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

Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients

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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

Activity of linezolid and tedizolid against clinical isolates of methicillin-resistant and methicillin and linezolid resistant Staphylococcus aureus: an in vitro comparison.

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Peñuelas, M; Candel, F J; Lejarraga, C; López-González, L; Viñuela-Prieto, J M; López de Mendoza, D

2016-10-01

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in Spain is approximately 20-30%. However, resistance to linezolid is rare, and the main reports are from nosocomial outbreaks. The objective of the present study was to compare the in vitro susceptibility of linezolid with that of tedizolid against MRSA isolates and methicillin-and linezolid-resistant isolates (MLRSA) mediated by the cfr gene. The in vitro susceptibility of linezolid and tedizolid was determined using the E-test with 18 MRSA strains and 18 cfr-mediated MLRSA strains obtained from clinical isolates in the microbiology service of a tertiary university hospital. All MRSA strains were susceptible to both antibiotics. Analysis of the MRSA isolates revealed that the MIC50 and MIC90 of linezolid were 1.5 and 2 mg/L, respectively; those of tedizolid were 0.25 and 0.4 mg/L. The MIC50 and MIC90 of tedizolid remained at 0.75 and 1 mg/L against the MLRSA strains (MIC90 ≥ 8 mg/L). Both for MRSA and for MLRSA, the MICs obtained for tedizolid were at least 2 dilutions lower than those of linezolid, thus demonstrating between 2 and 4 times greater activity in vitro than linezolid.

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

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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

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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

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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.

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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.

Linezolid susceptibility in Helicobacter pylori, including strains with multidrug resistance.

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Boyanova, Lyudmila; Evstatiev, Ivailo; Gergova, Galina; Yaneva, Penka; Mitov, Ivan

2015-12-01

Only a few studies have evaluated Helicobacter pylori susceptibility to linezolid. The aim of the present study was to assess linezolid susceptibility in H. pylori, including strains with double/multidrug resistance. The susceptibility of 53 H. pylori strains was evaluated by Etest and a breakpoint susceptibility testing method. Helicobacter pylori resistance rates were as follows: amoxicillin, 1.9%; metronidazole, 37.7%; clarithromycin, 17.0%; tetracycline, 1.9%; levofloxacin, 24.5%; and linezolid (>4 mg/L), 39.6%. The linezolid MIC50 value was 31.2-fold higher than that of clarithromycin and 10.5-fold higher than that of levofloxacin; however, 4 of 11 strains with double/multidrug resistance were linezolid-susceptible. The MIC range of the oxazolidinone agent was larger (0.125-64 mg/L) compared with those in the previous two reports. The linezolid resistance rate was 2.2-fold higher in metronidazole-resistant strains and in strains resistant to at least one antibiotic compared with the remaining strains. Briefly, linezolid was less active against H. pylori compared with clarithromycin and levofloxacin, and linezolid resistance was linked to resistance to metronidazole as well as to resistance to at least one antibiotic. However, linezolid activity against some strains with double/multidrug resistance may render the agent appropriate to treat some associated H. pylori infections following in vitro susceptibility testing of the strains. Clinical trials are required to confirm this suggestion. Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

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

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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.

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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.

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.

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

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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.

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

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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

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.

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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.

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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...

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

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.

A severe infective endocarditis successfully treated with linezolid

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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.

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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.

Pharmacokinetics of linezolid in bone tissue investigated by in vivo microdialysis

DEFF Research Database (Denmark)

Stolle, L.B.; Plock, N.; Joukhadar, C.

2008-01-01

Pharmacokinetics of unbound anti-infectives in bone is difficult to characterize. The aim of this study was to assess the feasibility of the microdialysis technique to cancellous bone for single dose pharmacokinetic investigations of the anti-infective linezolid. Serial bone biopsies (left tibia......) and microdialysate samples (right tibia: 2 catheters) as well as plasma and bone marrow samples were obtained from 10 pigs. The concentrations of linezolid reached bacteriostatic levels in plasma, bone marrow, bone biopsies and microdialysates. With the use of microdialysis we here present the first results...... for unbound linezolid bone penetration. Unbound linezolid concentrations in bone obtained by microdialysis were lower than might have been expected from previous bone biopsy studies. To achieve effective concentrations (24 h) for susceptible organisms the chosen dose of linezolid might not be sufficient...

Linezolid: a promising option in the treatment of Gram-positives.

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Zahedi Bialvaei, Abed; Rahbar, Mohammad; Yousefi, Mehdi; Asgharzadeh, Mohammad; Samadi Kafil, Hossein

2017-02-01

Linezolid, an oxazolidinone antimicrobial agent that acts by inhibiting protein synthesis in a unique fashion, is used in the treatment of community-acquired pneumonia, skin and soft-tissue infections and other infections caused by Gram-positive bacteria including VRE and methicillin-resistant staphylococci. Currently, linezolid resistance among these pathogens remains low, commonly linezolid susceptibility testing for this important agent and should be taken into account when considering its therapeutic use. Considering the importance of linezolid in the treatment of infections caused by Gram-positive bacteria, this review was undertaken to optimize the clinical use of 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 email: journals.permissions@oup.com.

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.

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

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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.

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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.

Investigation of Linezolid Resistance in Staphylococci and Enterococci

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Gallegos, Michael; Alspaugh, Debbie

2016-01-01

The objective of this study was to investigate an apparent increase in linezolid-nonsusceptible staphylococci and enterococci following a laboratory change in antimicrobial susceptibility testing from disk diffusion to an automated susceptibility testing system. Isolates with nonsusceptible results (n = 27) from Vitek2 were subjected to a battery of confirmatory testing which included disk diffusion, Microscan broth microdilution, Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution, gradient diffusion (Etest), 23S rRNA gene sequencing, and cfr PCR. Our results show that there is poor correlation between methods and that only 70 to 75% of isolates were confirmed as linezolid resistant with alternative phenotypic testing methods (disk diffusion, Microscan broth microdilution, CLSI broth microdilution, and Etest). 23S rRNA gene sequencing identified mutations previously associated with linezolid resistance in 16 (59.3%) isolates, and the cfr gene was detected in 3 (11.1%) isolates. Mutations located at positions 2576 and 2534 of the 23S rRNA gene were most common. In addition, two previously undescribed variants (at positions 2083 and 2345 of the 23S rRNA gene) were also identified and may contribute to linezolid resistance. PMID:26935728

Efficacy of Linezolid plus Rifampin in an Experimental Model of Methicillin-Susceptible Staphylococcus aureus Endocarditis

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Dailey, Charlene F.; Pagano, Paul J.; Buchanan, Lewis V.; Paquette, Jennifer A.; Haas, Joseph V.; Gibson, John K.

2003-01-01

The efficacy of linezolid, alone or in combination with rifampin, against methicillin-susceptible Staphylococcus aureus in rabbits with experimental endocarditis was investigated. Linezolid (50 or 75 mg/kg of body weight), rifampin, and linezolid (25, 50, or 75 mg/kg) plus rifampin produced statistically significant reductions in bacterial counts compared with those in untreated controls. Plasma or valvular vegetation levels of linezolid in the groups treated with the linezolid-rifampin combi...

Tedizolid susceptibility in linezolid- and vancomycin-resistant Enterococcus faecium isolates.

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Klupp, E-M; Both, A; Belmar Campos, C; Büttner, H; König, C; Christopeit, M; Christner, M; Aepfelbacher, M; Rohde, H

2016-12-01

Vancomycin-resistant enterococci (VRE) are of ever-increasing importance, most notably in high-risk patient populations. Therapy options are often limited for these isolates, and apart from tigecycline and daptomycin, oxazolidinone linezolid is frequently administered. The broad usage of linezolid, however, has driven the emergence of linezolid-resistant VRE strains (LR-VRE), further shortening therapeutic options. Second-generation oxazolidinone tedizolid has the advantage of being active against a specific subset of LR-VRE, i.e. isolates expressing the plasmid-encoded chloramphenicol-florfenicol resistance (cfr) gene. Here we tested tedizolid activity in a collection of 30 LR Enterococcus faecium VRE (MIC range 32-256 mg/l) isolated between 2012 and 2015 from clinical and screening specimens. By pulsed field gel electrophoresis (PFGE) isolates were assigned to 16 clonal lineages. In three cases, linezolid-susceptible progenitor isolates of LR-VRE were isolated, thus demonstrating the de-novo emergence of the linezolid-resistant phenotype. PCR did not detect cfr, cfr(B) or novel oxazolidinone resistance gene optrA in LR-VRE. All isolates, however, carried mutations within the 23S rDNA. Compared to linezolid, tedizolid MICs were lower in all isolates (MIC range 2-32 mg/l), but remained above the FDA tedizolid breakpoint for E. faecalis at 0.5 mg/l. Thus, related to the predominant resistance mechanism, tedizolid is of limited value for treatment of most LR-VRE and represents a therapeutic option only for a limited subset of isolates.

Linezolid as treatment for pulmonary Mycobacterium avium disease.

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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.

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

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

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.

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

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

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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.

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.

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

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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

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.

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.

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

Whole transcriptome analysis reveals potential novel mechanisms of low-level linezolid resistance in Enterococcus faecalis.

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Hua, Ruoyi; Xia, Yun; Wu, Wenyao; Yan, Jia; Yang, Mi

2018-03-20

Linezolid is an oxazolidinone antibiotic commonly used to treat serious infections caused by vancomycin-resistant enterococcus. Recently, low-level linezolid resistant Enterococcus faecalis strains have emerged worldwide, but the resistant mechanisms remain undefined. Whole-transcriptome profiling was performed on an E. faecalis strain P10748 with low-level linezolid resistance in comparison with a linezolid-susceptible strain 3138 and the standard control strain ATCC29212. The functions of differentially expressed genes (DEGs) were predicted, with some DEGs potentially involved in drug resistance were validated by PCR and quantitative PCR (qPCR). RNA-Seq on three E. faecalis strains generated 1920 unigenes, with 98% of them assigned to various function groups. A total of 150 DEGs were identified in the linezolid resistant strain P10748 compared to the linezolid susceptible strains 3138 and ATCC29212. Functional analysis indicated a significant transcriptomic shift to membrane transportation and biofilm formation in strain P10748, with three significantly up-regulated DEGs predicted to be associated with drug resistance through active efflux pumps and biofilm formation. The existence of these three DEGs was further confirmed by PCR and qPCR. The significant upregulation of genes associated with efflux pumps and biofilm formation in the linezolid resistant strain suggests their roles in low-level resistance to linezolid in E. faecalis. Copyright © 2018. Published by Elsevier B.V.

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.

Linezolid Surveillance Results for the United States (LEADER Surveillance Program 2014).

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Flamm, Robert K; Mendes, Rodrigo E; Hogan, Patricia A; Streit, Jennifer M; Ross, James E; Jones, Ronald N

2016-04-01

Thelinezolidexperience andaccuratedetermination ofresistance (LEADER) surveillance program has monitored linezolid activity, spectrum, and resistance since 2004. In 2014, a total of 6,865 Gram-positive pathogens from 60 medical centers from 36 states were submitted. The organism groups evaluated wereStaphylococcus aureus(3,106), coagulase-negative staphylococci (CoNS; 797), enterococci (855),Streptococcus pneumoniae(874), viridans group streptococci (359), and beta-hemolytic streptococci (874). Susceptibility testing was performed by reference broth microdilution at the monitoring laboratory. Linezolid-resistant isolates were confirmed by repeat testing. PCR and sequencing were performed to detect mutations in 23S rRNA, L3, L4, and L22 proteins and acquired genes (cfrandoptrA). The MIC50/90forStaphylococcus aureuswas 1/1 μg/ml, with 47.2% of isolates being methicillin-resistantStaphylococcus aureus Linezolid was active against allStreptococcus pneumoniaestrains and beta-hemolytic streptococci with a MIC50/90of 1/1 μg/ml and against viridans group streptococci with a MIC50/90of 0.5/1 μg/ml. Among the linezolid-nonsusceptible MRSA strains, one strain harboredcfronly (MIC, 4 μg/ml), one harbored G2576T (MIC, 8 μg/ml), and one containedcfrand G2576T with L3 changes (MIC, ≥8 μg/ml). Among CoNS, 0.75% (six isolates) of all strains demonstrated linezolid MIC results of ≥4 μg/ml. Five of these were identified asStaphylococcus epidermidis, four of which containedcfrin addition to the presence of mutations in the ribosomal proteins L3 and L4, alone or in combination with 23S rRNA (G2576T) mutations. Six enterococci (0.7%) were linezolid nonsusceptible (≥4 μg/ml; five with G2576T mutations, including one with an additionalcfrgene, and one strain withoptrAonly). Linezolid demonstrated excellent activity and a sustained susceptibility rate of 99.78% overall. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Risk assessment of topically applied products

DEFF Research Database (Denmark)

Søborg, Tue; Basse, Line Hollesen; Halling-Sørensen, Bent

2007-01-01

The human risk of harmful substances in semisolid topical dosage forms applied topically to normal skin and broken skin, respectively, was assessed. Bisphenol A diglycidyl ether (BADGE) and three derivatives of BADGE previously quantified in aqueous cream and the UV filters 3-BC and 4-MBC were used...... as model compounds. Tolerable daily intake (TDI) values have been established for BADGE and derivatives. Endocrine disruption was chosen as endpoint for 3-BC and 4-MBC. Skin permeation of the model compounds was investigated in vitro using pig skin membranes. Tape stripping was applied to simulate broken...... parameters for estimating the risk. The immediate human risk of BADGE and derivatives in topical dosage forms was found to be low. However, local treatment of broken skin may lead to higher exposure of BADGE and derivatives compared to application to normal skin. 3-BC permeated skin at higher flux than 4-MBC...

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

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.

[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.

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

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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.

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

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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.

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

Directory of Open Access Journals (Sweden)

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.

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

Science.gov (United States)

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.

Science.gov (United States)

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.

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

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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

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.

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

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

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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.

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.

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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.

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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.

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.

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.

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

Follicular and percutaneous penetration pathways of topically applied minoxidil foam.

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Blume-Peytavi, Ulrike; Massoudy, Lida; Patzelt, Alexa; Lademann, Jürgen; Dietz, Ekkehart; Rasulev, Utkur; Garcia Bartels, Natalie

2010-11-01

In the past, it was assumed that the intercellular route was the only relevant penetration pathway for topically applied substances. Recent results on follicular penetration emphasize that the hair follicles represent a highly relevant and efficient penetration pathway and reservoir for topically applied substances. This study investigates a selective closure technique of hair follicle orifices in vivo assessing interfollicular and follicular absorption rates of topical minoxidil foam in humans. In delimited skin area, single hair orifices or interfollicular skin were blocked with a microdrop of special varnish-wax-mixture in vivo. Minoxidil foam (5%) was topically applied, and transcutaneous absorption was measured by a new surface ionization mass spectrometry technique in serum. Different settings (open, closed or none of both) enabled to clearly distinguish between interfollicular and follicular penetration of the topically applied minoxidil foam. Five minutes after topical application, minoxidil was detected in blood samples when follicles remained open, whereas with closed follicles 30 min were needed. Highest levels were found first when both pathways were open, followed by open follicles and subsequently by closed follicles. These results demonstrate the high importance of the follicular penetration pathway. Hair follicles are surrounded by a dense network of blood capillaries and dendritic cells and have stem cells in their immediate vicinity, making them ideal targets for drug delivery. Copyright © 2010 Elsevier B.V. All rights reserved.

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

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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.

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.

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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.

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

Applied atomic and collision physics special topics

CERN Document Server

Massey, H S W; Bederson, Benjamin

1982-01-01

Applied Atomic Collision Physics, Volume 5: Special Topics deals with topics on applications of atomic collisions that were not covered in the first four volumes of the treatise. The book opens with a chapter on ultrasensitive chemical detectors. This is followed by separate chapters on lighting, magnetohydrodynamic electrical power generation, gas breakdown and high voltage insulating gases, thermionic energy converters, and charged particle detectors. Subsequent chapters deal with the operation of multiwire drift and proportional chambers and streamer chambers and their use in high energy p

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.

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

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.

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

Science.gov (United States)

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.

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

Science.gov (United States)

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.

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

Science.gov (United States)

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.

Science.gov (United States)

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.

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)

Examination of bedaquiline- and linezolid-resistant Mycobacterium tuberculosis isolates from the Moscow region.

Science.gov (United States)

Zimenkov, Danila V; Nosova, Elena Yu; Kulagina, Elena V; Antonova, Olga V; Arslanbaeva, Liaisan R; Isakova, Alexandra I; Krylova, Ludmila Yu; Peretokina, Irina V; Makarova, Marina V; Safonova, Svetlana G; Borisov, Sergey E; Gryadunov, Dmitry A

2017-07-01

To study the isolates with acquired resistance to bedaquiline and linezolid that were obtained from patients enrolled in a clinical study of a novel therapy regimen for drug-resistant TB in Moscow, Russia. Linezolid resistance was detected using MGIT 960 with a critical concentration of 1 mg/L. The MIC of bedaquiline was determined using the proportion method. To identify genetic determinants of resistance, sequencing of the mmpR ( Rv0678 ), atpE , atpC , pepQ , Rv1979c , rrl , rplC and rplD loci was performed. A total of 85 isolates from 27 patients with acquired resistance to linezolid and reduced susceptibility to bedaquiline (MIC ≥0.06 mg/L) were tested. Most mutations associated with a high MIC of bedaquiline were found in the mmpR gene. We identified for the first time two patients whose clinical isolates had substitutions D28N and A63V in AtpE, which had previously been found only in in vitro -selected strains. Several patients had isolates with elevated MICs of bedaquiline prior to treatment; four of them also bore mutations in mmpR , indicating the presence of some hidden factors in bedaquiline resistance acquisition. The C154R substitution in ribosomal protein L3 was the most frequent in the linezolid-resistant strains. Mutations in the 23S rRNA gene (g2294a and g2814t) associated with linezolid resistance were also found in two isolates. Heteroresistance was identified in ∼40% of samples, which reflects the complex nature of resistance acquisition. The introduction of novel drugs into treatment must be accompanied by continuous phenotypic susceptibility testing and the analysis of genetic determinants of resistance. © 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.

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.

Skin permeation and antioxidant efficacy of topically applied resveratrol.

