

A multipart phase 1 study was conducted to determine the safety, tolerability, pharmacokinetics, and food effect of the novel oral oxazolidinone, MRX-I, in healthy adults, as well as the tolerability of longer-term exposure of both oral MRX-I and linezolid. Thirty subjects in part 1 received single ascending doses of MRX-I or placebo under fasting or fed condition in a double-blind crossover design. Twelve subjects in part 2 received MRX-I at 800 mg every 12 h (q12h) for 14 days in a double-blind, placebo-controlled design. In part 3, 24 subjects were randomized to receive 28 days of MRX-I at 800 mg q12h or oral linezolid at 600 mg q12h for 28 days in a double-blind, double-dummy design. Oral MRX-I was associated with a greater bioavailability and exposure when administered with food, and minimal accumulation of MRX-I occurred after multiple-dose administration. Oral MRX-I was well tolerated at single doses of up to 1,200 and 800 mg q12h for up to 28 days; all adverse events were mild to moderate in severity, and there was no drug discontinuation due to adverse events. These data support further clinical development of oral MRX-I in the treatment of resistant Gram-positive bacterial infections. Copyright © 2017 American Society for Microbiology.

Rapid detection of ERG11 gene mutations in clinical Candida albicans isolates with reduced susceptibility to fluconazole by rolling circle amplification and DNA sequencing

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Ellis David

2009-08-01

Full Text Available Abstract Background Amino acid substitutions in the target enzyme Erg11p of azole antifungals contribute to clinically-relevant azole resistance in Candida albicans. A simple molecular method for rapid detection of ERG11 gene mutations would be an advantage as a screening tool to identify potentially-resistant strains and to track their movement. To complement DNA sequencing, we developed a padlock probe and rolling circle amplification (RCA-based method to detect a series of mutations in the C. albicans ERG11 gene using "reference" azole-resistant isolates with known mutations. The method was then used to estimate the frequency of ERG11 mutations and their type in 25 Australian clinical C. albicans isolates with reduced susceptibility to fluconazole and in 23 fluconazole-susceptible isolates. RCA results were compared DNA sequencing. Results The RCA assay correctly identified all ERG11 mutations in eight "reference" C. albicans isolates. When applied to 48 test strains, the RCA method showed 100% agreement with DNA sequencing where an ERG11 mutation-specific probe was used. Of 20 different missense mutations detected by sequencing in 24 of 25 (96% isolates with reduced fluconazole susceptibility, 16 were detected by RCA. Five missense mutations were detected by both methods in 18 of 23 (78% fluconazole-susceptible strains. DNA sequencing revealed that mutations in non-susceptible isolates were all due to homozygous nucleotide changes. With the exception of the mutations leading to amino acid substitution E266D, those in fluconazole-susceptible strains were heterozygous. Amino acid substitutions common to both sets of isolates were D116E, E266D, K128T, V437I and V488I. Substitutions unique to isolates with reduced fluconazole susceptibility were G464 S (n = 4 isolates, G448E (n = 3, G307S (n = 3, K143R (n = 3 and Y123H, S405F and R467K (each n = 1. DNA sequencing revealed a novel substitution, G450V, in one isolate. Conclusion The sensitive RCA

Reduced Insecticide Susceptibility in Aedes vexans (Diptera: Culicidae) Where Agricultural Pest Management Overlaps With Mosquito Abatement.

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Dunbar, Mike W; Bachmann, Amanda; Varenhorst, Adam J

2018-05-04

Mosquito abatement programs in Midwestern communities frequently exist within landscapes dominated by agriculture. Although separately managed, both agricultural pests and mosquitoes are targeted by similar classes of insecticides. As a result, there is the potential for unintended insecticide exposure to mosquito populations from agricultural pest management. To determine the impact that agricultural management practices have on mosquito insecticide susceptibility we compared the mortality of Aedes vexans (Meigen; Diptera: Culicidae) between populations sampled from locations with and without mosquito abatement in South Dakota, a region dominated by agricultural production. Collection locations were either within towns with mosquito abatement programs (n = 2; Brookings and Sioux Falls, SD) or located > 16 km from towns with mosquito abatement programs (n = 2; areas near Harrold and Willow Lake, SD). WHO bioassays were used to test susceptibly of adults to differing insecticide classes relative to their respective controls; 1) an organochlorine (dieldrin 4%), 2) an organophosphate (malathion 5%), and 3) a pyrethroid (lambda-cyhalothrin 0.05%). Corrected mortality did not significantly differ between locations with or without abatement; however, when locations were analized by proportion of developed land within the surrounding landscape pyrethroid mortality was significantly lower where crop production dominated the surrounding landscape and mosquito abatement was present. These data suggest that agricultural pest management may incidentally contribute to reduced mosquito susceptibility where overlap between agricultural pest management and mosquito abatement exists. Decoupling insecticide classes used by both agricultural and public health pest management programs may be necessary to ensure continued efficacy of pest management tools.

Ampicillin-resistant Enterococcus faecium clonal complex 17 is widespread in healthy dogs: anthropozoonosis or zooanthroponosis?

DEFF Research Database (Denmark)

Damborg, Peter Panduro; Williams, Nicola J; Willems, Rob

2008-01-01

%) or rifampicin (56%) was frequent. Only few isolates were resistant to gentamicin (5%), linezolid (14%) and quinopristin/dalfopristin (15%) and all were susceptible to vancomycin. Conclusion: This is the first report describing the occurrence of AREfm CC17 in dogs. The results suggest that dogs may contribute...

Occurrence of vancomycin-resistant Staphylococcus aureus in the oral cavity of patients with dental caries.

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Vellappally, Sajith; Divakar, Darshan Devang; Al Kheraif, Abdulaziz Abdullah; Ramakrishnaiah, Ravikumar; Alqahtani, Amer; Dalati, M H N; Anil, Sukumaran; Khan, Aftab Ahmed; Harikrishna Varma, P R

2017-09-01

Oral streptococci are the major group of microbes isolated from oral microflora. They represent frequent pathogens of infective endocarditis (IE), and it is assumed that in most of the cases oral streptococci are acquired via mucosa layer of oral cavity. Staphylococcus aureus is also frequently isolated from IE as it accounts for 20%-30% of all cases. Vancomycin has been the most reliable therapeutic agent against infections caused by methicillin-resistant S. aureus (MRSA). The main objective of this study was to examine the occurrence of S. aureus species in dental caries specimens. Antimicrobial susceptibility testing of S. aureus to four antibiotics namely vancomycin, linezolid, teicoplanin, and daptomycin was performed. Detection of vancomycin resistance was conducted using polymerase chain reaction. Among the tested 150 strains, 98 were MRSA and of that 54 were vancomycin sensitive and 27 were resistant. All 98 MRSA strains were positive for mecA and 36 yielded pvl, whereas 13 carried vanA and only 2 were positive for vanB. Majority of the isolates showed sensitivity toward daptomycin and linezolid. Strains of S. aureus exhibiting decreased susceptibility to different antibiotics like vancomycin, daptomycin, and linezolid severely compromise the therapeutic alternatives and require a considerable amount of time, public awareness, and integrative health-care strategies to prevent the emergence of resistance to these compounds.

Identification of highly susceptible individuals in complex networks

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Tang, Shaoting; Teng, Xian; Pei, Sen; Yan, Shu; Zheng, Zhiming

2015-08-01

Identifying highly susceptible individuals in spreading processes is of great significance in controlling outbreaks. In this paper, we explore the susceptibility of people in susceptible-infectious-recovered (SIR) and rumor spreading dynamics. We first study the impact of community structure on people's susceptibility. Although the community structure can reduce the number of infected people for same infection rate, it will not significantly affect nodes' susceptibility. We find the susceptibility of individuals is sensitive to the choice of spreading dynamics. For SIR spreading, since the susceptibility is highly correlated to nodes' influence, the topological indicator k-shell can better identify highly susceptible individuals, outperforming degree, betweenness centrality and PageRank. In contrast, in rumor spreading model, where nodes' susceptibility and influence have no clear correlation, degree performs the best among considered topological measures. Our finding highlights the significance of both topological features and spreading mechanisms in identifying highly susceptible population.

High-risk human papillomavirus E7 expression reduces cell-surface MHC class I molecules and increases susceptibility to natural killer cells

DEFF Research Database (Denmark)

Bottley, G; Watherston, O G; Hiew, Y-L

2007-01-01

a role for E7 in tumour immune evasion. We show that knockdown of E7 expression in HPV16- and HPV18-transformed cervical carcinoma cells by RNA interference increased expression of major histocompatibility complex (MHC) class I at the cell surface and reduced susceptibility of these cells to natural...... killer (NK) cells. Tetracycline-regulated induction of HPV16 E7 resulted in reduced expression of cell surface MHC class I molecules and increased NK cell killing. Our results suggest that, for HPV-associated malignancies, reduced MHC class I expression is the result of an active immune evasion strategy...

In vitro antimicrobial susceptibility in clinical isolates of Enterococcus species Susceptibilidad antimicrobiana in vitro en aislamientos clínicos de Enterococcus species

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Ernesto Calderón-Jaimes

2003-04-01

Full Text Available OBJECTIVE: To describe the antimicrobial activity of several antimicrobial agents against 97 clinical significant isolates of Enterococcus spp. MATHERIAL AND METHODS: During a 2-year prospective study at Instituto Nacional de Pediatria (National Institute of Pediatrics in Mexico City. Ninety seven strains of Enterococcus spp. (60 E. faecalis and 37 E. faecium were tested against 11 antibiotics. Susceptibility tests were performed with agar, according to the standards of the sNational Committee for Clinical Laboratory Standards (NCCLS. Isolates were screened for high-level resistance (HLR to beta-lactams, aminoglycosides, glycopeptides and other antibiotics, as well as for vancomycin-phenotypes. Differences between proportions were evaluated with chi2 of Fisher exact fest. RESULTS: Overall resistance rates to the antibiotics tested were: 17/97 (17.5% to penicillin, ampicillin, amoxicillin-clavulanate and imipenem. There was neither HLR nor beta-lactamase production; 74/97 (48.4% were resistant to erythromycin; 60% to ciprofloxacin; 31/97 (32% to gentamicin, and 55/97 (56.7% to streptomycin. Seven strains were vancomycin-resistant enterococci (VRE, all of them identified as E. faecium; 5/7 with Van A and 2/7 with Van B phenotypes. All the isolates were susceptible to linezolid. The difference in susceptibility among species was significant. CONCLUSIONS: Mutidrug-resistant enterococci is a real problem and continuous surveillance is necessary. The microbiology laboratory is the first line of defense against the spread of multiantibiotic-resistan enterococci in the hospital environment . All the strains recovered should be tested for susceptibility to ampicillin, streptomycin, gentamicin and glycopeptides.OBJECTIVO: Describir la actividad antimicrobiana de varios antibióticos, contra 97 cepas de Enterococcus spp., consideradas como aislamientos clínicamente significativos. MATERIAL Y MÉTODOS: En un estudio prospectivo de dos años, (enero de 1998

Síndrome serotoninérgico en anciano con falla renal crónica tratada con linezolid: reporte de caso

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Mauricio Montoya Cañón

2016-04-01

Entre los factores de riesgo para desarrollo de síndrome serotoninérgico se encuentra el uso de linezolid, que en combinación de otros medicamentos con acción serotoninérgica —como los inhibidores selectivos de recaptación de serotonina, el litio, la trazodona, entre otros— se asocia con la presentación de este cuadro. El síndrome serotoninérgico puede ser evitado con una buena educación al personal médico y la modificación de las conductas de prescripción de medicamentos; el pilar del tratamiento se basa en la suspensión de los fármacos que están causando el cuadro y el planteamiento de medidas de soporte.

Frequency and Antibiogram of Vancomycin Resistant Enterococcus in a Tertiary Care Hospital

International Nuclear Information System (INIS)

Babar, N.; Usman, J.; Munir, T.; Gill, M. M.; Anjum, R.; Gilani, M.; Latif, M.

2014-01-01

Objective: To determine the frequency of Vancomycin Resistant Enterococcus (VRE) in a tertiary care hospital of Rawalpindi, Pakistan. Study Design: Observational, cross-sectional study. Place and Duration of Study: Department of Microbiology, Army Medical College, Rawalpindi, from May 2011 to May 2012. Methodology: Vancomycin resistant Enterococcus isolated from the clinical specimens including blood, pus, double lumen tip, ascitic fluid, tracheal aspirate, non-directed bronchial lavage (NBL), cerebrospinal fluid (CSF), high vaginal swab (HVS) and catheter tips were cultured on blood agar and MacConkey agar, while the urine samples were grown on cystine lactose electrolyte deficient agar. Later the antimicrobial susceptibility testing of the isolates was carried out using the modified Kirby-Bauer disc diffusion method on Mueller Hinton agar. Results: A total of 190 enterococci were isolated. Of these, 22 (11.57%) were found to be resistant to vancomycin. The antimicrobial sensitivity pattern revealed maximum resistance against ampicillin (86.36%) followed by erythromycin (81.81%) and gentamicin (68.18%) while all the isolates were 100% susceptible to chloramphenicol and linezolid. Conclusion: The frequency of VRE was 11.57% with the highest susceptibility to linezolid and chloramphenicol. (author)

Effect of pre-strain on susceptibility of Indian Reduced Activation Ferritic Martensitic Steel to hydrogen embrittlement

International Nuclear Information System (INIS)

Sonak, Sagar; Tiwari, Abhishek; Jain, Uttam; Keskar, Nachiket; Kumar, Sanjay; Singh, Ram N.; Dey, Gautam K.

2015-01-01

The role of pre-strain on hydrogen embrittlement susceptibility of Indian Reduced Activation Ferritic Martensitic Steel was investigated using constant nominal strain-rate tension test. The samples were pre-strained to different levels of plastic strain and their mechanical behavior and mode of fracture under the influence of hydrogen was studied. The effect of plastic pre-strain in the range of 0.5–2% on the ductility of the samples was prominent. Compared to samples without any pre-straining, effect of hydrogen was more pronounced on pre-strained samples. Prior deformation reduced the material ductility under the influence of hydrogen. Up to 35% reduction in the total strain was observed under the influence of hydrogen in pre-strained samples. Hydrogen charging resulted in increased occurrence of brittle zones on the fracture surface. Hydrogen Enhanced Decohesion (HEDE) was found to be the dominant mechanism of fracture.

Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease.

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Stein, J H; Keevil, J G; Wiebe, D A; Aeschlimann, S; Folts, J D

1999-09-07

In vitro, the flavonoid components of red wine and purple grape juice are powerful antioxidants that induce endothelium-dependent vasodilation of vascular rings derived from rat aortas and human coronary arteries. Although improved endothelial function and inhibition of LDL oxidation may be potential mechanisms by which red wine and flavonoids reduce cardiovascular risk, the in vivo effects of grape products on endothelial function and LDL oxidation have not been investigated. This study assessed the effects of ingesting purple grape juice on endothelial function and LDL susceptibility to oxidation in patients with coronary artery disease (CAD). Fifteen adults with angiographically documented CAD ingested 7.7+/-1.2 mL. kg(-1). d(-1) of purple grape juice for 14 days. Flow-mediated vasodilation (FMD) was measured using high-resolution brachial artery ultrasonography. Susceptibility of LDL particles to oxidation was determined from the rate of conjugated diene formation after exposure to copper chloride. At baseline, FMD was impaired (2.2+/-2. 9%). After ingestion of grape juice, FMD increased to 6.4+/-4.7% (P=0.003). In a linear regression model that included age, artery diameter, lipid values, and use of lipid-lowering and antioxidant therapies, the effect of grape juice on FMD remained significant (mean change 4.2+/-4.4%, PFMD and reduces LDL susceptibility to oxidation in CAD patients. Improved endothelium-dependent vasodilation and prevention of LDL oxidation are potential mechanisms by which flavonoids in purple grape products may prevent cardiovascular events, independent of alcohol content.

Antimicrobial susceptibility of microorganisms isolated from sputum culture of patients with cystic fibrosis: Methicillin-resistant Staphylococcus aureus as a serious concern.

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Mazloomi Nobandegani, Narges; Mahmoudi, Shima; Pourakbari, Babak; Hosseinpour Sadeghi, Reihaneh; Najafi Sani, Mehri; Farahmand, Fateme; Motamed, Farzaneh; Nabavizadeh Rafsanjani, Raheleh; Mamishi, Setareh

2016-11-01

Infection is a major cause of morbidity and mortality in patients with cystic fibrosis (CF). Antimicrobial resistance of the bacterial spp. particularly methicillin resistance in Staphylococcus aureus has caused a lot of attention. The aim of this study was to describe the prevalence of S. aureus, Pseudomonas aeruginosa and Burkholderia cepacia-complex as well as their antimicrobial susceptibility patterns in CF patients in an Iranian referral pediatrics Hospital. From March 2011 until February 2012, 172 samples were collected at the Children Medical Center (CMC), an Iranian referral hospital in Tehran, Iran. Sputum specimens were cultured for the following bacterial pathogens: P. aeruginosa, S. aureus, B. cepacia complex. Antimicrobial susceptibility was performed according to the Clinical Laboratory Standards Institute recommendations. In our study, 54% of the patients (n = 93) harbored at least once S. aureus, 30% (n = 52) P. aeruginosa, and 2% (n = 3) Burkholderia cepacia. In 40 patients (23%), none of these organisms was grown. An increasing colonization rate of P. aeruginosa in the second decade of life was found. In contrast, the colonization rate of S. aureus was constant in both decades of life. Methicillin resistant S. aureus (MRSA) was detected in 40 isolates (43%). Among MRSA, no resistance against vancomycin, linezolid and quinupristin/dalfopristin occurred. The susceptibility of P. aeruginosa isolates to meropenem, imipenem, doripenem, levofloxacin and polymixin B were more than 90%. The prevalence of MRSA has been rising. Since its impact on clinical outcomes, optimal prevention and treatment strategies are unclear, further studies to expand the knowledge about the infection control strategies and MRSA treatment are highly recommended. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mutations in the Primary Sigma Factor σA and Termination Factor Rho That Reduce Susceptibility to Cell Wall Antibiotics

Science.gov (United States)

Lee, Yong Heon

2014-01-01

Combinations of glycopeptides and β-lactams exert synergistic antibacterial activity, but the evolutionary mechanisms driving resistance to both antibiotics remain largely unexplored. By repeated subculturing with increasing vancomycin (VAN) and cefuroxime (CEF) concentrations, we isolated an evolved strain of the model bacterium Bacillus subtilis with reduced susceptibility to both antibiotics. Whole-genome sequencing revealed point mutations in genes encoding the major σ factor of RNA polymerase (sigA), a cell shape-determining protein (mreB), and the ρ termination factor (rho). Genetic-reconstruction experiments demonstrated that the G-to-C substitution at position 336 encoded by sigA (sigAG336C), in the domain that recognizes the −35 promoter region, is sufficient to reduce susceptibility to VAN and works cooperatively with the rhoG56C substitution to increase CEF resistance. Transcriptome analyses revealed that the sigAG336C substitution has wide-ranging effects, including elevated expression of the general stress σ factor (σB) regulon, which is required for CEF resistance, and decreased expression of the glpTQ genes, which leads to fosfomycin (FOS) resistance. Our findings suggest that mutations in the core transcriptional machinery may facilitate the evolution of resistance to multiple cell wall antibiotics. PMID:25112476

Fabrification of electroreduced graphene oxide–bentonite sodium composite modified electrode and its sensing application for linezolid

International Nuclear Information System (INIS)

Prashanth, S.N.; Teradal, Nagappa L.; Seetharamappa, J.; Satpati, Ashis K.; Reddy, A.V.R.

2014-01-01

Graphene and its composites have attracted considerable attention in synthesis and electrochemical applications. In the present work, we have synthesized and characterized graphene oxide-bentonite composite (GO-BEN) and utilized it to fabricate an electrochemical sensor. For this, the solution of GO-BEN cast on glassy carbon electrode (GCE) was reduced electrochemically in phosphate buffer solution of pH 6 to obtain electrochemically reduced graphene oxide-bentonite composite (ERGO-BEN-GCE). This ERGO-BEN film was used for electrochemical investigation of an oxazolidinone class of antibiotic, linezolid (LIN) for the first time. The electrochemical sensor showed excellent enhancement and adsorptive ability towards the electrooxidation of LIN. LIN exhibited two each of oxidation and reduction peaks on ERGO-BEN film in phosphate buffer of pH 7.0. Effects of accumulation time, pH of solution and scan rate were studied and various electrochemical parameters were evaluated. The plot of pH versus E p gave a slope of 26.2 mV/pH in the pH range of 4.2-8.0 indicating the participation of two electrons and one proton in the electrode process. An adsorptive stripping differential pulse voltammetric method (AdSDPV) was developed for the determination of LIN in bulk, pharmaceutical formulations and urine samples. Adsorptive stripping linear sweep voltammetric (AdSLSV) and differential pulse voltammetric (DPV) methods were also developed and the results were compared. LIN showed linear relationship between the current density and concentration in the range of 0.25 - 31.25 μM with a LOD of 0.0337 μM in AdSDPV method; 0.5 - 31.25 μM with a LOD of 0.100 μM in DPV method and 1.25 - 37.5 μM with a LOD of 0.5461 μM in AdSLSV method respectively. The proposed AdSDPV method was observed to be simple, fast and inexpensive and hence, could be readily adopted for quality control in pharmaceutical products

Epidemiology and susceptibility to antimicrobial agents of the main Nocardia species in Spain.

Science.gov (United States)

Valdezate, Sylvia; Garrido, Noelia; Carrasco, Gema; Medina-Pascual, María J; Villalón, Pilar; Navarro, Ana M; Saéz-Nieto, Juan A

2017-03-01

The aims of this study were to explore the clinical distribution, by species, of the genus Nocardia and to assess the antimicrobial susceptibilities of the 10 most prevalent species identified in Spain. Over a 10 year period (2005-14), 1119 Nocardia strains were molecularly identified and subjected to the Etest. The distribution and resistance trends over the sub-periods 2005-09 and 2010-14 were also examined. Of the strains examined, 82.9% belonged to the following species: Nocardia cyriacigeorgica (25.3%), Nocardia nova (15.0%), Nocardia abscessus (12.7%), Nocardia farcinica (11.4%), Nocardia carnea (4.3%), Nocardia brasiliensis (3.5%), Nocardia otitidiscaviarum (3.1%), Nocardia flavorosea (2.6%), Nocardia rhamnosiphila (2.6%) and Nocardia transvalensis (2.4%). Their prevalence values were similar during 2005-09 and 2010-14, except for those of N. abscessus , N. farcinica and N. transvalensis , which fell significantly in the second sub-period ( P ≤  0.05). The major location of isolation was the respiratory tract (∼86%). Half (13/27) of all strains from the CNS were N. farcinica . Significant differences in MIC results were recorded for some species between the two sub-periods. According to the CLSI's breakpoints, low resistance rates (≤15%) were recorded for seven species with respect to cefotaxime, imipenem and tobramycin; five species showed similar rates with respect to trimethoprim/sulfamethoxazole. Linezolid and amikacin were the most frequently active agents. The accurate identification of the infecting species and the determination of its susceptibility to antimicrobial agents, given the large number of strains with atypical patterns, are crucial if patients with nocardiosis are to be successfully treated. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Phenotypic dissection of a Plasmodium-refractory strain of malaria vector Anopheles stephensi: the reduced susceptibility to P. berghei and P. yoelii.

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Naoaki Shinzawa

Full Text Available Anopheline mosquitoes are the major vectors of human malaria. Parasite-mosquito interactions are a critical aspect of disease transmission and a potential target for malaria control. Current investigations into parasite-mosquito interactions frequently assume that genetically resistant and susceptible mosquitoes exist in nature. Therefore, comparisons between the Plasmodium susceptibility profiles of different mosquito species may contribute to a better understanding of vectorial capacity. Anopheles stephensi is an important malaria vector in central and southern Asia and is widely used as a laboratory model of parasite transmission due to its high susceptibility to Plasmodium infection. In the present study, we identified a rodent malaria-refractory strain of A. stephensi mysorensis (Ehime by comparative study of infection susceptibility. A very low number of oocysts develop in Ehime mosquitoes infected with P. berghei and P. yoelii, as determined by evaluation of developed oocysts on the basal lamina. A stage-specific study revealed that this reduced susceptibility was due to the impaired formation of ookinetes of both Plasmodium species in the midgut lumen and incomplete crossing of the midgut epithelium. There were no apparent abnormalities in the exflagellation of male parasites in the ingested blood or the maturation of oocysts after the rounding up of the ookinetes. Overall, these results suggest that invasive-stage parasites are eliminated in both the midgut lumen and epithelium in Ehime mosquitoes by strain-specific factors that remain unknown. The refractory strain newly identified in this report would be an excellent study system for investigations into novel parasite-mosquito interactions in the mosquito midgut.

The knock-down of the expression of MdMLO19 reduces susceptibility to powdery mildew (Podosphaera leucotricha) in apple (Malus domestica).

Science.gov (United States)

Pessina, Stefano; Angeli, Dario; Martens, Stefan; Visser, Richard G F; Bai, Yuling; Salamini, Francesco; Velasco, Riccardo; Schouten, Henk J; Malnoy, Mickael

2016-10-01

Varieties resistant to powdery mildew (PM; caused by Podosphaera leucotricha) are a major component of sustainable apple production. Resistance can be achieved by knocking-out susceptibility S-genes to be singled out among members of the MLO (Mildew Locus O) gene family. Candidates are MLO S-genes of phylogenetic clade V up-regulated upon PM inoculation, such as MdMLO11 and 19 (clade V) and MdMLO18 (clade VII). We report the knock-down through RNA interference of MdMLO11 and 19, as well as the complementation of resistance with MdMLO18 in the Arabidopsis thaliana triple mlo mutant Atmlo2/6/12. The knock-down of MdMLO19 reduced PM disease severity by 75%, whereas the knock-down of MdMLO11, alone or in combination with MdMLO19, did not result in any reduction or additional reduction of susceptibility compared with MdMLO19 alone. The test in A. thaliana excluded a role for MdMLO18 in PM susceptibility. Cell wall appositions (papillae) were present in both PM-resistant and PM-susceptible plants, but were larger in resistant lines. No obvious negative phenotype was observed in plants with mlo genes knocked down. Apparently, MdMLO19 plays the pivotal role in apple PM susceptibility and its knock-down induces a very significant level of resistance. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

Antimicrobial Drug Resistance of Salmonella enterica Serovar Typhi in Asia and Molecular Mechanism of Reduced Susceptibility to the Fluoroquinolones▿

OpenAIRE

Chau, Tran Thuy; Campbell, James Ian; Galindo, Claudia M.; Van Minh Hoang, Nguyen; Diep, To Song; Nga, Tran Thu Thi; Van Vinh Chau, Nguyen; Tuan, Phung Quoc; Page, Anne Laure; Ochiai, R. Leon; Schultsz, Constance; Wain, John; Bhutta, Zulfiqar A.; Parry, Christopher M.; Bhattacharya, Sujit K.

2007-01-01

This study describes the pattern and extent of drug resistance in 1,774 strains of Salmonella enterica serovar Typhi isolated across Asia between 1993 and 2005 and characterizes the molecular mechanisms underlying the reduced susceptibilities to fluoroquinolones of these strains. For 1,393 serovar Typhi strains collected in southern Vietnam, the proportion of multidrug resistance has remained high since 1993 (50% in 2004) and there was a dramatic increase in nalidixic acid resistance between ...

Effectiveness of simple control measures on methicillin-resistant Staphylococcus aureus infection status and characteristics with susceptibility patterns in a teaching hospital in Peshawar.

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Rafiq, Muhammad Salman; Rafiq, Muhammad Imran; Khan, Taimur; Rafiq, Maria; Khan, Mah Muneer

2015-09-01

To determine the effectiveness of simple control measures on the infection status and characteristics of methicillin-resistant Staphylococcus aureus including susceptibility patterns among health professionals and patients in a teaching hospital. The cross-sectional study was conducted from September 2013 to January 2014, and comprised samples collected from healthcare personnel and patients in the various units of Khyber Teaching Hospital, Peshawar. The specimens were collected before and one month after the implementation of simple control measures for outbreak prevention of methicillin-resistant Staphylococcus aureus. These were tested for culture and antimicrobial susceptibility. Data about methicillin-sensitive and methicillin-resistant Staphylococcus aureus infection, wound characteristics and susceptibility patterns was collected and effectiveness of simple control measures was determined. SPSS 20 was used for statistical analysis. Of the total 390 isolates, 180(46.2%) were Staphylococcus aureus; 77(19.7%) from healthcare personnel and 103(26.4%) from patients. Of these, 164(42.1%) were methicillin-sensitive and 16(4.1%) were methicillin-resistant. Among the patients, 38(15.1%) methicillin-sensitive and 8(3.2%) methicillin-resistant isolates were recovered from wounds or skin and soft tissues. Pus with 33(13.1%) and 4(1.6%) cases respectively was the second most common source. Among methicillin-resistant isolates, resistance to Linezolid was 0%, all were resistant to Oxacillin, Cefoxitin, Amoxicillin, Cefotaxime and Cephradine, and resistance to both Co-Amoxiclav and Ciprofloxacin was 87.5%. After one month of implementation of simple control measures, the number of methicillin-resistant cases among healthcare professionals and patients dropped from 4(2.9%) and 7(10.8%) to 1(0.7%) and 5(2.7%), respectively. Methicillin-resistant and methicillin-sensitive Staphylococcus aureus differed in their anti-microbial susceptibility profiles. Selection of antibiotics

Surveillance for vancomycin resistant enterococci in a tertiary ...

African Journals Online (AJOL)

Three were resistant to Ampicillin and nine to Ciprofloxacin but all were susceptible to Linezolid. High-level resistance to Gentamicin was found in four VRE isolates. Conclusion: There is a low prevalence of VRE in Lagos University Teaching Hospital which may be spreading among patients in affected wards. Keywords: ...

Antipneumococcal activity of ceftobiprole, a novel broad-spectrum cephalosporin.