Science.gov (United States)

Alonso, Cristina; Martí, M; Barba, C; Carrer, V; Rubio, L; Coderch, L

2017-08-01

The permeation of resveratrol was assessed by in vitro and in vivo experiments 24 h after topical administration. The in vitro profile of resveratrol was assessed by Raman spectroscopy. Human skin permeation was analysed in vivo by the tape stripping method with the progressive removal of the stratum corneum layers using adhesive tape strips. Moreover, the free radical scavenging activity of resveratrol after its topical application was determined using the DPPH assay. The Raman spectra indicated that the topically applied resveratrol penetrates deep into the skin. The results showed high amounts of resveratrol in the different stratum corneum layers close to the surface and a constant lower amount in the upper layers of the viable epidermis. The concentration of resveratrol present in the outermost stratum corneum layers was obtained by tape stripping after in vivo application. The results demonstrated that resveratrol mainly remained in the human stratum corneum layers. After topical application, resveratrol maintained its antiradical activity. The antioxidant efficacy of the compound was higher in the inner layers of the stratum corneum. As these results have demonstrated, topically applied resveratrol reinforces the antioxidant system of the stratum corneum and provides an efficient means of increasing the tissue levels of antioxidants in the human epidermis.

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

Topics in theoretical and applied statistics

CERN Document Server

Giommi, Andrea

2016-01-01

This book highlights the latest research findings from the 46th International Meeting of the Italian Statistical Society (SIS) in Rome, during which both methodological and applied statistical research was discussed. This selection of fully peer-reviewed papers, originally presented at the meeting, addresses a broad range of topics, including the theory of statistical inference; data mining and multivariate statistical analysis; survey methodologies; analysis of social, demographic and health data; and economic statistics and econometrics.

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.

Science.gov (United States)

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.

Mutations in 23S rRNA at the Peptidyl Transferase Center and Their Relationship to Linezolid Binding and Cross-Resistance

DEFF Research Database (Denmark)

Long, Katherine; Munck, Christian

2010-01-01

The oxazolidinone antibiotic linezolid targets the peptidyl transferase center (PTC) on the bacterial ribosome. Thirteen single and four double 23S rRNA mutations were introduced into a Mycobacterium smegmatis strain with a single rRNA operon. Converting bacterial base identity by single mutations...... at positions 2032, 2453, and 2499 to human cytosolic base identity did not confer significantly reduced susceptibility to linezolid. The largest decrease in linezolid susceptibility for any of the introduced single mutations was observed with the G2576U mutation at a position that is 7.9 Å from linezolid....... Smaller decreases were observed with the A2503G, U2504G, and G2505A mutations at nucleotides proximal to linezolid, showing that the degree of resistance conferred is not simply inversely proportional to the nucleotide-drug distance. The double mutations G2032A-C2499A, G2032A-U2504G, C2055A-U2504G, and C...

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

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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.

Ocular pharmacokinetics and availability of topically applied baicalein in rabbits.

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Zhang, Li; Zhang, Junjie; Wang, Liya; Xia, Huiyun

2009-04-01

To evaluate the ocular pharmacokinetics and availability of baicalein following topical application. Hydroxypropyl beta-cyclodextrin (HP-beta -CD) was used to formulate an aqueous eye drop to improve aqueous solubility of baicalein. A single dose of either baicalein suspension (1%) (Bai-SP) or baicalein (1%)/HP-beta-CD (10%) solution (Bai-CD) was topically applied to rabbits. Aqueous humor and cornea were collected after 5, 10, 20, 30, 45, 60, 90, and 120 min. Baicalein concentrations were determined by high-performance liquid chromatography (HPLC) after extraction. After topically applying Bai-CD, the baicalein concentrations in aqueous humor were significantly increased at 20-120 min except at 90 min compared with those of Bai-SP (p cornea (56.53 +/- 17.02 microg/g) was achieved within 5 min after topical application of Bai-CD and 4.5 times higher than that of Bai-SP at the same timepoint. The baicalein levels in corneas obtained after application of Bai-CD were all much higher than those obtained by Bai-SP (p < 0.01), whereas the drug levels became undetectable 30 min after topical application of Bai-SP. Bai-CD formulation is superior to Bai-SP for increasing ocular bioavailability.

Linezolid as rescue treatment for left-sided infective endocarditis

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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...

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.

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

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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.

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

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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 ▿

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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.

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.

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

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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.

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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.

Comparison of in vitro efficacy of linezolid and vancomycin by determining their minimum inhibitory concentrations against methicillin resistant Staphylococcus aureus (MRSA)

International Nuclear Information System (INIS)

Kaleem, F.; Usman, J.; Hassan, A.

2011-01-01

Objectives: To compare the in vitro activities of vancomycin and linezolid against methicillin resistant Staphyloccus aureus in our set up to help in formulating a better empirical treatment and reduce the emergence of vancomycin resistant Staphylococcus aureus. Methods: The study was conducted over a period of 6 months(July 1, 2009 - Dec 1, 2009). Fifty Methicillin resistant Staphylococcus aureus isolated from the clinical isolates of Military Hospital Rawalpindi were subjected to the determination of Minimum inhibitory concentrations of linezolid and vancomycin using E-strips. Results: All the isolated organisms were uniformly susceptible to both the antibiotics. Vancomycin showed higher minimum inhibitory concentrations (MICs) as compared to linezolid MICs. Conclusion: This study suggests that linezolid and vancomycin have similar in vitro efficacy for methicillin resistant Staphyloccus aureus infections. (author)

Effect of supplemented and topically applied antioxidant substances on human tissue.

Science.gov (United States)

Darvin, M; Zastrow, L; Sterry, W; Lademann, J

2006-01-01

Systemic and topical application of antioxidant substances for the medical treatment and prophylaxis of many diseases as well as additional protection of the skin against the destructive action of free radicals and other reactive species has become very popular during the past years. Stimulated by the positive results of a fruit and vegetable diet in supporting medical treatment and in cosmetics, artificial and extracted antioxidant substances have been broadly applied. Surprisingly, not only positive but also strong negative results have been obtained by different authors. According to study reports artificial and extracted antioxidant substances support different kinds of medical therapies, if they are applied in mixtures of different compounds at low concentration levels. In the case of the application of high concentration of some single compounds, side effects were often observed. Regarding skin treatment by systemically applied antioxidant substances for cosmetic purposes, positive cosmetic effects as well as no effects, but almost no side effects, apart from a number of allergic reactions, were reported. One reason for this seems to be the lower concentration of systemically applied antioxidant substances in comparison with a medical application. Topical application of antioxidant substances is closely related to cosmetic treatment for skin protection and anti-aging. Positive results were also obtained in this case. The present review is an attempt to classify and summarize the published literature concerning the efficiency of action of systemic and topical applications of antioxidant substances, such as carotenoids and vitamins, on human organism and especially on the skin. The available literature on this topic is very extensive and the results are often contradictory. Nevertheless, there are some clear tendencies concerning systemic and topical application of antioxidant substances in medicine and cosmetics, and we summarize them in the present paper.

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.

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

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

Science.gov (United States)

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.

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.

Surveillance for linezolid resistance via the Zyvox® Annual Appraisal of Potency and Spectrum (ZAAPS) programme (2014): evolving resistance mechanisms with stable susceptibility rates.

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Mendes, Rodrigo E; Hogan, Patricia A; Jones, Ronald N; Sader, Helio S; Flamm, Robert K

2016-07-01

The objective of this study was to report the linezolid in vitro activity observed during the Zyvox(®) Annual Appraisal of Potency and Spectrum (ZAAPS) programme for 2014. In total, 7541 organisms causing documented infections were consecutively collected in 66 centres in 33 countries, excluding the USA. Susceptibility testing was performed by broth microdilution. Isolates displaying linezolid MIC results of ≥4 mg/L were molecularly characterized. Linezolid inhibited all Staphylococcus aureus at ≤2 mg/L, with MIC50 results of 1 mg/L, regardless of methicillin resistance. A similar linezolid MIC50 result (i.e. 0.5 mg/L) was observed against CoNS, with the vast majority of isolates (99.4%) also inhibited at ≤2 mg/L. Six CoNS that exhibited elevated linezolid MIC values were found to contain alterations in the 23S rRNA and/or L3 ribosomal protein. Linezolid exhibited consistent modal MIC and MIC50 results (1 mg/L) against enterococci, regardless of species or vancomycin resistance. Three Enterococcus faecalis from Galway and Dublin (Ireland) and Kelantan (Malaysia) showed MIC results of 4 to 8 mg/L and carried optrA. All Streptococcus pneumoniae, viridans-group streptococci and β-haemolytic streptococci were inhibited by linezolid at ≤2, ≤2 and ≤1 mg/L, respectively, with equivalent MIC90 results (1 mg/L for all groups). These results document the continued long-term and stable in vitro potency of linezolid and reveal a limited number of isolates with decreased susceptibility to linezolid (i.e. MIC ≥4 mg/L). The latter isolates primarily showed mutations in the 23S rRNA gene and/or L3 protein, but cfr was not detected. Moreover, this study shows that isolates carrying the newly described ABC transporter optrA are not restricted to China. © 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.

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

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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.

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.

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.

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.

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

Science.gov (United States)

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.

Science.gov (United States)

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.

Science.gov (United States)

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.

Science.gov (United States)

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.

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.

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

Directory of Open Access Journals (Sweden)

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.

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...

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

Science.gov (United States)

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.

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.

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

Science.gov (United States)

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

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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▿ †

Science.gov (United States)

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?

Science.gov (United States)

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).

Pain-relieving properties of topically applied morphine on arterial leg ulcers: a pilot study.

NARCIS (Netherlands)

Jansen, M.M.; Horst, J.C. van der; Valk, P.G.M. van der; Kuks, P.F.M.; Zylicz, Z.; Sorge, A.A. van

2009-01-01

OBJECTIVE: To assess whether topical morphine is pharmacologically effective in relieving pain from ulcers caused by arterial insufficiency and identify whether this effect is centrally or peripherally mediated. METHOD: The analgesic effect of a topically applied hydrogel containing 0.5% of morphine

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.

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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.

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

Science.gov (United States)

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.

Science.gov (United States)

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.

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

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.

Science.gov (United States)

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

A Faropenem, Linezolid, and Moxifloxacin Regimen for Both Drug-Susceptible and Multidrug-Resistant Tuberculosis in Children: FLAME Path on the Milky Way.

Science.gov (United States)

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

2016-11-01

 The regimen of linezolid and moxifloxacin was found to be efficacious in the hollow fiber system model of pediatric intracellular tuberculosis. However, its kill rate was slower than the standard 3-drug regimen of isoniazid, rifampin, and pyrazinamide. We wanted to examine the effect of adding a third oral agent, faropenem, to this dual combination.  We performed a series of studies in the hollow fiber system model of intracellular Mycobacterium tuberculosis, by mimicking pediatric pharmacokinetics of each antibiotic. First, we varied the percentage of time that faropenem persisted above minimum inhibitory concentration (T MIC ) on the moxifloxacin-linezolid regimen. After choosing the best faropenem exposure, we performed experiments in which we varied the moxifloxacin and linezolid doses in the triple regimen. Finally, we performed longer-duration therapy validation experiments. Bacterial burden was quantified using both colony-forming units per milliliter (CFU/mL) and time to positivity (TTP). Kill slopes were modeled using exponential regression.  TTP was a more sensitive measure of bacterial burden than CFU/mL. A faropenem T MIC > 62% was associated with steepest microbial kill slope. Regimens of standard linezolid and moxifloxacin plus faropenem T MIC > 60%, as well as higher-dose moxifloxacin, achieved slopes equivalent to those of the standard regimen based by both TTP and CFU/mL over 28 days of treatment.  We have developed an oral faropenem-linezolid-moxifloxacin (FLAME) regimen that is free of first-line drugs. The regimen could be effective against both multidrug-resistant and drug-susceptible tuberculosis in children. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

In vitro approach to studying cutaneous metabolism and disposition of topically applied xenobiotics

International Nuclear Information System (INIS)

Kao, J.; Hall, J.; Shugart, L.R.; Holland, J.M.

1984-01-01

The extent to which cutaneous metabolism may be involved in the penetration and fate of topically applied xenobiotics was examined by metabolically viable and structurally intact mouse skin in organ culture. Evidence that skin penetration of certain chemicals is coupled to cutaneous metabolism was based upon observations utilizing [ 14 C]benzo[a]pyrene (BP). As judged by the recovery of radioactivity in the culture medium 24 hr after in vitro topical application of [ 14 C]BP to the skin from both control and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced C3H mice, skin penetration of BP was higher in the induced tissue. All classes of metabolites of BP were found in the culture medium; water-soluble metabolites predominated and negligible amounts of unmetabolized BP were found. As shown by enzymatic hydrolysis of the medium, TCDD induction resulted in shifting the cutaneous metabolism of BP toward the synthesis of more water-soluble conjugates. Differences in the degree of covalent binding of BP, via diol epoxide intermediates to epidermal DNA, from control and induced tissues were observed. These differences may reflect a change in the pathways of metabolism as a consequence of TCDD induction. These results indicated that topically applied BP is metabolized by the skin during its passage through the skin; and the degree of percutaneous penetration and disposition of BP was dependent upon the metabolic status of the tissue. This suggests that cutaneous metabolism may play an important role in the translocation and subsequent physiological disposition of topically applied BP. 33 references, 5 figures, 2 tables

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

Directory of Open Access Journals (Sweden)

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

Directory of Open Access Journals (Sweden)

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

Subdermal penetration of topically applied clobetasol propionate in ointment base through intact human skin

DEFF Research Database (Denmark)

Petersen, Lars Jelstrup; Sindrup, J H; Kristensen, J K

1992-01-01

Some data have demonstrated a substantial subdermal accumulation of topically applied drugs in animals. The aim of this study was to evaluate a possible effect of epicutaneously applied clobetasol propionate on blood flow in human subcutaneous adipose tissue. Nine healthy subjects were studied...

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.

Science.gov (United States)

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.

Science.gov (United States)

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.

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...

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

In vivo Raman spectroscopy detects increased epidermal antioxidative potential with topically applied carotenoids

International Nuclear Information System (INIS)

Lademann, J; Richter, H; Patzelt, A; Darvin, M; Sterry, W; Fluhr, J W; Caspers, P J; Van der Pol, A; Zastrow, L

2009-01-01

In the present study, the distribution of the carotenoids as a marker for the complete antioxidative potential in human skin was investigated before and after the topical application of carotenoids by in vivo Raman spectroscopy with an excitation wavelength of 785 nm. The carotenoid profile was assessed after a short term topical application in 4 healthy volunteers. In the untreated skin, the highest concentration of natural carotenoids was detected in different layers of the stratum corneum (SC) close to the skin surface. After topical application of carotenoids, an increase in the antioxidative potential in the skin could be observed. Topically applied carotenoids penetrate deep into the epidermis down to approximately 24 μm. This study supports the hypothesis that antioxidative substances are secreted via eccrine sweat glands and/or sebaceous glands to the skin surface. Subsequently they penetrate into the different layers of the SC

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

Directory of Open Access Journals (Sweden)

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

In Vitro Resistance Studies with Bacteria That Exhibit Low Mutation Frequencies: Prediction of “Antimutant” Linezolid Concentrations Using a Mixed Inoculum Containing both Susceptible and Resistant Staphylococcus aureus

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Golikova, Maria V.; Strukova, Elena N.; Portnoy, Yury A.; Romanov, Andrey V.; Edelstein, Mikhail V.; Zinner, Stephen H.

2014-01-01

Bacterial resistance studies using in vitro dynamic models are highly dependent on the starting inoculum that might or might not contain spontaneously resistant mutants (RMs). To delineate concentration-resistance relationships with linezolid-exposed Staphylococcus aureus, a mixed inoculum containing both susceptible cells and RMs was used. An RM selected after the 9th passage of the parent strain (MIC, 2 μg/ml) on antibiotic-containing media (RM9; MIC, 8 μg/ml) was chosen for the pharmacodynamic studies, because the mutant prevention concentration (MPC) of linezolid against the parent strain in the presence of RM9 at 102 (but not at 104) CFU/ml did not differ from the MPC value determined in the absence of the RMs. Five-day treatments with twice-daily linezolid doses were simulated at concentrations either between the MIC and MPC or above the MPC. S. aureus RMs (resistant to 2× and 4× MIC but not 8× and 16× MIC) were enriched at ratios of the 24-h area under the concentration-time curve (AUC24) to the MIC that provide linezolid concentrations between the MIC and MPC for 100% (AUC24/MIC, 60 h) and 86% (AUC24/MIC, 120 h) of the dosing interval. No such enrichment occurred when linezolid concentrations were above the MIC and below the MPC for a shorter time (37% of the dosing interval; AUC24/MIC, 240 h) or when concentrations were consistently above the MPC (AUC24/MIC, 480 h). These findings obtained using linezolid-susceptible staphylococci supplemented with RMs support the mutant selection window hypothesis. This method provides an option to delineate antibiotic concentration-resistance relationships with bacteria that exhibit low mutation frequencies. PMID:25451050

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.

Science.gov (United States)

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.

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.

Vancomycin-resistant Enterococcus spp.: validation of susceptibility testing and in vitro activity of vancomycin, linezolid, tigecycline and daptomycin

DEFF Research Database (Denmark)

Rathe, Mathias; Kristensen, Lise; Ellermann-Eriksen, Svend

2010-01-01

Vancomycin-resistant enterococci (VRE) have emerged to become a significant nosocomial pathogen. However, detection may be challenging and treatment possibilities are limited. Reports of resistance to linezolide, daptomycin and tigecycline underline the need for reliable susceptibility testing wi...

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.

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.

Effect of topically applied minoxidil on the survival of rat dorsal skin flap.

Science.gov (United States)

Gümüş, Nazım; Odemiş, Yusuf; Yılmaz, Sarper; Tuncer, Ersin

2012-12-01

Flap necrosis still is a challenging problem in reconstructive surgery that results in irreversible tissue loss. This study evaluated the effect of topically applied minoxidil on angiogenesis and survival of a caudally based dorsal rat skin flap. For this study, 24 male Wistar rats were randomly divided into three groups of eight each. A caudally based dorsal skin flap with the dimensions of 9 × 3 cm was raised. After elevation of the flaps, they were sutured back into their initial positions. In group 1 (control group), 1 ml of isotonic saline was applied topically to the flaps of all the animals for 14 days. In group 2, minoxidil solution was spread uniformly over the flap surface for 7 days after the flap elevation. In group 3, minoxidil solution was applied topically to the flap surface during a 14-day period. On day 7 after the flap elevation, the rats were killed. The average area of flap survival was determined for each rat. Subdermal vascular architecture and angiogenesis were evaluated under a light microscope after two full-thickness skin biopsy specimens had been obtained from the midline of the flaps. The lowest flap survival rate was observed in group 1, and no difference was observed between groups 1 and 2. Compared with groups 1 and 2, group 3 had a significantly increased percentage of flap survival (P minoxidil is vasodilation and that prolonged use before flap elevation leads to angiogenesis, increasing flap viability. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

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

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

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

Directory of Open Access Journals (Sweden)

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

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

Directory of Open Access Journals (Sweden)

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.

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.

Topics in mathematical and applied statistics

NARCIS (Netherlands)

Pas, van der S.L.

2017-01-01

This thesis is composed of papers on four topics: Bayesian theory for the sparse normal means problem, specifically for the horseshoe prior (Chapters 1-3), Bayesian theory for community detection (Chapter 4), nested model selection (Chapter 5), and the application of competing risk methods in the

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

Laser-induced thermal coagulation enhances skin uptake of topically applied compounds

DEFF Research Database (Denmark)

Haak, C S; Hannibal, J; Paasch, U

2017-01-01

microchannels surrounded by CZ compared to channels with no CZ (CZ-20 and CZ-80>CZ-0).The thickness of CZ affected PEG distribution in skin. A thin CZ-20 favored significantly higher mean fluorescence intensities inside CZ areas compared to CZ-80 (PEG 350, 1,000, and 5,000; P ...BACKGROUND: Ablative fractional laser (AFL) generates microchannels in skin surrounded by a zone of thermally altered tissue, termed the coagulation zone (CZ). The thickness of CZ varies according to applied wavelength and laser settings. It is well-known that AFL channels facilitate uptake...... of topically applied compounds, but the importance of CZ is unknown. METHODS: Franz Cells were used to investigate skin uptake and permeation of fluorescent labeled polyethylene glycols (PEGs) with mean molecular weights (MW) of 350, 1,000, and 5,000 Da. Microchannels with CZ thicknesses ranging from 0 to 80...

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

Ocular pharmacokinetics of topically-applied ketoconazole solution containing hydroxypropyl beta-cyclodextrin to rabbits.

Science.gov (United States)

Zhang, Junjie; Wang, Liya; Gao, Changfeng; Zhang, Li; Xia, Huiyun

2008-10-01

The aim of this study was to develop an aqueous ketoconazole (KET) eye drop in order to increase the corneal permeability and improve ocular bioavailability following topical application. Hydroxypropyl beta-cyclodextrin (HP-beta-CD) was used to formulate an aqueous eye drop to improve the aqueous solubility of KET. A single dose of of either KET suspension (1.5%; KET-SP) or KET (1.5%)/HP-beta -CD (12.5%) solution (KET-CD) was applied to rabbits. Aqueous humor and cornea were collected after 5, 10, 20, 30, 45, 60, 90, 120, and 180 min. KET concentrations were determined by high-performance liquid chromatography after extraction. After topically applying KET-CD, the KET concentrations in aqueous humor were significantly increased at 10 approximately 120 min, compared with those of KET-SP (P cornea (118.24 microg/g) was achieved within 5 min after the instillation of KET-CD, 18.4 times higher than that of KET-SP at the same time point, whereas the highest KET level in cornea was only 8.57 microg/g after a 10-min application of KET-SP. The KET levels in corneas obtained after the application of KET-CD were all much higher than those obtained by KETSP (P corneas over the KET-SP.

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.

The Use of Linezolid in Children with Malignant Solid Tumors

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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.

Pharmacokinetics and Efficacy of Topically Applied Nonsteroidal Anti-Inflammatory Drugs in Retinochoroidal Tissues in Rabbits

Science.gov (United States)

Kida, Tetsuo; Kozai, Seiko; Takahashi, Hiroaki; Isaka, Mitsuyoshi; Tokushige, Hideki; Sakamoto, Taiji

2014-01-01

Purpose To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) in the retinochoroidal tissues of rabbits. Methods The cyclooxygenase (COX) inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits. Results The half-maximal inhibitory concentration (IC50) of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC50 of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (P = 0.026) but not the other two NSAIDs. Conclusions Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit than diclofenac and

Pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs in retinochoroidal tissues in rabbits.

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Tetsuo Kida

Full Text Available PURPOSE: To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs in the retinochoroidal tissues of rabbits. METHODS: The cyclooxygenase (COX inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits. RESULTS: The half-maximal inhibitory concentration (IC50 of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC50 of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (P = 0.026 but not the other two NSAIDs. CONCLUSIONS: Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit

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.

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.

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.

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

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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

Ocular penetration of topically applied 1% tigecycline in a rabbit model

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Yasar Sakarya

2017-05-01

Full Text Available AIM: To evaluate ocular penetration of topically applied 1% tigecycline. METHODS: Forty-two New Zealand White rabbits were divided into 3 groups. A 50 μL drop of 1% tigecycline was administered in group 1. In groups 2 and 3, the drop was administered every 15min for 60min (keratitis protocol. Aqueous humor samples in groups 1 and 2 were collected under general anesthesia at 15, 30, 45, 60, 120, and 180min after the last drop. All animals in group 3 were euthanatized. Cornea, vitreous and blood samples were collected 60 and 120min after the last drop. Tigecycline concentrations were measured using high performance liquid chromatography-mass spectrometry (LC-MS/MS. RESULTS: The peak aqueous humor tigecycline concentration [mean 0.73±0.14 mg/L (SD and 2.41±0.14 mg/L, respectively] occurred 45min after topical drug application in groups 1 and 2. Group 3 mean values in the cornea, and vitreous, were 3.27±0.50 µg/g, and 0.17±0.10 mg/L at 60min and 3.17±0.77 µg/g and 0.20±0.07 mg/L at 120min, respectively. Tigecycline serum concentrations were negligible. CONCLUSION: Tigecycline levels in the aqueous humor in groups 1 and 2, and in the cornea in group 3 exceeded the minimum inhibitory concentrations of most gram-positive organisms that cause bacterial keratitis and endophthalmitis.

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...

Topical Drugs for Pain Relief

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Anjali Srinivasan

2015-03-01

Full Text Available Topical therapy helps patients with oral and perioral pain problems such as ulcers, burning mouth syndrome, temporomandibular disorders, neuromas, neuropathies and neuralgias. Topical drugs used in the field of dentistry are topical anaesthetics, topical analgesics, topical antibiotics and topical corticosteroids. It provides symptomatic/curative effect. Topical drugs are easy to apply, avoids hepatic first pass metabolism and more sites specific. But it can only be used for medications that require low plasma concentrations to achieve a therapeutic effect.

21 CFR 310.530 - Topically applied hormone-containing drug products for over-the-counter (OTC) human use.

Science.gov (United States)

2010-04-01

... labeling or in the ingredient statement is an implied drug claim. The claim implied by the use of this term... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Topically applied hormone-containing drug products for over-the-counter (OTC) human use. 310.530 Section 310.530 Food and Drugs FOOD AND DRUG...

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

Science.gov (United States)

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.

Absorption of topically applied hydrocortisone from the eye of the rhesus monkey

International Nuclear Information System (INIS)

Oehman, L.; Johansson, E.D.B.; Edqvist, L.-E.

1982-01-01

Blood samples were collected from anaesthetized monkeys during one h a) afer topical application of an eyedrop of hydrocortisone acetate suspension, b) after topical application of a drop of the vehicle alone, and c) after no application at all. Radioimmunoassay (RIA) showed a rapid and similar increase of hydrocortisone plasma levels in all 3 kinds of experiments. RIA revealed that in monkeys the anaesthetic procedure alone was sufficient to cause a considerable increase of endogenous hydrocortisone levels overshadowing any systemic absorption of topical hydrocortisone. Using tritiated hydrocortisone instead a rapid increase of systemic absorption after topical application was found. A plasma concentration of 1% of the dose was found one min after topical instillation incresing to a maximum of 6-7% at 30 min. The half time of the slow phase of elimination was about 19 h. (author)

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

Vancomycin, linezolid and daptomycin susceptibility pattern among clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA from Sub- Himalyan Center

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Afzal Husain

2018-01-01

CONCLUSION: MIC creep was observed with vancomycin. Although linezolid MIC was within the susceptible zone, more than 40% strains showing MIC 3 μg/ml may herald the future development of either resistant or heteroresistant. Daptomycin showed good sensitivity against MRSA isolates. Therefore, it could be considered as an alternative agent for the treatment of infections caused by MRSA. However, it should be reserved where this class has a clear therapeutic advantage over other anti-MRSA drugs.

Pharmacokinetics of topically applied sparfloxacin in rabbits

Directory of Open Access Journals (Sweden)

Satia Milan

2005-01-01

Full Text Available PURPOSE: Fluoroquinolones are antimicrobial agents that have a broad spectrum of activity and are widely used against many of the ocular pathogens, responsible for conjunctivitis, blepharitis, corneal ulcers etc. The aim of our study was to evaluate the ocular pharmacokinetics of sparfloxacin (0.3% w/v in the aqueous humour of rabbits. MATERIALS AND METHODS: Pharmacokinetics of topically administered sparfloxacin were determined after a single application of 50 µl topically. The aqueous humour samples were collected at 0, 0.25, 0.5, 1, 2, 3, 4, 5 or 6 hours after instillation. High Performance Thin Layer Chromatographic method was used to analyse the drug concentration in the aqueous humour samples. RESULTS: Fifteen minutes after the instillation of 50 µl of sparfloxacin 0.3% solution, the mean concentration in aqueous humour was found to be 1.4 µg/ml, which reaches the peak level of 3.7 µg/ml after 1.3 hours. At 6 hours, the sparfloxacin aqueous levels were 0.562 µg/ml. The clinical efficacy was predicted based on the Maximum Concentration (Cmax: Minimum Inhibitory Concentration (MIC and Area Under the Concentration-time curve (AUC:MIC ratios. CONCLUSION: The sparfloxacin levels in aqueous humour of rabbits are sufficiently high up to the 6 hours after instillation in the conjunctival sac to provide bactericidal effect against most of the ocular pathogens. Both Cmax:MIC and AUC:MIC ratios are high enough to provide bactericidal effect against most of the ocular pathogens. Sparfloxacin (0.3% ophthalmic preparation has excellent penetration through cornea.

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.

Aminolevulinic acid-photodynamic therapy combined with topically applied vascular disrupting agent vadimezan leads to enhanced antitumor responses.

Science.gov (United States)

Marrero, Allison; Becker, Theresa; Sunar, Ulas; Morgan, Janet; Bellnier, David

2011-01-01

The tumor vascular-disrupting agent (VDA) vadimezan (5,6-dimethylxanthenone-4-acetic acid, DMXAA) has been shown to potentiate the antitumor activity of photodynamic therapy (PDT) using systemically administered photosensitizers. Here, we characterized the response of subcutaneous syngeneic Colon26 murine colon adenocarcinoma tumors to PDT using the locally applied photosensitizer precursor aminolevulinic acid (ALA) in combination with a topical formulation of vadimezan. Diffuse correlation spectroscopy (DCS), a noninvasive method for monitoring blood flow, was utilized to determine tumor vascular response to treatment. In addition, correlative CD31-immunohistochemistry to visualize endothelial damage, ELISA to measure induction of tumor necrosis factor-alpha (TNF-α) and tumor weight measurements were also examined in separate animals. In our previous work, DCS revealed a selective decrease in tumor blood flow over time following topical vadimezan. ALA-PDT treatment also induced a decrease in tumor blood flow. The onset of blood flow reduction was rapid in tumors treated with both ALA-PDT and vadimezan. CD31-immunostaining of tumor sections confirmed vascular damage following topical application of vadimezan. Tumor weight measurements revealed enhanced tumor growth inhibition with combination treatment compared with ALA-PDT or vadimezan treatment alone. In conclusion, vadimezan as a topical agent enhances treatment efficacy when combined with ALA-PDT. This combination could be useful in clinical applications. © 2011 The Authors. Photochemistry and Photobiology © 2011 The American Society of Photobiology.

Testosterone Topical

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... not apply any testosterone topical products to your penis or scrotum or to skin that has sores, ... are severe or do not go away: breast enlargement and/or pain decreased sexual desire acne depression ...

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

Directory of Open Access Journals (Sweden)

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.

Drug delivery with topically applied nanoparticles: science fiction or reality.

Science.gov (United States)

Lademann, J; Richter, H; Meinke, M C; Lange-Asschenfeldt, B; Antoniou, C; Mak, W C; Renneberg, R; Sterry, W; Patzelt, A

2013-01-01

The efficacy of topically applied drugs is determined by their action mechanism and their potential capacity of passing the skin barrier. Nanoparticles are assumed to be efficient carrier systems for drug delivery through the skin barrier. For flexible nanoparticles like liposomes, this effect has been well demonstrated. The penetration properties of solid nanoparticles are currently under intensive investigation. The crucial advantage of nanoparticles over non-particulate substances is their capability to penetrate deeply into the hair follicles where they can be stored for several days. There is no evidence, yet, that solid particles ≥40 nm are capable of passing through the healthy skin barrier. Therefore and in spite of the long-standing research efforts in this field, commercially available solid nanoparticle-based products for drug delivery through the healthy skin are still missing. Nevertheless, the prospects for the clinical use of nanoparticles in drug delivery are tremendous. They can be designed as transport systems delivering drugs efficiently into the hair follicles in the vicinity of specific target structures. Once deposited at these structures, specific signals might trigger the release of the drugs and exert their effects on the target cells. In this article, examples of such triggered drug release are presented. © 2013 S. Karger AG, Basel.

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.

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.

Laser-induced thermal coagulation enhances skin uptake of topically applied compounds.

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Haak, C S; Hannibal, J; Paasch, U; Anderson, R R; Haedersdal, M

2017-08-01

Ablative fractional laser (AFL) generates microchannels in skin surrounded by a zone of thermally altered tissue, termed the coagulation zone (CZ). The thickness of CZ varies according to applied wavelength and laser settings. It is well-known that AFL channels facilitate uptake of topically applied compounds, but the importance of CZ is unknown. Franz Cells were used to investigate skin uptake and permeation of fluorescent labeled polyethylene glycols (PEGs) with mean molecular weights (MW) of 350, 1,000, and 5,000 Da. Microchannels with CZ thicknesses ranging from 0 to 80 μm were generated from micro-needles (0 μm, CZ-0), and AFL (10,600 nm) applied to -80°C deep frozen skin (20 μm, CZ-20) and skin equilibrated to room temperature (80 μm, CZ-80). Channels penetrated into similar mid-dermal skin depths of 600-700 μm, and number of channels per skin area was similar. At 4 hours incubation, skin uptake of PEGs into CZ and dermis was evaluated by fluorescence microscopy at specific skin depths of 150, 400, and 1,000 μm and the transcutaneous permeation was quantified by fluorescence of receptor fluids. Overall, the highest uptake of PEGs was reached through microchannels surrounded by CZ compared to channels with no CZ (CZ-20 and CZ-80>CZ-0).The thickness of CZ affected PEG distribution in skin. A thin CZ-20 favored significantly higher mean fluorescence intensities inside CZ areas compared to CZ-80 (PEG 350, 1,000, and 5,000; P channels was significantly higher than through CZ-80 and CZ-0 at all skin depths (PEG 350, 1,000 and 5,000, 150-1,000 μm; P distribution, with highest PEG uptake achieved from microchannels surrounded by a thin CZ. Lasers Surg. Med. 49:582-591, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Proceedings of the Topical Session on Applying Decommissioning Experience to the Design and Operation of New Nuclear Power Plants. Topical Session of the 9. Meeting of the WPDD Held in Senec, Slovak Republic 12-13 November 2008

International Nuclear Information System (INIS)

Noviello, Luigi; O'Sullivan, Patrick; Laurent, Gerard; Tuomisto, Harri; Metcalfe, Doug; Duncan, Allan

2009-01-01

At its ninth meeting, the WPDD held a topical session on Applying Decommissioning Experience to the Design and Operation of New Plants. In preparation for this, a survey was issued to reactor design organisations, electricity producers and safety authorities and responses were compiled into a summary report that provided a basis for discussion at the topical session. This report is in two parts: Part A documents the topical session, summarising the main points from the presentations and discussions and including the rapporteurs' reports. Part B provides a summary compilation of the responses received to the survey undertaken prior to the topical session. The topical session facilitated an exchange of information and experience between policy makers, regulators, electricity producers, design organisations and decommissioners on approaches and experiences to taking account of decommissioning considerations in the design of third generation reactor systems

Ocular distribution of topically applied adrenaline in albino and pigmented rabbits

International Nuclear Information System (INIS)

Urtti, A.; Periviita, L.; Salminen, L.

1984-01-01

Systemic absorption, ocular distribution and ocular metabolism in albino and pigmented rabbit of topically applied 1% [ 3 H]1-adrenaline eye drops was studied by liquid scintillation counting and thin layer chromatography. The effect of adrenaline on the pupillary diameter was also registered. The peak plasma level of adrenaline was reached at 150 min. The corneal adrenaline metabolism was substantial, but did not vary with the rabbit strain. At 30 min after instillation, the total adrenaline concentration of pigmented iris and ciliary body exceeded that of corresponding albino tissues. At 180 min the drug concentration of the iris and ciliary body did not differ between the rabbit strains. Th time course of adrenaline induced mydriasis was equal in both rabbit strains. Since neither total adrenaline concentration at 180 min nor the time course of adrenaline induced mydriasis differed between the rabbit strains, the higher initial adrenaline uptake by pigmented tissues is not explained by pigment binding. It is proposed that the increased initial binding of adrenaline by pigmented tissues is caused by a difference between pigmented and albino tissues in the number of adrenergic neurones; this is also supported by the literature. (author)

Bimatoprost Topical

Science.gov (United States)

... not use a cotton swab or any other brush or applicator to apply topical bimatoprost.To use the solution, follow these steps: Wash your hands and face thoroughly with soap and water. Be sure that all makeup is removed. Do not let the tip of ...