Science.gov (United States)

Kosowska, Klaudia; Hoellman, Dianne B; Lin, Gengrong; Clark, Catherine; Credito, Kim; McGhee, Pamela; Dewasse, Bonifacio; Bozdogan, Bülent; Shapiro, Stuart; Appelbaum, Peter C

2005-05-01

Ceftobiprole (previously known as BAL9141), an anti-methicillin-resistant Staphylococcus aureus cephalosporin, was very highly active against a panel of 299 drug-susceptible and -resistant pneumococci, with MIC(50) and MIC(90) values (microg/ml) of 0.016 and 0.016 (penicillin susceptible), 0.06 and 0.5 (penicillin intermediate), and 0.5 and 1.0 (penicillin resistant). Ceftobiprole, imipenem, and ertapenem had lower MICs against all pneumococcal strains than amoxicillin, cefepime, ceftriaxone, cefotaxime, cefuroxime, or cefdinir. Macrolide and penicillin G MICs generally varied in parallel, whereas fluoroquinolone MICs did not correlate with penicillin or macrolide susceptibility or resistance. All strains were susceptible to linezolid, quinupristin-dalfopristin, daptomycin, vancomycin, and teicoplanin. Time-kill analyses showed that at 1x and 2x the MIC, ceftobiprole was bactericidal against 10/12 and 11/12 strains, respectively. Levofloxacin, moxifloxacin, vancomycin, and teicoplanin were each bactericidal against 10 to 12 strains at 2x the MIC. Azithromycin and clarithromycin were slowly bactericidal, and telithromycin was bactericidal against only 5/12 strains at 2x the MIC. Linezolid was mainly bacteriostatic, whereas quinupristin-dalfopristin and daptomycin showed marked killing at early time periods. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to yield mutants with high MICs towards this cephalosporin, and single-passage selection showed very low frequencies of spontaneous mutants with breakthrough MICs towards ceftobiprole.

Relaxin reduces susceptibility to post-infarct atrial fibrillation in mice due to anti-fibrotic and anti-inflammatory properties

DEFF Research Database (Denmark)

Beiert, Thomas; Tiyerili, Vedat; Knappe, Vincent

2017-01-01

Background Relaxin-2 (RLX) is a peptide hormone that exerts beneficial anti-fibrotic and anti-inflammatory effects in diverse models of cardiovascular disease. The goal of this study was to determine the effects of RLX treatment on the susceptibility to atrial fibrillation (AF) after myocardial...... infarction (MI). Methods Mice with cryoinfarction of the left anterior ventricular wall were treated for two weeks with either RLX (75 μg/kg/d) or vehicle (sodium acetate) delivered via subcutaneously implanted osmotic minipumps. Results RLX treatment significantly attenuated the increase in AF......-inducibility following cryoinfarction and reduced the mean duration of AF episodes. Furthermore, epicardial mapping of both atria revealed an increase in conduction velocity. In addition to an attenuation of atrial hypertrophy, chronic application of RLX reduced atrial fibrosis, which was linked to a significant...

Molecular characterization and antimicrobial susceptibility of nasal Staphylococcus aureus isolates from a Chinese medical college campus.

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Jimei Du

Full Text Available Staphylococcus aureus colonization and infection occur more commonly among persons living or working in crowded conditions, but characterization of S. aureus colonization within medical communities in China is lacking. A total of 144 (15.4%, 144/935 S. aureus isolates, including 28 (3.0%, 28/935 MRSA isolates, were recovered from the nares of 935 healthy human volunteers residing on a Chinese medical college campus. All S. aureus isolates were susceptible to vancomycin, quinupristin/dalfopristin and linezolid but the majority were resistant to penicillin (96.5%, ampicillin/sulbactam (83.3% and trimethoprim/sulfamethoxazole (93.1%. 82%, (23/28 of the MRSA isolates and 66% (77/116 of the MSSA isolates were resistant to multiple antibiotics, and 3 MRSA isolates were resistant to mupirocin--an agent commonly used for nasal decolonization. 16 different sequence types (STs, as well as SCCmec genes II, III, IVd, and V, were represented among MRSA isolates. We also identified, for the first time, two novel STs (ST1778 and ST1779 and 5 novel spa types for MRSA. MRSA isolates were distributed in different sporadic clones, and ST59-MRSA-VId- t437 was found within 3 MRSA isolates. Moreover, one isolate with multidrug resistance belonging to ST398-MRSA-V- t571 associated with animal infections was identified, and 3 isolates distributed in three different clones harbored PVL genes. Collectively, these data indicate a high prevalence of nasal MRSA carriage and molecular heterogeneity of S. aureus isolates among persons residing on a Chinese medical college campus. Identification of epidemic MRSA clones associated with community infection supports the need for more effective infection control measures to reduce nasal carriage and prevent dissemination of MRSA to hospitalized patients and health care workers in this community.

School connectedness and susceptibility to smoking among adolescents in Canada.

Science.gov (United States)

Azagba, Sunday; Asbridge, Mark

2013-08-01

Smoking susceptibility in early adolescence is strongly predictive of subsequent smoking behavior in youth. As such, smoking susceptibility represents a key modifiable factor in reducing the onset of smoking in young people. A growing literature has documented a number of factors that influence susceptibility to smoking; however, there is limited amount of research examining associations of susceptibility to smoking and school connectedness. The current study examines whether school connectedness has an independent protective effect on smoking susceptibility among younger adolescents. A nationally representative sample of 12,894 Canadian students in grades 6-8 (11-14 years old), surveyed as part of the 2010-2011 Youth Smoking Survey, was analyzed. Multilevel logistic regression models examined unadjusted and adjusted associations between school connectedness and smoking susceptibility. The impacts of other covariates on smoking susceptibility were also explored. Approximately 29% of never-smokers students in grades 6-8 in Canada were susceptible to future smoking. Logistic regression analysis, controlling for standard covariates, found that school connectedness had strong protective effects on smoking susceptibility (odds ratio [OR] 0.91, 95% CI 0.89-0.94). The finding that school connectedness is protective of smoking susceptibility, together with previous research, provides further evidence that improving school conditions that promote school connectedness could reduce risky behavior in adolescents. While prevention efforts should be directed at youth of all ages, particular attention must be paid to younger adolescents in the formative period of 11-14 years of age.

Using Reduced Inoculum Densities of Mycobacterium tuberculosis in MGIT Pyrazinamide Susceptibility Testing to Prevent False-Resistant Results and Improve Accuracy: A Multicenter Evaluation

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Glenn P. Morlock

2017-01-01

Full Text Available The primary platform used for pyrazinamide (PZA susceptibility testing of Mycobacterium tuberculosis is the MGIT culture system (Becton Dickinson. Since false-resistant results have been associated with the use of this system, we conducted a multicenter evaluation to determine the effect of using a reduced cell density inoculum on the rate of false resistance. Two reduced inoculum densities were compared with that prescribed by the manufacturer (designated as “BD” method. The reduced inoculum methods (designated as “A” and “C” were identical to the manufacturer’s protocol in all aspects with the exception of the cell density of the inoculum. Twenty genetically and phenotypically characterized M. tuberculosis isolates were tested in duplicate by ten independent laboratories using the three inoculum methods. False-resistant results declined from 21.1% using the standard “BD” method to 5.7% using the intermediate (“A” inoculum and further declined to 2.8% using the most dilute (“C” inoculum method. The percentages of the resistant results that were false-resistant declined from 55.2% for the “BD” test to 28.8% and 16.0% for the “A” and “C” tests, respectively. These results represent compelling evidence that the occurrence of false-resistant MGIT PZA susceptibility test results can be mitigated through the use of reduced inoculum densities.

New drugs and perspectives for new anti-tuberculosis regimens

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S. Tiberi

2018-03-01

Full Text Available Tuberculosis (TB is the ninth cause of global death, more than any other infectious disease. With growing drug resistance the epidemic remains and will require significant attention and investment for the elimination of this disease to occur. With susceptible TB treatment not changing over the last four decades and the advent of drug resistance, new drugs and regimens are required.Recently, through greater collaboration and research networks some progress with significant advances has taken place, not withstanding the comparatively low amount of resources invested. Of late the availability of the new drugs bedaquiline, delamanid and repurposed drugs linezolid, clofazimine and carbapenems are being used more frequently in drug-resistant TB regimens.The WHO shorter multidrug-resistant tuberculosis regimen promises to reach more patients and treat them more quickly and more cheaply.With this new enthusiasm and hope we this review gives an update on the new drugs and perspectives for the treatment of drug-susceptible and drug-resistant tuberculosis. Keywords: Bedaquiline, Delamanid, Linezolid, MDR, XDR-TB, TB

In vivo therapeutic effect of gatifloxacin on BALB/c mice infected with Nocardia brasiliensis.

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Daw-Garza, Alejandra; Welsh, Oliverio; Said-Fernández, Salvador; Lozano-Garza, Hector Gerardo; Waksman de Torres, Noemi; Rocha, Norma Cavazos; Ocampo-Candiani, Jorge; Vera-Cabrera, Lucio

2008-04-01

In the present work, we evaluated the effect of gatifloxacin on the evolution of experimental murine infection with Nocardia brasiliensis using linezolid as a control. Gatifloxacin was injected subcutaneously at 100 mg/kg body weight every 8 h for 4 weeks. This compound was equally as efficient as linezolid in reducing the production of lesions.

Mutation of a Nicotiana tabacum L. eukaryotic translation-initiation factor gene reduces susceptibility to a resistance-breaking strain of Potato Virus Y.

Science.gov (United States)

Takakura, Yoshimitsu; Udagawa, Hisashi; Shinjo, Akira; Koga, Kazuharu

2018-04-06

Eukaryotic translation-initiation factors eIF4E and eIF(iso)4E in plants play key roles in infection by potyviruses and other plant RNA viruses. Mutations in the genes encoding these factors reduce susceptibility to the viruses, and are the basis of several recessive virus-resistance genes widely used in plant breeding. Because virus variants occasionally break such resistance, the molecular basis for this process must be elucidated. Although deletion mutants of eIF4E1-S of tobacco (Nicotiana tabacum L.) resist Potato virus Y (PVY; the type member of the genus Potyvirus), resistance-breaking strains of PVY threaten tobacco production worldwide. Here, we used RNA interference technology to knock down tobacco eIF4E2-S and eIF4E2-T genes or eIF(iso)4E-S and eIF(iso)4E-T genes. Transgenic plants with reduced transcript levels of both eIF(iso)4E-S and eIF(iso)4E-T showed reduced susceptibility to a resistance-breaking PVY strain with a K105E mutation in the viral genome-associated protein (VPg). By screening a population of chemically-induced mutants of eIF(iso)4E-S and eIF(iso)4E-T, we showed that plants with a nonsense mutation in eIF(iso)4E-T, but not eIF(iso)4E-S, showed reduced susceptibility to the resistance-breaking PVY strain. In a yeast two-hybrid assay, VPg of the resistance-breaking strain, but not wild-type PVY, physically interacted with the eIF(iso)4E-T protein. Thus, eIF4E1-S is required for infection by PVY, but eIF(iso)4E-T is required for infection by the resistance-breaking strain. Our study provides the first evidence for the involvement of a host eukaryotic translation-initiation factor in the infection cycle of a resistance-breaking virus strain. The eIF(iso)4E-T mutants will be useful in tobacco breeding to introduce resistance against resistance-breaking PVY strains. This article is protected by copyright. All rights reserved. © 2018 BSPP and John Wiley & Sons Ltd.

Reduced susceptibility of Enterococcus spp. isolates from Cairo University Hospital to tigecycline: Highlight on the influence of proton pump inhibitors.

Science.gov (United States)

Hassan, Reem Mostafa; Ghaith, Doaa Mohammad; Ismail, Dalia Kadry; Zafer, Mai Mahmoud

2018-03-01

The incidence of reduced susceptibility to tigecycline (TIG) is increasing. This study aimed to analyse the in vitro activity of TIG against Enterococcus spp. isolates recovered from hospitalised patients and to evaluate the effect of omeprazole on the in vitro antimicrobial activity of TIG against several enterococcal species. A total of 67 Enterococcus clinical isolates were identified by MALDI-TOF/MS and multiplex PCR. Minimum inhibitory concentrations (MICs) of TIG alone and in combination with omeprazole (10, 30 and 60mg/L) were determined by broth microdilution. Antibiotic susceptibility to other antibiotics was determined by disk diffusion. The presence of van, tet(X) and tet(X1) genes was tested by multiplex PCR. Of the 67 Enterococcus isolates, 2 (3.0%) were resistant to TIG and 13 (19.4%) were intermediate-resistant according to EUCAST. The frequencies of resistance to norfloxacin (80.6%), doxycycline (80.6%), levofloxacin (74.6%) and ciprofloxacin (71.6%) were highest, whilst that of vancomycin (25.4%) was lowest. The vanA gene was detected in 11 Enterococcus isolates (8 Enterococcus faecalis, 3 Enterococcus faecium), vanB in 3 Enterococcus isolates (2 E. faecium, 1 E. faecalis) and vanC-2/3 in 3 Enterococcus casseliflavus. Nine isolates (13.4%) were positive for tet(X1). TIG resistance occurred both in patients receiving or not TIG and/or omeprazole. Omeprazole increased TIG MICs by 4-128-fold. The possibility of selection of TIG-non-susceptible Enterococcus in the gut may occur with long-term use of omeprazole. Omeprazole influenced TIG activity in a concentration-dependent manner. To our knowledge; this is the first report of TIG-non-susceptible Enterococcus spp. in Egypt. Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

Endogenous and Exogenous KdpF Peptide Increases Susceptibility of Mycobacterium bovis BCG to Nitrosative Stress and Reduces Intramacrophage Replication

Science.gov (United States)

Rosas Olvera, Mariana; Vivès, Eric; Molle, Virginie; Blanc-Potard, Anne-Béatrice; Gannoun-Zaki, Laila

2017-01-01

Emerging antibiotic resistance in pathogenic bacteria like Mycobacterium sp., poses a threat to human health and therefore calls for the development of novel antibacterial strategies. We have recently discovered that bacterial membrane peptides, such as KdpF, possess anti-virulence properties when overproduced in pathogenic bacterial species. Overproduction of the KdpF peptide in Mycobacterium bovis BCG decreased bacterial replication within macrophages, without presenting antibacterial activity. We propose that KdpF functions as a regulatory molecule and interferes with bacterial virulence, potentially through interaction with the PDIM transporter MmpL7. We demonstrate here that KdpF overproduction in M. bovis BCG, increased bacterial susceptibility to nitrosative stress and thereby was responsible for lower replication rate within macrophages. Moreover, in a bacterial two-hybrid system, KdpF was able to interact not only with MmpL7 but also with two membrane proteins involved in nitrosative stress detoxification (NarI and NarK2), and a membrane protein of unknown function that is highly induced upon nitrosative stress (Rv2617c). Interestingly, we showed that the exogenous addition of KdpF synthetic peptide could affect the stability of proteins that interact with this peptide. Finally, the exogenous KdpF peptide presented similar biological effects as the endogenously expressed peptide including nitrosative stress susceptibility and reduced intramacrophage replication rate for M. bovis BCG. Taken together, our results establish a link between high levels of KdpF and nitrosative stress susceptibility to further highlight KdpF as a potent molecule with anti-virulence properties. PMID:28428950

Reduced deep regional cerebral venous oxygen saturation in hemodialysis patients using quantitative susceptibility mapping.

Science.gov (United States)

Chai, Chao; Liu, Saifeng; Fan, Linlin; Liu, Lei; Li, Jinping; Zuo, Chao; Qian, Tianyi; Haacke, E Mark; Shen, Wen; Xia, Shuang

2018-02-01

Cerebral venous oxygen saturation (SvO 2 ) is an important indicator of brain function. There was debate about lower cerebral oxygen metabolism in hemodialysis patients and there were no reports about the changes of deep regional cerebral SvO 2 in hemodialysis patients. In this study, we aim to explore the deep regional cerebral SvO 2 from straight sinus using quantitative susceptibility mapping (QSM) and the correlation with clinical risk factors and neuropsychiatric testing . 52 hemodialysis patients and 54 age-and gender-matched healthy controls were enrolled. QSM reconstructed from original phase data of 3.0 T susceptibility-weighted imaging was used to measure the susceptibility of straight sinus. The susceptibility was used to calculate the deep regional cerebral SvO 2 and compare with healthy individuals. Correlation analysis was performed to investigate the correlation between deep regional cerebral SvO 2 , clinical risk factors and neuropsychiatric testing. The deep regional cerebral SvO 2 of hemodialysis patients (72.5 ± 3.7%) was significantly lower than healthy controls (76.0 ± 2.1%) (P deep regional cerebral SvO 2 in patients. The Mini-Mental State Examination (MMSE) scores of hemodialysis patients were significantly lower than healthy controls (P deep regional cerebral SvO 2 did not correlate with MMSE scores (P = 0.630). In summary, the decreased deep regional cerebral SvO 2 occurred in hemodialysis patients and dialysis duration, parathyroid hormone, hematocrit, hemoglobin and red blood cell may be clinical risk factors.

Rapidly growing mycobacteria in Singapore, 2006-2011.

Science.gov (United States)

Tang, S S; Lye, D C; Jureen, R; Sng, L-H; Hsu, L Y

2015-03-01

Nontuberculous mycobacteria infection is a growing global concern, but data from Asia are limited. This study aimed to describe the distribution and antibiotic susceptibility profiles of rapidly growing mycobacterium (RGM) isolates in Singapore. Clinical RGM isolates with antibiotic susceptibility tests performed between 2006 and 2011 were identified using microbiology laboratory databases and minimum inhibitory concentrations of amikacin, cefoxitin, clarithromycin, ciprofloxacin, doxycycline, imipenem, linezolid, moxifloxacin, sulfamethoxazole or trimethoprim-sulfamethoxazole, tigecycline and tobramycin were recorded. Regression analysis was performed to detect changes in antibiotic susceptibility patterns over time. A total of 427 isolates were included. Of these, 277 (65%) were from respiratory specimens, 42 (10%) were related to skin and soft tissue infections and 36 (8%) were recovered from blood specimens. The two most common species identified were Mycobacterium abscessus (73%) and Mycobacterium fortuitum group (22%), with amikacin and clarithromycin being most active against the former, and quinolones and trimethoprim-sulfamethoxazole against the latter. Decreases in susceptibility of M. abscessus to linezolid by 8.8% per year (p 0.001), M. fortuitum group to imipenem by 9.5% per year (p 0.023) and clarithromycin by 4.7% per year (p 0.033) were observed. M. abscessus in respiratory specimens is the most common RGM identified in Singapore. Antibiotic options for treatment of RGM infections are increasingly limited. Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Biofilm Formation and Antimicrobial Susceptibility of Staphylococcus epidermidis Strains from a Hospital Environment

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Robert D. Wojtyczka

2014-04-01

Full Text Available The hospital environment microflora comprise a wide variety of microorganisms which are more or less pathogenic and where staphylococci are one of the most common types. The aim of the presented study was to evaluate the prevalence of the biofilm forming coagulase-negative staphylococci (CoNS in a hospital environment as a risk factor for nosocomial infections. Among 122 isolated and tested strains of CoNS the most frequent were: S. epidermidis—32 strains, S. haemolyticus—31 strains, S. capitis subsp. capitis— 21 strains, S. hominis—11 strains, S. cohnii subsp. cohnii—nine strains. In case of CoNS, the main molecule responsible for intercellular adhesion is a polysaccharide intercellular adhesin (PIA, encoded on the ica gene operon. The analysis revealed the presence of the icaADBC operon genes in 46.88% of S. epidermidis isolates. IcaA and icaD were present in 34.38% and 28.13% of strains respectively while IcaC gene was present in 37.50% of strains. IcaB gene was found in 21.88% of S. epidermidis strains. In 15 (63% strains all icaADBC operon genes were observed. The assessment of antibacterial drugs susceptibility demonstrated that analyzed CoNS strains were highly resistant to macrolides and lincosamides and more sensitive to rifampicin and linezolid. Our data indicates that the hospital environment can be colonized by biofilm forming coagulase-negative staphylococci and transmission of these strains can cause an increased risk of serious nosocomial infections.

Biofilm formation and antimicrobial susceptibility of Staphylococcus epidermidis strains from a hospital environment.

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Wojtyczka, Robert D; Orlewska, Kamila; Kępa, Małgorzata; Idzik, Danuta; Dziedzic, Arkadiusz; Mularz, Tomasz; Krawczyk, Michał; Miklasińska, Maria; Wąsik, Tomasz J

2014-04-25

The hospital environment microflora comprise a wide variety of microorganisms which are more or less pathogenic and where staphylococci are one of the most common types. The aim of the presented study was to evaluate the prevalence of the biofilm forming coagulase-negative staphylococci (CoNS) in a hospital environment as a risk factor for nosocomial infections. Among 122 isolated and tested strains of CoNS the most frequent were: S. epidermidis-32 strains, S. haemolyticus-31 strains, S. capitis subsp. capitis- 21 strains, S. hominis-11 strains, S. cohnii subsp. cohnii-nine strains. In case of CoNS, the main molecule responsible for intercellular adhesion is a polysaccharide intercellular adhesin (PIA), encoded on the ica gene operon. The analysis revealed the presence of the icaADBC operon genes in 46.88% of S. epidermidis isolates. IcaA and icaD were present in 34.38% and 28.13% of strains respectively while IcaC gene was present in 37.50% of strains. IcaB gene was found in 21.88% of S. epidermidis strains. In 15 (63%) strains all icaADBC operon genes were observed. The assessment of antibacterial drugs susceptibility demonstrated that analyzed CoNS strains were highly resistant to macrolides and lincosamides and more sensitive to rifampicin and linezolid. Our data indicates that the hospital environment can be colonized by biofilm forming coagulase-negative staphylococci and transmission of these strains can cause an increased risk of serious nosocomial infections.

Comparative activity of ceftobiprole against Gram-positive and Gram-negative isolates from Europe and the Middle East: the CLASS study.

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Rossolini, Gian M; Dryden, Matthew S; Kozlov, Roman S; Quintana, Alvaro; Flamm, Robert K; Läuffer, Jörg M; Lee, Emma; Morrissey, Ian; CLASS Study Group

2011-01-01

to assess the in vitro activity of ceftobiprole and comparators against a recent collection of Gram-positive and Gram-negative pathogens, in order to detect potential changes in susceptibility patterns, and to evaluate the Etest assay for ceftobiprole susceptibility testing. contemporary Gram-positive and Gram-negative isolates (excluding extended-spectrum β-lactamase-producing isolates) from across Europe and the Middle East were collected, and their susceptibility to ceftobiprole, vancomycin, teicoplanin, linezolid, ceftazidime and cefepime was assessed using the Etest method. Quality testing [using Etest and broth microdilution (BMD)] was conducted at a central reference laboratory. some 5041 Gram-positive and 4026 Gram-negative isolates were included. Against Gram-positive isolates overall, ceftobiprole had the lowest MIC50 (0.5 mg/L), compared with 1 mg/L for its comparators (vancomycin, teicoplanin and linezolid). Against methicillin-resistant Staphylococcus aureus, all four agents had a similar MIC90 (2 mg/L), but ceftobiprole had a 4-fold better MIC90 (0.5 mg/L) against methicillin-susceptible strains. Only 38 Gram-positive isolates were confirmed as ceftobiprole resistant. Among Gram-negative strains, 86.9%, 91.7% and 95.2% were susceptible to ceftobiprole, ceftazidime and cefepime, respectively. Pseudomonas aeruginosa was less susceptible to all three antimicrobials than any other Gram-negative pathogen. There was generally good agreement between local Etest results and those obtained at the reference laboratory (for ceftobiprole: 86.8% with Gram-negatives; and 94.7% with Gram-positives), as well as between results obtained by BMD and Etest methods (for ceftobiprole: 98.2% with Gram-negatives; and 98.4% with Gram-positives). ceftobiprole exhibits in vitro activity against a wide range of Gram-positive and Gram-negative pathogens, including multidrug-resistant strains. No changes in its known susceptibility profile were identified.

Tobacco Marketing, E-cigarette Susceptibility, and Perceptions among Adults.

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Nicksic, Nicole E; Snell, L Morgan; Rudy, Alyssa K; Cobb, Caroline O; Barnes, Andrew J

2017-09-01

Understanding the impact of tobacco marketing on e-cigarette (EC) susceptibility and perceptions is essential to inform efforts to mitigate tobacco product burden on public health. Data were collected online in 2016 from 634 conventional cigarette (CC) smokers and 393 non-smokers using a convenience sample from Amazon Mechanical Turk. Logistic regression models, stratified by smoking status and adjusted for socio-demographics, examined the relationship among tobacco advertisements and coupons, EC and CC susceptibility, and EC perceptions. Among non-smokers, increased exposure to tobacco advertising and receiving tobacco coupons was significantly related to measures of EC and CC susceptibility (p marketing reduce EC use by decreasing susceptibility.

Stress Corrosion cracking susceptibility of reduced-activation martensitic steel F82H

Energy Technology Data Exchange (ETDEWEB)

Miwa, Y. [Nuclear Energy and Science Directorate, Japan Atomic Energy Agency, Tokai-mura, Ibaraki-ken (Japan); Jitsukawa, S.; Tsukada, T. [Japan Atomic Energy Agency, Tokai-mura, Naga-gun, Ibaraki-ken (Japan)

2007-07-01

Full text of publication follows: For fusion power source in near future, supercritical water-cooled type blanket system was planned in Japan Atomic Energy Agency. The blankest system was designed by the present knowledge base and a reasonable extrapolation in material and design technology. Reduced-activation martensitic steel, F82H, is one of the blanket system structural materials. Therefore durability of the F82H for corrosion and stress corrosion cracking (SCC) is one of the concerns for this water-cooling concept of the blanket system. In this paper, SCC susceptibility of F82H was studied after heat treatments simulating post weld heat treatment (PWHT) or neutron-irradiation at 493 K to a dose level of 2.2 dpa. In order to evaluate SCC susceptibility of F82H, slow strain rate testing (SSRT) in high-purity, circulating water was conducted at 513-603 K in an autoclave. The strain rate was 1.0- 2.0x10{sup -7} s{sup -1}. Concentration of dissolved oxygen and hydrogen of the circulating water was controlled by bubbling with these gases. Specimens were heat treated after normalization at 1313 K for 40 min and water quenching. Some of the specimens were tempered at 873-1073 K for 1 h. Since the temperature control during PWHT in vacuum vessel by remote handling will be difficult, it is expected the tempering temperature will be different at place to place. Some specimens after tempering at 1033 K for 1 h were irradiated at 493 K to 2.2 dpa in Japan Research Reactor No.3 at Japan Atomic Energy Agency. The SSRT results showed the as-normalized specimens failed by IGSCC in oxygenated temperature water at 573 K. SSRT results of specimens with other tempering temperature conditions will be presented at conference. In irradiated specimen, IGSCC did not occur in oxygenated water at 5113-603 K. IGSCC also did not occur in hydrogenated water at 573 K. However TGSCC occurred in the irradiated specimen with a round notch (radius= {approx}0.2 mm) in oxygenated water at 573 K

Brown dog tick, Rhipicephalus sanguineus sensu lato, infestation of susceptible dog hosts is reduced by slow release of semiochemicals from a less susceptible host.

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de Oliveira Filho, Jaires Gomes; Ferreira, Lorena Lopes; Sarria, André Lucio Franceschini; Pickett, John A; Birkett, Michael A; Mascarin, Gabriel Moura; de León, Adalberto A Pérez; Borges, Lígia Miranda Ferreira

2017-01-01

Domestic dog breeds are hosts for the brown dog tick, Rhipicephalus sanguineus sensu lato, but infestation levels vary among breeds. Beagles are less susceptible to tick infestations than English cocker spaniels due to enhanced production of 2-hexanone and benzaldehyde that act as volatile tick repellents. We report the use of prototype slow-release formulations of these compounds to reduce the burden of R. sanguineus s. l. on English cocker spaniel dogs. Twelve dogs were randomly assigned to two groups with six dogs each. The treated group received collars with slow-release formulations of the compounds attached, while the control group received collars with clean formulations attached. Five environmental infestations were performed, with the number of ticks (at all stages) on the dogs being counted twice a day for 45days. The counts on the number of tick stages found per dog were individually fitted to linear mixed effects models with repeated measures and normal distribution for errors. The mean tick infestation in the treated group was significantly lower than in the control group. For larvae and nymphs, a decrease in tick infestation was observed at the fifth count, and for adults, lower average counts were observed in all counts. The compounds did not interfere with the distribution of the ticks on the body of the dogs, as a similar percentage of ticks was found on the anterior half of the dogs (54.5% for the control group and 56.2% for the treated group). The biological and reproductive parameters of the ticks were not affected by the repellents. This study highlights for the first time the potential use of a novel allomone (repellent)-based formulation for reduction of tick infestation on susceptible dogs. Copyright © 2016 Elsevier GmbH. All rights reserved.

Current Microbial Isolates from Wound Swab and Their Susceptibility Pattern in a Private Medical College Hospital in Dhaka city

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Shahin Sultana

2015-03-01

Full Text Available Background: Wound infection is one of the major health problems that are caused and aggravated by the invasion of pathogenic organisms where empiric treatment is routine. Objective: To isolate and identify the bacteria causing wound infection and to determine the antimicrobial susceptibility pattern. Materials and method: A total of 263 wound swab and pus samples were collected during the period of January to December 2012 from Delta Medical College and Hospital, Dhaka, Bangladesh. Swabs from the wound were inoculated on appropriate media and cultured and the isolates were identified by standard procedures as needed. Antimicrobial susceptibility testing was performed by disk diffusion method according to ‘The Clinical Laboratory Standard Institute’ guidelines. Results: In this study 220 bacterial isolates were recovered from 263 samples showing an isolation rate of 83.65%. The predominant bacteria isolated from infected wounds were Staphylococcus aureus 89 (40.45% followed by Escherichia coli 62 (28.18%, Pseudomonas aeruginosa 34 (15.45%, Enterococci 18 (8.18%, Acinetobacter 5 (2.27%, Klebsiella 9 (4.09% and Proteus 3 (3.36%. Staphylococcus aureus was sensitive to linezolid (94.38%, fusidic acid (91.01%, vancomycin (87.64%, amikacin (74.15% and gentamicin (73.03%. Among the Gram negative isolates Escherichia coli was predominant and showed sensitivity to imipenem (93.54% amikacin (83.87% colistin (53.22% and piperacillin and tazobactum (53.22% and pseudomonas showed sensitivity to amikacin (73.52%, imipenem (70.58% and colistin (70.58%. Conclusion: Staphylococcus aureus was the most frequently isolated pathogen from wound swab and the antibiotic sensitivity pattern of various isolates help to assist the clinician in appropriate selection of empirical antibiotics against wound infection.