21 CFR 868.5170 - Laryngotracheal topical anesthesia applicator.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Laryngotracheal topical anesthesia applicator. 868... topical anesthesia applicator. (a) Identification. A laryngotracheal topical anesthesia applicator is a device used to apply topical anesthetics to a patient's laryngotracheal area. (b) Classification. Class...

Data Mining Thesis Topics in Finland

OpenAIRE

Bajo Rouvinen, Ari

2017-01-01

The Theseus open repository contains metadata about more than 100,000 thesis publications from the different universities of applied sciences in Finland. Different data mining techniques were applied to the Theseus dataset to build a web application to explore thesis topics and degree programmes using different libraries in Python and JavaScript. Thesis topics were extracted from manually annotated keywords by the authors and curated subjects by the librarians. During the project, the quality...

Salicylic Acid Topical

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... the package label for more information.Apply a small amount of the salicylic acid product to one or two small areas you want to treat for 3 days ... know that children and teenagers who have chicken pox or the flu should not use topical salicylic ...

Therapeutic Efficacy of Topically Applied Antioxidant Medicinal Plant Extracts in a Mouse Model of Experimental Dry Eye.

Science.gov (United States)

Choi, Won; Lee, Jee Bum; Cui, Lian; Li, Ying; Li, Zhengri; Choi, Ji Suk; Lee, Hyo Seok; Yoon, Kyung Chul

2016-01-01

Purpose. To investigate the therapeutic effects of topical administration of antioxidant medicinal plant extracts in a mouse model of experimental dry eye (EDE). Methods. Eye drops containing balanced salt solution (BSS) or 0.001%, 0.01%, and 0.1% extracts were applied for the treatment of EDE. Tear volume, tear film break-up time (BUT), and corneal fluorescein staining scores were measured 10 days after desiccating stress. In addition, we evaluated the levels of interleukin- (IL-) 1β, tumor necrosis factor- (TNF-) α, IL-6, interferon- (IFN-) γ, and IFN-γ associated chemokines, percentage of CD4+C-X-C chemokine receptor type 3 positive (CXCR3+) T cells, goblet cell density, number of 4-hydroxy-2-nonenal (4-HNE) positive cells, and extracellular reactive oxygen species (ROS) production. Results. Compared to the EDE and BSS control groups, the mice treated with topical application of the 0.1% extract showed significant improvements in all clinical parameters, IL-1β, IL-6, TNF-α, and IFN-γ levels, percentage of CD4+CXCR3+ T cells, goblet cell density, number of 4-HNE-positive cells, and extracellular ROS production (P model mice.

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

Science.gov (United States)

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.

Comparison of topical tretinoin and betamethasone in oral lichen planus

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Kar H

1996-01-01

Full Text Available Thirty-one patients of oral lichen planus were enrolled in this study and two groups were made. Group 1 consisting of 16 patients who applied topical tretinoin 0.05% and Group 2 comprising of 15 patients who were given topical betamethasone dipropionate 0.05%. The patients applying tretinoin showed statistically significant improvement as compared to patients applying betamethasone.

Advances in Applied Mechanics

OpenAIRE

2013-01-01

Advances in Applied Mechanics draws together recent significant advances in various topics in applied mechanics. Published since 1948, Advances in Applied Mechanics aims to provide authoritative review articles on topics in the mechanical sciences, primarily of interest to scientists and engineers working in the various branches of mechanics, but also of interest to the many who use the results of investigations in mechanics in various application areas, such as aerospace, chemical, civil, en...

Topic Model for Graph Mining.

Science.gov (United States)

Xuan, Junyu; Lu, Jie; Zhang, Guangquan; Luo, Xiangfeng

2015-12-01

Graph mining has been a popular research area because of its numerous application scenarios. Many unstructured and structured data can be represented as graphs, such as, documents, chemical molecular structures, and images. However, an issue in relation to current research on graphs is that they cannot adequately discover the topics hidden in graph-structured data which can be beneficial for both the unsupervised learning and supervised learning of the graphs. Although topic models have proved to be very successful in discovering latent topics, the standard topic models cannot be directly applied to graph-structured data due to the "bag-of-word" assumption. In this paper, an innovative graph topic model (GTM) is proposed to address this issue, which uses Bernoulli distributions to model the edges between nodes in a graph. It can, therefore, make the edges in a graph contribute to latent topic discovery and further improve the accuracy of the supervised and unsupervised learning of graphs. The experimental results on two different types of graph datasets show that the proposed GTM outperforms the latent Dirichlet allocation on classification by using the unveiled topics of these two models to represent graphs.

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.

Topics in Finance Part VI--Capital Budgeting

Science.gov (United States)

Laux, Judy

2011-01-01

This series on the theory of financial management offers insight into the roles of stockholder wealth maximization, the risk-return tradeoff, and agency conflicts as they apply to major topics in finance. The current article investigates capital budgeting. Much literature addresses this topic, with a number of articles challenging mainstream…

Simple protein precipitation extraction technique followed by validated chromatographic method for linezolid analysis in real human plasma samples to study its pharmacokinetics.

Science.gov (United States)

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.

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

Directory of Open Access Journals (Sweden)

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.

Full-thickness human skin explants for testing the toxicity of topically applied chemicals

International Nuclear Information System (INIS)

Nakamura, M.; Rikimaru, T.; Yano, T.; Moore, K.G.; Pula, P.J.; Schofield, B.H.; Dannenberg, A.M. Jr.

1990-01-01

This report describes a model organ-culture system for testing the toxicity of chemical substances that are topically applied to human skin. In this system, the viable keratinocytes in the full-thickness skin explants are protected by the same keratinized layer as skin remaining on the donor, and toxicity can be assessed microscopically and/or biochemically. The human skin specimens were discards from a variety of surgical procedures. They were cut into full-thickness 1.0-cm2 explants, and briefly exposed to the military vesicant sulfur mustard (SM), which was used as a model toxicant. The explants were then organ cultured in small Petri dishes for 24 h at 36 degrees C. In the 0.03-1.0% dosage range, a straight-line dose-response relationship occurred between the concentration of SM applied and the number of paranuclear vacuoles seen histologically in the epidermis. Within the same SM dosage range, there was also a proportional decrease in 14C-leucine incorporation by the explants. Thus, the number of paranuclear vacuoles reflected decreases in protein synthesis by the injured epidermal cells. The epidermis of full-thickness untreated (control) human skin explants usually remained viable for 7 d when stored at 4 degrees C in culture medium. During storage, a relatively small number of paranuclear vacuoles developed within the epidermis, but the explants were still quite satisfactory for testing SM toxicity. Incubation (for 4 or 24 h at 36 degrees C) of such control skin explants reduced (often by 50%) the small number of paranuclear vacuoles produced during 4-7 d of storage. This reduction was probably caused by autolysis of many of the vacuolated cells. Two types of paranuclear vacuoles could be identified by both light and electron microscopy: a storage type and a toxicant type. The storage type seemed to be caused by autolysis of cell components

Full-thickness human skin explants for testing the toxicity of topically applied chemicals

Energy Technology Data Exchange (ETDEWEB)

Nakamura, M.; Rikimaru, T.; Yano, T.; Moore, K.G.; Pula, P.J.; Schofield, B.H.; Dannenberg, A.M. Jr. (Johns Hopkins Univ., Baltimore, MD (USA))

1990-09-01

This report describes a model organ-culture system for testing the toxicity of chemical substances that are topically applied to human skin. In this system, the viable keratinocytes in the full-thickness skin explants are protected by the same keratinized layer as skin remaining on the donor, and toxicity can be assessed microscopically and/or biochemically. The human skin specimens were discards from a variety of surgical procedures. They were cut into full-thickness 1.0-cm2 explants, and briefly exposed to the military vesicant sulfur mustard (SM), which was used as a model toxicant. The explants were then organ cultured in small Petri dishes for 24 h at 36 degrees C. In the 0.03-1.0% dosage range, a straight-line dose-response relationship occurred between the concentration of SM applied and the number of paranuclear vacuoles seen histologically in the epidermis. Within the same SM dosage range, there was also a proportional decrease in 14C-leucine incorporation by the explants. Thus, the number of paranuclear vacuoles reflected decreases in protein synthesis by the injured epidermal cells. The epidermis of full-thickness untreated (control) human skin explants usually remained viable for 7 d when stored at 4 degrees C in culture medium. During storage, a relatively small number of paranuclear vacuoles developed within the epidermis, but the explants were still quite satisfactory for testing SM toxicity. Incubation (for 4 or 24 h at 36{degrees}C) of such control skin explants reduced (often by 50%) the small number of paranuclear vacuoles produced during 4-7 d of storage. This reduction was probably caused by autolysis of many of the vacuolated cells. Two types of paranuclear vacuoles could be identified by both light and electron microscopy: a storage type and a toxicant type. The storage type seemed to be caused by autolysis of cell components.

Infantile generalized hypertrichosis caused by topical minoxidil.

Science.gov (United States)

Rampon, Greice; Henkin, Caroline; de Souza, Paulo Ricardo Martins; Almeida, Hiram Larangeira de

2016-01-01

Rare cases of hypertrichosis have been associated with topically applied minoxidil. We present the first reported case in the Brazilian literature of generalized hypertrichosis affecting a 5-year-old child, following use of minoxidil 5%, 20 drops a day, for hair loss. The laboratory investigation excluded hyperandrogenism and thyroid dysfunction. Topical minoxidil should be used with caution in children.

Topically applied standardized aqueous extract of Curcuma longa Linn. suppresses endotoxin-induced uveal inflammation in rats.

Science.gov (United States)

Agarwal, Renu; Gupta, S K; Agarwal, Puneet; Srivastava, Sushma

2013-10-01

Aqueous extract of C. longa when administered 4 h after induction of E. coli lipopolysaccharide-induced uveitis in rats showed significantly suppressed inflammation with a significantly lower mean clinical grade, histopathological grade and aqueous humor (AH) protein level compared to vehicle treated group. Although, prednisolone group showed significantly lower clinical grade, histopathological grades and AH protein levels compared to C. longa group, TNF-alpha levels did not differ significantly. Moreover, when the aqueous extract was administered starting from 3 days before induction of uveitis, the mean clinical and histopathological grade as well as AH protein and TNF-alpha levels were comparable to C. longa group when treatment was administered 4 h after induction of uveitis. It is concluded that topically applied standardized aqueous extract of C. longa suppresses endotoxin-induced uveitis in rats by reducing TNF-alpha activity.

Effect of topical vitamin E on ethanol-induced corneal epithelial apoptosis.

Science.gov (United States)

Bilgihan, Kamil; Konuk, Onur; Hondur, Ahmet; Akyürek, Nalan; Ozogul, Candan; Hasanreisoglu, Berati

2005-01-01

Ethanol is used to loosen the corneal epithelium before photoablation in laser subepithelial keratomileusis (LASEK). In this study, the apoptotic index of corneal epithelium after ethanol exposure and the effects of topical vitamin E were evaluated. The study was performed on 28 rabbit eyes in four groups. Group 1 comprised the controls. In group 2, 20% ethanol was applied topically for 20 seconds. In group 3, topical vitamin E was applied following 20% ethanol application. In group 4, only topical vitamin E was applied. Apoptosis was evaluated with TUNEL assay and transmission electron microscopy. Epithelial apoptosis was detected in all specimens in group 2. No apoptosis was detected in other groups except for one eye in group 1. The apoptotic index in group 2 was statistically higher than other groups (P < .001).

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

International Nuclear Information System (INIS)

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)

Topics in supergravity and string theory

International Nuclear Information System (INIS)

Eastaugh, A.G.

1987-01-01

The first topic covered in this dissertation concerns the harmonic expansion technique and its application to the dimensional compactification of higher dimensional supergravity. A simple example is given to explain the method and then the method is applied to the problem of obtaining the mass spectrum of the squashed seven-sphere compactification of eleven dimensional supergravity. The second topic concerns the application of Fujikawa's method of anomaly calculation to the calculation of the critical dimension of various string models. The third topic is a study and explicit calculation of the Fock space representation of the vertex in Witten's formulation of the interacting open bosonic string field theory

Applied analysis and differential equations

CERN Document Server

Cârj, Ovidiu

2007-01-01

This volume contains refereed research articles written by experts in the field of applied analysis, differential equations and related topics. Well-known leading mathematicians worldwide and prominent young scientists cover a diverse range of topics, including the most exciting recent developments. A broad range of topics of recent interest are treated: existence, uniqueness, viability, asymptotic stability, viscosity solutions, controllability and numerical analysis for ODE, PDE and stochastic equations. The scope of the book is wide, ranging from pure mathematics to various applied fields such as classical mechanics, biomedicine, and population dynamics.

Infantile generalized hypertrichosis caused by topical minoxidil*

Science.gov (United States)

Rampon, Greice; Henkin, Caroline; de Souza, Paulo Ricardo Martins; de Almeida Jr, Hiram Larangeira

2016-01-01

Rare cases of hypertrichosis have been associated with topically applied minoxidil. We present the first reported case in the Brazilian literature of generalized hypertrichosis affecting a 5-year-old child, following use of minoxidil 5%, 20 drops a day, for hair loss. The laboratory investigation excluded hyperandrogenism and thyroid dysfunction. Topical minoxidil should be used with caution in children. PMID:26982785

Gram-positive bacteria as an antigen topically applied into gingival sulcus of immunized rat accelerates periodontal destruction.

Science.gov (United States)

Nagano, F; Kaneko, T; Yoshinaga, Y; Ukai, T; Kuramoto, A; Nakatsu, S; Oshino, K; Ichimura, I; Hara, Y

2013-08-01

Periodontitis is generally accepted to relate to gram-negative bacteria, and the host defense system influences its onset and progression. However, little is known about the relation between gram-positive bacteria and periodontitis. In this study, we topically applied gram-positive and gram-negative bacterial suspensions to the gingival sulcus in rats after immunization, and then histopathologically examined their influence on periodontal destruction. Rats previously immunized with heat-treated and sonicated Staphylococcus aureus or Aggregatibacter actinomycetemcomitans were used as immunized groups. The non-immunized group received only sterile phosphate-buffered saline. In each animal, S. aureus or A. actinomycetemcomitans suspension was applied topically to the palatal gingival sulcus of first molars every 24 h for 10 d. Blood samples were collected and the serum level of anti-S. aureus or anti-A. actinomycetemcomitans immunoglobulin G (IgG) antibodies was determined by enzyme-linked immunosorbent assay. The first molar regions were resected and observed histopathologically. Osteoclasts were stained with tartrate-resistant acid phosphatase (TRAP). The formation of immune complexes was confirmed by immunohistological staining of C1qB. Serum levels of anti-S. aureus and anti-A. actinomycetemcomitans IgG antibodies in the immunized groups were significantly higher than those in the non-immunized groups were. The loss of attachment, increase in apical migration of the junctional epithelium, and decreases in alveolar bone level and number of TRAP-positive multinuclear cells in each immunized group were significantly greater than in each non-immunized group. The presence of C1qB was observed in the junctional epithelium and adjacent connective tissue in the immunized groups. Heat-treated and sonicated S. aureus and A. actinomycetemcomitans induced attachment loss in rats immunized with their suspensions. Our results suggest that not only gram-negative but also gram

Measuring the effects of topically applied skin optical clearing agents and modeling the effects and consequences for laser therapies

Science.gov (United States)

Verkruysse, Wim; Khan, Misbah; Choi, Bernard; Svaasand, Lars O.; Nelson, J. Stuart

2005-04-01

Human skin prepared with an optical clearing agent manifests reduced scattering as a result of de-hydration and refractive index matching. This has potentially large effects for laser therapies of several skin lesions such as port wine stain, hair removal and tattoo removal. With most topically applied clearing agents the clearing effect is limited because they penetrate poorly through the intact superficial skin layer (stratum corneum). Agent application modi other than topical are impractical and have limited the success of optical clearing in laser dermatology. In recent reports, however, a mixture of lipofylic and hydrofylic agents was shown to successfully penetrate through the intact stratum corneum layer which has raised new interest in this field. Immediately after application, the optical clearing effect is superficial and, as the agent diffuses through the skin, reduced scattering is manifested in deeper skin layers. For practical purposes as well as to maximize therapeutic success, it is important to quantify the reduced scattering as well as the trans-cutaneous transport dynamics of the agent. We determined the time and tissue depth resolved effects of optically cleared skin by inserting a microscopic reflector array in the skin. Depth dependent light intensity was measured by quantifying the signal of the reflector array with optical coherence tomography. A 1-dimensional mass diffusion model was used to estimate a trans-cutaneous transport diffusion constant for the clearing agent mixture. The results are used in Monte Carlo modeling to determine the optimal time of laser treatment after topical application of the optical clearing agent.

Spectral Learning for Supervised Topic Models.

Science.gov (United States)

Ren, Yong; Wang, Yining; Zhu, Jun

2018-03-01

Supervised topic models simultaneously model the latent topic structure of large collections of documents and a response variable associated with each document. Existing inference methods are based on variational approximation or Monte Carlo sampling, which often suffers from the local minimum defect. Spectral methods have been applied to learn unsupervised topic models, such as latent Dirichlet allocation (LDA), with provable guarantees. This paper investigates the possibility of applying spectral methods to recover the parameters of supervised LDA (sLDA). We first present a two-stage spectral method, which recovers the parameters of LDA followed by a power update method to recover the regression model parameters. Then, we further present a single-phase spectral algorithm to jointly recover the topic distribution matrix as well as the regression weights. Our spectral algorithms are provably correct and computationally efficient. We prove a sample complexity bound for each algorithm and subsequently derive a sufficient condition for the identifiability of sLDA. Thorough experiments on synthetic and real-world datasets verify the theory and demonstrate the practical effectiveness of the spectral algorithms. In fact, our results on a large-scale review rating dataset demonstrate that our single-phase spectral algorithm alone gets comparable or even better performance than state-of-the-art methods, while previous work on spectral methods has rarely reported such promising performance.