Nanotoxicity overview: nano-threat to susceptible populations.

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Li, Yang; Zhang, Yi; Yan, Bing

2014-02-28

Due to the increasing applications of nanomaterials and nanotechnology, potential danger of nanoparticle exposure has become a critical issue. However, recent nanotoxicity studies have mainly focused on the health risks to healthy adult population. The nanotoxicity effects on susceptible populations (such as pregnant, neonate, diseased, and aged populations) have been overlooked. Due to the alterations in physiological structures and functions in susceptible populations, they often suffer more damage from the same exposure. Thus, it is urgent to understand the effects of nanoparticle exposure on these populations. In order to fill this gap, the potential effects of nanoparticles to pregnant females, neonate, diseased, and aged population, as well as the possible underlying mechanisms are reviewed in this article. Investigations show that responses from susceptible population to nanoparticle exposure are often more severe. Reduced protection mechanism, compromised immunity, and impaired self-repair ability in these susceptible populations may contribute to the aggravated toxicity effects. This review will help minimize adverse effects of nanoparticles to susceptible population in future nanotechnology applications.

Nanotoxicity Overview: Nano-Threat to Susceptible Populations

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Yang Li

2014-02-01

Full Text Available Due to the increasing applications of nanomaterials and nanotechnology, potential danger of nanoparticle exposure has become a critical issue. However, recent nanotoxicity studies have mainly focused on the health risks to healthy adult population. The nanotoxicity effects on susceptible populations (such as pregnant, neonate, diseased, and aged populations have been overlooked. Due to the alterations in physiological structures and functions in susceptible populations, they often suffer more damage from the same exposure. Thus, it is urgent to understand the effects of nanoparticle exposure on these populations. In order to fill this gap, the potential effects of nanoparticles to pregnant females, neonate, diseased, and aged population, as well as the possible underlying mechanisms are reviewed in this article. Investigations show that responses from susceptible population to nanoparticle exposure are often more severe. Reduced protection mechanism, compromised immunity, and impaired self-repair ability in these susceptible populations may contribute to the aggravated toxicity effects. This review will help minimize adverse effects of nanoparticles to susceptible population in future nanotechnology applications.

Inhibition of IL-1β Signaling Normalizes NMDA-Dependent Neurotransmission and Reduces Seizure Susceptibility in a Mouse Model of Creutzfeldt-Jakob Disease.

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Bertani, Ilaria; Iori, Valentina; Trusel, Massimo; Maroso, Mattia; Foray, Claudia; Mantovani, Susanna; Tonini, Raffaella; Vezzani, Annamaria; Chiesa, Roberto

2017-10-25

Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder caused by prion protein (PrP) misfolding, clinically recognized by cognitive and motor deficits, electroencephalographic abnormalities, and seizures. Its neurophysiological bases are not known. To assess the potential involvement of NMDA receptor (NMDAR) dysfunction, we analyzed NMDA-dependent synaptic plasticity in hippocampal slices from Tg(CJD) mice, which model a genetic form of CJD. Because PrP depletion may result in functional upregulation of NMDARs, we also analyzed PrP knock-out (KO) mice. Long-term potentiation (LTP) at the Schaffer collateral-commissural synapses in the CA1 area of ∼100-d-old Tg(CJD) mice was comparable to that of wild-type (WT) controls, but there was an inversion of metaplasticity, with increased GluN2B phosphorylation, which is indicative of enhanced NMDAR activation. Similar but less marked changes were seen in PrP KO mice. At ∼300 d of age, the magnitude of LTP increased in Tg(CJD) mice but decreased in PrP KO mice, indicating divergent changes in hippocampal synaptic responsiveness. Tg(CJD) but not PrP KO mice were intrinsically more susceptible than WT controls to focal hippocampal seizures induced by kainic acid. IL-1β-positive astrocytes increased in the Tg(CJD) hippocampus, and blocking IL-1 receptor signaling restored normal synaptic responses and reduced seizure susceptibility. These results indicate that alterations in NMDA-dependent glutamatergic transmission in Tg(CJD) mice do not depend solely on PrP functional loss. Moreover, astrocytic IL-1β plays a role in the enhanced synaptic responsiveness and seizure susceptibility, suggesting that targeting IL-1β signaling may offer a novel symptomatic treatment for CJD. SIGNIFICANCE STATEMENT Dementia and myoclonic jerks develop in individuals with Creutzfeldt-Jakob disease (CJD), an incurable brain disorder caused by alterations in prion protein structure. These individuals are prone to seizures and have high

Determination of in vitro synergy between linezolid and other antimicrobial agents against Mycobacterium tuberculosis isolates.

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Zou, Lin; Liu, Min; Wang, Yufeng; Lu, Jie; Pang, Yu

2015-12-01

In this study, our objective was to explore the potential in vitro synergy between linezolid (LZD) and six other anti-TB drugs in Mycobacterium tuberculosis strains, especially multidrug-resistant tuberculosis (MDR-TB) strains. Among the different combinations, the LZD-clarithromycin (CLA) combination showed the best synergism, which was observed in 85% (34/40) of 40 isolates. In addition, one (2.5%) and twenty-one (52.5%) of 40 isolates showed synergism for the LZD-levofloxcin (LEV) and LZD-moxifloxacin (MOX) combinations, respectively, and the difference in the proportion of synergy between these two combinations was significantly different (P synergy against non-MDR group seemed higher than that against MDR group in each combination, while the significant difference was only observed in the LZD-EMB combination (P = 0.046). In conclusion, our findings demonstrate that LZD shows the synergistic activity against both non-MDR and MDR M. tuberculosis strains when in combination with CLA, EMB, MOX, amikacin and clofazimine, indicating that LZD may be considered as a promising component involving the regimen for the treatment of MDR-TB. Copyright © 2015 Elsevier Ltd. All rights reserved.

Spectrofluorimetric determination of gemifloxacin mesylate and linezolid in pharmaceutical formulations: Application of quinone-based fluorophores and enhanced native fluorescence

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Moussa Bahia Abbas

2014-03-01

Full Text Available Quinone-based fluorophores and enhanced native fluorescence techniques were applied for a fast quantitative analysis of gemifloxacin mesylate (GEM and linezolid (LIN in pharmaceutical formulations. For this purpose, three sensitive, accurate and precise spectrofluorimetric methods were developed. GEM, as an n-electron donor, reacts with 7,7,8,8-tetracyanoquinodimethane (method A and 2,5-dichloro-3,6-dihydroxy-p-benzoquinone (method B as п-electron acceptors, forming charge transfer complexes that exhibit high fluorescence intensity at 441 and 390 nm upon excitation at 260 and 339 nm, respectively. Method C depends on measurement of enhanced native fluorescence of LIN in phosphate buffer (pH 5 at 380 nm upon excitation at 260 nm. Experimental factors affecting fluorescence intensity were optimized. Linearity was obtained over concentration ranges 50-500, 10-60 and 20-400 ng mL-1 for methods A, B and C, respectively. The developed methods were validated and successfully applied for determination of the cited drugs in tablets.

Cfr-mediated linezolid-resistance among methicillin-resistant coagulase-negative staphylococci from infections of humans.

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Lanqing Cui

Full Text Available Four methicillin-resistant coagulase-negative staphylococci (MRCoNS, one Staphylococcus haemolyticus and three Staphylococcus cohnii, from infections of humans collected via the Ministry of Health National Antimicrobial Resistance Surveillance Net (Mohnarin program in China were identified as linezolid-resistant. These four isolates were negative for the 23S rRNA mutations, but positive for the gene cfr. Mutations in the gene for the ribosomal protein L3, which resulted in the amino acid exchanges Gly152Asp and Tyr158Phe, were identified in S. haemolyticus 09D279 and S. cohnii NDM113, respectively. In each isolate, the cfr gene was located on a plasmid of ca. 35.4 kb, as shown by S1 nuclease pulsed-field gel electrophoresis and Southern blotting experiments. This plasmid was indistinguishable from the previously described plasmid pSS-02 by its size, restriction pattern, and a sequenced 14-kb cfr-carrying segment. Plasmid pSS-02 was originally identified in staphylococci isolated from pigs. This is the first time that a cfr-carrying plasmid has been detected in MRCoNS obtained from intensive care patients in China. Based on the similarities to the cfr-carrying plasmid pSS-02 from porcine coagulase-negative staphylococci, a transmission of this cfr-carrying plasmid between staphylococci from pigs and humans appears to be likely.

Cfr-mediated linezolid-resistance among methicillin-resistant coagulase-negative staphylococci from infections of humans.

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Cui, Lanqing; Wang, Yang; Li, Yun; He, Tao; Schwarz, Stefan; Ding, Yujing; Shen, Jianzhong; Lv, Yuan

2013-01-01

Four methicillin-resistant coagulase-negative staphylococci (MRCoNS), one Staphylococcus haemolyticus and three Staphylococcus cohnii, from infections of humans collected via the Ministry of Health National Antimicrobial Resistance Surveillance Net (Mohnarin) program in China were identified as linezolid-resistant. These four isolates were negative for the 23S rRNA mutations, but positive for the gene cfr. Mutations in the gene for the ribosomal protein L3, which resulted in the amino acid exchanges Gly152Asp and Tyr158Phe, were identified in S. haemolyticus 09D279 and S. cohnii NDM113, respectively. In each isolate, the cfr gene was located on a plasmid of ca. 35.4 kb, as shown by S1 nuclease pulsed-field gel electrophoresis and Southern blotting experiments. This plasmid was indistinguishable from the previously described plasmid pSS-02 by its size, restriction pattern, and a sequenced 14-kb cfr-carrying segment. Plasmid pSS-02 was originally identified in staphylococci isolated from pigs. This is the first time that a cfr-carrying plasmid has been detected in MRCoNS obtained from intensive care patients in China. Based on the similarities to the cfr-carrying plasmid pSS-02 from porcine coagulase-negative staphylococci, a transmission of this cfr-carrying plasmid between staphylococci from pigs and humans appears to be likely.

Characteristics of Japanese inflammatory bowel disease susceptibility loci.

Science.gov (United States)

Arimura, Yoshiaki; Isshiki, Hiroyuki; Onodera, Kei; Nagaishi, Kanna; Yamashita, Kentaro; Sonoda, Tomoko; Matsumoto, Takayuki; Takahashi, Atsushi; Takazoe, Masakazu; Yamazaki, Keiko; Kubo, Michiaki; Fujimiya, Mineko; Imai, Kohzoh; Shinomura, Yasuhisa

2014-08-01

There are substantial differences in inflammatory bowel disease (IBD) genetics depending on the populations examined. We aimed to identify Japanese population-specific or true culprit susceptibility genes through a meta-analysis of past genetic studies of Japanese IBD. For this study, we reviewed 2,703 articles. The review process consisted of three screening stages: we initially searched for relevant studies and then relevant single nucleotide polymorphisms (SNPs). Finally, we adjusted them for the meta-analysis. To maximize our chances of analysis, we introduced proxy SNPs during the first stage. To minimize publication bias, no significant SNPs and solitary SNPs without pairs were combined to be reconsidered during the third stage. Additionally, two SNPs were newly genotyped. Finally, we conducted a meta-analysis of 37 published studies in 50 SNPs located at 22 loci corresponding to the total number of 4,853 Crohn's disease (CD), 5,612 ulcerative colitis (UC) patients, and 14,239 healthy controls. We confirmed that the NKX2-3 polymorphism is associated with common susceptibility to IBD and that HLA-DRB1*0450 alleles increase susceptibility to CD but reduce risk for UC while HLA-DRB1*1502 alleles increase susceptibility to UC but reduce CD risk. Moreover, we found individual disease risk loci: TNFSF15 and TNFα to CD and HLA-B*5201, and NFKBIL1 to UC. The genetic risk of HLA was substantially high (odds ratios ranged from 1.54 to 2.69) while that of common susceptibility loci to IBD was modest (odds ratio ranged from 1.13 to 1.24). Results indicate that Japanese IBD susceptibility loci identified by the meta-analysis are closely associated with the HLA regions.

Role of vanadium carbide traps in reducing the hydrogen embrittlement susceptibility of high strength alloy steels. Final report

Energy Technology Data Exchange (ETDEWEB)

Spencer, G.L.; Duquette, D.J.

1998-08-01

High strength alloy steels typically used for gun steel were investigated to determine their susceptibility to hydrogen embrittlement. Although AISI grade 4340 was quite susceptible to hydrogen embrittlement, ASTM A723 steel, which has identical mechanical properties but slightly different chemistries, was not susceptible to hydrogen embrittlement when exposed to the same conditions. The degree of embrittlement was determined by conducting notched tensile testing on uncharged and cathodically charged specimens. Chemical composition was modified to isolate the effect of alloying elements on hydrogen embrittlement susceptibility. Two steels-Modified A723 (C increased from 0.32% to 0.40%) and Modified 4340 (V increased from 0 to O.12%) were tested. X-ray diffraction identified the presence of vanadium carbide, V{sub 4}C{sub 3}, in A-23 steels, and subsequent hydrogen extraction studies evaluated the trapping effect of vanadium carbide. Based on these tests, it was determined that adding vanadium carbide to 4340 significantly decreased hydrogen embrittlement susceptibility because vanadium carbide traps ties up diffusible hydrogen. The effectiveness of these traps is examined and discussed in this paper.

Antimicrobial susceptibility of Haemophilus parasuis and Histophilus somni from pigs and cattle in Denmark

DEFF Research Database (Denmark)

Aarestrup, Frank Møller; Seyfarth, Anne Mette; Angen, Øystein

2004-01-01

A total of 52 Haemophilus parasuis and 80 Histophilus somni isolates were tested for antimicrobial susceptibility by MIC-determinations. None of the isolates were resistant to ampicillin, ceftiofur, ciprofloxacin, erythromycin, florphenicol, penicillin, spectinomycin, tetracycline, tiamulin......, or tilmicosin. Two H. parasuis isolates were resistant to trimethoprim + sulfamethoxazole. Six H. parasuis isolates had reduced susceptibility (0.06-0.5 mug/ml) to ciprofloxacin and 10 reduced susceptibility to TMP + sulfamethoxazole (1-2 mug/ml). This study showed that Danish isolates of H. parasuis and H...

Vancomycin resistant enterococci in urine cultures: Antibiotic susceptibility trends over a decade at a tertiary hospital in the United Kingdom.

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Toner, Liam; Papa, Nathan; Aliyu, Sani H; Dev, Harveer; Lawrentschuk, Nathan; Al-Hayek, Samih

2016-03-01

Enterococci are a common cause of urinary tract infection and vancomycin-resistant strains are more difficult to treat. The purpose of this surveillance program was to assess the prevalence of and determine the risk factors for vancomycin resistance in adults among urinary isolates of Enterococcus sp. and to detail the antibiotic susceptibility profile, which can be used to guide empirical treatment. From 2005 to 2014 we retrospectively reviewed 5,528 positive Enterococcus sp. urine cultures recorded in a computerized laboratory results database at a tertiary teaching hospital in Cambridge, United Kingdom. Of these cultures, 542 (9.8%) were vancomycin resistant. No longitudinal trend was observed in the proportion of vancomycin-resistant strains over the course of the study. We observed emerging resistance to nitrofurantoin with rates climbing from near zero to 40%. Ampicillin resistance fluctuated between 50% and 90%. Low resistance was observed for linezolid and quinupristin/dalfopristin. Female sex and inpatient status were identified as risk factors for vancomycin resistance. The incidence of vancomycin resistance among urinary isolates was stable over the last decade. Although resistance to nitrofurantoin has increased, it still serves as an appropriate first choice in uncomplicated urinary tract infection caused by vancomycin-resistant Enterococcus sp.

Vancomycin resistant enterococci in urine cultures: Antibiotic susceptibility trends over a decade at a tertiary hospital in the United Kingdom

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Liam Toner

2016-03-01

Full Text Available Purpose: Enterococci are a common cause of urinary tract infection and vancomycin-resistant strains are more difficult to treat. The purpose of this surveillance program was to assess the prevalence of and determine the risk factors for vancomycin resistance in adults among urinary isolates of Enterococcus sp. and to detail the antibiotic susceptibility profile, which can be used to guide empirical treatment. Materials and Methods: From 2005 to 2014 we retrospectively reviewed 5,528 positive Enterococcus sp. urine cultures recorded in a computerized laboratory results database at a tertiary teaching hospital in Cambridge, United Kingdom. Results: Of these cultures, 542 (9.8% were vancomycin resistant. No longitudinal trend was observed in the proportion of vancomycin- resistant strains over the course of the study. We observed emerging resistance to nitrofurantoin with rates climbing from near zero to 40%. Ampicillin resistance fluctuated between 50% and 90%. Low resistance was observed for linezolid and quinupristin/ dalfopristin. Female sex and inpatient status were identified as risk factors for vancomycin resistance. Conclusions: The incidence of vancomycin resistance among urinary isolates was stable over the last decade. Although resistance to nitrofurantoin has increased, it still serves as an appropriate first choice in uncomplicated urinary tract infection caused by vancomycin- resistant Enterococcus sp.

Antifungal susceptibility and phylogeny of opportunistic members of the order mucorales.

Science.gov (United States)

Vitale, Roxana G; de Hoog, G Sybren; Schwarz, Patrick; Dannaoui, Eric; Deng, Shuwen; Machouart, Marie; Voigt, Kerstin; van de Sande, Wendy W J; Dolatabadi, Somayeh; Meis, Jacques F; Walther, Grit

2012-01-01

The in vitro susceptibilities of 66 molecularly identified strains of the Mucorales to eight antifungals (amphotericin B, terbinafine, itraconazole, posaconazole, voriconazole, caspofungin, micafungin, and 5-fluorocytosine) were tested. Molecular phylogeny was reconstructed based on the nuclear ribosomal large subunit to reveal taxon-specific susceptibility profiles. The impressive phylogenetic diversity of the Mucorales was reflected in susceptibilities differing at family, genus, and species levels. Amphotericin B was the most active drug, though somewhat less against Rhizopus and Cunninghamella species. Posaconazole was the second most effective antifungal agent but showed reduced activity in Mucor and Cunninghamella strains, while voriconazole lacked in vitro activity for most strains. Genera attributed to the Mucoraceae exhibited a wide range of MICs for posaconazole, itraconazole, and terbinafine and included resistant strains. Cunninghamella also comprised strains resistant to all azoles tested but was fully susceptible to terbinafine. In contrast, the Lichtheimiaceae completely lacked strains with reduced susceptibility for these antifungals. Syncephalastrum species exhibited susceptibility profiles similar to those of the Lichtheimiaceae. Mucor species were more resistant to azoles than Rhizopus species. Species-specific responses were obtained for terbinafine where only Rhizopus arrhizus and Mucor circinelloides were resistant. Complete or vast resistance was observed for 5-fluorocytosine, caspofungin, and micafungin. Intraspecific variability of in vitro susceptibility was found in all genera tested but was especially high in Mucor and Rhizopus for azoles and terbinafine. Accurate molecular identification of etiologic agents is compulsory to predict therapy outcome. For species of critical genera such as Mucor and Rhizopus, exhibiting high intraspecific variation, susceptibility testing before the onset of therapy is recommended.

Degree of Tissue Differentiation Dictates Susceptibility to BRAF-Driven Colorectal Cancer

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Kevin Tong

2017-12-01

Full Text Available Oncogenic mutations in BRAF are believed to initiate serrated colorectal cancers; however, the mechanisms of BRAF-driven colon cancer are unclear. We find that oncogenic BRAF paradoxically suppresses stem cell renewal and instead promotes differentiation. Correspondingly, tumor formation is inefficient in BRAF-driven mouse models of colon cancer. By reducing levels of differentiation via genetic manipulation of either of two distinct differentiation-promoting factors (Smad4 or Cdx2, stem cell activity is restored in BRAFV600E intestines, and the oncogenic capacity of BRAFV600E is amplified. In human patients, we observe that reduced levels of differentiation in normal tissue is associated with increased susceptibility to serrated colon tumors. Together, these findings help resolve the conditions necessary for BRAF-driven colon cancer initiation. Additionally, our results predict that genetic and/or environmental factors that reduce tissue differentiation will increase susceptibility to serrated colon cancer. These findings offer an opportunity to identify susceptible individuals by assessing their tissue-differentiation status.

Clinical outcomes of linezolid and vancomycin in patients with nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus stratified by baseline renal function: a retrospective, cohort analysis.

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Liu, Ping; Capitano, Blair; Stein, Amy; El-Solh, Ali A

2017-05-22

The primary objective of this study is to assess whether baseline renal function impacts treatment outcomes of linezolid and vancomycin (with a dose-optimized regimen) for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. We conducted a retrospective cohort analysis of data generated from a prospective, randomized, controlled clinical trial (NCT 00084266). The analysis included 405 patients with culture-proven MRSA pneumonia. Baseline renal function was stratified based on creatinine clearance. Clinical and microbiological success rates and presence of nephrotoxicity were assessed at the end of treatment (EOT) and end of study (EOS). Multivariate logistic regression analyses of baseline patient characteristics, including treatment, were performed to identify independent predictors of efficacy. Vancomycin concentrations were analyzed using a nonlinear mixed-effects modeling approach. The relationships between vancomycin exposures, pharmacokinetic-pharmacodynamic index (trough concentration, area under the curve over a 24-h interval [AUC 0-24 ], and AUC 0-24 /MIC) and efficacy/nephrotoxicity were assessed in MRSA pneumonia patients using univariate logistic regression or Cox proportional hazards regression analysis approach. After controlling for use of vasoactive agents, choice of antibiotic therapy and bacteremia, baseline renal function was not correlated with clinical and microbiological successes in MRSA pneumonia at either end of treatment or at end of study for both treatment groups. No positive association was identified between vancomycin exposures and efficacy in these patients. Higher vancomycin exposures were correlated with an increased risk of nephrotoxicity (e.g., hazards ratio [95% confidence interval] for a 5 μg/ml increase in trough concentration: 1.42 [1.10, 1.82]). In non-dialysis patients, baseline renal function did not impact the differences in efficacy or nephrotoxicity with treatment of linezolid versus vancomycin in MRSA

Interventions on Metabolism: Making Antibiotic-Susceptible Bacteria

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Fernando Baquero

2017-11-01

Full Text Available Antibiotics act on bacterial metabolism, and antibiotic resistance involves changes in this metabolism. Interventions on metabolism with drugs might therefore modify drug susceptibility and drug resistance. In their recent article, Martin Vestergaard et al. (mBio 8:e01114-17, 2017, https://doi.org/10.1128/mBio.01114-17 illustrate the possibility of converting intrinsically resistant bacteria into susceptible ones. They reported that inhibition of a central metabolic enzyme, ATP synthase, allows otherwise ineffective polymyxin antibiotics to act on Staphylococcus aureus. The study of the intrinsic resistome of bacterial pathogens has shown that several metabolic genes, including multigene transcriptional regulators, contribute to antibiotic resistance. In some cases, these genes only marginally increase antibiotic resistance, but reduced levels of susceptibility might be critical in the evolution or resistance under low antibiotic concentrations or in the clinical response of highly resistant bacteria. Drug interventions on bacterial metabolism might constitute a critical adjuvant therapy in combination with antibiotics to ensure susceptibility of pathogens with intrinsic or acquired antimicrobial resistance.

Treatment failure in a typhoid patient infected with nalidixic acid resistant S. enterica serovar Typhi with reduced susceptibility to Ciprofloxacin: a case report from Cameroon

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Asonganyi Etienne DN

2005-06-01

Full Text Available Abstract Background Fluoroquinolones or third generation cephalosporins are the drugs of choice for the treatment of typhoid fever. Treatment failure with fluoroquinolones has been reported in Asia and Europe. We report a case of ciprofloxacin treatment failure in typhoid fever in Cameroon. Case presentation A 29-year-old female patient with suspected typhoid fever from Kumba, Cameroon, yielded growth of Salmonella enterica serovar Typhi in blood culture. The isolate was resistant to nalidixic acid but sensitive to ciprofloxacin by disc diffusion test. However, the patient did not respond to treatment with ciprofloxacin, although the isolate was apparently susceptible to ciprofloxacin. Conclusion Treatment failure with ciprofloxacin in our case indicates the presence of nalidixic acid resistant S. enterica serovar Typhi (NARST with reduced susceptibility to ciprofloxacin in Cameroon (Central Africa.

Frequency of Reduced Vancomycin Susceptibility among Clinical Staphylococcus aureus Isolated in Ahvaz Iran

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Mojtaba Moosavian

2015-11-01

Full Text Available Introduction:   One   of   the   most   important   agents   in   hospital-acquired   infections   is Staphylococcus aureus. Treatment of methicillin-resistant S. aureus (MRSA infections with decreased susceptibility to vancomycin has recently been more difficult. The aim of this study was to evaluate the possible presence of vancomycin intermediate S. aureus (VISA and vancomycin- resistant S. aureus (VRSA and also to determine the frequency of MRSA in clinical specimens.Methods: In this study, 195 S. aureus isolates were collected from the patients were examined. All of the isolates were identified using standard biochemical tests.  Susceptibility of S. aureus isolates against 10 antibiotics was detected by disk diffusion method and was followed by E-test and vancomycin screen agar methods. Minimum inhibitory concentration (MIC of vancomycin was determined according to the CLSI guidelines.  Also, detection of mecA gene was performed by PCR and finally, the results were compared.Results: All of the isolates were susceptible to vancomycin (i.e. MIC range of vancomycin was between 0.25-2 µg/ml. Out of 195 S. aureus isolates, 99 isolates (50.8% were resistant to methicillin, and mecA gene was detected in 96 isolates. These results also showed that the highest and lowest resistance rate of isolates was to penicillin (96.9% and chloramphenicol (0%, respectively.Conclusion: Our findings showed that vancomycin can still be used as a valuable drug for treatment of S. aureus infections in our region. However, periodic evaluation of vancomycin MIC of S. aureus isolates is critical for monitoring MRSA and preventing the spread of VISA or VRSA among patients.

Routine disc diffusion antimicrobial susceptibility testing of Clostridium difficile and association with PCR ribotype 027

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Holt, H M; Danielsen, T K; Justesen, U S

2015-01-01

Reduced susceptibility to metronidazole and vancomycin in Clostridium difficile has been reported, which emphasises the need for simple antimicrobial susceptibility testing methods. The aim of this study was to apply a published disc diffusion method and zone diameter breakpoint correlates...... the published breakpoint (difficile PCR ribotype 027 isolates had smaller zone...... diameters than non-027 isolates. The disc diffusion method is very simple and inexpensive, and the published zone diameter breakpoints will detect C. difficile isolates with reduced susceptibility to metronidazole and vancomycin....

Magnetic Susceptibilities as they appeared to me - An Amperian approach

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Van den Bosch, A.

2008-08-15

Starting from scratch, the book narrates a systematic story of the basic ideas you need for understanding quasi static magnetic susceptibilities. The story leans on the authors 25 year experience measuring susceptibilities following the Faraday technique (related with solid state physics, radiation effects, materials and magneto chemistry). The base of magnetism, the current-current interaction, is the linkage between the topics treated. The number of mathematical equations are reduced to a minimum and can be skipped without losing the thread of the story. The story is positive towards the sound bases of magnetism. However, room is left for the interpretation of measuring data. As the word susceptibility covers different meanings, the story answers for different situations the question: what is susceptible to what for creating what?

Magnetic Susceptibilities as they appeared to me - An Amperian approach

International Nuclear Information System (INIS)

Van den Bosch, A.

2008-01-01

Starting from scratch, the book narrates a systematic story of the basic ideas you need for understanding quasi static magnetic susceptibilities. The story leans on the authors 25 year experience measuring susceptibilities following the Faraday technique (related with solid state physics, radiation effects, materials and magneto chemistry). The base of magnetism, the current-current interaction, is the linkage between the topics treated. The number of mathematical equations are reduced to a minimum and can be skipped without losing the thread of the story. The story is positive towards the sound bases of magnetism. However, room is left for the interpretation of measuring data. As the word susceptibility covers different meanings, the story answers for different situations the question: what is susceptible to what for creating what?

Umbilical Sepsis Caused by Multidrug Resistant Strain of Kocuria kristinae in a New Born: A Case Report.

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Sivaraman, Umadevi; Subramanian, Pramodhini; Ramakrishnan, Kalaivani; Seetha, K S

2016-04-01

Kocuria species were placed previously under the genus Micrococcus, are skin and oropharynx commensals in mammals, including man. A rare bacteria, Kocuria kristinae isolated from a new born with umbilical sepsis. Identification and antibiotic susceptibility was done by Vitek 2 compact system (Biomerieux). The isolate was sensitive to higher antibiotics like vancomycin, teicoplanin and linezolid. As this new pathogen resembles coagulase negative staphylococcus, it should not be misidentified.

Susceptibility-Weighted Imaging and Quantitative Susceptibility Mapping in the Brain

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Liu, Chunlei; Li, Wei; Tong, Karen A.; Yeom, Kristen W.; Kuzminski, Samuel

2015-01-01

Susceptibility-weighted imaging (SWI) is a magnetic resonance imaging (MRI) technique that enhances image contrast by using the susceptibility differences between tissues. It is created by combining both magnitude and phase in the gradient echo data. SWI is sensitive to both paramagnetic and diamagnetic substances which generate different phase shift in MRI data. SWI images can be displayed as a minimum intensity projection that provides high resolution delineation of the cerebral venous architecture, a feature that is not available in other MRI techniques. As such, SWI has been widely applied to diagnose various venous abnormalities. SWI is especially sensitive to deoxygenated blood and intracranial mineral deposition and, for that reason, has been applied to image various pathologies including intracranial hemorrhage, traumatic brain injury, stroke, neoplasm, and multiple sclerosis. SWI, however, does not provide quantitative measures of magnetic susceptibility. This limitation is currently being addressed with the development of quantitative susceptibility mapping (QSM) and susceptibility tensor imaging (STI). While QSM treats susceptibility as isotropic, STI treats susceptibility as generally anisotropic characterized by a tensor quantity. This article reviews the basic principles of SWI, its clinical and research applications, the mechanisms governing brain susceptibility properties, and its practical implementation, with a focus on brain imaging. PMID:25270052

Susceptibility-weighted imaging and quantitative susceptibility mapping in the brain.

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Liu, Chunlei; Li, Wei; Tong, Karen A; Yeom, Kristen W; Kuzminski, Samuel

2015-07-01

Susceptibility-weighted imaging (SWI) is a magnetic resonance imaging (MRI) technique that enhances image contrast by using the susceptibility differences between tissues. It is created by combining both magnitude and phase in the gradient echo data. SWI is sensitive to both paramagnetic and diamagnetic substances which generate different phase shift in MRI data. SWI images can be displayed as a minimum intensity projection that provides high resolution delineation of the cerebral venous architecture, a feature that is not available in other MRI techniques. As such, SWI has been widely applied to diagnose various venous abnormalities. SWI is especially sensitive to deoxygenated blood and intracranial mineral deposition and, for that reason, has been applied to image various pathologies including intracranial hemorrhage, traumatic brain injury, stroke, neoplasm, and multiple sclerosis. SWI, however, does not provide quantitative measures of magnetic susceptibility. This limitation is currently being addressed with the development of quantitative susceptibility mapping (QSM) and susceptibility tensor imaging (STI). While QSM treats susceptibility as isotropic, STI treats susceptibility as generally anisotropic characterized by a tensor quantity. This article reviews the basic principles of SWI, its clinical and research applications, the mechanisms governing brain susceptibility properties, and its practical implementation, with a focus on brain imaging. © 2014 Wiley Periodicals, Inc.

LANDSLIDE SUSCEPTIBILITY ASSESSMENT THROUGH FUZZY LOGIC INFERENCE SYSTEM (FLIS

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T. Bibi

2016-09-01

Full Text Available Landslide is among one of the most important natural hazards that lead to modification of the environment. It is a regular feature of a rapidly growing district Mansehra, Pakistan. This caused extensive loss of life and property in the district located at the foothills of Himalaya. Keeping in view the situation it is concluded that besides structural approaches the non-structural approaches such as hazard and risk assessment maps are effective tools to reduce the intensity of damage. A landslide susceptibility map is base for engineering geologists and geomorphologists. However, it is not easy to produce a reliable susceptibility map due to complex nature of landslides. Since 1980s, several mathematical models have been developed to map landslide susceptibility and hazard. Among various models this paper is discussing the effectiveness of fuzzy logic approach for landslide susceptibility mapping in District Mansehra, Pakistan. The factor maps were modified as landslide susceptibility and fuzzy membership functions were assessed for each class. Likelihood ratios are obtained for each class of contributing factors by considering the expert opinion. The fuzzy operators are applied to generate landslide susceptibility maps. According to this map, 17% of the study area is classified as high susceptibility, 32% as moderate susceptibility, 51% as low susceptibility and areas. From the results it is found that the fuzzy model can integrate effectively with various spatial data for landslide hazard mapping, suggestions in this study are hope to be helpful to improve the applications including interpretation, and integration phases in order to obtain an accurate decision supporting layer.

Housing under the pyramid reduces susceptibility of hippocampal CA3 pyramidal neurons to prenatal stress in the developing rat offspring.

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Murthy, Krishna Dilip; George, Mitchel Constance; Ramasamy, Perumal; Mustapha, Zainal Arifin

2013-12-01

Mother-offspring interaction begins before birth. The foetus is particularly vulnerable to environmental insults and stress. The body responds by releasing excess of the stress hormone cortisol, which acts on glucocorticoid receptors. Hippocampus in the brain is rich in glucocorticoid receptors and therefore susceptible to stress. The stress effects are reduced when the animals are placed under a model wooden pyramid. The present study was to first explore the effects of prenatal restraint-stress on the plasma corticosterone levels and the dendritic arborisation of CA3 pyramidal neurons in the hippocampus of the offspring. Further, to test whether the pyramid environment would alter these effects, as housing under a pyramid is known to reduce the stress effects, pregnant Sprague Dawley rats were restrained for 9 h per day from gestation day 7 until parturition in a wire-mesh restrainer. Plasma corticosterone levels were found to be significantly increased. In addition, there was a significant reduction in the apical and the basal total dendritic branching points and intersections of the CA3 hippocampal pyramidal neurons. The results thus suggest that, housing in the pyramid dramatically reduces prenatal stress effects in rats.

Apparent competition in canopy trees determined by pathogen transmission rather than susceptibility.

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Richard Cobb; Ross Meentemeyer; David Rizzo

2010-01-01

Epidemiological theory predicts that asymmetric transmission, susceptibility, and mortality within a community will drive pathogen and disease dynamics. These epidemiological asymmetries can result in apparent competition, where a highly infectious host reduces the abundance of less infectious or more susceptible members in a community via a shared pathogen. We show...

Enriched Housing Reduces Disease Susceptibility to Co-Infection with Porcine Reproductive and Respiratory Virus (PRRSV) and Actinobacillus pleuropneumoniae (A. pleuropneumoniae) in Young Pigs.

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van Dixhoorn, Ingrid D E; Reimert, Inonge; Middelkoop, Jenny; Bolhuis, J Elizabeth; Wisselink, Henk J; Groot Koerkamp, Peter W G; Kemp, Bas; Stockhofe-Zurwieden, Norbert

2016-01-01

Until today, anti-microbial drugs have been the therapy of choice to combat bacterial diseases. Resistance against antibiotics is of growing concern in man and animals. Stress, caused by demanding environmental conditions, can reduce immune protection in the host, influencing the onset and outcome of infectious diseases. Therefore psychoneuro-immunological intervention may prove to be a successful approach to diminish the impact of diseases and antibiotics use. This study was designed to investigate the effect of social and environmental enrichment on the impact of disease, referred to as "disease susceptibility", in pigs using a co-infection model of PRRSV and A. pleuropneumoniae. Twenty-eight pigs were raised in four pens under barren conditions and twenty-eight other pigs were raised in four pens under enriched conditions. In the enriched pens a combination of established social and environmental enrichment factors were introduced. Two pens of the barren (BH) and two pens of the enriched housed (EH) pigs were infected with PRRSV followed by A. pleuropneumoniae, the other two pens in each housing treatment served as control groups. We tested if differences in disease susceptibility in terms of pathological and clinical outcome were related to the different housing regimes and if this was reflected in differences in behavioural and immunological states of the animals. Enriched housed pigs showed a faster clearance of viral PRRSV RNA in blood serum (p = 0.014) and histologically 2.8 fold less interstitial pneumonia signs in the lungs (p = 0.014). More barren housed than enriched housed pigs developed lesions in the lungs (OR = 19.2, p = 0.048) and the lesions in the barren housed pigs showed a higher total pathologic tissue damage score (ppigs. EH pigs showed less stress-related behaviour and differed immunologically and clinically from BH pigs. We conclude that enriched housing management reduces disease susceptibility to co-infection of PRRSV and A

Enriched Housing Reduces Disease Susceptibility to Co-Infection with Porcine Reproductive and Respiratory Virus (PRRSV and Actinobacillus pleuropneumoniae (A. pleuropneumoniae in Young Pigs.

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Ingrid D E van Dixhoorn

Full Text Available Until today, anti-microbial drugs have been the therapy of choice to combat bacterial diseases. Resistance against antibiotics is of growing concern in man and animals. Stress, caused by demanding environmental conditions, can reduce immune protection in the host, influencing the onset and outcome of infectious diseases. Therefore psychoneuro-immunological intervention may prove to be a successful approach to diminish the impact of diseases and antibiotics use. This study was designed to investigate the effect of social and environmental enrichment on the impact of disease, referred to as "disease susceptibility", in pigs using a co-infection model of PRRSV and A. pleuropneumoniae. Twenty-eight pigs were raised in four pens under barren conditions and twenty-eight other pigs were raised in four pens under enriched conditions. In the enriched pens a combination of established social and environmental enrichment factors were introduced. Two pens of the barren (BH and two pens of the enriched housed (EH pigs were infected with PRRSV followed by A. pleuropneumoniae, the other two pens in each housing treatment served as control groups. We tested if differences in disease susceptibility in terms of pathological and clinical outcome were related to the different housing regimes and if this was reflected in differences in behavioural and immunological states of the animals. Enriched housed pigs showed a faster clearance of viral PRRSV RNA in blood serum (p = 0.014 and histologically 2.8 fold less interstitial pneumonia signs in the lungs (p = 0.014. More barren housed than enriched housed pigs developed lesions in the lungs (OR = 19.2, p = 0.048 and the lesions in the barren housed pigs showed a higher total pathologic tissue damage score (p<0.001 than those in enriched housed pigs. EH pigs showed less stress-related behaviour and differed immunologically and clinically from BH pigs. We conclude that enriched housing management reduces disease

Multiresistant-MRSA tricuspid valve infective endocarditis with ancient osteomyelitis locus

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Gambarati Gianpaolo

2006-07-01

Full Text Available Abstract Background Methicillin-resistant S. aureus (MRSA with low susceptibility to glycopeptides is uncommon. Case presentation The case of a 50-year-old non-drug addict patient presenting with tricuspid valve infective endocarditis (IE by MRSA resistant to vancomycin and linezolid is presented. There was response only to quinupristin/dalfopristin. He had a motorcycling accident four years before undergoing right above-the-knee amputation and orthopaedic fixation of the left limb. There were multiple episodes of left MRSA-osteomyelitis controlled after surgery and vancomycin therapy. MRSA isolated from the blood at the time of IE presented with the same profile than the isolated four years earlier. Sequential treatment with teicoplanin-cotrimoxazole and Linezolid associated to vancomycin – rifampicin – cotrimoxazole had no improvement. Infection was controlled after 28 days of therapy with quinupristin/dalfopristin. Conclusion The literature presents only a few cases of MRSA IE not susceptible to glycopeptides in not drug addicted patients. This case shows the comparison of a highly-resistant MRSA after previous S. aureus osteomyelitis treated with glycopeptides. This is the first description of successful treatment of resistant-MRSA IE of the tricuspid valve complicated by multiple pulmonary septic infarction with quinupristin/dalfopristin

Spectrum and potency of ceftaroline against leading pathogens causing community-acquired respiratory tract and skin and soft tissue infections in Latin America, 2010

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Robert K. Flamm

Full Text Available Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with in vitro bactericidal activity against Gram-positive organisms, including methicillinsusceptible and -resistant Staphylococcus aureus, β-haemolytic and viridans group streptococci, and Streptococcus pneumoniae, as well as common Gram-negative organisms. In this study a total of 986 isolates collected in 2010 from patients in 15 medical centers in five Latin American countries from the Assessing Worldwide Antimicrobial Resistance Evaluation Program were identified as community-acquired respiratory tract or skin and soft tissue infection pathogens. Ceftaroline was the most potent agent tested against S. pneumoniae with a MIC90 value (0.12 µg/mL that was eight-fold lower than ceftriaxone, levofloxacin, and linezolid. Its spectrum of coverage (100.0% susceptible was similar to tigecycline, linezolid, levofloxacin and vancomycin. Against Haemophilus influenzae and Moraxella catarrhalis, ceftaroline was the most active agent tested. The activity of ceftaroline against S. aureus (including MRSA was similar to that of vancomycin and tetracycline (MIC90,1 µg/mL and linezolid (MIC90,2 Jg/mL. The 1-haemolytic streptococci exhibited 100.0% susceptibility to ceftaroline. Ceftaroline activity against Escherichia coli, Klebsiella spp., and Enterobacter spp. was similar to that of ceftriaxone and ceftazidime. These parenteral cephalosporin agents have potent activity against non-extended-spectrum These parenteral cephalosporin agents have potent activity against non-extended-spectrum-lactamase-phenotype strains, but are not active against extended-spectrum β-lactamase-phenotype strains. These results confirm the in vitro activity of ceftaroline against pathogens common in communityacquired respiratory tract and skin and soft tissue infection in Latin America, and suggest that ceftaroline fosamil could be an important therapeutic option for these infections.

Combined Effect of the Cfr Methyltransferase and Ribosomal Protein L3 Mutations on Resistance to Ribosome-Targeting Antibiotics.

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Pakula, Kevin K; Hansen, Lykke H; Vester, Birte

2017-09-01

Several groups of antibiotics inhibit bacterial growth by binding to bacterial ribosomes. Mutations in ribosomal protein L3 have been associated with resistance to linezolid and tiamulin, which both bind at the peptidyl transferase center in the ribosome. Resistance to these and other antibiotics also occurs through methylation of 23S rRNA at position A2503 by the methyltransferase Cfr. The mutations in L3 and the cfr gene have been found together in clinical isolates, raising the question of whether they have a combined effect on antibiotic resistance or growth. We transformed a plasmid-borne cfr gene into a uL3-depleted Escherichia coli strain containing either wild-type L3 or L3 with one of seven mutations, G147R, Q148F, N149S, N149D, N149R, Q150L, or T151P, expressed from plasmid-carried rplC genes. The L3 mutations are well tolerated, with small to moderate growth rate decreases. The presence of Cfr has a very minor influence on the growth rate. The resistance of the transformants to linezolid, tiamulin, florfenicol, and Synercid (a combination of quinupristin and dalfopristin [Q-D]) was measured by MIC assays. The resistance from Cfr was, in all cases, stronger than the effects of the L3 mutations, but various effects were obtained with the combinations of Cfr and L3 mutations ranging from a synergistic to an antagonistic effect. Linezolid and tiamulin susceptibility varied greatly among the L3 mutations, while no significant effects on florfenicol and Q-D susceptibility were seen. This study underscores the complex interplay between various resistance mechanisms and cross-resistance, even from antibiotics with overlapping binding sites. Copyright © 2017 American Society for Microbiology.

Effects of white matter microstructure on phase and susceptibility maps.

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Wharton, Samuel; Bowtell, Richard

2015-03-01

To investigate the effects on quantitative susceptibility mapping (QSM) and susceptibility tensor imaging (STI) of the frequency variation produced by the microstructure of white matter (WM). The frequency offsets in a WM tissue sample that are not explained by the effect of bulk isotropic or anisotropic magnetic susceptibility, but rather result from the local microstructure, were characterized for the first time. QSM and STI were then applied to simulated frequency maps that were calculated using a digitized whole-brain, WM model formed from anatomical and diffusion tensor imaging data acquired from a volunteer. In this model, the magnitudes of the frequency contributions due to anisotropy and microstructure were derived from the results of the tissue experiments. The simulations suggest that the frequency contribution of microstructure is much larger than that due to bulk effects of anisotropic magnetic susceptibility. In QSM, the microstructure contribution introduced artificial WM heterogeneity. For the STI processing, the microstructure contribution caused the susceptibility anisotropy to be significantly overestimated. Microstructure-related phase offsets in WM yield artifacts in the calculated susceptibility maps. If susceptibility mapping is to become a robust MRI technique, further research should be carried out to reduce the confounding effects of microstructure-related frequency contributions. © 2014 Wiley Periodicals, Inc.

Deposition and transport of linezolid mediated by a synthetic surfactant Synsurf® within a pressurized metered dose inhaler: a Calu-3 model

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van Rensburg, Lyné; van Zyl, Johann M; Smith, Johan

2018-01-01

Background Previous studies in our laboratory demonstrated that a synthetic peptide containing lung surfactant enhances the permeability of chemical compounds through bronchial epithelium. The purpose of this study was to test two formulations of Synsurf® combined with linezolid as respirable compounds using a pressurized metered dose inhaler (pMDI). Methods Aerosolization efficiency of the surfactant-drug microparticles onto Calu-3 monolayers as an air interface culture was analyzed using a Next Generation Impactor™. Results The delivered particles and drug dose showed a high dependency from the preparation that was aerosolized. Scanning electron microscopy imaging allowed for visualization of the deposited particles, establishing them as liposomal-type structures (diameter 500 nm to 2 μm) with filamentous features. Conclusion The different surfactant drug combinations allow for an evaluation of the significance of the experimental model system, as well as assessment of the formulations providing a possible noninvasive, site-specific, delivery model via pMDI.

Loss of function in Mlo orthologs reduces susceptibility of pepper and tomato to powdery mildew disease caused by Leveillula taurica.

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Zheng Zheng

Full Text Available Powdery mildew disease caused by Leveillula taurica is a serious fungal threat to greenhouse tomato and pepper production. In contrast to most powdery mildew species which are epiphytic, L. taurica is an endophytic fungus colonizing the mesophyll tissues of the leaf. In barley, Arabidopsis, tomato and pea, the correct functioning of specific homologues of the plant Mlo gene family has been found to be required for pathogenesis of epiphytic powdery mildew fungi. The aim of this study was to investigate the involvement of the Mlo genes in susceptibility to the endophytic fungus L. taurica. In tomato (Solanum lycopersicum, a loss-of-function mutation in the SlMlo1 gene results in resistance to powdery mildew disease caused by Oidium neolycopersici. When the tomato Slmlo1 mutant was inoculated with L. taurica in this study, it proved to be less susceptible compared to the control, S. lycopersicum cv. Moneymaker. Further, overexpression of SlMlo1 in the tomato Slmlo1 mutant enhanced susceptibility to L. taurica. In pepper, the CaMlo2 gene was isolated by applying a homology-based cloning approach. Compared to the previously identified CaMlo1 gene, the CaMlo2 gene is more similar to SlMlo1 as shown by phylogenetic analysis, and the expression of CaMlo2 is up-regulated at an earlier time point upon L. taurica infection. However, results of virus-induced gene silencing suggest that both CaMlo1 and CaMlo2 may be involved in the susceptibility of pepper to L. taurica. The fact that overexpression of CaMlo2 restored the susceptibility of the tomato Slmlo1 mutant to O. neolycopersici and increased its susceptibility to L. taurica confirmed the role of CaMlo2 acting as a susceptibility factor to different powdery mildews, though the role of CaMlo1 as a co-factor for susceptibility cannot be excluded.

Integrated SSFP for functional brain mapping at 7 T with reduced susceptibility artifact

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Sun, Kaibao; Xue, Rong; Zhang, Peng; Zuo, Zhentao; Chen, Zhongwei; Wang, Bo; Martin, Thomas; Wang, Yi; Chen, Lin; He, Sheng; Wang, Danny J. J.

2017-03-01

Balanced steady-state free precession (bSSFP) offers an alternative and potentially important tool to the standard gradient-echo echo-planar imaging (GE-EPI) for functional MRI (fMRI). Both passband and transition band based bSSFP have been proposed for fMRI. The applications of these methods, however, are limited by banding artifacts due to the sensitivity of bSSFP signal to off-resonance effects. In this article, a unique case of the SSFP-FID sequence, termed integrated-SSFP or iSSFP, was proposed to overcome the obstacle by compressing the SSFP profile into the width of a single voxel. The magnitude of the iSSFP signal was kept constant irrespective of frequency shift. Visual stimulation studies were performed to demonstrate the feasibility of fMRI using iSSFP at 7 T with flip angles of 4° and 25°, compared to standard bSSFP and gradient echo (GRE) imaging. The signal changes for the complex iSSFP signal in activated voxels were 2.48 ± 0.53 (%) and 2.96 ± 0.87 (%) for flip angles (FA) of 4° and 25° respectively at the TR of 9.88 ms. Simultaneous multi-slice acquisition (SMS) with the CAIPIRIHNA technique was carried out with iSSFP scanning to detect the anterior temporal lobe activation using a semantic processing task fMRI, compared with standard 2D GE-EPI. This study demonstrates the feasibility of iSSFP for fMRI with reduced susceptibility artifacts, while maintaining robust functional contrast at 7 T.

Passive therapy with humanized anti-staphylococcal enterotoxin B antibodies attenuates systemic inflammatory response and protects from lethal pneumonia caused by staphylococcal enterotoxin B-producing Staphylococcus aureus.

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Karau, Melissa J; Tilahun, Mulualem E; Krogman, Ashton; Osborne, Barbara A; Goldsby, Richard A; David, Chella S; Mandrekar, Jayawant N; Patel, Robin; Rajagopalan, Govindarajan

2017-10-03

Drugs such as linezolid that inhibit bacterial protein synthesis may be beneficial in treating infections caused by toxigenic Staphylococcus aureus. As protein synthesis inhibitors have no effect on preformed toxins, neutralization of pathogenic exotoxins with anti-toxin antibodies may be beneficial in conjunction with antibacterial therapy. Herein, we evaluated the efficacy of human-mouse chimeric high-affinity neutralizing anti-staphylococcal enterotoxin B (SEB) antibodies in the treatment of experimental pneumonia caused by SEB-producing S. aureus. Since HLA class II transgenic mice mount a stronger systemic immune response following challenge with SEB and are more susceptible to SEB-induced lethal toxic shock than conventional mice strains, HLA-DR3 transgenic mice were used. Lethal pneumonia caused by SEB-producing S. aureus in HLA-DR3 transgenic mice was characterized by robust T cell activation and elevated systemic levels of several pro-inflammatory cytokines and chemokines. Prophylactic administration of a single dose of linezolid 30 min prior to the onset of infection attenuated the systemic inflammatory response and protected from mortality whereas linezolid administered 60 min after the onset of infection failed to confer significant protection. Human-mouse chimeric high-affinity neutralizing anti-SEB antibodies alone, but not polyclonal human IgG, mitigated this response and protected from death when administered immediately after initiation of infection. Further, anti-SEB antibodies as well as intact polyclonal human IgG, but not its Fab or Fc fragments, protected from lethal pneumonia when followed with linezolid therapy 60 min later. In conclusion, neutralization of superantigens with high-affinity antibodies may have beneficial effects in pneumonia.

Six-year susceptibility trends and effect of revised Clinical Laboratory Standards Institute breakpoints on ciprofloxacin susceptibility reporting in typhoidal Salmonellae in a tertiary care paediatric hospital in Northern India

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R Saksena

2016-01-01

Full Text Available The antimicrobial trends over 6 years were studied, and the effect of revised Clinical Laboratory Standards Institute (CLSI breakpoints (2012 for ciprofloxacin susceptibility reporting in typhoidal Salmonellae was determined. A total of 874 (95.4% isolates were nalidixic acid-resistant (NAR. Using the CLSI 2011 guidelines (M100-S21, 585 (66.9% isolates were ciprofloxacin susceptible. The susceptibility reduced to 11 (1.25% isolates when interpreted using 2012 guidelines (M100-S22. Among the forty nalidixic acid susceptible (NAS Salmonellae, susceptibility to ciprofloxacin decreased from 37 isolates (M100-S21 to 12 isolates (M100-S22. The 25 cases which appeared resistant with newer guidelines had a minimum inhibitory concentration (MIC range between 0.125 and 0.5 μg/ml. MIC50 for the third generation cephalosporins varied between 0.125 and 0.5 μg/ml over 6 years whereas MIC90 varied with a broader range of 0.19–1 μg/ml. The gap between NAR and ciprofloxacin-resistant strains identified using 2011 guidelines has been reduced; however, it remains to be seen whether additional NAS, ciprofloxacin-resistant isolates are truly resistant to ciprofloxacin by other mechanisms of resistance.

TGF-b2 induction regulates invasiveness of Theileria-transformed leukocytes and disease susceptibility.

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Marie Chaussepied

2010-11-01

Full Text Available Theileria parasites invade and transform bovine leukocytes causing either East Coast fever (T. parva, or tropical theileriosis (T. annulata. Susceptible animals usually die within weeks of infection, but indigenous infected cattle show markedly reduced pathology, suggesting that host genetic factors may cause disease susceptibility. Attenuated live vaccines are widely used to control tropical theileriosis and attenuation is associated with reduced invasiveness of infected macrophages in vitro. Disease pathogenesis is therefore linked to aggressive invasiveness, rather than uncontrolled proliferation of Theileria-infected leukocytes. We show that the invasive potential of Theileria-transformed leukocytes involves TGF-b signalling. Attenuated live vaccine lines express reduced TGF-b2 and their invasiveness can be rescued with exogenous TGF-b. Importantly, infected macrophages from disease susceptible Holstein-Friesian (HF cows express more TGF-b2 and traverse Matrigel with great efficiency compared to those from disease-resistant Sahiwal cattle. Thus, TGF-b2 levels correlate with disease susceptibility. Using fluorescence and time-lapse video microscopy we show that Theileria-infected, disease-susceptible HF macrophages exhibit increased actin dynamics in their lamellipodia and podosomal adhesion structures and develop more membrane blebs. TGF-b2-associated invasiveness in HF macrophages has a transcription-independent element that relies on cytoskeleton remodelling via activation of Rho kinase (ROCK. We propose that a TGF-b autocrine loop confers an amoeboid-like motility on Theileria-infected leukocytes, which combines with MMP-dependent motility to drive invasiveness and virulence.

Antibiotic susceptibility patterns and prevalence of group B Streptococcus isolated from pregnant women in Misiones, Argentina Sensibilidade a antibióticos e prevalência de Streptococcus do grupo B em mulheres grávidas em Missiones, Argentina

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M. Quiroga

2008-06-01

Full Text Available This study was performed to determine the susceptibility patterns and the colonization rate of Group B Streptococcus (GBS in a population of pregnant women. From January 2004 to December 2006, vaginal-rectal swabs were obtained from 1105 women attending Dr. Ramón Madariaga Hospital, in Posadas, Misiones, Argentina. The carriage rate of GBS among pregnant women was 7.6%. A total of 62 GBS strains were randomly selected for in vitro susceptibility testing to penicillin G, ampicillin, tetracycline, levofloxacin, gatifloxacin, ciprofloxacin, quinupristin-dalfopristin, linezolid, vancomycin, rifampicin, trimethoprim-sulfametoxazol, nitrofurantoin, gentamicin, clindamycin and erythromycin, and determination of resistance phenotypes. No resistance to penicillin, ampicillin, quinupristin-dalfopristin, linezolid, and vancomycin was found. Of the isolates examined 96.8%, 98.3%, 46.8%, and 29.0% were susceptible to rifampicin, nitrofurantoin, trimethoprim-sulfametoxazol and tetracycline, respectively. Rank order of susceptibility for the quinolones was: gatifloxacin (98.4% > levofloxacin (93.5% > ciprofloxacin (64.5%. The rate of resistance to erythromycin (9.7% was higher than that of other reports from Argentina. High-level resistance to gentamicin was not detected in any of the isolates. Based on our finding of 50% of GBS isolates with MIC to gentamicin equal o lower than 8 µg/ml, a concentration used in one of the selective media recommended for GBS isolation, we suggested, at least in our population, the use of nalidixic acid and colistin in selective media with the aim to improve the sensitivity of screening cultures for GBS carriage in women.Esse estudo objetivou determinar os padrões de sensibilidade a antibióticos e as taxas de colonização de Streptococcus do grupo B (GBS em uma população de mulheres grávidas. Entre janeiro de 2004 e dezembro de 2006, foram obtidos swabs vaginais-retais de 1105 mulheres no Hospital Dr. Ramon Madariaga, em

Heightened vulnerability to MDR-TB epidemics after controlling drug-susceptible TB.

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Jason D Bishai

2010-09-01

Full Text Available Prior infection with one strain TB has been linked with diminished likelihood of re-infection by a new strain. This paper attempts to determine the role of declining prevalence of drug-susceptible TB in enabling future epidemics of MDR-TB.A computer simulation of MDR-TB epidemics was developed using an agent-based model platform programmed in NetLogo (See http://mdr.tbtools.org/. Eighty-one scenarios were created, varying levels of treatment quality, diagnostic accuracy, microbial fitness cost, and the degree of immunogenicity elicited by drug-susceptible TB. Outcome measures were the number of independent MDR-TB cases per trial and the proportion of trials resulting in MDR-TB epidemics for a 500 year period after drug therapy for TB is introduced.MDR-TB epidemics propagated more extensively after TB prevalence had fallen. At a case detection rate of 75%, improving therapeutic compliance from 50% to 75% can reduce the probability of an epidemic from 45% to 15%. Paradoxically, improving the case-detection rate from 50% to 75% when compliance with DOT is constant at 75% increases the probability of MDR-TB epidemics from 3% to 45%.The ability of MDR-TB to spread depends on the prevalence of drug-susceptible TB. Immunologic protection conferred by exposure to drug-susceptible TB can be a crucial factor that prevents MDR-TB epidemics when TB treatment is poor. Any single population that successfully reduces its burden of drug-susceptible TB will have reduced herd immunity to externally or internally introduced strains of MDR-TB and can experience heightened vulnerability to an epidemic. Since countries with good TB control may be more vulnerable, their self interest dictates greater promotion of case detection and DOTS implementation in countries with poor control to control their risk of MDR-TB.

Characterization and antimicrobial susceptibility of one antibiotic-sensitive and one multidrug-resistant Corynebacterium kroppenstedtii strain isolated from patients with granulomatous mastitis

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I. Fernández-Natal

2016-11-01

Full Text Available Human infections associated with Corynebacterium kroppenstedtii are rarely reported, and this organism is usually described as antibiotic sensitive. Almost all published cases of C. kroppenstedtii infections have been associated with breast pathology in women and have been described in New Zealand, France, Canada, India and Japan. Here we describe the microbiologic characteristics of two strains isolated from two women diagnosed of granulomatous mastitis in Spain. One C. kroppenstedtii isolate was antibiotic sensitive while the other was multidrug resistant. Biochemical identification was possible using a wide battery of methods including API Coryne V2.0, API Strep, API NH, API NE, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 16S rRNA gene amplification and sequencing. Antimicrobial susceptibility to 28 antibiotics as determined by Etest showed one isolate being sensitive to benzylpenicillin, ciprofloxacin, moxifloxacin, gentamicin, vancomycin, clindamycin, tetracycline, linezolid and rifampin. The second isolate showed resistance to ciprofloxacin, moxifloxacin, clindamycin, tetracycline and rifampin. The multidrug-resistant isolate contained the erm(X, tet(W, cmx, aphA1-IAB, strAB and sul1 resistance genes known from the R plasmid pJA144188 of Corynebacterium resistens. These genes were absent in the genome of the antibiotic-sensitive isolate. This report confirms the tropism of this microorganism for women's breasts and presents the first description of a multidrug-resistant C. kroppenstedtii strain.