Photocarcinogenicity of selected topically applied dermatological drugs: calcineurin inhibitors, corticosteroids, and vitamin D analogs

Directory of Open Access Journals (Sweden)

Catharina Margrethe Lerche

2010-09-01

Full Text Available Topical therapies constitute the mainstay of dermatological treatments for skin disorders, such as atopic dermatitis, contact dermatitis, psoriasis, or acne. Since some of these diseases are often chronic, treatment duration may last for years and may even last the patient’s entire lifetime. Obviously, such long-term therapy may raise safety concerns, which also include the potential photocarcinogenic effect. Most patients are exposed to ultraviolet radiation (UVR during leisure, work, vacations, or in tanning beds. Additionally, the patients may receive UVR via UVB phototherapy or psoralens plus UVA radiation (PUVA. The use of immunosuppressant’s, such as corticosteroids and calcineurin inhibitors, has markedly increased. Patients with skin diseases have benefited from both systemic and topical treatment of both new and established drugs. The issue of a black box warning by the US Food and Drug Administration has increased concerns about photocarcinogenesis, which raises the question: “Are these drugs safe?” This review focuses on the mechanism of action and photocarcinogenic potential of commonly used topical treatments, such as corticosteroids, calcineurin inhibitors, and vitamin D analogs.

Clinical outcomes and response of patients applying topical therapy for pyoderma gangrenosum: A prospective cohort study.

Science.gov (United States)

Thomas, Kim S; Ormerod, Anthony D; Craig, Fiona E; Greenlaw, Nicola; Norrie, John; Mitchell, Eleanor; Mason, James M; Johnston, Graham A; Wahie, Shyamal; Williams, Hywel C

2016-11-01

Pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment. We sought to estimate the effectiveness of topical therapies in the treatment of patients with PG. This was a prospective cohort study of UK secondary care patients with a clinical diagnosis of PG that was suitable for topical treatment (recruited between July 2009 and June 2012). Participants received topical therapy after normal clinical practice (primarily topical corticosteroids [classes I-III] and tacrolimus 0.03% or 0.1%). The primary outcome was speed of healing at 6 weeks. Secondary outcomes included the following: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality of life; treatment failure; and recurrence. Sixty-six patients (22-85 years of age) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28 of 66 (43.8%) ulcers healed by 6 months. The median time to healing was 145 days (95% confidence interval, 96 days to ∞). Initial ulcer size was a significant predictor of time to healing (hazard ratio, 0.94 [95% confidence interval, 0.88-1.00); P = .043). Four patients (15%) had a recurrence. Our study did not include a randomized comparator. Topical therapy is potentially an effective first-line treatment for PG that avoids the possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Applied evaluative informetrics

CERN Document Server

Moed, Henk F

2017-01-01

This book focuses on applied evaluative informetric artifacts or topics. It explains the base notions and assumptions of evaluative informetrics by discussing a series of important applications. The structure of the book is therefore not organized by methodological characteristics, but is centered around popular, often discussed or used informetric artifacts - indicators, methodologies, products, databases - or so called hot topics in which informetric indicators play an important role. Most of the artifacts and topics emerged during the past decade. The principal aim of the book is to present a state of the art in applied evaluative informetrics, and to inform the readers about the pros and cons, potentialities and limitations of the use of informetric/bibliometric indicators in research assessment. The book is a continuation of the book Citation Analysis in Research Evaluation (Springer, 2005). It is of interest to non-specialists, especially research students at advanced master level and higher, all thos...

Anti-inflammatory activity of Punica granatum L. (Pomegranate) rind extracts applied topically to ex vivo skin.

Science.gov (United States)

Houston, David M J; Bugert, Joachim; Denyer, Stephen P; Heard, Charles M

2017-03-01

Coadministered pomegranate rind extract (PRE) and zinc (II) produces a potent virucidal activity against Herpes simplex virus (HSV); however, HSV infections are also associated with localised inflammation and pain. Here, the objective was to determine the anti-inflammatory activity and relative depth penetration of PRE, total pomegranate tannins (TPT) and zinc (II) in skin, ex vivo. PRE, TPT and ZnSO 4 were dosed onto freshly excised ex vivo porcine skin mounted in Franz diffusion cells and analysed for COX-2, as a marker for modulation of the arachidonic acid inflammation pathway, by Western blotting and immunohistochemistry. Tape stripping was carried out to construct relative depth profiles. Topical application of PRE to ex vivo skin downregulated expression of COX-2, which was significant after just 6h, and maintained for up to 24h. This was achieved with intact stratum corneum, proving that punicalagin penetrated skin, further supported by the depth profiling data. When PRE and ZnSO 4 were applied together, statistically equal downregulation of COX-2 was observed when compared to the application of PRE alone; no effect followed the application of ZnSO 4 alone. TPT downregulated COX-2 less than PRE, indicating that tannins alone may not be entirely responsible for the anti-inflammatory activity of PRE. Punicalagin was found throughout the skin, in particular the lower regions, indicating appendageal delivery as a significant route to the viable epidermis. Topical application of TPT and PRE had significant anti-inflammatory effects in ex vivo skin, confirming that PRE penetrates the skin and modulates COX-2 regulation in the viable epidermis. Pomegranates have potential as a novel approach in ameliorating the inflammation and pain associated with a range of skin conditions, including cold sores and herpetic stromal keratitis. Copyright © 2016 Elsevier B.V. All rights reserved.

Topic Modeling of NASA Space System Problem Reports: Research in Practice

Science.gov (United States)

Layman, Lucas; Nikora, Allen P.; Meek, Joshua; Menzies, Tim

2016-01-01

Problem reports at NASA are similar to bug reports: they capture defects found during test, post-launch operational anomalies, and document the investigation and corrective action of the issue. These artifacts are a rich source of lessons learned for NASA, but are expensive to analyze since problem reports are comprised primarily of natural language text. We apply topic modeling to a corpus of NASA problem reports to extract trends in testing and operational failures. We collected 16,669 problem reports from six NASA space flight missions and applied Latent Dirichlet Allocation topic modeling to the document corpus. We analyze the most popular topics within and across missions, and how popular topics changed over the lifetime of a mission. We find that hardware material and flight software issues are common during the integration and testing phase, while ground station software and equipment issues are more common during the operations phase. We identify a number of challenges in topic modeling for trend analysis: 1) that the process of selecting the topic modeling parameters lacks definitive guidance, 2) defining semantically-meaningful topic labels requires nontrivial effort and domain expertise, 3) topic models derived from the combined corpus of the six missions were biased toward the larger missions, and 4) topics must be semantically distinct as well as cohesive to be useful. Nonetheless,topic modeling can identify problem themes within missions and across mission lifetimes, providing useful feedback to engineers and project managers.

Special topics in the theory of piezoelectricity

CERN Document Server

Yang, Jiashi

2009-01-01

Piezoelectricity has been a steadily growing field, with recent advances made by researchers from applied physics, acoustics, materials science, and engineering. This collective work presents a comprehensive treatment of selected advanced topics in the subject. The book is written for an intermediate graduate level and is intended for researchers, mechanical engineers, and applied mathematicians interested in the advances and new applications in piezoelectricity.

Formulation Study of Topically Applied Lotion: In Vitro and In Vivo Evaluation

Directory of Open Access Journals (Sweden)

Syed Nisar Hussain Shah

2013-01-01

Full Text Available ntroduction: This article presents the development and evaluation of a new topical formulation of diclofenac diethylamine (DDA as a locally applied analgesic lotion. Methods: To this end, the lotion formulations were formulated with equal volume of varying concentrations (1%, 2%, 3%, 4%; v/v of permeation enhancers, namely propylene glycol (PG and turpentine oil (TO. These lotions were subjected to physical studies (pH, viscosity, spreadability, homogeneity, and accelerated stability, in vitro permeation, in vivo animal studies and sensatory perception testing. In vitro permeation of DDA from lotion formulations was evaluated across polydimethylsiloxane membrane and rabbit skin using Franz cells. Results: It was found that PG and TO content influenced the permeation of DDA across model membranes with the lotion containing 4% v/v PG and TO content showed maximum permeation enhancement of DDA. The flux values for L4 were 1.20±0.02 μg.cm-2.min-1 and 0.67 ± 0.02 μg.cm-2.min-1 for polydimethylsiloxane and rabbit skin, respectively. Flux values were significantly different (p < 0.05 from that of the control. The flux enhancement ratio of DDA from L4 was 31.6-fold and 4.8-fold for polydimethylsiloxane and rabbit skin, respectively. In the in vivo animal testing, lotion with 4% v/v enhancer content showed maximum anti-inflammatory and analgesic effect without inducing any irritation. Sensatory perception tests involving healthy volunteers rated the formulations between 3 and 4 (values ranging between -4 to +4, indicating a range of very bad to excellent, respectively. Conclusion: It was concluded that the DDA lotion containing 4% v/v PG and TO exhibit the best performance overall and that this specific formulation should be the basis for further clinical investigations.

Cobalt chloride induces metaphase when topically applied to larvae and pupae of the stingless bee Melipona scutellaris (Hymenoptera, Apidae, Meliponini).

Science.gov (United States)

Ueira-Vieira, C; Tavares, R R; Morelli, S; Pereira, B B; Silva, R P; Torres-Mariano, A R; Kerr, W E; Bonetti, A M

2013-06-20

In order to optimize preparations of bee metaphases, we tested cobalt chloride, which has been used as a metaphase inducer in other organisms, such as hamsters and fish. Four microliters of 65 mM cobalt chloride aqueous solution was topically applied to larval and pupal stages of the stingless bee Melipona scutellaris. The cerebral ganglion was removed after treatment and prepared for cytogenetic analysis. Identically manipulated untreated individuals were used as controls. The number of metaphases was increased 3-fold in treated individuals compared to controls. The micronucleus test showed no mutagenic effects of cobalt chloride on M. scutellaris cells. We concluded that cobalt chloride is a metaphase-inducing agent in M. scutellaris, thus being useful for cytogenetic analyses.

Topics and topic prominence in two sign languages

NARCIS (Netherlands)

Kimmelman, V.

2015-01-01

In this paper we describe topic marking in Russian Sign Language (RSL) and Sign Language of the Netherlands (NGT) and discuss whether these languages should be considered topic prominent. The formal markers of topics in RSL are sentence-initial position, a prosodic break following the topic, and

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

Science.gov (United States)

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.

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.

Science.gov (United States)

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.

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

Science.gov (United States)

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.

Topical fentanyl stimulates healing of ischemic wounds in diabetic rats

Science.gov (United States)

FAROOQUI, Mariya; ERICSON, Marna E; GUPTA, Kalpna

2016-01-01

Background Topically applied opioids promote angiogenesis and healing of ischemic wounds in rats. We examined if topical fentanyl stimulates wound healing in diabetic rats by stimulating growth-promoting signaling, angiogenesis, lymphangiogenesis and nerve regeneration. Methods We used Zucker diabetic fatty rats that develop obesity and diabetes on a high fat diet due to a mutation in the Leptin receptor. Fentanyl blended with hydrocream was applied topically on ischemic wounds twice daily, and wound closure was analyzed regularly. Wound histology was analyzed by hematoxylin and eosin staining. Angiogenesis, lymphangiogenesis, nerve fibers and phospho-PDGFR-β were visualized by CD31-, lymphatic vessel endothelium-1, protein gene product 9.5- and anti-phospho PDGFR-β-immunoreactivity, respectively. Nitric oxide synthase (NOS) and PDGFR-β signaling were analyzed using Western immunoblotting. Results Fentanyl significantly promoted wound closure as compared to PBS. Histology scores were significantly higher in fentanyl-treated wounds, indicative of increased granulation tissue formation, reduced edema and inflammation, and increased matrix deposition. Fentanyl treatment resulted in increased wound angiogenesis, lymphatic vasculature, nerve fibers, nitric oxide, NOS and PDGFR-β signaling as compared to PBS. Phospho PDGFR-β co-localized with CD31 co-staining for vasculature. Conclusions Topically applied fentanyl promotes closure of ischemic wounds in diabetic rats. Increased angiogenesis, lymphangiogenesis, peripheral nerve regeneration, NO and PDGFR-β signaling are associated with fentanyl-induced tissue remodeling and wound healing. PMID:25266258

Topical sirolimus for the treatment of angiofibromas in tuberous sclerosis

Directory of Open Access Journals (Sweden)

Salih Levent Cinar

2017-01-01

Full Text Available Background: The skin is one of the most affected organs in tuberous sclerosis complex and angiofibromas are seen in almost 80% of such patients. These benign tumors impose a great psycho-social burden on patients. Objective: The aim of the study was to evaluate the effectiveness and tolerability of topical sirolimus for facial angiofibromas in patients with tuberous sclerosis complex. Methods: This was a prospective, single-blinded, cross-over study which involved twelve patients. We investigated the effect and safety of topical 0.1% sirolimus, which was obtained by crushing sirolimus tablets and mixing it with petrolatum. The patients were asked to apply the cream to one side of their face, and vaseline to the other side. The effect of topical sirolimus was evaluated using the “facial angiofibroma severity index.” Results: There was a significant improvement in the redness and extension of the tumors on the sides to which the active ingredient was applied. Some side effects such as itching and irritation occurred in three patients, which were treated with topical hydrocortisone cream. Conclusion: Topical sirolimus appears to be a promising, fairly well tolerated treatment for facial angiofibromas in patients with tuberous sclerosis complex. Although its efficacy diminishes with time, repetitive usage is effective.

Increasing topical anesthetic efficacy with microneedle application.

Science.gov (United States)

Buhsem, Ömer; Aksoy, Alper; Kececi, Yavuz; Sir, Emin; Güngör, Melike

2016-10-01

Since topical anesthetics alone seldom provide adequate analgesia for laser resurfacing procedures, injectable forms of anesthesia are often required. However, their application is uncomfortable for the patient. In this study, it is investigated whether microneedle application would enhance the efficacy of topical anesthetics. Forty-seven patients participated in the study. Topical anesthetic agent EMLA was applied to the whole face of the patients. Microneedle treatment was applied to one side of the face with a roller-type device. Whole-face carbon dioxide laser resurfacing therapy was carried out then. The pain that patients experienced was assessed by using visual analog scale (VAS) method. VAS scores of two sides of the face were compared by using Wilcoxon signed-rank test. The mean of VAS score of the microneedle treated side was 2.1 ± 1.1 while that of the untreated side was 5.9 ± 0.9 and this difference was statistically significant (Wilcoxon signed-rank test, the Z-value is - 5.9683 and the p-value is < 0.001). This study revealed that microneedle application, with a roller-type device, is a safe and easy procedure in providing sufficient anesthesia for facial laser resurfacing without the need for supplementary nerve blocks or injections.

Simultaneous determination and stability studies of linezolid, meropenem and vancomycin in bacterial growth medium by high-performance liquid chromatography.

Science.gov (United States)

Wicha, Sebastian G; Kloft, Charlotte

2016-08-15

For pharmacokinetic/pharmacodynamic (PK/PD) assessment of antibiotics combinations in in vitro infection models, accurate and precise quantification of drug concentrations in bacterial growth medium is crucial for derivation of valid PK/PD relationships. We aimed to (i) develop a high-performance liquid chromatography (HPLC) assay to simultaneously quantify linezolid (LZD), vancomycin (VAN) and meropenem (MER), as typical components of broad-spectrum antibiotic combination therapy, in bacterial growth medium cation-adjusted Mueller-Hinton broth (CaMHB) and (ii) determine the stability profiles of LZD, VAN and MER under conditions in in vitro infection models. To separate sample matrix components, the final method comprised the pretreatment of 100μL sample with 400μL methanol, the evaporation of supernatant and its reconstitution in water. A low sample volume of 2μL processed sample was injected onto an Accucore C-18 column (2.6μm, 100×2.1mm) coupled to a Dionex Ultimate 3000 HPLC+ system. UV detection at 251, 240 and 302nm allowed quantification limits of 0.5, 2 and 0.5μg/mL for LZD, VAN and MER, respectively. The assay was successfully validated according to the relevant EMA guideline. The rapid method (14min) was successfully applied to quantify significant degradation of LZD, VAN and MER in in vitro infection models: LZD was stable, VAN degraded to 90.6% and MER to 62.9% within 24h compared to t=0 in CaMHB at 37°C, which should be considered when deriving PK/PD relationships in in vitro infection models. Inclusion of further antibiotics into the flexible gradient-based HPLC assay seems promising. Copyright © 2016 Elsevier B.V. All rights reserved.

Topically applied methotrexate is rapidly delivered into skin by fractional laser ablation

DEFF Research Database (Denmark)

Taudorf, Elisabeth Hjardem; Lerche, Catharina; Vissing, Anne-Cathrine

2015-01-01

Objectives: Methotrexate (MTX) is a chemotherapeutic and anti-inflammatory drug that may cause systemic adverse effects. This study investigated kinetics and biodistribution of MTX delivered topically by ablative fractional laser (AFXL). Methods: In vitro passive diffusion of 10 mg/ml MTX (1 w...... sections, donor and receiver compartments. Fluorescence microscopy of UVC-activated MTX-fluorescence and desorption electro-spray ionization mass spectrometry imaging (DESI-MSI) evaluated MTX biodistribution. Results: AFXL-processed skin facilitated rapid MTX delivery through cone-shaped microchannels.......30 mg/cm3, p = 0.002). Transdermal permeation was

Identifying biological concepts from a protein-related corpus with a probabilistic topic model

Directory of Open Access Journals (Sweden)

Lu Xinghua

2006-02-01

Full Text Available Abstract Background Biomedical literature, e.g., MEDLINE, contains a wealth of knowledge regarding functions of proteins. Major recurring biological concepts within such text corpora represent the domains of this body of knowledge. The goal of this research is to identify the major biological topics/concepts from a corpus of protein-related MEDLINE© titles and abstracts by applying a probabilistic topic model. Results The latent Dirichlet allocation (LDA model was applied to the corpus. Based on the Bayesian model selection, 300 major topics were extracted from the corpus. The majority of identified topics/concepts was found to be semantically coherent and most represented biological objects or concepts. The identified topics/concepts were further mapped to the controlled vocabulary of the Gene Ontology (GO terms based on mutual information. Conclusion The major and recurring biological concepts within a collection of MEDLINE documents can be extracted by the LDA model. The identified topics/concepts provide parsimonious and semantically-enriched representation of the texts in a semantic space with reduced dimensionality and can be used to index text.