Analysis of multidrug resistant group B streptococci with reduced penicillin susceptibility forming small, less hemolytic colonies.

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Hirotsugu Banno

Full Text Available Group B streptococci (GBS; Streptococcus agalactiae are the leading cause of neonatal invasive diseases and are also important pathogens for elderly adults. Until now, nearly all GBS with reduced penicillin susceptibility (PRGBS have shown β-hemolytic activity and grow on sheep blood agar. However, we have previously reported three PRGBS clinical isolates harboring a CylK deletion that form small less hemolytic colonies. In this study, we examined the causes of small, less hemolytic colony formation in these clinical isolates. Isogenic strains were sequenced to identify the mutation related to a small colony size. We identified a 276_277insG nucleic acid insertion in the thiamin pyrophosphokinase (tpk gene, resulting in premature termination at amino acid 103 in TPK, as a candidate mutation responsible for small colony formation. The recombinant strain Δtpk, which harbored the 276_277insG insertion in the tpk gene, showed small colony formation. The recombinant strain ΔcylK, which harbored the G379T substitution in cylK, showed a reduction in hemolytic activity. The phenotypes of both recombinant strains were complemented by the expression of intact TPK or CylK, respectively. Moreover, the use of Rapid ID 32 API and VITEK MS to identify strains as GBS was evaluated clinical isolates and recombinant strains. VITEK MS, but not Rapid ID 32 API, was able to accurately identify the strains as GBS. In conclusion, we determined that mutations in tpk and cylK caused small colonies and reduced hemolytic activity, respectively, and characterized the clinical isolates in detail.

Serological Susceptibility to Varicella Among U.S. Immigration and Customs Enforcement Detainees.

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Varan, Aiden K; Lederman, Edith R; Stous, Shanon S; Elson, Diana; Freiman, Jennifer L; Marin, Mona; Lopez, Adriana S; Stauffer, William M; Joseph, Rachael H; Waterman, Stephen H

2018-01-01

U.S. Immigration and Customs Enforcement (ICE) is responsible for detaining unauthorized aliens during immigration proceedings. During 2014 to 2015, adult ICE detainees at a California facility were invited to complete a survey concerning self-reported varicella history and risk factors. Participants underwent serological testing for varicella-zoster virus (VZV) IgG; susceptible individuals were offered varicella vaccination. Among 400 detainees with available serology results, 48 (12%) were susceptible to varicella. Self-reported varicella history was negatively associated with susceptibility (adjusted odds ratio = 0.16; 95% confidence interval [0.07, 0.35]). Among 196 detainees reporting a positive history, 95% had VZV IgG levels suggestive of varicella immunity. Among 44 susceptible detainees offered vaccination, 86% accepted. Given relatively high varicella susceptibility, targeted screening and vaccination among ICE detainees lacking a positive history might reduce varicella transmission risks.

Antiretroviral drug susceptibility among drug-naive adults with recent HIV infection in Rakai, Uganda.

Science.gov (United States)

Eshleman, Susan H; Laeyendecker, Oliver; Parkin, Neil; Huang, Wei; Chappey, Colombe; Paquet, Agnes C; Serwadda, David; Reynolds, Steven J; Kiwanuka, Noah; Quinn, Thomas C; Gray, Ronald; Wawer, Maria

2009-04-27

To analyze antiretroviral drug susceptibility in HIV from recently infected adults in Rakai, Uganda, prior to the availability of antiretroviral drug treatment. Samples obtained at the time of HIV seroconversion (1998-2003) were analyzed using the GeneSeq HIV and PhenoSense HIV assays (Monogram Biosciences, Inc., South San Francisco, California, USA). Test results were obtained for 104 samples (subtypes: 26A, 1C, 66D, 9A/D, 1C/D, 1 intersubtype recombinant). Mutations used for genotypic surveillance of transmitted antiretroviral drug resistance were identified in six samples: three had nucleoside reverse transcriptase inhibitor (NRTI) surveillance mutations (two had M41L, one had K219R), and three had protease inhibitor surveillance mutations (I47V, F53L, N88D); none had nonnucleoside reverse transcriptase inhibitor (NNRTI) surveillance mutations. Other resistance-associated mutations were identified in some samples. However, none of the samples had a sufficient number of mutations to predict reduced antiretroviral drug susceptibility. Ten (9.6%) of the samples had reduced phenotypic susceptibility to at least one drug (one had partial susceptibility to didanosine, one had nevirapine resistance, and eight had resistance or partial susceptibility to at least one protease inhibitor). Fifty-three (51%) of the samples had hypersusceptibility to at least one drug (seven had zidovudine hypersusceptibility, 28 had NNRTI hypersusceptibility, 34 had protease inhibitor hypersusceptibility). Delavirdine hypersusceptibility was more frequent in subtype A than D. In subtype D, efavirenz hypersusceptibility was associated with substitutions at codon 11 in HIV-reverse transcriptase. Phenotyping detected reduced antiretroviral drug susceptibility and hypersusceptibility in HIV from some antiretroviral-naive Ugandan adults that was not predicted by genotyping. Phenotyping may complement genotyping for analysis of antiretroviral drug susceptibility in populations with nonsubtype B

Effects of mineral nutrients on ozone susceptibility of Lemna minor

Energy Technology Data Exchange (ETDEWEB)

Craker, L E

1971-01-01

Susceptibility of Lemna minor L. to ozone injury was influenced by the mineral nutrients available to the Lemna plants. Additional nitrogen or additional iron in the nutrient media respectively enhanced or reduced chlorophyll loss of Lemna plants fumigated with ozone. Lemna plants growing on a nutrient medium lacking copper had significantly less injury from ozone fumigation than Lemna plants growing on a complete nutrient medium. There were apparent interactions among phosphorus and potassium nutrient levels in determing the Lemna plant's susceptibility to ozone.

The invasive MenC cc103 lineage with penicillin reduced susceptibility persisting in Brazil.

Science.gov (United States)

Fonseca, Érica L; Marin, Michel A; Freitas, Fernanda S; Vitório, Bruna S A; de Araújo, Flávio M G; Camargo, Dhian R A; Coimbra, Roney S; De Filippis, Ivano R; Vicente, Ana Carolina P

2017-09-01

Penicillin is the antibiotic of choice for the treatment of meningococcal infections, and mutations in penA gene are involved with reduced susceptibility (pen I ) emergence to this antibiotic. This study aimed to characterize the penA allelic diversity, their association with pen I phenotype and distribution among prevalent meningococci serogroups in Brazil. The entire penA from 49 invasive strains of distinct serogroups circulating in Brazil for more than two decades were obtained by PCR and sequencing. Additionally, the penA from 22 publicly available complete Neisseria meningitidis genomes from Brazil were included in the study. The allelic diversity was determined and a genetic tree was built using the penA sequence alignment. The penicillin MIC was obtained by the E-Test method. In general, the identified penA alleles correlated with the observed pen I phenotype. The canonical penA1 was the most prevalent allele, however, several altered penA were also identified in strains presenting increased penicillin MICs. It was identified a new penA amino acid position (residue 480) that possibly influence the penicillin MIC in some strains. Interestingly, the altered penA14 was found in pen I invasive MenC cc103 strains spread in Brazil and persisting since 2011, indicating that the biological cost imposed by pen I phenotype can be ameliorated by particular features present in this lineage, which represents an additional public health threat. Copyright © 2017 Elsevier GmbH. All rights reserved.

The human clone ST22 SCCmec IV methicillin-resistant Staphylococcus aureus isolated from swine herds and wild primates in Nepal: is man the common source?

Science.gov (United States)

Roberts, Marilyn C; Joshi, Prabhu Raj; Greninger, Alexander L; Melendez, Daira; Paudel, Saroj; Acharya, Mahesh; Bimali, Nabin Kishor; Koju, Narayan P; No, David; Chalise, Mukesh; Kyes, Randall C

2018-05-01

Swine nasal samples [n = 282] were collected from 12 randomly selected farms around Kathmandu, Nepal, from healthy animals. In addition, wild monkey (Macaca mulatta) saliva samples [n = 59] were collected near temples areas in Kathmandu using a non-invasive sampling technique. All samples were processed for MRSA using standardized selective media and conventional biochemical tests. MRSA verification was done and isolates characterized by SCCmec, multilocus sequence typing, whole genome sequencing [WGS] and antibiotic susceptibilities. Six (2.1%) swine MRSA were isolated from five of the different swine herds tested, five were ST22 type IV and one ST88 type V. Four (6.8%) macaques MRSA were isolated, with three ST22 SCCmec type IV and one ST239 type III. WGS sequencing showed that the eight ciprofloxacin resistant ST22 isolates carried gyrA mutation [S84L]. Six isolates carried the erm(C) genes, five isolates carried aacC-aphD genes and four isolates carried blaZ genes. The swine linezolid resistant ST22 did not carry any known acquired linezolid resistance genes but had a mutation in ribosomal protein L22 [A29V] and an insertion in L4 [68KG69], both previously associated with linezolid resistance. Multiple virulence factors were also identified. This is the first time MRSA ST22 SCCmec IV has been isolated from livestock or primates.

Assessing landslide susceptibility by applying fuzzy sets, possibility evidence-based theories

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Ibsen Chivatá Cárdenas

2008-01-01

Full Text Available A landslide susceptibility model was developed for the city of Manizales, Colombia; landslides have been the city’s main environmental problem. Fuzzy sets and possibility and evidence-based theories were used to construct the mo-del due to the set of circumstances and uncertainty involved in the modelling; uncertainty particularly concerned the lack of representative data and the need for systematically coordinating subjective information. Susceptibility and the uncertainty were estimated via data processing; the model contained data concerning mass vulnerability and uncer-tainty. Output data was expressed on a map defined by linguistic categories or uncertain labels as having low, me-dium, high and very high susceptibility; this was considered appropriate for representing susceptibility. A fuzzy spec-trum was developed for classifying susceptibility levels according to perception and expert opinion. The model sho-wed levels of susceptibility in the study area, ranging from low to high susceptibility (medium susceptibility being mo-re frequent. This article shows the details concerning systematic data processing by presenting theories and tools regarding uncertainty. The concept of fuzzy parameters is introduced; this is useful in modelling phenomena regar-ding uncertainty, complexity and nonlinear performance, showing that susceptibility modelling can be feasible. The paper also shows the great convenience of incorporating uncertainty into modelling and decision-making. However, quantifying susceptibility is not suitable when modelling identified uncertainty because incorporating model output information cannot be reduced into exact or real numerical quantities when the nature of the variables is particularly uncertain. The latter concept is applicable to risk assessment.

The use of machine learning methodologies to analyse antibiotic and biocide susceptibility in Staphylococcus aureus.

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Joana Rosado Coelho

Full Text Available BACKGROUND: The rise of antibiotic resistance in pathogenic bacteria is a significant problem for the treatment of infectious diseases. Resistance is usually selected by the antibiotic itself; however, biocides might also co-select for resistance to antibiotics. Although resistance to biocides is poorly defined, different in vitro studies have shown that mutants presenting low susceptibility to biocides also have reduced susceptibility to antibiotics. However, studies with natural bacterial isolates are more limited and there are no clear conclusions as to whether the use of biocides results in the development of multidrug resistant bacteria. METHODS: The main goal is to perform an unbiased blind-based evaluation of the relationship between antibiotic and biocide reduced susceptibility in natural isolates of Staphylococcus aureus. One of the largest data sets ever studied comprising 1632 human clinical isolates of S. aureus originated worldwide was analysed. The phenotypic characterization of 13 antibiotics and 4 biocides was performed for all the strains. Complex links between reduced susceptibility to biocides and antibiotics are difficult to elucidate using the standard statistical approaches in phenotypic data. Therefore, machine learning techniques were applied to explore the data. RESULTS: In this pioneer study, we demonstrated that reduced susceptibility to two common biocides, chlorhexidine and benzalkonium chloride, which belong to different structural families, is associated to multidrug resistance. We have consistently found that a minimum inhibitory concentration greater than 2 mg/L for both biocides is related to antibiotic non-susceptibility in S. aureus. CONCLUSIONS: Two important results emerged from our work, one methodological and one other with relevance in the field of antibiotic resistance. We could not conclude on whether the use of antibiotics selects for biocide resistance or vice versa. However, the observation of

Susceptibility analysis of landslide in Chittagong City Corporation Area, Bangladesh

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Sourav Das

2015-06-01

Full Text Available In Chittagong city, landslide phenomena is the most burning issue which causes great problems to the life and properties and it is increasing day by day and becoming one of the main problems of city life. On 11 June 2007, a massive landslide happened in Chittagong City Corporation (CCC area, a large number of foothill settlements and slums were demolished; more than 90 people died and huge resource destruction took place. It is therefore essential to analyze the landslide susceptibility for CCC area to prepare mitigation strategies as well as assessing the impacts of climate change. To assess community susceptibility of landslide hazard, a landslide susceptibility index map has been prepared using analytical hierarchy process (AHP model based on geographic information system (GIS and remote sensing (RS and its susceptibility is analyzed through community vulnerability assessment tool (CVAT. The major findings of the research are 27% of total CCC area which is susceptible to landslide hazard and whereas 6.5 sq.km areas are found very highly susceptible. The landslide susceptible areas of CCC have also been analyzed in respect of physical, social, economic, environmental and critical facilities and it is found that the overall CCC area is highly susceptible to landslide hazard. So the findings of the research can be utilized to prioritize risk mitigation investments, measures to strengthen the emergency preparedness and response mechanisms for reducing the losses and damages due to future landslide events. DOI: http://dx.doi.org/10.3126/ije.v4i2.12635 International Journal of Environment Vol.4(2 2015: 157-181

Measurement of magnetic susceptibility on tailings cores report on cores obtained from the Ontario Research Foundation lysimeter experiment

International Nuclear Information System (INIS)

1984-10-01

Bulk susceptibility and induced magnetic remanence results are reported for 40 cores obtained from the uranium tailings lysimeter experiment at the Ontario Research Foundation. Both methods indicate a broad threefold subdivision of the tailings pile. An upper zone is characterized by an enhanced susceptibility level, which is related to enhanced concentration of both magnetite and hematite. Depletion zones, where present, are of limited areal extent and strongly developed. An intermediate zone is characterized by a mixture of large areas of reduced susceptibility that separate smaller regions of slightly enhanced susceptibility. The zones of susceptibility depletion appear to define a dendritic drainage pattern. Locally in this zone magnetite is enhanced and hematite depleted. In the lowermost zone susceptibility levels are reduced over most of the tailings bed. Only in the upper most right hand corner is there any vestige of a positive susceptibility concentration. Both magnetite and hematite are strongly depleted in this lower zone. Visually it is apparent that this lowermost depleted zone correlates to the zones of strongest 'yellowcake' development

Effects of mineral nutrients on ozone susceptibility of Lemna minor

Energy Technology Data Exchange (ETDEWEB)

Craker, L.E.

1971-01-01

Susceptibility of Lemna minor L. to ozone injury was influenced by the mineral nutrients available to the Lemna plants. Additional nitrogen or additional iron in the nutrient media respectively enhanced or reduced chlorophyll loss of Lemna plants fumigated with ozone. Lemna plants growing on a nutrient medium lacking copper had significantly less injury from ozone fumigation than Lemna plants growing on a complete nutrient medium. There were apparent interactions among phosphorus and potassium nutrient levels in determing the Lemna plant's susceptibility to ozone.

Assessing the antibiotic susceptibility of freshwater cyanobacteria spp.

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Elsa eDias

2015-08-01

Full Text Available Freshwater is a vehicle for the emergence and dissemination of antibiotic resistance. Cyanobacteria are ubiquitous in freshwater, where they are exposed to antibiotics and resistant organisms, but their role on water resistome was never evaluated. Data concerning the effects of antibiotics on cyanobacteria, obtained by distinct methodologies, is often contradictory. This emphasizes the importance of developing procedures to understand the trends of antibiotic susceptibility in cyanobacteria. In this study we aimed to evaluate the susceptibility of four cyanobacterial isolates from different genera (Microcystis aeruginosa, Aphanizomenon gracile, Chrisosporum bergii, Planktothix agradhii, and among them nine isolates from the same specie (M. aeruginosa to distinct antibiotics (amoxicillin, ceftazidime, ceftriaxone, kanamycine, gentamicine, tetracycline, trimethoprim, nalidixic acid, norfloxacin. We used a method adapted from the bacteria standard broth microdilution. Cyanobacteria were exposed to serial dilution of each antibiotic (0.0015-1.6 mg/L in Z8 medium (20 ± 1 ºC; 14/10 h L/D cycle; light intensity 16 ± 4 µEm-2 s-1. Cell growth was followed overtime (OD450nm/microscopic examination and the minimum inhibitory concentrations (MICs were calculated for each antibiotic/isolate. We found that -lactams exhibited the lower MICs, aminoglycosides, tetracycline and norfloxacine presented intermediate MICs; none of the isolates were susceptible to trimethoprim and nalidixic acid. The reduced susceptibility of all tested cyanobacteria to some antibiotics suggests that they might be naturally non-susceptible to these compounds, or that that they might became non-susceptible due to antibiotic contamination pressure, or to the transfer of genes from resistant bacteria present in the environment.

Mutations in ribosomal protein L3 and 23S ribosomal RNA at the peptidyl transferase centre are associated with reduced susceptibility to tiamulin in Brachyspira spp. isolates.

Science.gov (United States)

Pringle, Märit; Poehlsgaard, Jacob; Vester, Birte; Long, Katherine S

2004-12-01

The pleuromutilin antibiotic tiamulin binds to the ribosomal peptidyl transferase centre. Three groups of Brachyspira spp. isolates with reduced tiamulin susceptibility were analysed to define resistance mechanisms to the drug. Mutations were identified in genes encoding ribosomal protein L3 and 23S rRNA at positions proximal to the peptidyl transferase centre. In two groups of laboratory-selected mutants, mutations were found at nucleotide positions 2032, 2055, 2447, 2499, 2504 and 2572 of 23S rRNA (Escherichia coli numbering) and at amino acid positions 148 and 149 of ribosomal protein L3 (Brachyspira pilosicoli numbering). In a third group of clinical B. hyodysenteriae isolates, only a single mutation at amino acid 148 of ribosomal protein L3 was detected. Chemical footprinting experiments show a reduced binding of tiamulin to ribosomal subunits from mutants with decreased susceptibility to the drug. This reduction in drug binding is likely the resistance mechanism for these strains. Hence, the identified mutations located near the tiamulin binding site are predicted to be responsible for the resistance phenotype. The positions of the mutated residues relative to the bound drug advocate a model where the mutations affect tiamulin binding indirectly through perturbation of nucleotide U2504.

Review of magnetic susceptibility logging and its application to uranium exploration

International Nuclear Information System (INIS)

George, D.C.; Scott, J.H.

1982-01-01

Borehole measurement of magnetic susceptibility can show anomalies associated with mineralization or alteration. The detection of small anomalies is necessary, so efforts have been made in recent years to improve the sensitivity and the stability of magnetic susceptibility logging tools. Typical tools contain a single coil constructed as a solenoid wound on ferrite rods about 30cm long. The coil is heated to a constant temperature to reduce drift, and careful design is necessary to optimize temperature control and to maximize sensitivity. Measurements of coil resistance and inductance, which indicate conductivity and susceptibility, are made using a Maxwell bridge circuit. Circuit analysis shows that conductivity measurements are difficult and that stringent requirements are placed on phase stability of measurement circuitry. Corrections to the observed log are necessary to account for borehole size. The response of the tool to a thin zones of anomalous susceptibility is double peaked and a set of curves has been developed for interpretation. Calibrations of the tools are made by measuring the tool's response in models of known susceptibility

Repetitive immunization enhances the susceptibility of mice to peripherally administered prions.

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Juliane Bremer

Full Text Available The susceptibility of humans and animals to prion infections is determined by the virulence of the infectious agent, by genetic modifiers, and by hitherto unknown host and environmental risk factors. While little is known about the latter two, the activation state of the immune system was surmised to influence prion susceptibility. Here we administered prions to mice that were repeatedly immunized by two initial injections of CpG oligodeoxynucleotides followed by repeated injections of bovine serum albumin/alum. Immunization greatly reduced the required dosage of peripherally administered prion inoculum necessary to induce scrapie in 50% of mice. No difference in susceptibility was observed following intracerebral prion challenge. Due to its profound impact onto scrapie susceptibility, the host immune status may determine disease penetrance after low-dose prion exposure, including those that may give rise to iatrogenic and variant Creutzfeldt-Jakob disease.

Magnetic susceptibility imaging with a nonionic contrast agent

International Nuclear Information System (INIS)

Cacheris, W.; Rocklage, S.M.; Quay, S.; Dow, W.; Love, D.; Worah, D.; Lim, K.

1988-01-01

The magnetic susceptibility mechanism for MR imaging contrast enhancement has the advantage of providing useful information, such as cerebral blood flow, without crossing the blood-brain barrier. In this paper the authors report the use of a highly effective, relatively nontoxic chelate as a magnetic susceptibility agent. Dy-DTPA-bis(methylamide) (Dy-DTPA-BMA) has an extremely low acute toxicity (LD-50, intravenous, mice ∼ 40 mmol/kg). Doses of 1 mmol/kg and 2 mmol/kg Dy-DTPA-BMA lowered the initial signal intensity 63% to 57%, respectively. The utility of this technique in detecting areas of reduced blood flow within the brain was demonstrated by imaging a rabbit with a cerebral perfusion deficit

Susceptibility of Aeromonas Hydophila Isolates to Antimicrobial Drugs

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Igor Stojanov

2010-05-01

Full Text Available Aeromonas hydrophila is a microorganism widely distributed in nature: in water, soil, food. It is also part of the normal bacterial flora of many animals. As an opportune microorganism it is a secondary biological agent that contributes to the occurrence of a fish disease and its deterioration. Frequently, its presence is an indication of bad zoohygiene and zootechnical conditions in fish ponds. Reduced quality and quantity of feed, mechanical injuries, parasitosis, seasonal oscillation in temperature present some of the factors that produce favorable conditions for bacterial proliferation of aeromonas in fish ponds, so clinical symptoms of the disease occur. Aeromonas is almost always present in clinical isolates and may be unjustly accused for bad health of fish. Antibiotic therapy is applied even when the clinical findings are clear, what certainly effects the susceptibility to chemotherapeutics. The subject of our work was bacteriological examination of the material obtained from the carps with the observed skin changes and the carps without these changes. Also, antimicrobial susceptibility of Aeromonas hydrophila was tested. The aim of this research was to determined the presence of Aeromonas hydrophilia in the carp ponds and to test antibiotic susceptibility. The material consisted of the samples from the fish ponds where the carps were with and without changed skin. The method the isolation of Aeromonas hydrophila was used. The diffusion disk technique was used for testing antibiotic susceptibility. The isolates were tested for their susceptibility to Florephenikol, Flumequine, Olaqindox and Oxitetracycline. The obtained results point that antimicrobial susceptibility was the same regardless of the origin of the samples, i.e. the resistance was the same for both groups of samples (the strains isolated from the fish with skin changes and the strains from fish without changes on skin. The strains were highly resistant: 35% were resistant to

Magnetic susceptibility of functional groups

International Nuclear Information System (INIS)

Herr, T.; Ferraro, M.B.; Contreras, R.H.

1990-01-01

Proceeding with a series of works where new criteria are applied to the the calculation of the contribution of molecular fragments to certain properties, results are presented for a group of 1-X-benzenes and 1-X-naphtalenes for the magnetic susceptibility constant. Both the diamagnetic and paramagnetic parts are taken into account. To reduce the problems associated with the Gauge dependence originated in the approximations made, Gauge independent atomic orbitals (GIAO) orbitals are used in the atomic orbital basis. Results are discussed in terms of functional groups. (Author). 17 refs., 1 fig., 3 tabs

Quantitative influence of minor and impurity elements on hot cracking susceptibility of extra high-purity type 310 stainless steel

International Nuclear Information System (INIS)

Saida, Kazuyoshi; Matsushita, Hideki; Nishimoto, Kazutoshi; Kiuchi, Kiyoshi; Nakayama, Junpei

2013-01-01

To evaluate the influence of minor and impurity elements such as C, Mn, P and S on the solidification and ductility-dip cracking susceptibilities of extra high-purity type 310 stainless steels, the transverse-Varestraint test was conducted by using several type 310 stainless steels with different amounts of C, Mn, P and S. Two types of hot cracks occurred in these steels by Varestraint test; solidification and ductility-dip cracks. The solidification cracking susceptibility was significantly reduced as the amounts of C, P and S decreased. The ductility-dip cracking susceptibility also reduced with a decrease in P and S contents. It adversely, however, increased as the C content of the steels was reduced. Mn didn't greatly affect the hot cracking susceptibility of the extra high-purity steels. The characteristic influence on solidification cracking was the ratio of P:S:C=1:1.3:0.56, while Mn negligibly ameliorated solidification cracking in the extra low S (and P) steels. The numerical analysis on the solidification brittle temperature range (BTR) revealed that the reduced solidification cracking susceptibility with decreasing the amounts of C, P and S in steel could be attributed to the reduced BTR due to the suppression of solidification segregation of minor and impurity elements in the finally solidified liquid film between dendrites. On the other hand, a molecular orbital analysis to estimate the binding strength of the grain boundary suggested that the increased ductility-dip cracking susceptibility in extra high-purity steels was caused by grain boundary embrittlement due to the refining of beneficial elements for grain boundary strengthening such as C. (author)

In vitro activities of the new semisynthetic glycopeptide telavancin (TD-6424), vancomycin, daptomycin, linezolid, and four comparator agents against anaerobic gram-positive species and Corynebacterium spp.

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Goldstein, Ellie J C; Citron, Diane M; Merriam, C Vreni; Warren, Yumi A; Tyrrell, Kerin L; Fernandez, Helen T

2004-06-01

Telavancin is a new semisynthetic glycopeptide anti-infective with multiple mechanisms of action, including inhibition of bacterial membrane phospholipid synthesis and inhibition of bacterial cell wall synthesis. We determined the in vitro activities of telavancin, vancomycin, daptomycin, linezolid, quinupristin-dalfopristin, imipenem, piperacillin-tazobactam, and ampicillin against 268 clinical isolates of anaerobic gram-positive organisms and 31 Corynebacterium strains using agar dilution methods according to National Committee for Clinical Laboratory Standards procedures. Plates with daptomycin were supplemented with Ca(2+) to 50 mg/liter. The MICs at which 90% of isolates tested were inhibited (MIC(90)s) for telavancin and vancomycin were as follows: Actinomyces spp. (n = 45), 0.25 and 1 microg/ml, respectively; Clostridium difficile (n = 14), 0.25 and 1 microg/ml, respectively; Clostridium ramosum (n = 16), 1 and 4 microg/ml, respectively; Clostridium innocuum (n = 15), 4 and 16 microg/ml, respectively; Clostridium clostridioforme (n = 15), 8 and 1 microg/ml, respectively; Eubacterium group (n = 33), 0.25 and 2 microg/ml, respectively; Lactobacillus spp. (n = 26), 0.5 and 4 microg/ml, respectively; Propionibacterium spp. (n = 34), 0.125 and 0.5 microg/ml, respectively; Peptostreptococcus spp. (n = 52), 0.125 and 0.5 microg/ml, respectively; and Corynebacterium spp. (n = 31), 0.03 and 0.5 microg/ml, respectively. The activity of TD-6424 was similar to that of quinupristin-dalfopristin for most strains except C. clostridioforme and Lactobacillus casei, where quinupristin-dalfopristin was three- to fivefold more active. Daptomycin had decreased activity (MIC > 4 microg/ml) against 14 strains of Actinomyces spp. and all C. ramosum, Eubacterium lentum, and Lactobacillus plantarum strains. Linezolid showed decreased activity (MIC > 4 microg/ml) against C. ramosum, two strains of C. difficile, and 15 strains of Lactobacillus spp. Imipenem and piperacillin

In vitro susceptibilities of Brucella melitensis isolates to eleven antibiotics

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Loukaides Feidias

2006-10-01

Full Text Available Abstract Background Brucellosis is an endemic disease present in many countries worldwide, but it is rare in Europe and North America. Nevertheless brucella is included in the bacteria potentially used for bioterrorism. The aim of this study was the investigation of the antibiotic susceptibility profile of brucella isolates from areas of the eastern Mediterranean where it has been endemic. Methods The susceptibilities of 74 Brucella melitensis isolates derived from clinical samples (57 and animal products (17 were tested in vitro. The strains originate from Crete (59, Cyprus (10, and Syria (5. MICs of tetracycline, rifampicin, streptomycin, gentamicin, norfloxacin, ciprofloxacin, levofloxacin, trimethoprim/sulfamethoxazole, ampicillin, amoxicillin/clavulanic acid, and erythromycin were detected by E-test method. The NCCLS criteria for slow growing bacteria were considered to interpret the results. Results All the isolates were susceptible to tetracycline, streptomycin, gentamicin, ciprofloxacin, norfloxacin, and levofloxacin. Two isolates presented reduced susceptibility to rifampicin (MIC value: 1.5 mg/l and eight to SXT (MIC values: 0.75–1.5 mg/l. Erythromycin had the highest (4 mg/l MIC90value and both norfloxacin and erythromycin the highest (1.5 mg/l MIC50 value. Conclusion Brucella isolates remain susceptible in vitro to most antibiotics used for treatment of brucellosis. The establishment of a standardized antibiotic susceptibility method for Brucella spp would be useful for resistance determination in these bacteria and possible evaluation of bioterorism risks.

Insecticide susceptibility of Aedes aegypti populations from Senegal and Cape Verde Archipelago.

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Dia, Ibrahima; Diagne, Cheikh Tidiane; Ba, Yamar; Diallo, Diawo; Konate, Lassana; Diallo, Mawlouth

2012-10-22

Two concomitant dengue 3 (DEN-3) epidemics occurred in Cape Verde Archipelago and Senegal between September and October 2009. Aedes aegypti was identified as the vector of these epidemics as several DEN-3 virus strains were isolated from this species in both countries. The susceptibility to pyrethroids, organochlorine, organophosphates and carbamate was investigated in two field strains of Aedes aegypti from both countries using WHO diagnostic bioassay kits in order to monitor their the current status of insecticide susceptibility. The two tested strains were highly resistant to DDT. The Cape Verde strain was found to be susceptible to all others tested insecticides except for propoxur 0.1%, which needs further investigation. The Dakar strain was susceptible to fenitrothion 1% and permethrin 0.75%, but displayed reduced susceptibility to deltamethrin, lambda-cyhalothrin and propoxur. As base-line results, our observations stress a careful management of insecticide use for the control of Ae. aegypti. Indeed, they indicate that DDT is no longer efficient for the control of Ae. aegypti populations in Cape Verde and Dakar and further suggest a thorough follow-up of propoxur susceptibility status in both sites and that of deltamethrin and lambda-cyhalothrin in Ae. aegypti populations in Dakar. Thus, regular monitoring of susceptibility is greatly needed as well as the knowing if this observed resistance/susceptibility is focal or not and for observed resistance, the use of biochemical methods is needed with detailed comparison of resistance levels over a large geographic area. Aedes aegypti, Insecticides, Susceptibility, Cape Verde, Senegal.

Analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis.

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George L Drusano

Full Text Available Tuberculosis remains a worldwide problem, particularly with the advent of multi-drug resistance. Shortening therapy duration for Mycobacterium tuberculosis is a major goal, requiring generation of optimal kill rate and resistance-suppression. Combination therapy is required to attain the goal of shorter therapy.Our objective was to identify a method for identifying optimal combination chemotherapy. We developed a mathematical model for attaining this end. This is accomplished by identifying drug effect interaction (synergy, additivity, antagonism for susceptible organisms and subpopulations resistant to each drug in the combination.We studied the combination of linezolid plus rifampin in our hollow fiber infection model. We generated a fully parametric drug effect interaction mathematical model. The results were subjected to Monte Carlo simulation to extend the findings to a population of patients by accounting for between-patient variability in drug pharmacokinetics.All monotherapy allowed emergence of resistance over the first two weeks of the experiment. In combination, the interaction was additive for each population (susceptible and resistant. For a 600 mg/600 mg daily regimen of linezolid plus rifampin, we demonstrated that >50% of simulated subjects had eradicated the susceptible population by day 27 with the remaining organisms resistant to one or the other drug. Only 4% of patients had complete organism eradication by experiment end.These data strongly suggest that in order to achieve the goal of shortening therapy, the original regimen may need to be changed at one month to a regimen of two completely new agents with resistance mechanisms independent of the initial regimen. This hypothesis which arose from the analysis is immediately testable in a clinical trial.

Retrospective Analysis of Clinical and Cost Outcomes Associated with Methicillin-Resistant Staphylococcus aureus Complicated Skin and Skin Structure Infections Treated with Daptomycin, Vancomycin, or Linezolid

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Bradley M. Wright

2011-01-01

Full Text Available Objective. The objective of this analysis was to compare clinical and cost outcomes associated with patients who had suspected or documented methicillin-resistant Staphylococcus aureus (MRSA infections treated with daptomycin, vancomycin, or linezolid in complicated skin and skin structure infections (cSSSIs. Design. This was a retrospective analysis conducted from February to June of 2007. Appropriate data was collected, collated, and subsequently evaluated with the purpose of quantifying length of stay, antibiotic therapy duration, clinical cure rates, adverse drug events, and cost of hospitalization. Results. All 82 patients included in the analysis experienced clinical cure. The duration of antibiotic therapy was similar among the three groups yet the length of hospitalization was slightly shorter in the daptomycin group. Conclusions. The incidence of resistant staphylococcal infections is increasing; therefore, judicious use of MRSA active agents is paramount. Future studies are necessary to determine if MRSA treatment options can be stratified based on the severity of the infectious process.

In vitro efficacy and pharmacodynamic indices for antibiotics against coagulase-negative staphylococcus endophthalmitis isolates.

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Harper, Tom; Miller, Darlene; Flynn, Harry W

2007-05-01

To compare pharmacodynamic indices and minimal inhibitory concentrations for vancomycin, gatifloxacin, moxifloxacin, linezolid, and combined quinupristin and dalfopristin for historic and current human coagulase-negative staphylococcus (CoNS) endophthalmitis isolates. Experimental study. Fifty-nine CoNS endophthalmitis isolates retrieved from patients at the Bascom Palmer Eye Institute from 1993 through 2006. Coagulase-negative staphylococcal endophthalmitis isolates were recovered from the microbiology specimen bank, rehydrated, and processed for susceptibility testing using standard microbiological protocols. E tests were used to determine and compare mean inhibitory concentration for 50% of isolates (MIC50) and mean inhibitory concentration for 90% of isolates (MIC90) values. Peak concentration (C(max)) was defined as the maximum attainable aqueous concentration using topical or oral therapy, or both. The MIC50 and MIC90 values for each antibiotic are the minimum concentrations that inhibit 50% and 90% of CoNS endophthalmitis isolates, respectively. Significance was determined by the McNemar test. Pharmacodynamic indices (C(max)/MIC) were calculated using determined MIC values and published intraocular drug concentrations for topical and oral dosing. The pharmacodynamic index was defined as the achievable aqueous humor concentration of an antibiotic divided by the concentration of the antibiotic required to inhibit a specified percentage of microbiologic isolates. Pharmacodynamic indices for new and conventional antibiotics. General in vitro susceptibility patterns in descending order were vancomycin (100%), linezolid (100%), quinupristin and dalfopristin (98%), moxifloxacin (48%), and gatifloxacin (47%). The corresponding MIC50 and MIC90 values were vancomycin, 2 microg/ml and 3 microg/ml, respectively; linezolid, 1 microg/ml and 4 microg/ml; quinupristin and dalfopristin, 0.25 microg/ml and 0.5 microg/ml; moxifloxacin, 0.75 microg/ml and > or =32 microg

Interaction of Vesicular-Arbuscular Mycorrhizae and Cultivars of Alfalfa Susceptible and Resistant to Meloidogyne hapla.

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Grandison, G S; Cooper, K M

1986-04-01

The interaction between vesicular-arbuscular mycorrhizal (VAM) fungi and the root-knot nematode (Meloidogyne hapla) was investigated using both nematode-susceptible (Grasslands Wairau) and nematode-resistant (Nevada Synthetic XX) cultivars of alfalfa (Medicago sativa) at four levels of applied phosphate. Mycorrhizal inoculation improved plant growth and reduced nematode numbers and adult development in roots in dually infected cultures of the susceptible cultivar. The tolerance of plants to nematode infection and development when preinfected with mycorrhizal fungi was no greater than when they were inoculated with nematodes and mycorrhizal fungi simultaneously. Growth of plants of the resistant cultivar was unaffected by nematode inoculation but was improved by mycorrhizal inoculation. Numbers of nematode juveniles were lower in the roots of the resistant than of the susceptible cultivar and were further reduced by mycorrhizal inoculation, although no adult nematodes developed in any resistant cultivar treatment. Inoculation of alfalfa with VAM fungi increased the tolerance and resistance of a cultivar susceptible to M. hapla and improved the resistance of a resistant cultivar.

Colitis susceptibility in p47(phox-/-) mice is mediated by the microbiome.

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Falcone, E Liana; Abusleme, Loreto; Swamydas, Muthulekha; Lionakis, Michail S; Ding, Li; Hsu, Amy P; Zelazny, Adrian M; Moutsopoulos, Niki M; Kuhns, Douglas B; Deming, Clay; Quiñones, Mariam; Segre, Julia A; Bryant, Clare E; Holland, Steven M

2016-04-05

Chronic granulomatous disease (CGD) is caused by defects in nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) complex subunits (gp91(phox) (a.k.a. Nox2), p47(phox), p67(phox), p22(phox), p40(phox)) leading to reduced phagocyte-derived reactive oxygen species production. Almost half of patients with CGD develop inflammatory bowel disease, and the involvement of the intestinal microbiome in relation to this predisposing immunodeficiency has not been explored. Although CGD mice do not spontaneously develop colitis, we demonstrate that p47(phox-/-) mice have increased susceptibility to dextran sodium sulfate colitis in association with a distinct colonic transcript and microbiome signature. Neither restoring NOX2 reactive oxygen species production nor normalizing the microbiome using cohoused adult p47(phox-/-) with B6Tac (wild type) mice reversed this phenotype. However, breeding p47(phox+/-) mice and standardizing the microflora between littermate p47(phox-/-) and B6Tac mice from birth significantly reduced dextran sodium sulfate colitis susceptibility in p47(phox-/-) mice. We found similarly decreased colitis susceptibility in littermate p47(phox-/-) and B6Tac mice treated with Citrobacter rodentium. Our findings suggest that the microbiome signature established at birth may play a bigger role than phagocyte-derived reactive oxygen species in mediating colitis susceptibility in CGD mice. These data further support bacteria-related disease in CGD colitis.

Penicillin-susceptible Staphylococcus aureus: susceptibility testing, resistance rates and outcome of infection.

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Hagstrand Aldman, Malin; Skovby, Annette; I Påhlman, Lisa

2017-06-01

Staphylococcus aureus (SA) is an important human pathogen that causes both superficial and invasive infections. Penicillin is now rarely used in the treatment of SA infections due to widespread resistance and a concern about the accuracy of existing methods for penicillin susceptibility testing. The aims of the present study were to determine the frequency of penicillin-susceptible SA isolates from blood and wound cultures in Lund, Sweden, and to evaluate methods for penicillin testing in SA. We also wanted to investigate if penicillin-susceptible isolates are associated with higher mortality. Hundred blood culture isolates collected 2008/2009, 140 blood culture isolates from 2014/2015, and 141 superficial wound culture strains from 2015 were examined. Penicillin susceptibility was tested with disk diffusion according to EUCAST guidelines, and results were confirmed with a cloverleaf assay and PCR amplification of the BlaZ gene. Patient data for all bacteraemia cases were extracted from medical records. The disk diffusion method with assessment of both zone size and zone edge appearance had high accuracy in our study. About 57% of bacteraemia isolates from 2008/2009 were sensitive to penicillin compared to 29% in 2014/2015 (p penicillin susceptible. There was no difference in co-morbidity or mortality rates between patients with penicillin resistant and penicillin sensitive SA bacteraemia. Disk-diffusion is a simple and reliable method to detect penicillin resistance in SA, and susceptibility rates are significant. Penicillin has many theoretical advantages and should be considered in the treatment of SA bacteraemia when susceptible.

Mutations in the Bacterial Ribosomal Protein L3 and Their Association with Antibiotic Resistance

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Klitgaard, Rasmus N.; Ntokou, Eleni; Nørgaard, Katrine; Biltoft, Daniel; Hansen, Lykke H.; Trædholm, Nicolai M.; Kongsted, Jacob

2015-01-01

Different groups of antibiotics bind to the peptidyl transferase center (PTC) in the large subunit of the bacterial ribosome. Resistance to these groups of antibiotics has often been linked with mutations or methylations of the 23S rRNA. In recent years, there has been a rise in the number of studies where mutations have been found in the ribosomal protein L3 in bacterial strains resistant to PTC-targeting antibiotics but there is often no evidence that these mutations actually confer antibiotic resistance. In this study, a plasmid exchange system was used to replace plasmid-carried wild-type genes with mutated L3 genes in a chromosomal L3 deletion strain. In this way, the essential L3 gene is available for the bacteria while allowing replacement of the wild type with mutated L3 genes. This enables investigation of the effect of single mutations in Escherichia coli without a wild-type L3 background. Ten plasmid-carried mutated L3 genes were constructed, and their effect on growth and antibiotic susceptibility was investigated. Additionally, computational modeling of the impact of L3 mutations in E. coli was used to assess changes in 50S structure and antibiotic binding. All mutations are placed in the loops of L3 near the PTC. Growth data show that 9 of the 10 mutations were well accepted in E. coli, although some of them came with a fitness cost. Only one of the mutants exhibited reduced susceptibility to linezolid, while five exhibited reduced susceptibility to tiamulin. PMID:25845869

Molecular characterization of vancomycin-intermediate Staphylococcus aureus isolates from Tehran

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Shahin Najar-Peerayeh

2016-09-01

Full Text Available Objective: To determine the prevalence and some genetic characteristics of clinical isolates of Staphylococcus aureus (S. aureus with reduced susceptibility to vancomycin. Methods: A total of 414 isolates of S. aureus were collected from clinical specimens from hospitals in Tehran. Vancomycin-intermediate S. aureus (VISA was determined by brain heart infusion agar containing 4 μg/mL vancomycin screening plate and confirmed via E-test. VISA isolates were analysed for vanA, vanB, mecA, staphylococcal cassette chromosome mec types, surface protein A (Spa types and agr specific groups. Results: Brain heart infusion agar containing 4 μg/mL vancomycin screening tests revealed that 17.14% (n = 71 of S. aureus isolates were VISA phenotype. Ten of the 71 isolates were confirmed by E-test method (minimal inhibitory concentration was 4 to 8 μg/mL. All VISA isolates were susceptible to linezolid and 6 isolates (60% were methicillin-resistant S. aureus. Five isolates belonged to agr Group II, 4 belonged to agr Group I and 1 belonged to agr Group III. Spa type t030, and staphylococcal cassette chromosome mec Type III were dominant among VISA isolates. Conclusions: This study provides further evidence of the global dissemination of VISA isolates and emphasizes to vancomycin susceptibility testing prior to antibiotic therapy.

Nodal infection in Markovian susceptible-infected-susceptible and susceptible-infected-removed epidemics on networks are non-negatively correlated.

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Cator, E; Van Mieghem, P

2014-05-01

By invoking the famous Fortuin, Kasteleyn, and Ginibre (FKG) inequality, we prove the conjecture that the correlation of infection at the same time between any pair of nodes in a network cannot be negative for (exact) Markovian susceptible-infected-susceptible (SIS) and susceptible-infected-removed (SIR) epidemics on networks. The truth of the conjecture establishes that the N-intertwined mean-field approximation (NIMFA) upper bounds the infection probability in any graph so that network design based on NIMFA always leads to safe protections against malware spread. However, when the infection or/and curing are not Poisson processes, the infection correlation between two nodes can be negative.

Nodal infection in Markovian susceptible-infected-susceptible and susceptible-infected-removed epidemics on networks are non-negatively correlated

Science.gov (United States)

Cator, E.; Van Mieghem, P.

2014-05-01

By invoking the famous Fortuin, Kasteleyn, and Ginibre (FKG) inequality, we prove the conjecture that the correlation of infection at the same time between any pair of nodes in a network cannot be negative for (exact) Markovian susceptible-infected-susceptible (SIS) and susceptible-infected-removed (SIR) epidemics on networks. The truth of the conjecture establishes that the N-intertwined mean-field approximation (NIMFA) upper bounds the infection probability in any graph so that network design based on NIMFA always leads to safe protections against malware spread. However, when the infection or/and curing are not Poisson processes, the infection correlation between two nodes can be negative.

Nocardia abscessus brain abscess in an immunocompetent host.

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Al Tawfiq, Jaffar A; Mayman, Talal; Memish, Ziad A

2013-06-01

Nocardia brain abscesses typically occur in immunocompromised patients. Most cases of nocardiosis are caused by the Nocardia asteroides complex and Nocardia brasiliensis. Here, we present a patient with a Nocardia abscessus brain abscess. The diagnosis was confirmed by DNA sequencing, and the organism was susceptible to linezolid, clarithromycin, ceftriaxone, imipenem, tobramycin, amikacin, minocycline and sulfamethoxazole. The patient was successfully treated medically in combination with surgical excision. Copyright © 2013 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

Overview of Implant Infections in Orthopaedics Department: Retrospective Study

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Tugrul Bulut

2014-12-01

Full Text Available In this study, our aim was to evaluate the antibiotic susceptibility of bacteria isolated from orthopedic implant infections. Within two years operated 1996 patients in an orthopedics and traumatology clinic were retrospectively investigated. Seventy-six (76/1996, 3.8% orthopedic implant infections were detected. Isolated bacteria and their antibiotic susceptibility patterns were analyzed. The bacteries isolated from implant related infections and antibiotic sensitivity patterns were evaluated retrospectively in our orthopaedics and traumatology clinic. Staphylococcus aureus was the predominant organism (30.3%. Gram negative bacterias were isolated in 65.8% of our patients. No resistance was determined against vancomycin and linezolid in gram positive bacterias. Imipenem, amicasin and cefepim was seen as the most effective antibiotics for gram negative bacterias.

Susceptibility to β-lactams in β-hemolytic streptococci.

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Bonofiglio, Laura; Gagetti, Paula; García Gabarrot, Gabriela; Kaufman, Sara; Mollerach, Marta; Toresani, Inés; Vigliarolo, Laura; von Specht, Martha; Lopardo, Horacio A

2018-03-13

Group A (GAS), B (GBS), C (GCS) and G (GGS) β-hemolytic streptococci are important human pathogens. They cause infections of different severity and frequency. Nowadays, after 70 years of use, penicillin is still universally active against GAS, GCS and GGS. However, therapeutic failures have been recorded in 2-28% of pharyngitis cases (median: 12%) attributable to different causes. By contrast, some GBS with reduced susceptibility to penicillin have been described, especially in Japan. In this group of bacteria, it is important to highlight that confirmation by reference methods is mandatory when decreased susceptibility to penicillin is suspected as well as checked for the detection of the mechanisms involved. Copyright © 2017 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

Individual and cumulative effects of GWAS susceptibility loci in lung cancer: associations after sub-phenotyping for COPD.

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Robert P Young

2011-02-01

Full Text Available Epidemiological studies show that approximately 20-30% of chronic smokers develop chronic obstructive pulmonary disease (COPD while 10-15% develop lung cancer. COPD pre-exists lung cancer in 50-90% of cases and has a heritability of 40-77%, much greater than for lung cancer with heritability of 15-25%. These data suggest that smokers susceptible to COPD may also be susceptible to lung cancer. This study examines the association of several overlapping chromosomal loci, recently implicated by GWA studies in COPD, lung function and lung cancer, in (n = 1400 subjects sub-phenotyped for the presence of COPD and matched for smoking exposure. Using this approach we show; the 15q25 locus confers susceptibility to lung cancer and COPD, the 4q31 and 4q22 loci both confer a reduced risk to both COPD and lung cancer, the 6p21 locus confers susceptibility to lung cancer in smokers with pre-existing COPD, the 5p15 and 1q23 loci both confer susceptibility to lung cancer in those with no pre-existing COPD. We also show the 5q33 locus, previously associated with reduced FEV(1, appears to confer susceptibility to both COPD and lung cancer. The 6p21 locus previously linked to reduced FEV(1 is associated with COPD only. Larger studies will be needed to distinguish whether these COPD-related effects may reflect, in part, associations specific to different lung cancer histology. We demonstrate that when the "risk genotypes" derived from the univariate analysis are incorporated into an algorithm with clinical variables, independently associated with lung cancer in multivariate analysis, modest discrimination is possible on receiver operator curve analysis (AUC = 0.70. We suggest that genetic susceptibility to lung cancer includes genes conferring susceptibility to COPD and that sub-phenotyping with spirometry is critical to identifying genes underlying the development of lung cancer.

Resistance to first-line anti-TB drugs is associated with reduced nitric oxide susceptibility in Mycobacterium tuberculosis

DEFF Research Database (Denmark)

Idh, Jonna; Mekonnen, Mekidim; Abate, Ebba

2012-01-01

The relative contribution of nitric oxide (NO) to the killing of Mycobacterium tuberculosis in human tuberculosis (TB) is controversial, although this has been firmly established in rodents. Studies have demonstrated that clinical strains of M. tuberculosis differ in susceptibility to NO, but how...

Studies on maize inbred lines susceptibility to herbicides

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Stefanović Lidija

2010-01-01

Full Text Available This paper presents the analysis of results obtained during long- term studies on the response of maize inbred lines to herbicides. Under the agroecological conditions of Zemun Polje the response (reaction of maize inbred lines to herbicides of different classes was investigated. Biological tests were performed and some agronomic, morphological, physiological and biochemical parameters were determined when the response of maize inbred lines to herbicides was estimated. The use of active ingredients of herbicides from triazine, acetanilide, thiocarbamate to new chemical groups (sulfonylurea etc., have been resulted in changes in weed suppression and susceptibility of inbred lines. Obtained results show that effects of herbicides on susceptible maize genotypes can be different: they can slowdown the growth and development and affect the plant height; they can also affect the stages of the tassel and ear development and at the end they can reduced grain yield of the tested inbreds. Numerous studies confirmed the existence of differences in susceptibility level of maize genotypes in relation to herbicides. According to gained results the recommendations for growers are made on the possibility of the application of new herbicides in the hybrid seed production.

Landslide Susceptibility Statistical Methods: A Critical and Systematic Literature Review

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Mihir, Monika; Malamud, Bruce; Rossi, Mauro; Reichenbach, Paola; Ardizzone, Francesca

2014-05-01

Landslide susceptibility assessment, the subject of this systematic review, is aimed at understanding the spatial probability of slope failures under a set of geomorphological and environmental conditions. It is estimated that about 375 landslides that occur globally each year are fatal, with around 4600 people killed per year. Past studies have brought out the increasing cost of landslide damages which primarily can be attributed to human occupation and increased human activities in the vulnerable environments. Many scientists, to evaluate and reduce landslide risk, have made an effort to efficiently map landslide susceptibility using different statistical methods. In this paper, we do a critical and systematic landslide susceptibility literature review, in terms of the different statistical methods used. For each of a broad set of studies reviewed we note: (i) study geography region and areal extent, (ii) landslide types, (iii) inventory type and temporal period covered, (iv) mapping technique (v) thematic variables used (vi) statistical models, (vii) assessment of model skill, (viii) uncertainty assessment methods, (ix) validation methods. We then pulled out broad trends within our review of landslide susceptibility, particularly regarding the statistical methods. We found that the most common statistical methods used in the study of landslide susceptibility include logistic regression, artificial neural network, discriminant analysis and weight of evidence. Although most of the studies we reviewed assessed the model skill, very few assessed model uncertainty. In terms of geographic extent, the largest number of landslide susceptibility zonations were in Turkey, Korea, Spain, Italy and Malaysia. However, there are also many landslides and fatalities in other localities, particularly India, China, Philippines, Nepal and Indonesia, Guatemala, and Pakistan, where there are much fewer landslide susceptibility studies available in the peer-review literature. This

Reduced lentivirus susceptibility in sheep with TMEM154 mutations.

Science.gov (United States)

Heaton, Michael P; Clawson, Michael L; Chitko-Mckown, Carol G; Leymaster, Kreg A; Smith, Timothy P L; Harhay, Gregory P; White, Stephen N; Herrmann-Hoesing, Lynn M; Mousel, Michelle R; Lewis, Gregory S; Kalbfleisch, Theodore S; Keen, James E; Laegreid, William W

2012-01-01

Visna/Maedi, or ovine progressive pneumonia (OPP) as it is known in the United States, is an incurable slow-acting disease of sheep caused by persistent lentivirus infection. This disease affects multiple tissues, including those of the respiratory and central nervous systems. Our aim was to identify ovine genetic risk factors for lentivirus infection. Sixty-nine matched pairs of infected cases and uninfected controls were identified among 736 naturally exposed sheep older than five years of age. These pairs were used in a genome-wide association study with 50,614 markers. A single SNP was identified in the ovine transmembrane protein (TMEM154) that exceeded genome-wide significance (unadjusted p-value 3×10(-9)). Sanger sequencing of the ovine TMEM154 coding region identified six missense and two frameshift deletion mutations in the predicted signal peptide and extracellular domain. Two TMEM154 haplotypes encoding glutamate (E) at position 35 were associated with infection while a third haplotype with lysine (K) at position 35 was not. Haplotypes encoding full-length E35 isoforms were analyzed together as genetic risk factors in a multi-breed, matched case-control design, with 61 pairs of 4-year-old ewes. The odds of infection for ewes with one copy of a full-length TMEM154 E35 allele were 28 times greater than the odds for those without (p-valuesheep from Nebraska, Idaho, and Iowa, the relative risk of infection was 2.85 times greater for sheep with a full-length TMEM154 E35 allele (p-valuesheep were homozygous for TMEM154 deletion mutations and remained uninfected despite a lifetime of significant exposure. Together, these findings indicate that TMEM154 may play a central role in ovine lentivirus infection and removing sheep with the most susceptible genotypes may help eradicate OPP and protect flocks from reinfection.

Iota(1440), anomalous Ward identities, and topological susceptibility for QCD

International Nuclear Information System (INIS)

Williams, P.G.

1986-01-01

Anomalous Ward identities for QCD are comprehensively analyzed taking into account contributions of all known pseudoscalar mesons, including the iota(1440 MeV) which is a possible glueball candidate. Implications for the standard resolution of the U(1) problem are examined by imposing the important and crucial constraint of positivity for the topological susceptibility. The pure Yang-Mills susceptibility: a quantity relevant in quenched lattice calculations: is shown to increase quite considerably in the presence of the iota, while the total susceptibility is reduced and may even vanish. Allowed ranges for the axial couplings are delineated and two classes of solution emerge: one corresponding to an iota with suppressed singlet axial coupling; the other to a large eta'-like coupling. It may be possible to discriminate between these two alternatives by measurements of the branching ratio for iota→KK-barπ: values near 100% give suppressed couplings; values below 50% unsuppressed ones

[Analysis of antibiotic susceptibility of foodborne Listeria monocytogenes in China].

Science.gov (United States)

Yang, Yang; Fu, Ping; Guo, Yunchang; Liu, Xiurmei

2008-03-01

To study the antibiotic susceptibility of foodborne Listeria monocytogenes in China. The susceptibilities of 476 strains of foodborne Listeria monocytogenes to antibiotics were determined in Broth Microdilution Susceptibility Testing in Clinical and Laboratory Standards Institute. The antibiotics of gentamicin, ampicillin, penicillin, tetracycline, doxycycline, imipenem, erythromycin, ciprofloxacin, levofloxacin, cephalothin, rifampin, vancomycin, chloramphenicol, Trimethoprim-sulfamethoxazole, ampicillin-sulbactam were used. The rates of antibiotic resistance in 467 is olates were 4.5%. Tetracycline resistance was most prevalent, accouting for 4.07% . The foods that the rates of antibiotic resistance were highest were vegetable (10%). Among 14 provinces, Jilin, Hubei and Hebei were the third top, the rate of which were 19.6% and 9.1% and 8%, respectively. It was suggested that antibiotic resistance exists in foodborne Listeria monocytogenes to a certain extent in China. It should pay more attention to the use of drugs in prevention and clinic treatment to reduce the antibiotic resistant strains.

Reduction in soil loss from erosion-susceptible soils amended with humic substances from oxidized coal

International Nuclear Information System (INIS)

Piccolo, A.; Pietramellara, G.; Mbagwu, J.S.C.

1997-01-01

Soils that pose high risk of erosion require amendment with either natural or synthetic soil conditioners to reduce soil loss hazards. The objective of this study was to evaluate the potential of using coal-derived humic substances (as soil conditioners) to reduce runoff erosion on erosion-susceptible soils. Surface samples of severely degraded soils from Principina in Tuscany and Bovolone in Venice in Italy were used to assess the effects of five rates (0, 0.05, 0.01, 0.50 and 1.00 g/kg) of humic acids (HA) on soil loss and other hydrological parameters. The results showed that amending erosion-susceptible soils with low rates of coal-derived humic substances is a potentially effective soil management practice for reducing erosion rates

Nonlinear electromagnetic susceptibilities of unmagnetized plasmas

International Nuclear Information System (INIS)

Yoon, Peter H.

2005-01-01

Fully electromagnetic nonlinear susceptibilities of unmagnetized plasmas are analyzed in detail. Concrete expressions of the second-order nonlinear susceptibility are found in various forms in the literature, usually in connection with the discussions of various three-wave decay processes, but the third-order susceptibilities are rarely discussed. The second-order susceptibility is pertinent to nonlinear wave-wave interactions (i.e., the decay/coalescence), whereas the third-order susceptibilities affect nonlinear wave-particle interactions (i.e., the induced scattering). In the present article useful approximate analytical expressions of these nonlinear susceptibilities that can be readily utilized in various situations are derived

Antibiotic susceptibility profiles for mastitis treatment.

Science.gov (United States)

Hinckley, L S; Benson, R H; Post, J E; DeCloux, J C

1985-10-01

Susceptibility tests were performed on milk samples representing prevalent mastitis infections in certain herds. Susceptibility patterns of the same bacterial species from several mastitis infections in the same herd were consistent. The herd antibiotic susceptibility profiles were used as a basis for selecting antibiotics for treatment of all such mastitis cases in that herd. A high degree of correlation was seen between the susceptibility test results and treatment results. Susceptibility patterns of the same bacterial species from mastitis infections in different herds varied greatly, which indicated that any one antibiotic would not work equally well against the same bacterial infection in every herd. Therefore, treatment should be selected on the basis of susceptibility test results. When both Streptococcus and Staphylococcus mastitis occurred in the same herd, the susceptibility patterns for the 2 bacterial species varied widely. Therefore, for herds that experienced both streptococcal and staphylococcal mastitis, antibiotics to which both bacterial species were susceptible were used for treatment.

Entitlement Can Both Decrease and Increase Consumer Susceptibility to Social Influence

NARCIS (Netherlands)

van der Heide, Martine; Fennis, Bob; van Ittersum, Koert; Trampe, Debra; Diehl, Kristin; Yoon, Carolyn

2015-01-01

Two studies indicate that entitlement—a sense that one deserves special treatment and is exempt from normal social demands—can both buffer and boost consumers’ proneness to social influence. Specifically, Study 1 shows that entitlement reduces susceptibility to consistency appeals. Study 2, however,

Analysis of triclosan-selected Salmonella enterica mutants of eight serovars revealed increased aminoglycoside susceptibility and reduced growth rates.