Vaccine Hesitancy in Discussion Forums: Computer-Assisted Argument Mining with Topic Models.

Science.gov (United States)

Skeppstedt, Maria; Kerren, Andreas; Stede, Manfred

2018-01-01

Arguments used when vaccination is debated on Internet discussion forums might give us valuable insights into reasons behind vaccine hesitancy. In this study, we applied automatic topic modelling on a collection of 943 discussion posts in which vaccine was debated, and six distinct discussion topics were detected by the algorithm. When manually coding the posts ranked as most typical for these six topics, a set of semantically coherent arguments were identified for each extracted topic. This indicates that topic modelling is a useful method for automatically identifying vaccine-related discussion topics and for identifying debate posts where these topics are discussed. This functionality could facilitate manual coding of salient arguments, and thereby form an important component in a system for computer-assisted coding of vaccine-related discussions.

Topic models: A novel method for modeling couple and family text data

Science.gov (United States)

Atkins, David C.; Rubin, Tim N.; Steyvers, Mark; Doeden, Michelle A.; Baucom, Brian R.; Christensen, Andrew

2012-01-01

Couple and family researchers often collect open-ended linguistic data – either through free response questionnaire items or transcripts of interviews or therapy sessions. Because participant's responses are not forced into a set number of categories, text-based data can be very rich and revealing of psychological processes. At the same time it is highly unstructured and challenging to analyze. Within family psychology analyzing text data typically means applying a coding system, which can quantify text data but also has several limitations, including the time needed for coding, difficulties with inter-rater reliability, and defining a priori what should be coded. The current article presents an alternative method for analyzing text data called topic models (Steyvers & Griffiths, 2006), which has not yet been applied within couple and family psychology. Topic models have similarities with factor analysis and cluster analysis in that topic models identify underlying clusters of words with semantic similarities (i.e., the “topics”). In the present article, a non-technical introduction to topic models is provided, highlighting how these models can be used for text exploration and indexing (e.g., quickly locating text passages that share semantic meaning) and how output from topic models can be used to predict behavioral codes or other types of outcomes. Throughout the article a collection of transcripts from a large couple therapy trial (Christensen et al., 2004) is used as example data to highlight potential applications. Practical resources for learning more about topic models and how to apply them are discussed. PMID:22888778

Principles of topical treatment: advancement in gel vehicle technology.

Science.gov (United States)

Feldman, Steven R

2014-04-01

Topical treatment is a pillar of dermatologic practice. The delivery of drug by a topical vehicle is dependent on complex physical chemistry and on how well patients apply the product. The potency of topical agents is not solely dependent on the concentration of active drug in the vehicle. A corticosteroid molecule may have vastly different potency depending on what vehicle is used to deliver it. Similarly, a new gel vehicle is able to deliver considerably more active antifungal than an older vehicle technology and may represent a promising vehicle for other novel formulations. The use of new vehicles can provide more effective means for treating patients with skin disease.

INST7150 - Advanced Topics in Learning Object Design and Reuse, Fall 2005

OpenAIRE

Wiley, David

2005-01-01

This course is designed to help you understand and apply advanced topics in the design, creation, and reuse of learning objects. The course is structured around a practical, hands-on project using learning objects, intermingled with readings and discussion on a variety of topics.

Topical minoxidil in the treatment of alopecia areata.

Science.gov (United States)

Fenton, D A; Wilkinson, J D

1983-01-01

A modified double blind crossover study was performed to assess the effect of 1% topical minoxidil as compared with placebo in 30 patients with alopecia areata and alopecia totalis. The active preparation produced a highly significant incidence of hair regrowth. A cosmetically acceptable response was noted in 16 patients. No side effects were seen. The study confirmed that topical minoxidil will induce new hair growth in alopecia areata but that it is less likely to do so in more severe and extensive disease. Furthermore, patients with alopecia universalis and totalis may not respond at all. Nevertheless, as compared with other drugs minoxidil applied topically is relatively non-toxic, is easy to use, and has no systemic or local side effects. Images p1016-a PMID:6412929

Antimicrobial topical agents used in the vagina.

Science.gov (United States)

Frey Tirri, Brigitte

2011-01-01

Vaginally applied antimicrobial agents are widely used in the vagina in women with lower genital tract infections. An 'antimicrobial' is a general term that refers to a group of drugs that are effective against bacteria, fungi, viruses and protozoa. Topical treatments can be prescribed for a wide variety of vaginal infections. Many bacterial infections, such as bacterial vaginosis, desquamative inflammatory vaginitis or, as some European authors call it, aerobic vaginitis as well as infection with Staphylococcus aureus or group A streptococci, may be treated in this way. Candida vulvovaginitis is a fungal infection that is very amenable to topical treatment. The most common viral infections which can be treated with topical medications are condylomata acuminata and herpes simplex. The most often encountered protozoal vaginitis, which is caused by Trichomonas vaginalis, may be susceptible to topical medications, although this infection is treated systemically. This chapter covers the wide variety of commonly used topical antimicrobial agents for these diseases and focuses on the individual therapeutic agents and their clinical efficacy. In addition, potential difficulties that can occur in practice, as well as the usage of these medications in the special setting of pregnancy, are described in this chapter. Copyright © 2011 S. Karger AG, Basel.

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.

Science.gov (United States)

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

Topics in Nonlinear Dynamics

DEFF Research Database (Denmark)

Mosekilde, Erik

Through a significant number of detailed and realistic examples this book illustrates how the insights gained over the past couple of decades in the fields of nonlinear dynamics and chaos theory can be applied in practice. Aomng the topics considered are microbiological reaction systems, ecological...... food-web systems, nephron pressure and flow regulation, pulsatile secretion of hormones, thermostatically controlled radiator systems, post-stall maneuvering of aircrafts, transfer electron devices for microwave generation, economic long waves, human decision making behavior, and pattern formation...... in chemical reaction-diffusion systems....

Topics in Finance: Part VIII--Mergers & Acquisitions

Science.gov (United States)

Laux, Judy

2012-01-01

In this series, three key axioms--stockholder wealth maximization, the risk-return tradeoff, and agency conflicts--are applied to the major topics in financial management. The current article looks at mergers and acquisitions, reviewing the presumed motivations, the ethical challenges, and the literature dedicated to this financial activity.

A Lack of Systemic Absorption Following the Repeated Application of Topical Quetiapine in Healthy Adults.

Science.gov (United States)

Kayhart, Bryce; Lapid, Maria I; Nelson, Sarah; Cunningham, Julie L; Thompson, Virginia H; Leung, Jonathan G

2018-01-01

In the absence of suitable oral or intravenous access for medication administration and when the intramuscular medications are undesirable, alternative routes for drug delivery may be considered. Antipsychotics administered via an inhaled, intranasal, rectal, or topical route have been described in the literature. Topically administered antipsychotics have been previously reported to produce negligible systemic absorption despite being used in clinical practice for nausea and behavioral symptoms associated with dementia. Additionally, the American Academy of Hospice and Palliative Medicine recommends against the use of topical medications that lack supporting literature. Three studies have assessed the systemic absorption of different antipsychotics after administration of only a single, topically applied dose. To evaluate whether the repeated administration of a topically applied antipsychotic may result in detectable serum levels in an accumulating fashion, a pharmacokinetic study was conducted. Five healthy, adult participants consented to receive extemporaneously prepared topical quetiapine in Lipoderm every 4 hours for a total of 5 doses. Blood samples were drawn at baseline and hours 2, 4, 8, 12, 16, and 24, and serum quetiapine concentrations were measured using high-performance liquid chromatography. Quetiapine was undetectable in every sample from 3 participants. Two participants had minimally detectable serum quetiapine levels no sooner than hour 12 of the study period. Extemporaneously prepared quetiapine in Lipoderm resulted in nonexistent or minimal serum level following repeated topical administration. The use of topically applied quetiapine should still be questioned.

Applied mathematics

CERN Document Server

Logan, J David

2013-01-01

Praise for the Third Edition"Future mathematicians, scientists, and engineers should find the book to be an excellent introductory text for coursework or self-study as well as worth its shelf space for reference." -MAA Reviews Applied Mathematics, Fourth Edition is a thoroughly updated and revised edition on the applications of modeling and analyzing natural, social, and technological processes. The book covers a wide range of key topics in mathematical methods and modeling and highlights the connections between mathematics and the applied and nat

Transport phenomena an introduction to advanced topics

CERN Document Server

Glasgow, Larry A

2010-01-01

Enables readers to apply transport phenomena principles to solve advanced problems in all areas of engineering and science This book helps readers elevate their understanding of, and their ability to apply, transport phenomena by introducing a broad range of advanced topics as well as analytical and numerical solution techniques. Readers gain the ability to solve complex problems generally not addressed in undergraduate-level courses, including nonlinear, multidimensional transport, and transient molecular and convective transport scenarios. Avoiding rote memorization, the author em

What Patients Can Tell Us: Topic Analysis for Social Media on Breast Cancer.

Science.gov (United States)

Tapi Nzali, Mike Donald; Bringay, Sandra; Lavergne, Christian; Mollevi, Caroline; Opitz, Thomas

2017-07-31

Social media dedicated to health are increasingly used by patients and health professionals. They are rich textual resources with content generated through free exchange between patients. We are proposing a method to tackle the problem of retrieving clinically relevant information from such social media in order to analyze the quality of life of patients with breast cancer. Our aim was to detect the different topics discussed by patients on social media and to relate them to functional and symptomatic dimensions assessed in the internationally standardized self-administered questionnaires used in cancer clinical trials (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Core 30 [QLQ-C30] and breast cancer module [QLQ-BR23]). First, we applied a classic text mining technique, latent Dirichlet allocation (LDA), to detect the different topics discussed on social media dealing with breast cancer. We applied the LDA model to 2 datasets composed of messages extracted from public Facebook groups and from a public health forum (cancerdusein.org, a French breast cancer forum) with relevant preprocessing. Second, we applied a customized Jaccard coefficient to automatically compute similarity distance between the topics detected with LDA and the questions in the self-administered questionnaires used to study quality of life. Among the 23 topics present in the self-administered questionnaires, 22 matched with the topics discussed by patients on social media. Interestingly, these topics corresponded to 95% (22/23) of the forum and 86% (20/23) of the Facebook group topics. These figures underline that topics related to quality of life are an important concern for patients. However, 5 social media topics had no corresponding topic in the questionnaires, which do not cover all of the patients' concerns. Of these 5 topics, 2 could potentially be used in the questionnaires, and these 2 topics corresponded to a total of 3.10% (523

Machine Learning and Applied Linguistics

OpenAIRE

Vajjala, Sowmya

2018-01-01

This entry introduces the topic of machine learning and provides an overview of its relevance for applied linguistics and language learning. The discussion will focus on giving an introduction to the methods and applications of machine learning in applied linguistics, and will provide references for further study.

Non-adherence to topical treatments for actinic keratosis

Directory of Open Access Journals (Sweden)

Shergill B

2013-12-01

Full Text Available Bav Shergill,1 Simon Zokaie,2 Alison J Carr3 1Department of Dermatology, Brighton and Sussex University Hospitals, Elm Grove, Brighton, UK; 2Leo Pharma, Princes Risborough, 3Hamell, London, UK Background: There is limited information on the patterns of use, adherence rates, and factors that impact adherence with topical treatments for actinic keratosis (AK. Objectives: To establish patterns of use and adherence with topical treatments for AK and to identify treatment-related factors that impact on adherence. Methods: A community-based, cross-sectional study was performed using a standardized questionnaire completed online or via telephone interview. Patients were stratified according to the presence of AK lesions on the scalp and/or other extremities; and presence of scarring resulting from treatment. Results: This study included 305 patients with AK who were currently using a patient-applied topical therapy for AK or had used one within the previous 12 months. In total, 88% (n = 268/305 of patients were either non-adherent, non-persistent or both non-adherent and non-persistent to topical therapy. Duration of treatment was associated with increasing rates of non-adherence (adjusted odds ratio [OR]; for treatment durations greater than 4 weeks, 2.2, P < 0.01: 52% of patients were non-adherent with 3–4 week treatment duration; 69% of patients with 4–8 week treatment duration; and 71% of patients with 6–12 week treatment duration. There were similar increases in non-persistence with increasing treatment duration (adjusted OR; for treatment durations greater than 4 weeks, 2.1, P < 0.05. Conclusion: This study found high rates of non-adherence and non-persistence in patients with AK. Duration of treatment was a significant factor contributing to non-adherence and non-persistence to topical treatments. Patient-applied topical therapies that require less frequent application and have shorter treatment duration may be associated with improved

Co-occurrence of medical conditions: Exposing patterns through probabilistic topic modeling of snomed codes.

Science.gov (United States)

Bhattacharya, Moumita; Jurkovitz, Claudine; Shatkay, Hagit

2018-04-12

Patients associated with multiple co-occurring health conditions often face aggravated complications and less favorable outcomes. Co-occurring conditions are especially prevalent among individuals suffering from kidney disease, an increasingly widespread condition affecting 13% of the general population in the US. This study aims to identify and characterize patterns of co-occurring medical conditions in patients employing a probabilistic framework. Specifically, we apply topic modeling in a non-traditional way to find associations across SNOMED-CT codes assigned and recorded in the EHRs of >13,000 patients diagnosed with kidney disease. Unlike most prior work on topic modeling, we apply the method to codes rather than to natural language. Moreover, we quantitatively evaluate the topics, assessing their tightness and distinctiveness, and also assess the medical validity of our results. Our experiments show that each topic is succinctly characterized by a few highly probable and unique disease codes, indicating that the topics are tight. Furthermore, inter-topic distance between each pair of topics is typically high, illustrating distinctiveness. Last, most coded conditions grouped together within a topic, are indeed reported to co-occur in the medical literature. Notably, our results uncover a few indirect associations among conditions that have hitherto not been reported as correlated in the medical literature. Copyright © 2018. Published by Elsevier Inc.

Topics in Operator Theory

CERN Document Server

Ball, Joseph A; Helton, JWilliam; Rodman, Leiba; Spitkovsky, Iiya

2010-01-01

This is the first volume of a collection of original and review articles on recent advances and new directions in a multifaceted and interconnected area of mathematics and its applications. It encompasses many topics in theoretical developments in operator theory and its diverse applications in applied mathematics, physics, engineering, and other disciplines. The purpose is to bring in one volume many important original results of cutting edge research as well as authoritative review of recent achievements, challenges, and future directions in the area of operator theory and its applications.

Detecting Hotspot Information Using Multi-Attribute Based Topic Model.

Directory of Open Access Journals (Sweden)

Jing Wang

Full Text Available Microblogging as a kind of social network has become more and more important in our daily lives. Enormous amounts of information are produced and shared on a daily basis. Detecting hot topics in the mountains of information can help people get to the essential information more quickly. However, due to short and sparse features, a large number of meaningless tweets and other characteristics of microblogs, traditional topic detection methods are often ineffective in detecting hot topics. In this paper, we propose a new topic model named multi-attribute latent dirichlet allocation (MA-LDA, in which the time and hashtag attributes of microblogs are incorporated into LDA model. By introducing time attribute, MA-LDA model can decide whether a word should appear in hot topics or not. Meanwhile, compared with the traditional LDA model, applying hashtag attribute in MA-LDA model gives the core words an artificially high ranking in results meaning the expressiveness of outcomes can be improved. Empirical evaluations on real data sets demonstrate that our method is able to detect hot topics more accurately and efficiently compared with several baselines. Our method provides strong evidence of the importance of the temporal factor in extracting hot topics.

Detecting Hotspot Information Using Multi-Attribute Based Topic Model

Science.gov (United States)

Wang, Jing; Li, Li; Tan, Feng; Zhu, Ying; Feng, Weisi

2015-01-01

Microblogging as a kind of social network has become more and more important in our daily lives. Enormous amounts of information are produced and shared on a daily basis. Detecting hot topics in the mountains of information can help people get to the essential information more quickly. However, due to short and sparse features, a large number of meaningless tweets and other characteristics of microblogs, traditional topic detection methods are often ineffective in detecting hot topics. In this paper, we propose a new topic model named multi-attribute latent dirichlet allocation (MA-LDA), in which the time and hashtag attributes of microblogs are incorporated into LDA model. By introducing time attribute, MA-LDA model can decide whether a word should appear in hot topics or not. Meanwhile, compared with the traditional LDA model, applying hashtag attribute in MA-LDA model gives the core words an artificially high ranking in results meaning the expressiveness of outcomes can be improved. Empirical evaluations on real data sets demonstrate that our method is able to detect hot topics more accurately and efficiently compared with several baselines. Our method provides strong evidence of the importance of the temporal factor in extracting hot topics. PMID:26496635

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.

Analyzing research trends on drug safety using topic modeling.

Science.gov (United States)

Zou, Chen

2018-04-06

Published drug safety data has evolved in the past decade due to scientific and technological advances in the relevant research fields. Considering that a vast amount of scientific literature has been published in this area, it is not easy to identify the key information. Topic modeling has emerged as a powerful tool to extract meaningful information from a large volume of unstructured texts. Areas covered: We analyzed the titles and abstracts of 4347 articles in four journals dedicated to drug safety from 2007 to 2016. We applied Latent Dirichlet allocation (LDA) model to extract 50 main topics, and conducted trend analysis to explore the temporal popularity of these topics over years. Expert Opinion/Commentary: We found that 'benefit-risk assessment and communication', 'diabetes' and 'biologic therapy for autoimmune diseases' are the top 3 most published topics. The topics relevant to the use of electronic health records/observational data for safety surveillance are becoming increasingly popular over time. Meanwhile, there is a slight decrease in research on signal detection based on spontaneous reporting, although spontaneous reporting still plays an important role in benefit-risk assessment. The topics related to medical conditions and treatment showed highly dynamic patterns over time.

Topical tags vs non-topical tags : Towards a bipartite classification?

NARCIS (Netherlands)

Basile, Valerio; Peroni, Silvio; Tamburini, Fabio; Vitali, Fabio

2015-01-01

In this paper we investigate whether it is possible to create a computational approach that allows us to distinguish topical tags (i.e. talking about the topic of a resource) and non-topical tags (i.e. describing aspects of a resource that are not related to its topic) in folksonomies, in a way that

Topicality and impact in social media: diverse messages, focused messengers.

Science.gov (United States)

Weng, Lilian; Menczer, Filippo

2015-01-01

We have a limited understanding of the factors that make people influential and topics popular in social media. Are users who comment on a variety of matters more likely to achieve high influence than those who stay focused? Do general subjects tend to be more popular than specific ones? Questions like these demand a way to detect the topics hidden behind messages associated with an individual or a keyword, and a gauge of similarity among these topics. Here we develop such an approach to identify clusters of similar hashtags in Twitter by detecting communities in the hashtag co-occurrence network. Then the topical diversity of a user's interests is quantified by the entropy of her hashtags across different topic clusters. A similar measure is applied to hashtags, based on co-occurring tags. We find that high topical diversity of early adopters or co-occurring tags implies high future popularity of hashtags. In contrast, low diversity helps an individual accumulate social influence. In short, diverse messages and focused messengers are more likely to gain impact.

Enhanced uptake and photoactivation of topical methyl aminolevulinate after fractional CO2 laser pretreatment

DEFF Research Database (Denmark)

Haedersdal, M; Katsnelson, J; Sakamoto, F H

2011-01-01

Photodynamic therapy (PDT) of thick skin lesions is limited by topical drug uptake. Ablative fractional resurfacing (AFR) creates vertical channels that may facilitate topical PDT drug penetration and improve PDT-response in deep skin layers. The purpose of this study was to evaluate whether pre......-treating the skin with AFR before topically applied methyl aminolevulinate (MAL) could enable a deep PDT-response....

In-vivo remission spectroscopy on tattoos and topically applied photosensitizers in man

Science.gov (United States)

Koenig, Karsten; Beck, Gerd C.; Boehncke, Wolf-Henning; Kaufmann, Roland; Hibst, Raimund

1994-02-01

In-vivo remission spectra of the human skin in the spectral region of 400 nm to 800 nm were recorded using a xenon lamp as an excitation source, a fiberoptical sensor combined with a polychromator, and a multichannel analyzer. The remission of amateur tattoos before and after laser treatment (Q-switched Nd:YAG) was measured and the degree of blanching determined. It was found that the process of blanching proceeds partly reversible. In another study, the time-dependent remission of human skin after topical administration of the photosensitizer Methylene Blue was studied. The additional application of the ceratolytic agent urea promotes the penetration of the thiazine dye. The experimental data were analyzed by the Kubelka Munk theory.

Topical Antimycotics for Oral Candidiasis in Warfarin Users

DEFF Research Database (Denmark)

Hellfritzsch, Maja; Pottegård, Anton; Pedersen, Andreas James Thestrup

2017-01-01

Treatment for oral candidiasis in warfarin users may be complicated by drug-drug interactions (DDIs) between warfarin and topically applied antimycotics. However, current knowledge of these putative DDIs is merely based on case series. We therefore performed a cohort cross-over study with the obj......Treatment for oral candidiasis in warfarin users may be complicated by drug-drug interactions (DDIs) between warfarin and topically applied antimycotics. However, current knowledge of these putative DDIs is merely based on case series. We therefore performed a cohort cross-over study...... increased from 2.5 (95% CI: 2.1-2.8) to 3.8 (95% CI: 2.8-4.8) after exposure, corresponding to a mean INR increase of 1.4 (95% CI: 0.3-2.4). Among 30 warfarin users exposed to nystatin oral solution, the mean INR was 2.7 (95% CI: 2.3-3.1) before and 2.5 (95% CI: 2.2-2.9) after exposure. In conclusion, we...

Severe hyperkalemia as a complication of timolol, a topically applied beta-adrenergic antagonist

International Nuclear Information System (INIS)

Swenson, E.R.

1986-01-01

Severe hyperkalemia occurred in a patient with radiation pneumonitis and glaucoma shortly after beginning prednisone therapy. There was no evidence of renal failure, diabetes, acidosis, increased potassium intake, or significant tissue trauma. Medications having adverse effects on potassium metabolism were considered, and the patient's use of timolol maleate eyedrops was discontinued. His serum potassium level normalized despite continuation of the prednisone therapy. He became hyperkalemic on rechallenge with timolol and normokalemic following its withdrawal. This case indicates that the potential for beta-blocker-induced hyperkalemia exists even with topical appreciation

The Rise of Applied Geography.

Science.gov (United States)

Philpponneau, Michel

1981-01-01

Presents an historical overview of the use of the science of geography for practical purposes. Topics discussed include British schools of geography during the 19th century, contributions of many of the founders of applied geography, forms in which geographical work can be used for practical purposes, and the status of applied geography in various…

Understanding the Correlations between Social Attention and Topic Trends of Scientific Publications

Directory of Open Access Journals (Sweden)

Xianlei Dong

2016-03-01

Full Text Available Purpose: We propose and apply a simplified nowcasting model to understand the correlations between social attention and topic trends of scientific publications. Design/methodology/approach: First, topics are generated from the obesity corpus by using the latent Dirichlet allocation (LDA algorithm and time series of keyword search trends in Google Trends are obtained. We then establish the structural time series model using data from January 2004 to December 2012, and evaluate the model using data from January 2013. We employ a state-space model to separate different non-regression components in an observational time series (i.e. the tendency and the seasonality and apply the “spike and slab prior” and stepwise regression to analyze the correlations between the regression component and the social media attention. The two parts are combined using Markov-chain Monte Carlo sampling techniques to obtain our results. Findings: The results of our study show that (1 the number of publications on child obesity increases at a lower rate than that of diabetes publications; (2 the number of publication on a given topic may exhibit a relationship with the season or time of year; and (3 there exists a correlation between the number of publications on a given topic and its social media attention, i.e. the search frequency related to that topic as identified by Google Trends. We found that our model is also able to predict the number of publications related to a given topic. Research limitations: First, we study a correlation rather than causality between topics' trends and social media. As a result, the relationships might not be robust, so we cannot predict the future in the long run. Second, we cannot identify the reasons or conditions that are driving obesity topics to present such tendencies and seasonal patterns, so we might need to do “field” study in the future. Third, we need to improve the efficiency of our model by finding more efficient

Journal of Applied Science and Technology: Submissions

African Journals Online (AJOL)

The Journal of Applied Science and Technology (JAST) seeks to promote and ... knowledge of various research topics in the applied sciences which address issues of ... Numerical value must be separated from the Physical Unit by 1 spacing.

The use of biodegradable microneedle patches to increase penetration of topical steroid for prurigo nodularis.

Science.gov (United States)

Shin, Jung U; Kim, Jung Dong; Kim, Hong Kee; Kang, Hong Kyu; Joo, Chulmin; Lee, Ju Hee; Jeong, Do Hyeon; Song, Seungri; Chu, Howard; Lee, Jung Soo; Lee, Hemin; Lee, Kwang Hoon

2018-02-01

The stratum corneum is an almost impermeable barrier. Recently, microneedles have been used to increase drug delivery passing the stratum corneum by incorporating the drug within the microneedle or by coating the surface of the microneedle with the drug. This study was performed to investigate whether applying a biodegradable microneedle patch after topical steroid application increases penetration of the steroid in vitro, as well as treatment efficacy in patients with prurigo nodularis. In vitro penetration of topical steroids after biodegradable microneedle patch application was measured using a 3D skin model. To evaluate the treatment efficacy of the combination of biodegradable microneedle and topical steroids, a split-body clinical study was performed. Penetration of topical steroid in the in vitro skin model was significantly greater in the microneedle-applied skin. In a split-body clinical study with prurigo nodularis patients, the area and height of skin lesions decreased after four weeks of treatment on both sides, however, the microneedle patch side exhibited a significantly greater decrease in both area and height, compared to the control side. The pruritus visual analogue scale was also significantly lower on the microneedle side. We suggest that simply applying a microneedle patch after topical steroid application could be a useful strategy for treating refractory skin diseases such as prurigo nodularis.

Deposition and transport of linezolid mediated by a synthetic surfactant Synsurf® within a pressurized metered dose inhaler: a Calu-3 model

Science.gov (United States)

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.

Changing the Topic. Topic Position in Ancient Greek Word Order

NARCIS (Netherlands)

Allan, R.J.

2014-01-01

Ancient Greek, topics can be expressed as intra-clausal constituents but they can also precede or follow the main clause as extra-clausal constituents. Together, these various topic expressions constitute a coherent system of complementary pragmatic functions. For a comprehensive account of topic

Methods of applied mathematics with a software overview

CERN Document Server

Davis, Jon H

2016-01-01

This textbook, now in its second edition, provides students with a firm grasp of the fundamental notions and techniques of applied mathematics as well as the software skills to implement them. The text emphasizes the computational aspects of problem solving as well as the limitations and implicit assumptions inherent in the formal methods. Readers are also given a sense of the wide variety of problems in which the presented techniques are useful. Broadly organized around the theme of applied Fourier analysis, the treatment covers classical applications in partial differential equations and boundary value problems, and a substantial number of topics associated with Laplace, Fourier, and discrete transform theories. Some advanced topics are explored in the final chapters such as short-time Fourier analysis and geometrically based transforms applicable to boundary value problems. The topics covered are useful in a variety of applied fields such as continuum mechanics, mathematical physics, control theory, and si...

Cutaneous in vivo metabolism of topical lidocaine formulation in human skin

DEFF Research Database (Denmark)

Rolsted, K; Benfeldt, E; Kissmeyer, A-M

2009-01-01

Little is known about the metabolising capacity of the human skin in relation to topically applied drugs and formulations. We chose lidocaine as a model compound since the metabolic pathways are well known from studies concerning hepatic metabolism following systemic drug administration. However......, the enzymes involved are also expressed in the skin. Hence, the aim of the current study was to investigate the extent of the cutaneous in vivo metabolism of topically applied lidocaine in human volunteers. A dose of 5 mg/cm(2) of Xylocaine(R) (5% lidocaine) ointment was applied onto the buttock skin...... of the volunteers. After 2 h, residual formulation was removed, and two 4-mm punch biopsies were taken from each volunteer. The quantity of lidocaine extracted from the skin samples (epidermis + dermis) was 109 +/- 43 ng/mm(2) skin. One metabolite (monoethylglycine xylidide, MEGX) was detected in skin from 7...

In vitro efficacy and pharmacodynamic indices for antibiotics against coagulase-negative staphylococcus endophthalmitis isolates.

Science.gov (United States)

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

Efficacy, tolerability and consumer acceptability of terbinafine topical spray versus terbinafine topical solution: a phase IIa, randomised, observer-blind, comparative study.

Science.gov (United States)

Brown, Marc; Evans, Charles; Muddle, Andrew; Turner, Rob; Lim, Sian; Reed, Jessica; Traynor, Matt

2013-10-01

spray and the topical solution showed comparable anti-fungal activity. Furthermore, the non-inferiority of topical spray to the topical solution was confirmed as determined by the proportion of patients categorised as successfully treated at week 1. This confirms that a topical spray product, which can be applied once without touching the affected skin, is equally as effective in the treatment of tinea pedis and removes the risk of organism transfer associated with touching infected areas. EudraCT-No. 2008-002399-92.

Genetic algorithms applied to nonlinear and complex domains; TOPICAL

International Nuclear Information System (INIS)

Barash, D; Woodin, A E

1999-01-01

The dissertation, titled ''Genetic Algorithms Applied to Nonlinear and Complex Domains'', describes and then applies a new class of powerful search algorithms (GAS) to certain domains. GAS are capable of solving complex and nonlinear problems where many parameters interact to produce a ''final'' result such as the optimization of the laser pulse in the interaction of an atom with an intense laser field. GAS can very efficiently locate the global maximum by searching parameter space in problems which are unsuitable for a search using traditional methods. In particular, the dissertation contains new scientific findings in two areas. First, the dissertation examines the interaction of an ultra-intense short laser pulse with atoms. GAS are used to find the optimal frequency for stabilizing atoms in the ionization process. This leads to a new theoretical formulation, to explain what is happening during the ionization process and how the electron is responding to finite (real-life) laser pulse shapes. It is shown that the dynamics of the process can be very sensitive to the ramp of the pulse at high frequencies. The new theory which is formulated, also uses a novel concept (known as the (t,t') method) to numerically solve the time-dependent Schrodinger equation Second, the dissertation also examines the use of GAS in modeling decision making problems. It compares GAS with traditional techniques to solve a class of problems known as Markov Decision Processes. The conclusion of the dissertation should give a clear idea of where GAS are applicable, especially in the physical sciences, in problems which are nonlinear and complex, i.e. difficult to analyze by other means

Mining FDA drug labels using an unsupervised learning technique--topic modeling.

Science.gov (United States)

Bisgin, Halil; Liu, Zhichao; Fang, Hong; Xu, Xiaowei; Tong, Weida

2011-10-18

The Food and Drug Administration (FDA) approved drug labels contain a broad array of information, ranging from adverse drug reactions (ADRs) to drug efficacy, risk-benefit consideration, and more. However, the labeling language used to describe these information is free text often containing ambiguous semantic descriptions, which poses a great challenge in retrieving useful information from the labeling text in a consistent and accurate fashion for comparative analysis across drugs. Consequently, this task has largely relied on the manual reading of the full text by experts, which is time consuming and labor intensive. In this study, a novel text mining method with unsupervised learning in nature, called topic modeling, was applied to the drug labeling with a goal of discovering "topics" that group drugs with similar safety concerns and/or therapeutic uses together. A total of 794 FDA-approved drug labels were used in this study. First, the three labeling sections (i.e., Boxed Warning, Warnings and Precautions, Adverse Reactions) of each drug label were processed by the Medical Dictionary for Regulatory Activities (MedDRA) to convert the free text of each label to the standard ADR terms. Next, the topic modeling approach with latent Dirichlet allocation (LDA) was applied to generate 100 topics, each associated with a set of drugs grouped together based on the probability analysis. Lastly, the efficacy of the topic modeling was evaluated based on known information about the therapeutic uses and safety data of drugs. The results demonstrate that drugs grouped by topics are associated with the same safety concerns and/or therapeutic uses with statistical significance (P<0.05). The identified topics have distinct context that can be directly linked to specific adverse events (e.g., liver injury or kidney injury) or therapeutic application (e.g., antiinfectives for systemic use). We were also able to identify potential adverse events that might arise from specific

2015 ICSA/Graybill Applied Statistics Symposium

CERN Document Server

Wang, Bushi; Hu, Xiaowen; Chen, Kun; Liu, Ray

2016-01-01

The papers in this volume represent a broad, applied swath of advanced contributions to the 2015 ICSA/Graybill Applied Statistics Symposium of the International Chinese Statistical Association, held at Colorado State University in Fort Collins. The contributions cover topics that range from statistical applications in business and finance to applications in clinical trials and biomarker analysis. Each papers was peer-reviewed by at least two referees and also by an editor. The conference was attended by over 400 participants from academia, industry, and government agencies around the world, including from North America, Asia, and Europe. Focuses on statistical applications from clinical trials, biomarker analysis, and personalized medicine to applications in finance and business analytics A unique selection of papers from broad and multi-disciplinary critical hot topics - from academic, government, and industry perspectives - to appeal to a wide variety of applied research interests All papers feature origina...

Experimental model of the burn wound topical treatment

Directory of Open Access Journals (Sweden)

Amra Čabaravdić

2003-11-01

Full Text Available AbstractBACKGROUND AND PURPOSE:Clinical research of drugs is a researching step subsequent to the preclinical studies in experimental animals. The aim of our research was to evaluate animal model of wound healing process after the burninducement and effects of the ointment containing natural plants on the process of burn healing.MATERIAL AND METHODS:Burn wounds were experimentally induced in two species of experimental animals which were treated with topically applied herbal preparation with concomitant monitoring of the healing process. Experimental groups (1 of 15 animals each (mice and rats, while control group (2 of 10 animals each (mice and rats that were not being treated with herbal ointment. After the hair removal, burn was induced on the back of animals by heated brass seal. Different clinical symptoms including oedema of surrounding tissue, redness, exudation, size of the burn surface, histological and microbiological findings were monitored on the days 1, 3, 7, 14 and 21. A statistically significant difference was observed throughout descriptive statistics and paired Student's t-test.CONCLUSION:Physiological healing processes of the acute burn wound following the topical application of herbal preparation can be monitored on the utilized animal model. A three-week treatment resulted in the 90% of completed epithelization in both animal species, indicating the effectiveness of topically applied herbal preparation.

Simplifying Skin Disease Diagnosis with Topical Nanotechnology.

Science.gov (United States)

Yeo, David C; Xu, Chenjie

2018-05-01

A new study published in the journal Nature Biomedical Engineering 1 documents a novel diagnostic technology that exploits topically applied nanotechnology to detect skin tissue biomarkers for diagnosis. This concept is demonstrated by noninvasively imaging connective tissue growth factor (CTGF) mRNA in abnormal scar cells, whole tissue, and animal models. In this commentary, we highlight the main findings and discuss their implications. Successful implementation in the clinic could give rise to self-applied, biopsy-free diagnostic technology and significantly reduce healthcare burden. Crucially, noninvasive visualization of disease biomarkers, mobile device signal acquisition, and Internet-enabled transmission could significantly transform the diagnosis of skin disease and other superficial tissues.

High death rate in mice treated topically with diclofenac

DEFF Research Database (Denmark)

Lerche, Catharina M; Philipsen, Peter A; Poulsen, Thomas

2011-01-01

). Diclofenac was applied topically on the backs of hairless, female, C3.Cg/TifBomTac immunocompetent mice three times weekly followed by ultraviolet radiation (2, 3, or 4 Standard Erythema Dose) until death. There was a significant difference in survival between diclofenac-treated groups and control groups (P...