Directory of Open Access Journals (Sweden)

Ulrike Rensch

Full Text Available The biocide triclosan (TRC is used in a wide range of household, personal care, veterinary, industrial and medical products to control microbial growth. This extended use raises concerns about a possible association between the application of triclosan and the development of antibiotic resistance. In the present study we determined triclosan mutant prevention concentrations (MPC for Salmonella enterica isolates of eight serovars and investigated selected mutants for their mechanisms mediating decreased susceptibility to triclosan. MPCTRC values were 8-64-fold higher than MIC values and ranged between 1-16 µg/ml. The frequencies at which mutants were selected varied between 1.3 x 10(-10-9.9 x 10(-11. Even if MIC values of mutants decreased by 3-7 dilution steps in the presence of the efflux pump inhibitor Phe-Arg-β-naphtylamide, only minor changes were observed in the expression of genes encoding efflux components or regulators, indicating that neither the major multidrug efflux pump AcrAB-TolC nor AcrEF are up-regulated in triclosan-selected mutants. Nucleotide sequence comparisons confirmed the absence of alterations in the regulatory regions acrRA, soxRS, marORAB, acrSE and ramRA of selected mutants. Single bp and deduced Gly93→Val amino acid exchanges were present in fabI, the target gene of triclosan, starting from a concentration of 1 µg/ml TRC used for MPC determinations. The fabI genes were up to 12.4-fold up-regulated. Complementation experiments confirmed the contribution of Gly93→Val exchanges and fabI overexpression to decreased triclosan susceptibility. MIC values of mutants compared to parent strains were even equal or resulted in a more susceptible phenotype (1-2 dilution steps for the aminoglycoside antibiotics kanamycin and gentamicin as well as for the biocide chlorhexidine. Growth rates of selected mutants were significantly lower and hence, might partly explain the rare occurrence of Salmonella field isolates exhibiting

Magnetic susceptibility of CoFeBSiNb alloys in liquid state

Energy Technology Data Exchange (ETDEWEB)

Sidorov, V., E-mail: vesidor@mail.ru [Ural State Pedagogical University, Ekaterinburg (Russian Federation); Hosko, J. [Institute of Physics SAS, Bratislava (Slovakia); Mikhailov, V.; Rozkov, I.; Uporova, N. [Ural State Pedagogical University, Ekaterinburg (Russian Federation); Svec, P.; Janickovic, D.; Matko, I.; Svec Sr, P. [Institute of Physics SAS, Bratislava (Slovakia); Malyshev, L. [Ural Federal University, Ekaterinburg (Russian Federation)

2014-03-15

The influence of small additions of gallium and antimony on magnetic susceptibility of the bulk glass forming Co{sub 47}Fe{sub 20.9}B{sub 21.2}Si{sub 4.6}Nb{sub 6.3} alloy was studied in a wide temperature range up to 1830 K by the Faraday’s method. The undercooling for all the samples was measured experimentally. Both Ga and Sb additions were found to increase liquidus and solidification temperatures. However, gallium atoms strengthen interatomic interaction in the melts, whereas antimony atoms reduce it. - Highlights: • Bulk metallic glasses from CoFeBSiNb-based alloys were produced as in situ composites. • Magnetic susceptibility of these alloys was measured in a wide temperature range including liquid state. • Undercooling of these melts was measured experimentally. • Ga additions strengthen interatomic interaction in BMG melts, whereas Sb atoms reduce it.

Phenotypic and genotypic characterization of Klebsiella pneumoniae strains with reduced susceptibiliy to carbapenems

Directory of Open Access Journals (Sweden)

Simone Ambretti

2009-12-01

Full Text Available Reduced susceptibility to carbapenems in Gram-negative pathogens is an emerging feature of the antibiotic-resistance phenomenom Reports about strains resistant to this class of antibiotics among Enterobacteriaceae, particularly in Klebsiella pneumoniae, are increasing.The aims of this study were to assess the incidence of Klebsiella pneumoniae with reduced susceptibility to carbapenems in Bologna area and to carry out the characterization of these strains.The study included isolates of K. pneumoniae that showed reduced susceptibility to carbapenems, as detected by an automated system (Vitek2, bioMérieux. Between January and May 2009, 26 strains were collected (mainly isolated from urinary samples.These isolates were tested for susceptibility to carbapenems by E-test, to define MIC values for meropenem and ertapenem. Moreover, to detect the production of metallo-beta lactamases (MBL and carbapenemases (KPC were respectively performed the Etest with imipenem and imipenem/EDTA (IPM-IPM/EDTA and the modified Hodge test. Susceptibility assays performed by E-test showed that 25/26 strains were susceptible to meropenem, while for ertapenem 20/26 strains resulted resistant.The modified Hodge test was positive for 1 strain, while all the isolates were negative to the IPM-IPM/EDTA E-test.These results show that, as recently reported, the majority of strains of K. pneumoniae exhibiting reduced susceptibility to carbapenems, especially to ertapenem, are characterized by the production of ESBLs, which likely is associated with the loss of porins. On the other side, one strain was found to produce KPC and this finding confirms that the diffusion of carbapenemases producing K. pneumoniae has also to be considered in this geographic area.

Field susceptibility of 13 scab-resistant apple cultivars to apple powdery mildew [Podosphaera leucotricha (Ell. et Ev. Salmon

Directory of Open Access Journals (Sweden)

Zbigniew Borecki

2013-12-01

Full Text Available Field susceptibility of 13 scab-resistant apple cultivars to apple powdery mildew was evaluated in 1983-1986. Four groups of susceptibility were distinguished. None of the 13 tested scab-resistant apple trees exhibited complete field immunity to apple powdery mildew. Two cultivars, 'Prima' and 'Primula', were practically resistant. 'Liberty' and two numbered selections, NY-140-9 and NY-158-2, belonged to the group of lower susceptibility. Moderate susceptibility was shown by: 'Novamac', 'Freedom', 'Gavin', 'Prima' and 'Florina'. The group of apple trees most susceptible to Podosphaera leucotricha included: 'Macfree', 'Priscilla' and 'Nova Easygro'. It is not necessary to use chemical sprays to control powdery mildew on 'Prima' and 'Primula'. A reduced spraying program may be recommended only under high disease pressure on less susceptible apple cultivars. A regular spray schedule is needed on moderately susceptible apple trees, but improved chemical control is necessary on the most susceptible ones.

Personality traits as potential susceptibility markers : Differential susceptibility to support among parents

NARCIS (Netherlands)

Slagt, M.; Dubas, J.S.; Denissen, J.J.A.; Deković, M.; van Aken, M.A.G.

2015-01-01

In this study, we examined whether parents are differentially susceptible to support from their spouse and adolescent child depending on their personality traits, and whether differences in susceptibility to support among parents, in turn, are linked to the quality of support parents give to their

Impact of spores on the comparative efficacies of five antibiotics for treatment of Bacillus anthracis in an in vitro hollow fiber pharmacodynamic model.

Science.gov (United States)

Louie, Arnold; VanScoy, Brian D; Brown, David L; Kulawy, Robert W; Heine, Henry S; Drusano, George L

2012-03-01

Bacillus anthracis, the bacterium that causes anthrax, is an agent of bioterrorism. The most effective antimicrobial therapy for B. anthracis infections is unknown. An in vitro pharmacodynamic model of B. anthracis was used to compare the efficacies of simulated clinically prescribed regimens of moxifloxacin, linezolid, and meropenem with the "gold standards," doxycycline and ciprofloxacin. Treatment outcomes for isogenic spore-forming and non-spore-forming strains of B. anthracis were compared. Against spore-forming B. anthracis, ciprofloxacin, moxifloxacin, linezolid, and meropenem reduced the B. anthracis population by 4 log(10) CFU/ml over 10 days. Doxycycline reduced the population of this B. anthracis strain by 5 log(10) CFU/ml (analysis of variance [ANOVA] P = 0.01 versus other drugs). Against an isogenic non-spore-forming strain, meropenem killed the vegetative B. anthracis the fastest, followed by moxifloxacin and ciprofloxacin and then doxycycline. Linezolid offered the lowest bacterial kill rate. Heat shock studies using the spore-producing B. anthracis strain showed that with moxifloxacin, ciprofloxacin, and meropenem therapies the total population was mostly spores, while the population was primarily vegetative bacteria with linezolid and doxycycline therapies. Spores have a profound impact on the rate and extent of killing of B. anthracis. Against spore-forming B. anthracis, the five antibiotics killed the total (spore and vegetative) bacterial population at similar rates (within 1 log(10) CFU/ml of each other). However, bactericidal antibiotics killed vegetative B. anthracis faster than bacteriostatic drugs. Since only vegetative-phase B. anthracis produces the toxins that may kill the infected host, the rate and mechanism of killing of an antibiotic may determine its overall in vivo efficacy. Further studies are needed to examine this important observation.

Identification of non-tuberculous mycobacteria isolated from clinical specimens at a tertiary care hospital: a cross-sectional study.

Science.gov (United States)

Ahmed, Imran; Jabeen, Kauser; Hasan, Rumina

2013-10-22

Non-tuberculous mycobacteria (NTM) are opportunistic pathogens in immuno-compromised patients. They are also increasingly recognized as pathogens in immuno-competent individuals. Globally, an increase in NTM isolation is being reported with a varied geographic prevalence of different species around the world. There is lack of data on species distribution of these organisms from Pakistan. Treatment options differ according to the species isolated and its susceptibility profile. Knowledge of local species variation would help targeted therapy. This study was performed to determine frequencies of different NTM species isolated from various clinical specimens submitted at a tertiary care hospital laboratory. NTM isolated from 25955 clinical specimens over a period of two years (2010 to 2011) were included. All NTM were identified using conventional tests. Drug susceptibility testing (DST) was performed by broth microdilution and interpreted according to Clinical and Laboratory Standards Institute's document M24-A2. A total of 104 NTM were included in the study. Of these, 76% (54/71) rapidly growing mycobacteria (RGM) and 57.6% (19/33) slow growing mycobacteria (SGM) could be further identified. Mycobacterium fortuitum (21/54) was the commonest NTM identified among RGM followed by M. mucogenicum (12/54) and M. smegmatis (11/54). Among SGM, M. avium complex (MAC) was the most frequent (14/19). Clinical significance could be assessed in a limited number (52/104) of NTM isolates and MAC appeared to be the commonest significant NTM. Three extra-pulmonary cases were found to be healthcare associated infections. DST results for RGM showed susceptibility to amikacin (100%), clarithromycin (100%, except M. fortuitum where it is not reportable), linezolid (90%) and moxifloxacin (75%). Whereas SGM were susceptible to clarithromycin (100%), linezolid (58.8%) and moxifloxacin (64.7%). This is the first study reporting NTM species and their clinical significance isolated from

Reduced lentivirus susceptibility in sheep with TMEM154 mutations.

Directory of Open Access Journals (Sweden)

Michael P Heaton

2012-01-01

Full Text Available Visna/Maedi, or ovine progressive pneumonia (OPP as it is known in the United States, is an incurable slow-acting disease of sheep caused by persistent lentivirus infection. This disease affects multiple tissues, including those of the respiratory and central nervous systems. Our aim was to identify ovine genetic risk factors for lentivirus infection. Sixty-nine matched pairs of infected cases and uninfected controls were identified among 736 naturally exposed sheep older than five years of age. These pairs were used in a genome-wide association study with 50,614 markers. A single SNP was identified in the ovine transmembrane protein (TMEM154 that exceeded genome-wide significance (unadjusted p-value 3×10(-9. Sanger sequencing of the ovine TMEM154 coding region identified six missense and two frameshift deletion mutations in the predicted signal peptide and extracellular domain. Two TMEM154 haplotypes encoding glutamate (E at position 35 were associated with infection while a third haplotype with lysine (K at position 35 was not. Haplotypes encoding full-length E35 isoforms were analyzed together as genetic risk factors in a multi-breed, matched case-control design, with 61 pairs of 4-year-old ewes. The odds of infection for ewes with one copy of a full-length TMEM154 E35 allele were 28 times greater than the odds for those without (p-value<0.0001, 95% CI 5-1,100. In a combined analysis of nine cohorts with 2,705 sheep from Nebraska, Idaho, and Iowa, the relative risk of infection was 2.85 times greater for sheep with a full-length TMEM154 E35 allele (p-value<0.0001, 95% CI 2.36-3.43. Although rare, some sheep were homozygous for TMEM154 deletion mutations and remained uninfected despite a lifetime of significant exposure. Together, these findings indicate that TMEM154 may play a central role in ovine lentivirus infection and removing sheep with the most susceptible genotypes may help eradicate OPP and protect flocks from reinfection.

Susceptibility Tensor Imaging (STI) of the Brain

Science.gov (United States)

Li, Wei; Liu, Chunlei; Duong, Timothy Q.; van Zijl, Peter C.M.; Li, Xu

2016-01-01

Susceptibility tensor imaging (STI) is a recently developed MRI technique that allows quantitative determination of orientation-independent magnetic susceptibility parameters from the dependence of gradient echo signal phase on the orientation of biological tissues with respect to the main magnetic field. By modeling the magnetic susceptibility of each voxel as a symmetric rank-2 tensor, individual magnetic susceptibility tensor elements as well as the mean magnetic susceptibility (MMS) and magnetic susceptibility anisotropy (MSA) can be determined for brain tissues that would still show orientation dependence after conventional scalar-based quantitative susceptibility mapping (QSM) to remove such dependence. Similar to diffusion tensor imaging (DTI), STI allows mapping of brain white matter fiber orientations and reconstruction of 3D white matter pathways using the principal eigenvectors of the susceptibility tensor. In contrast to diffusion anisotropy, the main determinant factor of susceptibility anisotropy in brain white matter is myelin. Another unique feature of susceptibility anisotropy of white matter is its sensitivity to gadolinium-based contrast agents. Mechanistically, MRI-observed susceptibility anisotropy is mainly attributed to the highly ordered lipid molecules in myelin sheath. STI provides a consistent interpretation of the dependence of phase and susceptibility on orientation at multiple scales. This article reviews the key experimental findings and physical theories that led to the development of STI, its practical implementations, and its applications for brain research. PMID:27120169

In Vitro Synergy of Telavancin and Rifampin Against Enterococcus faecium Resistant to Both Linezolid and Vancomycin.

Science.gov (United States)

Pankey, George A; Ashcraft, Deborah S

2013-01-01

An emerging pathogen is Enterococcus faecium resistant to both linezolid and vancomycin (LRVRE). Antimicrobial combinations may be required for therapy and need to be evaluated. The combination of daptomycin and rifampin has demonstrated good in vitro activity against gram-positive bacteria, including E faecium. Telavancin, a newer lipoglycopeptide, has shown in vitro activity against E faecium. We evaluated the combination of telavancin and rifampin and compared the results to the combination of daptomycin and rifampin used previously on the same isolates. Twenty-four genetically unique (by pulsed-field gel electrophoresis), clinical LRVRE isolates were collected in the United States from 2001-2004. Etest minimal inhibitory concentrations (MICs) (μg/mL) were 0.064-8 for telavancin, 1-4 for daptomycin, and 0.012 to >32 for rifampin. In vitro synergy testing was performed in triplicate by an Etest MIC:MIC ratio method, and summation fractional inhibitory concentration (ΣFIC) was calculated: synergy ≤0.5; indifference >0.5-4; and antagonism >4. The Etest method showed synergy (ΣFICs of 0.1-0.5) with telavancin + rifampin in 20/24 (83%) isolates and indifference (ΣFICs of 0.6-0.8) in 4/24 (17%) isolates. Similarly, the daptomycin + rifampin combination showed synergy (ΣFICs of 0.1-0.5) in 21/24 (88%) isolates and indifference (ΣFICs of 0.6-1.0) in 3/24 (12%) isolates by the Etest method. No antagonism was found. In vitro synergy with both combinations (rifampin + telavancin or daptomycin) was 83% and 88%, respectively, by Etest against these LRVRE isolates. Although both daptomycin and telavancin in combination with rifampin showed a high incidence of synergistic activity, further in vitro synergy testing with this combination should be performed against additional E faecium isolates. In vitro synergy may or may not translate into in vivo effectiveness.

Use of Pinus sylvestris L. (Pinaceae), Origanum vulgare L. (Lamiaceae), and Thymus vulgaris L. (Lamiaceae) essential oils and their main components to enhance itraconazole activity against azole susceptible/not-susceptible Cryptococcus neoformans strains.

Science.gov (United States)

Scalas, Daniela; Mandras, Narcisa; Roana, Janira; Tardugno, Roberta; Cuffini, Anna Maria; Ghisetti, Valeria; Benvenuti, Stefania; Tullio, Vivian

2018-05-03

Cryptococcal infections, besides being a problem for immunocompromised patients, are occasionally being a problem for immunocompetent patients. In addition, the lower susceptibility of this yeast to azoles is a growing problem in health care. To date, there are very few molecules with any activity towards Cryptococcus neoformans, leading to heightened interest in finding new alternatives or adjuvants to conventional drugs for the treatment of mycosis caused by this yeast. Since the essential oils (EOs) are considered as a potential rich source of bioactive antimicrobial compounds, we evaluated the antifungal activity of Origanum vulgare (oregano), Pinus sylvestris (pine), and Thymus vulgaris (thyme red) EOs, and their components (α-pinene, carvacrol, thymol) compared with fluconazole, itraconazole, and voriconazole, against C.neoformans clinical strains. Then, we investigated the effect of EOs and components in combination with itraconazole. EO composition was analysed by Gas chromatography-mass spectrometry (GC-MS). A broth microdilution method was used to evaluate the susceptibility of C.neoformans to azoles, EOs and components. Checkerboard tests, isobolograms and time-kill assays were carried out for combination studies. Six C.neoformans isolates were susceptible to azoles, while one C.neoformans exhibited a reduced susceptibility to all tested azole drugs. All EOs exerted a good inhibitory activity against all C.neoformans strains. Pine EO was the most effective. Among components, thymol exerted the most remarkable activity. By checkerboard testing and isobolographic analysis, combinations of itraconazole with oregano, pine, or thyme EOs, and carvacrol were found to be synergistic (FICI≤0.5) against azole susceptible C.neoformans. Regarding the azole not susceptible C.neoformans strain, the synergistic effect with itraconazole was observed with thyme EO (chemotype: thymol 26.52%; carvacrol 7.85%), and carvacrol. Time-kill assays confirmed the synergistic

Advertising literacy and children’s susceptibility to advertising

OpenAIRE

Rozendaal, E.

2011-01-01

This dissertation covers two areas of research that expand our knowledge on children’s advertising literacy (i.e., advertising-related knowledge). The first part addresses the development of children’s advertising literacy into adult-like levels. The second part focuses on the role of advertising literacy in reducing children’s susceptibility to advertising effects. In doing so, this dissertation not only deepens the existing theoretical and empirical insights on children’s advertising litera...

Adult bacterial meningitis: aetiology, penicillin susceptibility, risk factors, prognostic factors and guidelines for empirical antibiotic treatment.

Science.gov (United States)

Meyer, C N; Samuelsson, I S; Galle, M; Bangsborg, J M

2004-08-01

Episodes of adult bacterial meningitis (ABM) at a Danish hospital in 1991-2000 were identified from the databases of the Department of Clinical Microbiology, and compared with data from the Danish National Patient Register and the Danish National Notification System. Reduced penicillin susceptibility occurred in 21 (23%) of 92 cases of known aetiology, compared to an estimated 6% in nationally notified cases (p ABM cases in the study population, and in 99.6% of nationally notified cases. The notification rate was 75% for penicillin-susceptible episodes, and 24% for penicillin-non-susceptible episodes (p ABM cases with no identified risk factors, nine of 11 cases with penicillin-non-susceptible bacteria were community-acquired. Severe sequelae correlated independently with age, penicillin non-susceptibility, mechanical ventilation and non-transferral to a tertiary hospital (p ABM should not be based exclusively on clinical notification systems with possible unbalanced under-reporting.

Degree of host susceptibility in the initial disease outbreak influences subsequent epidemic spread

Science.gov (United States)

Severns, Paul M.; Estep, Laura K.; Sackett, Kathryn E.; Mundt, Christopher C.

2014-01-01

Summary Disease epidemics typically begin as an outbreak of a relatively small, spatially explicit population of infected individuals (focus), in which disease prevalence increases and rapidly spreads into the uninfected, at-risk population. Studies of epidemic spread typically address factors influencing disease spread through the at-risk population, but the initial outbreak may strongly influence spread of the subsequent epidemic.We initiated wheat stripe rust Puccinia striiformis f. sp. tritici epidemics to assess the influence of the focus on final disease prevalence when the degree of disease susceptibility differed between the at-risk and focus populations.When the focus/at-risk plantings consisted of partially genetic resistant and susceptible cultivars, final disease prevalence was statistically indistinguishable from epidemics produced by the focus cultivar in monoculture. In these experimental epidemics, disease prevalence was not influenced by the transition into an at-risk population that differed in disease susceptibility. Instead, the focus appeared to exert a dominant influence on the subsequent epidemic.Final disease prevalence was not consistently attributable to either the focus or the at-risk population when focus/at-risk populations were planted in a factorial set-up with a mixture (~28% susceptible and 72% resistant) and susceptible individuals. In these experimental epidemics, spatial heterogeneity in disease susceptibility within the at-risk population appeared to counter the dominant influence of the focus.Cessation of spore production from the focus (through fungicide/glyphosate application) after 1.3 generations of stripe rust spread did not reduce final disease prevalence, indicating that the focus influence on disease spread is established early in the epidemic.Synthesis and applications. Our experiments indicated that outbreak conditions can be highly influential on epidemic spread, even when disease resistance in the at-risk population

Critical current density measurement of thin films by AC susceptibility based on the penetration parameter h

DEFF Research Database (Denmark)

Li, Xiao-Fen; Grivel, Jean-Claude; Abrahamsen, Asger B.

2012-01-01

We have numerically proved that the dependence of AC susceptibility χ of a E(J) power law superconducting thin disc on many parameters can be reduced to one penetration parameter h, with E the electric field and J the current density. Based on this result, we propose a way of measuring the critical...... current density Jc of superconducting thin films by AC susceptibility. Compared with the normally used method based on the peak of the imaginary part, our method uses a much larger range of the AC susceptibility curve, thus allowing determination of the temperature (T) dependence of Jc from a normally...

Susceptibility tensor imaging (STI) of the brain.

Science.gov (United States)

Li, Wei; Liu, Chunlei; Duong, Timothy Q; van Zijl, Peter C M; Li, Xu

2017-04-01

Susceptibility tensor imaging (STI) is a recently developed MRI technique that allows quantitative determination of orientation-independent magnetic susceptibility parameters from the dependence of gradient echo signal phase on the orientation of biological tissues with respect to the main magnetic field. By modeling the magnetic susceptibility of each voxel as a symmetric rank-2 tensor, individual magnetic susceptibility tensor elements as well as the mean magnetic susceptibility and magnetic susceptibility anisotropy can be determined for brain tissues that would still show orientation dependence after conventional scalar-based quantitative susceptibility mapping to remove such dependence. Similar to diffusion tensor imaging, STI allows mapping of brain white matter fiber orientations and reconstruction of 3D white matter pathways using the principal eigenvectors of the susceptibility tensor. In contrast to diffusion anisotropy, the main determinant factor of the susceptibility anisotropy in brain white matter is myelin. Another unique feature of the susceptibility anisotropy of white matter is its sensitivity to gadolinium-based contrast agents. Mechanistically, MRI-observed susceptibility anisotropy is mainly attributed to the highly ordered lipid molecules in the myelin sheath. STI provides a consistent interpretation of the dependence of phase and susceptibility on orientation at multiple scales. This article reviews the key experimental findings and physical theories that led to the development of STI, its practical implementations, and its applications for brain research. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Rapid bacterial antibiotic susceptibility test based on simple surface-enhanced Raman spectroscopic biomarkers

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Liu, Chia-Ying; Han, Yin-Yi; Shih, Po-Han; Lian, Wei-Nan; Wang, Huai-Hsien; Lin, Chi-Hung; Hsueh, Po-Ren; Wang, Juen-Kai; Wang, Yuh-Lin

2016-03-01

Rapid bacterial antibiotic susceptibility test (AST) and minimum inhibitory concentration (MIC) measurement are important to help reduce the widespread misuse of antibiotics and alleviate the growing drug-resistance problem. We discovered that, when a susceptible strain of Staphylococcus aureus or Escherichia coli is exposed to an antibiotic, the intensity of specific biomarkers in its surface-enhanced Raman scattering (SERS) spectra drops evidently in two hours. The discovery has been exploited for rapid AST and MIC determination of methicillin-susceptible S. aureus and wild-type E. coli as well as clinical isolates. The results obtained by this SERS-AST method were consistent with that by the standard incubation-based method, indicating its high potential to supplement or replace existing time-consuming methods and help mitigate the challenge of drug resistance in clinical microbiology.

Magnetization and susceptibility of a parabolic InAs quantum dot with electron–electron and spin–orbit interactions in the presence of a magnetic field at finite temperature

Energy Technology Data Exchange (ETDEWEB)

Kumar, D. Sanjeev, E-mail: sanjeevchs@gmail.com [School of Physics, University of Hyderabad, Hyderabad 500046 (India); Mukhopadhyay, Soma [Department of Physics, CMR College of Engineering and Technology, Hyderabad (India); Chatterjee, Ashok [School of Physics, University of Hyderabad, Hyderabad 500046 (India)

2016-11-15

The magnetization and susceptibility of a two-electron parabolic quantum dot are studied in the presence of electron–electron and spin–orbit interactions as a function of magnetic field and temperature. The spin–orbit interactions are treated by a unitary transformation and an exactly soluble parabolic interaction model is considered to mimic the electron–electron interaction. The theory is finally applied to an InAs quantum dot. Magnetization and susceptibility are calculated using canonical ensemble approach. Our results show that Temperature has no effect on magnetization and susceptibility in the diamagnetic regime whereas electron–electron interaction reduces them. The temperature however reduces the height of the paramagnetic peak. The Rashba spin–orbit interaction is shown to shift the paramagnetic peak towards higher magnetic fields whereas the Dresselhaus spin–orbit interaction shifts it to the lower magnetic field side. Spin–orbit interaction has no effect on magnetization and susceptibility at larger temperatures. - Highlights: • Temperature has no effect on magnetization and susceptibility in the diamagnetic regime but reduces the height of the paramagnetic peak. • Electron-electron interaction reduces magnetization and susceptibility in the diamagnetic region. • Rashba spin–orbit interaction shifts the paramagnetic peak towards higher magnetic fields. • Dresselhaus spin–orbit interaction shifts the paramagnetic peak towards lower magnetic fields. • Spin–orbit interaction has no effect on magnetization and susceptibility at larger temperatures.

Simple protein precipitation extraction technique followed by validated chromatographic method for linezolid analysis in real human plasma samples to study its pharmacokinetics.

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Mohammed, Samah A; Eissa, Maya S; Ahmed, Hytham M

2017-02-01

Fast and sensitive HPLC method was developed, optimized and validated for quantification of linezolid (LNZ) in human plasma using guaifenesin as an internal standard (IS). Analyte and IS were extracted from plasma by simple protein precipitation extraction technique using methanol as the precipitating solvent. The pretreated samples were injected in a mobile phase formed of acetonitrile:water:methanol (20:70:10v/v/v) in an isocratic mode at a flow rate of 1.5mL/min with UV detection at 251nm. Separation was done using Aglient ODS C 18 . The method showed linearity in the range of 0.75-50μg/mL with correlation coefficients equals to 0.9991. Precision and accuracy were in conformity with the criteria normally accepted in bio-analytical method validation. The RSDs for intra- and inter-day assays were <3.56 and 4.63%, respectively. The intra- and inter-day accuracies were 94.67-98.28% and 91.25-96.18%, respectively. The mean absolute recoveries ranged from 92.56±1.78 to 95.24±2.84. According to stability results, LNZ was stable in human plasma during the storage and analysis. LNZ a pharmacokinetic behavior was studied by applying the proposed analytical method. Copyright © 2016 Elsevier B.V. All rights reserved.

Reversion of High-level Mecillinam Resistance to Susceptibility in Escherichia coli During Growth in Urine

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Elisabeth Thulin

2017-09-01

This is the first example describing conditional resistance where a genetically stable antibiotic resistance can be phenotypically reverted to susceptibility by metabolites present in urine. These findings have several important clinical implications regarding the use of mecillinam to treat UTIs. First, they suggest that mecillinam can be used to treat also those clinical strains that are identified as MecR in standard laboratory tests. Second, the results suggest that testing of mecillinam susceptibility in the laboratory ought to be performed in media that mimics urine to obtain clinically relevant susceptibility testing results. Third, these findings imply that changes in patient behavior, such as increased water intake or use of diuretics to reduce urine osmolality and increased intake of cysteine, might induce antibiotic susceptibility in an infecting MecR E. coli strain and thereby increase treatment efficiency.

Characterization of a Mycobacterium avium subsp. avium Operon Associated with Virulence and Drug Detoxification

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Mariana Noelia Viale

2014-01-01

Full Text Available The lprG-p55 operon of Mycobacterium tuberculosis and Mycobacterium bovis is involved in the transport of toxic compounds. P55 is an efflux pump that provides resistance to several drugs, while LprG is a lipoprotein that modulates the host's immune response against mycobacteria. The knockout mutation of this operon severely reduces the replication of both mycobacterial species during infection in mice and increases susceptibility to toxic compounds. In order to gain insight into the function of LprG in the Mycobacterium avium complex, in this study, we assayed the effect of the deletion of lprG gene in the D4ER strain of Mycobacterium avium subsp. avium. The replacement of lprG gene with a hygromycin cassette caused a polar effect on the expression of p55. Also, a twofold decrease in ethidium bromide susceptibility was observed and the resistance to the antibiotics rifampicin, amikacin, linezolid, and rifabutin was impaired in the mutant strain. In addition, the mutation decreased the virulence of the bacteria in macrophages in vitro and in a mice model in vivo. These findings clearly indicate that functional LprG and P55 are necessary for the correct transport of toxic compounds and for the survival of MAA in vitro and in vivo.

Alterations in the transcriptome and antibiotic susceptibility of Staphylococcus aureus grown in the presence of diclofenac

Science.gov (United States)

2011-01-01

Background Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) which has been shown to increase the susceptibility of various bacteria to antimicrobials and demonstrated to have broad antimicrobial activity. This study describes transcriptome alterations in S. aureus strain COL grown with diclofenac and characterizes the effects of this NSAID on antibiotic susceptibility in laboratory, clinical and diclofenac reduced-susceptibility (DcRS) S. aureus strains. Methods Transcriptional alterations in response to growth with diclofenac were measured using S. aureus gene expression microarrays and quantitative real-time PCR. Antimicrobial susceptibility was determined by agar diffusion MICs and gradient plate analysis. Ciprofloxacin accumulation was measured by fluorescence spectrophotometry. Results Growth of S. aureus strain COL with 80 μg/ml (0.2 × MIC) of diclofenac resulted in the significant alteration by ≥2-fold of 458 genes. These represented genes encoding proteins for transport and binding, protein and DNA synthesis, and the cell envelope. Notable alterations included the strong down-regulation of antimicrobial efflux pumps including mepRAB and a putative emrAB/qacA-family pump. Diclofenac up-regulated sigB (σB), encoding an alternative sigma factor which has been shown to be important for antimicrobial resistance. Staphylococcus aureus microarray metadatabase (SAMMD) analysis further revealed that 46% of genes differentially-expressed with diclofenac are also σB-regulated. Diclofenac altered S. aureus susceptibility to multiple antibiotics in a strain-dependent manner. Susceptibility increased for ciprofloxacin, ofloxacin and norfloxacin, decreased for oxacillin and vancomycin, and did not change for tetracycline or chloramphenicol. Mutation to DcRS did not affect susceptibility to the above antibiotics. Reduced ciprofloxacin MICs with diclofenac in strain BB255, were not associated with increased drug accumulation. Conclusions The results of

Genetic Testing for TMEM154 Mutations Associated with Lentivirus Susceptibility in Sheep

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Petrik, Dustin T.; Simpson, Barry; Kijas, James W.; Clawson, Michael L.; Chitko-McKown, Carol G.; Harhay, Gregory P.; Leymaster, Kreg A.

2013-01-01

In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affects millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV) in the U.S., and Visna/Maedi virus (VMV) elsewhere, these viruses reduce an animal’s health, productivity, and lifespan. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154) has been previously associated with OPPV infection in U.S. sheep. Sheep with the ancestral TMEM154 haplotype encoding glutamate (E) at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation. Our current overall aim was to characterize TMEM154 in sheep from around the world to develop an efficient genetic test for reduced susceptibility. The average frequency of TMEM154 E35 among 74 breeds was 0.51 and indicated that highly-susceptible alleles were present in most breeds around the world. Analysis of whole genome sequences from an international panel of 75 sheep revealed more than 1,300 previously unreported polymorphisms in a 62 kb region containing TMEM154 and confirmed that the most susceptible haplotypes were distributed worldwide. Novel missense mutations were discovered in the signal peptide (A13V) and the extracellular domains (E31Q, I74F, and I102T) of TMEM154. A matrix-assisted laser desorption/ionization–time-of flight mass spectrometry (MALDI-TOF MS) assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154. In blinded trials, the call rate for the eight most common coding polymorphisms was 99.4% for 499 sheep tested and 96.0% of the animals were assigned paired TMEM154 haplotypes (i.e., diplotypes). The widespread distribution of highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks. PMID:23408992

Genetic testing for TMEM154 mutations associated with lentivirus susceptibility in sheep.

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Michael P Heaton

Full Text Available In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affects millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV in the U.S., and Visna/Maedi virus (VMV elsewhere, these viruses reduce an animal's health, productivity, and lifespan. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154 has been previously associated with OPPV infection in U.S. sheep. Sheep with the ancestral TMEM154 haplotype encoding glutamate (E at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation. Our current overall aim was to characterize TMEM154 in sheep from around the world to develop an efficient genetic test for reduced susceptibility. The average frequency of TMEM154 E35 among 74 breeds was 0.51 and indicated that highly-susceptible alleles were present in most breeds around the world. Analysis of whole genome sequences from an international panel of 75 sheep revealed more than 1,300 previously unreported polymorphisms in a 62 kb region containing TMEM154 and confirmed that the most susceptible haplotypes were distributed worldwide. Novel missense mutations were discovered in the signal peptide (A13V and the extracellular domains (E31Q, I74F, and I102T of TMEM154. A matrix-assisted laser desorption/ionization-time-of flight mass spectrometry (MALDI-TOF MS assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154. In blinded trials, the call rate for the eight most common coding polymorphisms was 99.4% for 499 sheep tested and 96.0% of the animals were assigned paired TMEM154 haplotypes (i.e., diplotypes. The widespread distribution of highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks.

Reduced mitochondrial mass and function add to age-related susceptibility toward diet-induced fatty liver in C57BL/6J mice.

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Lohr, Kerstin; Pachl, Fiona; Moghaddas Gholami, Amin; Geillinger, Kerstin E; Daniel, Hannelore; Kuster, Bernhard; Klingenspor, Martin

2016-10-01

Nonalcoholic fatty liver disease (NAFLD) is a major health burden in the aging society with an urging medical need for a better understanding of the underlying mechanisms. Mitochondrial fatty acid oxidation and mitochondrial-derived reactive oxygen species (ROS) are considered critical in the development of hepatic steatosis, the hallmark of NAFLD. Our study addressed in C57BL/6J mice the effect of high fat diet feeding and age on liver mitochondria at an early stage of NAFLD development. We therefore analyzed functional characteristics of hepatic mitochondria and associated alterations in the mitochondrial proteome in response to high fat feeding in adolescent, young adult, and middle-aged mice. Susceptibility to diet-induced obesity increased with age. Young adult and middle-aged mice developed fatty liver, but not adolescent mice. Fat accumulation was negatively correlated with an age-related reduction in mitochondrial mass and aggravated by a reduced capacity of fatty acid oxidation in high fat-fed mice. Irrespective of age, high fat diet increased ROS production in hepatic mitochondria associated with a balanced nuclear factor erythroid-derived 2 like 2 (NFE2L2) dependent antioxidative response, most likely triggered by reduced tethering of NFE2L2 to mitochondrial phosphoglycerate mutase 5. Age indirectly influenced mitochondrial function by reducing mitochondrial mass, thus exacerbating diet-induced fat accumulation. Therefore, consideration of age in metabolic studies must be emphasized. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Bleaching Gels Containing Calcium and Fluoride: Effect on Enamel Erosion Susceptibility

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Alessandra B. Borges

2012-01-01

Full Text Available This in vitro study evaluated the effect of 35% hydrogen peroxide (HP bleaching gel modified or not by the addition of calcium and fluoride on enamel susceptibility to erosion. Bovine enamel samples (3 mm in diameter were divided into four groups (n=15 according to the bleaching agent: control—without bleaching (C; 35% hydrogen peroxide (HP; 35% HP with the addition of 2% calcium gluconate (HP + Ca; 35% HP with the addition of 0.6% sodium fluoride (HP + F. The bleaching gels were applied on the enamel surface for 40 min, and the specimens were subjected to erosive challenge with Sprite Zero and remineralization with artificial saliva for 5 days. Enamel wear was assessed using profilometry. The data were analyzed by ANOVA/ Tukey’s test (P<0.05. There were significant differences among the groups (P=0.009. The most enamel wear was seen for C (3.37±0.80 μm, followed by HP (2.89 ± 0.98 μm and HP + F (2.72 ± 0.64 μm. HP + Ca (2.31 ± 0.92 μm was the only group able to significantly reduce enamel erosion compared to C. The application of HP bleaching agent did not increase the enamel susceptibility to erosion. However, the addition of calcium gluconate to the HP gel resulted in reduced susceptibility of the enamel to erosion.

Mechanisms of antibiotic resistance in Staphylococcus aureus.

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Pantosti, Annalisa; Sanchini, Andrea; Monaco, Monica

2007-06-01

Staphylococcus aureus can exemplify better than any other human pathogen the adaptive evolution of bacteria in the antibiotic era, as it has demonstrated a unique ability to quickly respond to each new antibiotic with the development of a resistance mechanism, starting with penicillin and methicillin, until the most recent, linezolid and daptomycin. Resistance mechanisms include enzymatic inactivation of the antibiotic (penicillinase and aminoglycoside-modification enzymes), alteration of the target with decreased affinity for the antibiotic (notable examples being penicillin-binding protein 2a of methicillin-resistant S. aureus and D-Ala-D-Lac of peptidoglycan precursors of vancomycin-resistant strains), trapping of the antibiotic (for vancomycin and possibly daptomycin) and efflux pumps (fluoroquinolones and tetracycline). Complex genetic arrays (staphylococcal chromosomal cassette mec elements or the vanA operon) have been acquired by S. aureus through horizontal gene transfer, while resistance to other antibiotics, including some of the most recent ones (e.g., fluoroquinolones, linezolid and daptomycin) have developed through spontaneous mutations and positive selection. Detection of the resistance mechanisms and their genetic basis is an important support to antibiotic susceptibility surveillance in S. aureus.

Reduced expression IRF7 in nasal epithelial cells from smokers as a potential mechanism mediating enhanced susceptibility to influenza

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Rationale: Smokers are more susceptible to viral infections, including influenza virus, yet the mechanisms mediating this effect are not known. Methods: We have established an in vitro model of differentiated nasal epithelial cells from smokers, which maintain enhanced levels...

BACTERIOLOGICAL PROFILE AND ANTIBIOTIC SENSITIVITY PATTERN IN ACUTE EXACERBATION OF ADVANCED CASES OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD

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Avik

2016-01-01

Full Text Available Acute exacerbations are significant and frequent events in the natural history of chronic obstructive pulmonary disease. Majority of these exacerbations are of infectious aetiology, bacteria being responsible for 30-50% of these cases. With not many studies of similar type being conducted in the Indian context, this study was undertaken with the purpose of determining the bacteriology of acute exacerbations of chronic obstructive pulmonary disease in hospitalized patients with advanced disease and their antibiotic susceptibility pattern to formulate a cost effective algorithm for antibiotic usage while at the same time reducing the chances of emergence of drug resistance. Sputum sample from a total of 338 patients were send for Gram’s stain and culture sensitivity testing using an array of the commonly used antibiotics. Pathogenic bacteria were isolated from 203 (60.1% samples. Gram negative bacteria were isolated from 79.8 percent (162/203 cases while the rest were Gram positive. Klebsiella species were the commonest (49.2%; 100/203 Gram negative isolates from the sputum samples. Among the gram negative organisms, Carbapenem had the highest sensitivity (90.2% followed by Amikacin, Ciprofloxacin and Piperacillin-Tazobactam. Linezolid was found to be 100 percent sensitive amongst the Gram positive organisms while both Amoxicillin Clavulanate and Azithromycin showed a rather low sensitivity profile overall. 5.0 percent of the Klebsiella infections were multi drug resistant. It was thereby concluded that either Amikacin, Ciprofloxacin or Piperacillin-Tazobactam for be considered for Gram negative organisms and Linezolid be considered for Gram positive organisms as first line antibiotics in empirical therapy while Carbapenems may be kept as reserve drugs should the first line drugs fail.

Species Distribution and Susceptibility to Azoles of Vaginal Yeasts Isolated Prostitutes

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Norma T. Gross

2007-01-01

Full Text Available Objective. We investigated the use of miconazole among female prostitutes in Costa Rica as well as the distribution of vaginal yeasts and the susceptibility pattern to azoles of strains obtained from this population. Our intention was to relate a frequent use of miconazole to occurrence of vaginal yeasts resistant to azoles. Methods. Vaginal samples were taken from 277 patients that have previously used azoles. Vaginal swabs were obtained for direct microscopy and culture. Yeast isolates were identified by germ tube test and assimilation pattern. Susceptibility testing was determined using a tablet diffusion method. Results. The number of clinical Candida isolates (one from each patient was 57 (20.6%. C. albicans was the predominant species (70%, followed by C. parapsilosis (12%, C. tropicalis (5.3%, C. glabrata and C. famata (3.5% each, C. krusei, C. inconspicua and C. guilliermondii (1.7% each. The majority of vaginal Candida isolates were susceptible to ketoconazole (91%, fluconazole (96.5%, and itraconazole (98%. A lower susceptibility of some isolates to miconazole (63% was observed as compared to the other azoles tested. Moreover, the strains, nonsusceptible to miconazole, were more often obtained from patients that have used this antifungal at least four times within the last year before taking the samples as compared to those with three or less treatments (P<.01. Conclusion. An indiscriminate use of miconazole, such as that observed among female prostitutes in Costa Rica, results in a reduced susceptibility of vaginal yeasts to miconazole but not to other azoles.

Changing the Smoking Trajectory: Evaluating the Impact of School-Based Tobacco Interventions on Changes to Susceptibility to Future Smoking

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Adam G. Cole

2017-10-01

Full Text Available School-based programs and policies can reduce student smoking rates. However, their impact on never-smoking students has not been investigated despite the clear transition between non-susceptible, susceptible, and ever tried smoking statuses. The objective of this paper was to examine the longitudinal student-level impact of six changes in school-based tobacco control programs and policies on student transitions in susceptibility to smoking over one year. Two multinomial logistic regression models identified the relative risk of a change in self-reported susceptibility to smoking or in trying a cigarette among never-smoking students in each of the six intervention schools compared to the relative risk among never-smoking students in control schools. Model 1 identified the relative risk of a change in smoking susceptibility status among baseline non-susceptible never smoking students, while Model 2 identified the relative risk of a change in smoking susceptibility status among baseline susceptible never smoking students. Students at some intervention schools were at increased risk of becoming susceptible to or trying a cigarette at one year follow-up. Intervention studies should examine changes to susceptibility to future smoking when evaluating impact to ensure that school-based tobacco control programs and policies do not negatively change the risk status of never-smoking students.

Association of aldose reductase gene Z+2 polymorphism with reduced susceptibility to diabetic nephropathy in Caucasian Type 1 diabetic patients

DEFF Research Database (Denmark)

Lajer, Mathilde; Tarnow, L; Fleckner, Jan

2004-01-01

AIMS: The Z-2 allele of the (AC)n polymorphism in the aldose reductase gene (ALR2) confers increased risk of microvascular diabetic complications, whereas the Z+2 allele has been proposed to be a marker of protection. However data are conflicting. Therefore, we investigated whether this polymorph......AIMS: The Z-2 allele of the (AC)n polymorphism in the aldose reductase gene (ALR2) confers increased risk of microvascular diabetic complications, whereas the Z+2 allele has been proposed to be a marker of protection. However data are conflicting. Therefore, we investigated whether...... this polymorphism is associated with diabetic nephropathy and retinopathy in Type 1 diabetes mellitus in a large case-control study and a family-based analysis. METHODS: A total of 431 Type 1 diabetic patients with diabetic nephropathy and 468 patients with longstanding Type 1 diabetes and persistent...... of the ALR2 promoter polymorphism is associated with a reduced susceptibility to diabetic nephropathy in Danish Type 1 diabetic patients, suggesting a minor role for the polyol pathway in the pathogenesis of diabetic kidney disease. No association of the ALR2 polymorphism with diabetic retinopathy was found....

Magnetic susceptibility measurements on Bi - Sn alloys

International Nuclear Information System (INIS)

Mustaffa bin Haji Abdullah

1985-01-01

Magnetic susceptibility measurements on eight samples of tin-rich and three samples of bismuth-rich Bi-Sn alloys were made from 85K to 300K by Faraday's method. The susceptibilities of the eight tin-rich samples are positive and greater than the susceptibility of pure tin. The values are approximately constant at low temperatures but decreasing a little bit with increasing temperature. This result is interpreted as due to the predominant contribution of the Pauli spin paramagnetic susceptibility. A small decrease in susceptibility with temperature is interpreted as due to the effect of the second order term in the expression for spin paramagnetic susceptibility. The fluctuation of the susceptibility for alloys of different composition is interpreted as due to the effect of the density of states at the Fermi levels. The three samples of bismuth-rich alloys show a transition to diamagnetic property, where the diamagnetism is increased with temperature. This result is predominant and due to the diamagnetic contribution from the ions. The increase in susceptibility with temperature is interpreted as due to an increase in the effective radii of the ions due to thermal expansion. (author)

Usefulness of IDEAL T2 imaging for homogeneous fat suppression and reducing susceptibility artefacts in brachial plexus MRI at 3.0 T.

Science.gov (United States)

Tagliafico, Alberto; Bignotti, Bianca; Tagliafico, Giulio; Martinoli, Carlo

2016-01-01

To quantitatively and qualitatively compare fat-suppressed MR imaging quality using iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) with that using frequency-selective fat-suppressed (FSFS) T2 images of the brachial plexus at 3.0 T. Prospective MR image analysis was performed in 40 volunteers and 40 patients at a single centre. Oblique-sagittal and coronal IDEAL fat-suppressed T2 images and FSFS T2 images were compared. Visual assessment was performed by two independent musculoskeletal radiologists with respect to: (1) susceptibility artefacts around the neck, (2) homogeneity of fat suppression, (3) image sharpness and (4) tissue resolution contrast of pathologies. The signal-to-noise ratios (SNR) for each image sequence were assessed. Compared to FSFS sequences, IDEAL fat-suppressed T2 images significantly reduced artefacts around the brachial plexus and significantly improved homogeneous fat suppression (p < 0.05). IDEAL significantly improved sharpness and lesion-to-tissue contrast (p < 0.05). The mean SNRs were significantly improved on T2-weighted IDEAL images (p < 0.05). IDEAL technique improved image quality by reducing artefacts around the brachial plexus while maintaining a high SNR and provided superior homogeneous fat suppression than FSFS sequences.

Susceptibility Genes in Thyroid Autoimmunity

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Yoshiyuki Ban

2005-01-01

Full Text Available The autoimmune thyroid diseases (AITD are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD and Hashimoto's thyroiditis (HT and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4 and thyroid specific genes (e.g. TSHR, Tg. Most likely, these loci interact and their interactions may influence disease phenotype and severity.

In vivo emergence of Aspergillus terreus with reduced azole susceptibility and a Cyp51a M217I alteration

DEFF Research Database (Denmark)

Arendrup, Maiken C; Jensen, Rasmus; Grif, Katharina

2012-01-01

Azole resistance in Aspergillus terreus isolates was explored. Twenty related (MB) and 6 unrelated A. terreus isolates were included. CYP51A sequencing and RAPD genotyping was performed. Five MB isolates were itraconazole susceptible, whereas the minimum inhibitory concentrations (MICs) for 15 MB...

CovR Regulates Streptococcus mutans Susceptibility To Complement Immunity and Survival in Blood

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Alves, Lívia A.; Nomura, Ryota; Mariano, Flávia S.; Harth-Chu, Erika N.; Stipp, Rafael N.; Nakano, Kazuhiko

2016-01-01

Streptococcus mutans, a major pathogen of dental caries, may promote systemic infections after accessing the bloodstream from oral niches. In this study, we investigate pathways of complement immunity against S. mutans and show that the orphan regulator CovR (CovRSm) modulates susceptibility to complement opsonization and survival in blood. S. mutans blood isolates showed reduced susceptibility to C3b deposition compared to oral isolates. Reduced expression of covRSm in blood strains was associated with increased transcription of CovRSm-repressed genes required for S. mutans interactions with glucans (gbpC, gbpB, and epsC), sucrose-derived exopolysaccharides (EPS). Consistently, blood strains showed an increased capacity to bind glucan in vitro. Deletion of covRSm in strain UA159 (UAcov) impaired C3b deposition and binding to serum IgG and C-reactive protein (CRP) as well as phagocytosis through C3b/iC3b receptors and killing by neutrophils. Opposite effects were observed in mutants of gbpC, epsC, or gtfBCD (required for glucan synthesis). C3b deposition on UA159 was abolished in C1q-depleted serum, implying that the classical pathway is essential for complement activation on S. mutans. Growth in sucrose-containing medium impaired the binding of C3b and IgG to UA159, UAcov, and blood isolates but had absent or reduced effects on C3b deposition in gtfBCD, gbpC, and epsC mutants. UAcov further showed increased ex vivo survival in human blood in an EPS-dependent way. Consistently, reduced survival was observed for the gbpC and epsC mutants. Finally, UAcov showed an increased ability to cause bacteremia in a rat model. These results reveal that CovRSm modulates systemic virulence by regulating functions affecting S. mutans susceptibility to complement opsonization. PMID:27572331

MICs of Oxazolidinones for Rhodococcus equi Strains Isolated from Humans and Animals

OpenAIRE

Bowersock, Terry L.; Salmon, Sarah A.; Portis, Ellen S.; Prescott, John F.; Robison, Denise A.; Ford, Charles W.; Watts, Jeffrey L.

2000-01-01

Eperezolid and linezolid are representatives of a new class of orally active, synthetic antimicrobial agents. The in vitro activity values (MICs) of linezolid, eperezolid, and comparator antibiotics against 102 strains of Rhodococcus equi isolated from humans and animals were determined. Linezolid was more active than eperezolid against the strains tested; premafloxacin was the most active comparator antibiotic.

Parental behaviours, but not parental smoking, influence current smoking and smoking susceptibility among 14 and 15 year-old children.

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Waa, Andrew; Edwards, Richard; Newcombe, Rhiannon; Zhang, Jane; Weerasekera, Deepa; Peace, Jo; McDuff, Ingrid

2011-12-01

To explore whether parental behaviours related to smoking socialisation and parenting are associated with smoking susceptibility and current smoking in 14-15 year old students. Data were sourced from the New Zealand 2006 Year 10 In-depth Survey, a school-based survey of 3,189 students. Outcome measures were susceptibility to smoking and current smoking. Potential determinants were second-hand smoke exposure in the home, parental smoking, parental anti-smoking expectations, anti-smoking rules, pocket money, monitoring of pocket money expenditure, general rule setting and monitoring, and concern about education. Analysis used logistic regression to adjust for potential confounding factors. Exposure to second-hand smoke and lack of parental anti-smoking expectations were independently associated with smoking susceptibility and current smoking. Parental smoking was not independently associated with current smoking or susceptibility. Receiving pocket money and an absence of monitoring of expenditure were associated with smoking susceptibility and current smoking. Lack of parental rule setting was associated with smoking susceptibility. Findings were similar whether or not one or more parents were smokers. Not allowing smoking in the home, communicating non-smoking expectations to children, monitoring pocket money, and setting rules to guide behaviour are strategies which are likely to reduce risk of smoking uptake. The study provides evidence to inform the development of parent-focused interventions to reduce the risk of smoking initiation by children. © 2011 The Authors. ANZJPH © 2011 Public Health Association of Australia.

Hyperinducibility of Ia antigen on astrocytes correlates with strain-specific susceptibility to experimental autoimmune encephalomyelitis

International Nuclear Information System (INIS)

Massa, P.T.; ter Meulen, V.; Fontana, A.

1987-01-01

In search of a phenotypic marker determining genetically controlled susceptibility to delayed-type hypersensitivity (DTH) reactions in the brain-in particular, experimental autoimmune encephalomyelitis (EAE)- the authors have compared the γ-interferon (IFN-γ) induction of Ia molecules on astrocytes and macrophages from rat and mouse strains that are susceptible or resistant to this disease. They focused on Ia expression because DTH reactions to self or foreign antigens are largely mediated by lymphocytes restricted by class II (Ia) antigens of the major histocompatibility complex (MHC). The data demonstrate that Lewis (fully susceptible) and Brown Norway (BN) (fully resistant) rats are very different in that Lewis astrocytes express much higher levels of Ia than BN astrocytes. Similar data were obtained from an analysis of EAE-susceptible and -resistant mouse strains (SJL and BALB/c, respectively), which suggest that this phenomenon may be universal and not limited to only one mammalian species. At least one gene responsible for Ia hyperinduction is located outside the rat RT-1 or the mouse MHC locus. Animals congenic at the RT-1 or MHC locus of the resistant strain but with background genes of the susceptible strain exhibit intermediate levels of Ia compared to fully resistant and susceptible rodents, which fits well with the reduced EAE susceptibility of these congenic animals. Furthermore, hyperinduction of Ia is astrocyte specific, since peritoneal macrophages of susceptible and resistant strains exhibit identical profiles of Ia induction. Thus, astrocyte Ia hyperinducibility may be a major strain- and tissue-specific factor that contributes to Ia-restricted DTH reactions in the brain

The effect of an intervention on schoolchildren's susceptibility to a peer's candy intake

NARCIS (Netherlands)

Bevelander, K.E.; Engels, R.C.M.E.; Anschutz, D.J.; Wansink, B.

2013-01-01

BACKGROUND/OBJECTIVES: The aim of the study was to pilot test two interventions designed to reduce children's susceptibility to peers' candy intake and to determine if interventions had different effects on boys and girls. SUBJECTS/METHODS: In the standard intervention, peer modeling was explained

Tobacco marketing awareness on youth smoking susceptibility and perceived prevalence before and after an advertising ban.

Science.gov (United States)

Moodie, Crawford; MacKintosh, Anne Marie; Brown, Abraham; Hastings, Gerard B

2008-10-01

The Tobacco Advertising and Promotion Act (TAPA) was implemented in the United Kingdom in 2003. This study is the first to assess its impact on young people, examining smoking susceptibility (intention to smoke among never smokers) and perceived prevalence across three British cross-sectional samples (aged 11-16) before and after the introduction of the ban. Three in-home surveys (n = 1078, 1121 and 1121) were conducted before (1999 and 2002) and after (2004) the implementation of the TAPA. Significant declines in awareness of tobacco marketing and perceived prevalence occurred across the three waves. Higher levels of awareness and perceived prevalence were associated with increased susceptibility, but direct measures of susceptibility remained stable. The TAPA is protecting young people in United Kingdom from tobacco marketing and reducing perceived prevalence, both of which are linked to susceptibility. The stability of susceptibility across the three waves is probably best explained by both the partial implementation of TAPA at the final survey point and the time such effects take to emerge. The evidence from this and previous studies is, however, that, ultimately, they will appear.

A new rapid method for direct antimicrobial susceptibility testing of bacteria from positive blood cultures.

Science.gov (United States)

Barnini, Simona; Brucculeri, Veronica; Morici, Paola; Ghelardi, Emilia; Florio, Walter; Lupetti, Antonella

2016-08-12

Rapid identification and antimicrobial susceptibility testing (AST) of the causative agent(s) of bloodstream infections can lead to prompt appropriate antimicrobial therapy. To shorten species identification, in this study bacteria were recovered from monomicrobial blood cultures by serum separator tubes and spotted onto the target plate for direct MALDI-TOF MS identification. Proper antibiotics were selected for direct AST based on species identification. In order to obtain rapid AST results, bacteria were recovered from positive blood cultures by two different protocols: by serum separator tubes (further referred to as PR1), or after a short-term subculture in liquid medium (further referred to as PR2). The results were compared with those obtained by the method currently used in our laboratory consisting in identification by MALDI-TOF and AST by Vitek 2 or Sensititre on isolated colonies. The direct MALDI-TOF method concordantly identified with the current method 97.5 % of the Gram-negative bacteria and 96.1 % of the Gram-positive cocci contained in monomicrobial blood cultures. The direct AST by PR1 and PR2 for all isolate/antimicrobial agent combinations was concordant/correct with the current method for 87.8 and 90.5 % of Gram-negative bacteria and for 93.1 and 93.8 % of Gram-positive cocci, respectively. In particular, 100 % categorical agreement was found with levofloxacin for Enterobacteriaceae by both PR1 and PR2, and 99.0 and 100 % categorical agreement was observed with linezolid for Gram-positive cocci by PR1 and PR2, respectively. There was no significant difference in accuracy between PR1 and PR2 for Gram-negative bacteria and Gram-positive cocci. This newly described method seems promising for providing accurate AST results. Most importantly, these results would be available in a few hours from blood culture positivity, which would help clinicians to promptly confirm or streamline an effective antibiotic therapy in patients with bloodstream

Accuracy of magnetic resonance based susceptibility measurements

Science.gov (United States)

Erdevig, Hannah E.; Russek, Stephen E.; Carnicka, Slavka; Stupic, Karl F.; Keenan, Kathryn E.

2017-05-01

Magnetic Resonance Imaging (MRI) is increasingly used to map the magnetic susceptibility of tissue to identify cerebral microbleeds associated with traumatic brain injury and pathological iron deposits associated with neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Accurate measurements of susceptibility are important for determining oxygen and iron content in blood vessels and brain tissue for use in noninvasive clinical diagnosis and treatment assessments. Induced magnetic fields with amplitude on the order of 100 nT, can be detected using MRI phase images. The induced field distributions can then be inverted to obtain quantitative susceptibility maps. The focus of this research was to determine the accuracy of MRI-based susceptibility measurements using simple phantom geometries and to compare the susceptibility measurements with magnetometry measurements where SI-traceable standards are available. The susceptibilities of paramagnetic salt solutions in cylindrical containers were measured as a function of orientation relative to the static MRI field. The observed induced fields as a function of orientation of the cylinder were in good agreement with simple models. The MRI susceptibility measurements were compared with SQUID magnetometry using NIST-traceable standards. MRI can accurately measure relative magnetic susceptibilities while SQUID magnetometry measures absolute magnetic susceptibility. Given the accuracy of moment measurements of tissue mimicking samples, and the need to look at small differences in tissue properties, the use of existing NIST standard reference materials to calibrate MRI reference structures is problematic and better reference materials are required.

Habitat productivity and pyrethroid susceptibility status of Aedes aegypti mosquitoes in Dar es Salaam, Tanzania.

Science.gov (United States)

Mathias, Leah; Baraka, Vito; Philbert, Anitha; Innocent, Ester; Francis, Filbert; Nkwengulila, Gamba; Kweka, Eliningaya J