Freshman Health Topics

Science.gov (United States)

Hovde, Karen

2011-01-01

This article examines a cluster of health topics that are frequently selected by students in lower division classes. Topics address issues relating to addictive substances, including alcohol and tobacco, eating disorders, obesity, and dieting. Analysis of the topics examines their interrelationships and organization in the reference literature.…

Mining FDA drug labels using an unsupervised learning technique - topic modeling

Science.gov (United States)

2011-01-01

Background The Food and Drug Administration (FDA) approved drug labels contain a broad array of information, ranging from adverse drug reactions (ADRs) to drug efficacy, risk-benefit consideration, and more. However, the labeling language used to describe these information is free text often containing ambiguous semantic descriptions, which poses a great challenge in retrieving useful information from the labeling text in a consistent and accurate fashion for comparative analysis across drugs. Consequently, this task has largely relied on the manual reading of the full text by experts, which is time consuming and labor intensive. Method In this study, a novel text mining method with unsupervised learning in nature, called topic modeling, was applied to the drug labeling with a goal of discovering “topics” that group drugs with similar safety concerns and/or therapeutic uses together. A total of 794 FDA-approved drug labels were used in this study. First, the three labeling sections (i.e., Boxed Warning, Warnings and Precautions, Adverse Reactions) of each drug label were processed by the Medical Dictionary for Regulatory Activities (MedDRA) to convert the free text of each label to the standard ADR terms. Next, the topic modeling approach with latent Dirichlet allocation (LDA) was applied to generate 100 topics, each associated with a set of drugs grouped together based on the probability analysis. Lastly, the efficacy of the topic modeling was evaluated based on known information about the therapeutic uses and safety data of drugs. Results The results demonstrate that drugs grouped by topics are associated with the same safety concerns and/or therapeutic uses with statistical significance (P<0.05). The identified topics have distinct context that can be directly linked to specific adverse events (e.g., liver injury or kidney injury) or therapeutic application (e.g., antiinfectives for systemic use). We were also able to identify potential adverse events that

Skin penetration and tissue permeation after topical administration of diclofenac.

Science.gov (United States)

Hagen, Martina; Baker, Mark

2017-09-01

Topical delivery of drugs is an alternative to oral administration, often with similar efficacy but potentially a more favorable tolerability profile. However, topical formulations need to be able to penetrate the skin and permeate to the target areas in quantities sufficient to exert a therapeutic effect. Many factors can affect this process, including the physicochemical properties of the drug, the formulation used, and the site and mode of application. It is believed that measurement of drug concentrations at the sites of action may be an indicator of their likely efficacy. This review addresses these issues, with reference to topically administered diclofenac in osteoarthritis. Articles relevant to this review were identified after a systematic search of Medline and Embase, using the key words "diclofenac", "topical administration" and "osteoarthritis" in the search strategy. The sparse data available indicate that topical diclofenac can penetrate and permeate to deeper tissues, with a lower plasma to tissue ratio than oral diclofenac. The tissue diclofenac levels after topical delivery are sustained over time (at least several hours). However, there is not enough data to establish how diclofenac levels in the joint compare with IC 50 levels (50% of the maximum inhibition of prostaglandin synthesis) established following oral administration. After topical application, diclofenac can penetrate the skin and permeate to deeper tissues, where it reaches a concentration that appears to be sufficient to exert a therapeutic effect. More robust methods are required for in vivo characterization to better estimate the clinical efficacy of topically applied drugs.

Effective photoprotection of human skin against infrared A radiation by topically applied antioxidants: results from a vehicle controlled, double-blind, randomized study.

Science.gov (United States)

Grether-Beck, Susanne; Marini, Alessandra; Jaenicke, Thomas; Krutmann, Jean

2015-01-01

Infrared A radiation (IRA) from solar sunlight contributes to photoaging of human skin, e.g. by upregulating MMP-1 expression in dermal fibroblasts, indicating the need for photoprotection of human skin against IRA. Up to now, however, there has been no controlled study to show that effective protection of human skin against IRA radiation is possible. Here, we have conducted a randomized, controlled, double-blinded prospective study in 30 healthy volunteers to assess the capacity of an SPF 30 sunscreen versus the same sunscreen supplemented with an antioxidant cocktail containing grape seed extract, vitamin E, ubiquinone and vitamin C to protect human skin against IRA radiation-induced MMP-1 upregulation. As expected, exposure to IRA radiation significantly upregulated MMP-1 expression, as compared to unirradiated skin, and this response was significantly reduced, if the SPF30 sunscreen plus the antioxidant cocktail had been applied prior to IRA radiation. In contrast, treatment of human skin with the SPF30 sunscreen alone did not provide significant protection. These results indicate that topically applied antioxidants effectively protect human skin against IRA radiation and that regular sunscreens need to be supplemented with specific antioxidants in order to achieve IRA photoprotection. © 2014 The American Society of Photobiology.

Evaluating topic models with stability

CSIR Research Space (South Africa)

De Waal, A

2008-11-01

Full Text Available Topic models are unsupervised techniques that extract likely topics from text corpora, by creating probabilistic word-topic and topic-document associations. Evaluation of topic models is a challenge because (a) topic models are often employed...

A study of an ethics education topic for undergraduate nursing students.

Science.gov (United States)

Kalaitzidis, Evdokia; Schmitz, Karl

2012-01-01

The study aims to explore nursing students' perceptions of the relative value of various aspects of the ethical component of the undergraduate topic, 'Ethics and Law applied to Nursing' (topic NURS2104). To enable time for reflection on ethics in nursing, sampling occurred 1 year after successful completion of the above-mentioned topic and after successful completion of all but the final clinical experience components of the Bachelor of Nursing (BN) degree. A significant proportion of respondents perceived ethics education as relevant to professional practices. It is also noteworthy that the ethical decision-making strategies that had been incorporated into the topic (NURS2104) became transformed by the clinical experience of each particular student. While results of this study are not conclusive, they nevertheless provide important information for future nursing students on the evolutionary development of ethics education. Copyright © 2011 Elsevier Ltd. All rights reserved.

Comprehensive review on additives of topical dosage forms for drug delivery.

Science.gov (United States)

Garg, Tarun; Rath, Goutam; Goyal, Amit K

2015-12-01

Skin is the largest organ of the human body and plays the most important role in protecting against pathogen and foreign matter. Three important modes such as topical, regional and transdermal are widely used for delivery of various dosage forms. Among these modes, the topical dosage forms are preferred because it provides local therapeutic activity when applied to the skin or mucous membranes. Additives or pharmaceutical excipients (non-drug component of dosage form) are used as inactive ingredients in dosage form or tools for structuring dosage forms. The main use of topical dosage form additives are controling the extent of absorption, maintaining the viscosity, improving the stability as well as organoleptic property and increasing the bulk of the formulation. The overall goal of this article is to provide the clinician with information related to the topical dosage form additives and their current major applications against various diseases.

Topical report review status

International Nuclear Information System (INIS)

1997-08-01

This report provides industry with procedures for submitting topical reports, guidance on how the U.S. Nuclear Regulatory Commission (NRC) processes and responds to topical report submittals, and an accounting, with review schedules, of all topical reports currently accepted for review schedules, of all topical reports currently accepted for review by the NRC. This report will be published annually. Each sponsoring organization with one or more topical reports accepted for review copies

Dressings and topical agents for preventing pressure ulcers.

Science.gov (United States)

Moore, Zena E H; Webster, Joan

2013-08-18

authors working independently, using pre-determined inclusion and quality criteria. Five trials (940 participants) of unclear or high risk of bias compared a topical agent with a placebo. Four of these trials randomised by individual and one by cluster. When results from the five trials were combined, the risk ratio (RR) was 0.78 (95% CI 0.47 to 1.31; P value 0.35) indicating no overall beneficial effect of the topical agents. When the cluster randomised trial was omitted from the analysis, use of topical agents reduced the pressure ulcer incidence by 36%; RR 0.64 (95% CI 0.49 to 0.83; P value 0.0008).Four trials (561 participants), all of which were of high or unclear risk of bias, showed that dressings applied over bony prominences reduced pressure ulcer incidence; RR 0.21 (95% CI 0.09 to 0.51; P value 0.0006). There is insufficient evidence from RCTs to support or refute the use of topical agents applied over bony prominences to prevent pressure ulcers. Although the incidence of pressure ulcers was reduced when dressings were used to protect the skin, results were compromised by the low quality of the included trials. These trials contained substantial risk of bias and clinical heterogeneity (variations in populations and interventions); consequently, results should be interpreted as inconclusive. Further well designed trials addressing important clinical, quality of life and economic outcomes are justified, based on the incidence of the problem and the high costs associated with pressure ulcer management.

Topics in inflationary cosmology

International Nuclear Information System (INIS)

Kahn, R.N.

1985-01-01

This thesis examines several topics in the theory of inflationary cosmology. It first proves the existence of Hawking Radiation during the slow-rolling period of a new inflationary universe. It then derives and somewhat extends Bardeen's gauge invariant formalism for calculating the growth of linear gravitational perturbations in a Friedmann-Robertson-Walker cosmological background. This formalism is then applied, first to several new inflationary universe models all of which show a Zel'dovich spectrum of fluctuations, but with amplitude sigma(100 4 ) above observational limits. The general formalism is next applied to models that exhibit primordial inflation. Fluctuations in these models also exhibit a Zel'dovich spectrum here with an acceptable amplitude. Finally the thesis presents the results of new, numerical calculations. A classical, (2 + 1) dimensional computer model is developed that includes a Higgs field (which drives inflation) along with enough auxiliary fields to generate dynamically not only a thermal bath, but also the fluctuations that naturally accompany that bath. The thesis ends with a discussion of future prospects

Syntacticized topics in Kurmuk

DEFF Research Database (Denmark)

Andersen, Torben

2015-01-01

This article argues that Kurmuk, a little-described Western Nilotic language, is characterized by a syntacticized topic whose grammatical relation is variable. In this language, declarative clauses have as topic an obligatory preverbal NP which is either a subject, an object or an adjunct....... The grammatical relation of the topic is expressed by a voice-like inflection of the verb, here called orientation. While subject-orientation is morphologically unmarked, object-oriented and adjunct-oriented verbs are marked by a subject suffix or by a suffix indicating that the topic is not subject, and adjunct......-orientation differs from object-orientation by a marked tone pattern. Topic choice largely reflects information structure by indicating topic continuity. The topic also plays a crucial role in relative clauses and in clauses with contrastive constituent focus, in that objects and adjuncts can only be relativized...

Applied survival analysis using R

CERN Document Server

Moore, Dirk F

2016-01-01

Applied Survival Analysis Using R covers the main principles of survival analysis, gives examples of how it is applied, and teaches how to put those principles to use to analyze data using R as a vehicle. Survival data, where the primary outcome is time to a specific event, arise in many areas of biomedical research, including clinical trials, epidemiological studies, and studies of animals. Many survival methods are extensions of techniques used in linear regression and categorical data, while other aspects of this field are unique to survival data. This text employs numerous actual examples to illustrate survival curve estimation, comparison of survivals of different groups, proper accounting for censoring and truncation, model variable selection, and residual analysis. Because explaining survival analysis requires more advanced mathematics than many other statistical topics, this book is organized with basic concepts and most frequently used procedures covered in earlier chapters, with more advanced topics...

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.

Nigeria Journal of Pure and Applied Physics

African Journals Online (AJOL)

Nigeria Journal of Pure and Applied Physics publishes papers of the highest quality and significance in specific areas of physics, pure and applied, as listed below. The journal content reflects core physics disciplines, but is also open to a broad range of topics whose central theme falls within the bounds of physics.

Topics in multivariate approximation and interpolation

CERN Document Server

Jetter, Kurt

2005-01-01

This book is a collection of eleven articles, written by leading experts and dealing with special topics in Multivariate Approximation and Interpolation. The material discussed here has far-reaching applications in many areas of Applied Mathematics, such as in Computer Aided Geometric Design, in Mathematical Modelling, in Signal and Image Processing and in Machine Learning, to mention a few. The book aims at giving a comprehensive information leading the reader from the fundamental notions and results of each field to the forefront of research. It is an ideal and up-to-date introduction for gr

Introduction to applied thermodynamics

CERN Document Server

Helsdon, R M; Walker, G E

1965-01-01

Introduction to Applied Thermodynamics is an introductory text on applied thermodynamics and covers topics ranging from energy and temperature to reversibility and entropy, the first and second laws of thermodynamics, and the properties of ideal gases. Standard air cycles and the thermodynamic properties of pure substances are also discussed, together with gas compressors, combustion, and psychrometry. This volume is comprised of 16 chapters and begins with an overview of the concept of energy as well as the macroscopic and molecular approaches to thermodynamics. The following chapters focus o

Transdermal and Topical Drug Administration in the Treatment of Pain

Directory of Open Access Journals (Sweden)

Wojciech Leppert

2018-03-01

Full Text Available The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. An effective therapy for pain depends on the intensity and type of pain, the patients’ age, comorbidities, and appropriate choice of analgesic, its dose and route of administration. This review is aimed at presenting current knowledge on analgesics administered by transdermal and topical routes for physicians, nurses, pharmacists, and other health care professionals dealing with patients suffering from pain. Analgesics administered transdermally or topically act through different mechanisms. Opioids administered transdermally are absorbed into vessels located in subcutaneous tissue and, subsequently, are conveyed in the blood to opioid receptors localized in the central and peripheral nervous system. Non–steroidal anti–inflammatory drugs (NSAIDs applied topically render analgesia mainly through a high concentration in the structures of the joint and a provision of local anti–inflammatory effects. Topically administered drugs such as lidocaine and capsaicin in patches, capsaicin in cream, EMLA cream, and creams containing antidepressants (i.e., doxepin, amitriptyline act mainly locally in tissues through receptors and/or ion channels. Transdermal and topical routes offer some advantages over systemic analgesic administration. Analgesics administered topically have a much better profile for adverse effects as they relieve local pain with minimal systemic effects. The transdermal route apart from the above-mentioned advantages and provision of long period of analgesia may be more convenient, especially for patients who are unable to take drugs orally. Topically and transdermally administered opioids are characterised by a lower risk of addiction compared to oral and parenteral routes.

The Effectiveness of Topical Pimecrolimus in the Treatment of Oral Lichen Planus

Directory of Open Access Journals (Sweden)

Mehmet Kamil Mülayim

2016-12-01

Full Text Available Objectives: Oral lichen planus (OLP is a chronic inflammatory disorder of unknown etiology that affects the skin and the mucosa, especially the oral mucosa. Several therapeutic agents have been investigated for the treatment of OLP. All agents used in the OLP therapy are palliative. Potent topical steroids are used as the conventional therapy for OLP. Since side-effects or steroid resistance may be encountered, alternative treatments may be necessary. This study aimed to evaluate the efficacy and safety of the topical pimecrolimus in the treatment of OLP. Methods: Seventeen patients with OLP were recruited into this study. Topical pimecrolimus 1% cream was applied twice a day to the affected areas. Patients were followed up for 3-6 months. Photographs of the lesions were taken and analyzed for areas of ulceration, erythema, and reticulation in every clinical examination. Results: We found that topical pimecrolimus 1% cream was an effective treatment for OLP. Two patients could not complete the treatment protocol because of the side effects such as local irritation and nausea. Conclusion: Topical pimecrolimus may be a valuable second treatment choice for patients with steroid-related side-effects or steroid-resistant OLP. However further randomized controlled studies have to be conducted to compare conventional treatment of topical corticosteroid with topical pimecrolimus.

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.

Science.gov (United States)

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

The effects of oral and topical corticosteroid in rabbit corneas.

Science.gov (United States)

Araki-Sasaki, Kaoru; Katsuta, Osamu; Mano, Hidetoshi; Nagano, Takashi; Nakamura, Masatsugu

2016-09-05

To determine the most effective route of administration of corticosteroids in the treatment of ocular surface disease, by characterizing the difference between oral prednisolone and topical dexamethasone administration using an animal model. Pharmacokinetic analyses determined the corticosteroid concentrations in the normal ocular tissues of rabbits after oral or topical administration of corticosteroids using LC-MS/MS. In wound healing analyses, the area of the epithelial defect created by keratectomy using a 6-mm trephine was calculated with an image analyzer using an orally or topically steroid-administrated animal model. The average size of basal epithelial cells, the frequency of mitotic basal epithelial cells, the number of squamous cells, and the number of hypertrophic stromal fibroblasts were determined in the enucleated corneal tissues after wound closure. By slit lamp examination, no remarkable differences were observed between orally and topically administered groups. Pharmacokinetic analyses showed that the distribution of dexamethasone after topical administration was superior to that after oral administration in the cornea. In contrast, both concentrations of corticosteroid applied topically and orally were similar with regards to AUCs (area under the concentration-time curve) in the conjunctiva. Although the healing rate was slower in the topical group, all corneas were almost healed within 96 h in the wound healing analysis. According to the histological analyses of epithelial cells, the average basal cell size was larger, the frequency of mitotic basal cells was greater, and the number of squamous epithelial cell layers was lower in the topically administered group although all of these differences were with no statistical significance. However, the number of hypertrophic stromal fibroblasts in the topically administered group was significantly lower than that in the orally administered group. There are different distributions and effects between

Topical therapy of recurrent herpes - acyclovir versus tromantidine

Directory of Open Access Journals (Sweden)

Kumar Bhushan

1991-01-01

Full Text Available Fifty men with recurrent genital herpes were treated with either acyclovir 5% cream or tromantidine 1 % ointment applied topically. Acyclovir cream was applied 5 times and tromantidine cream 4 times daily for 5 days. At least one pre-treatment episode was observed by one of the authors. Self assessment charts were provided to the patients to record prodromal symptoms and healing time. For comparison at least 3 post treatment episodes were observed and com-pared with mean healing time of 3 pre-treatment episodes. Both acyclovir cream and tromantidine ointment significantly reduced the duration of prodrome, hastened healing and so reduced mean healing time.

Micropatch-arrayed pads for non-invasive spatial and temporal profiling of topical drugs on skin surface.

Science.gov (United States)

Dutkiewicz, Ewelina P; Chiu, Hsien-Yi; Urban, Pawel L

2015-11-01

Micropatch-arrayed pads (MAPAs) are presented as a facile and sensitive sampling method for spatial profiling of topical agents adsorbed on the surface of skin. MAPAs are 28 × 28 mm sized pieces of polytetrafluoroethylene containing plurality of cavities filled with agarose hydrogel. They are affixed onto skin for 10 min with the purpose to collect drugs applied topically. Polar compounds are absorbed by the hydrogel micropatches. The probes are subsequently scanned by an automated nanospray desorption electrospray ionization mass spectrometry system operated in the tapping dual-polarity mode. When the liquid junction gets into contact with every micropatch, polar compounds absorbed in the hydrogel matrix are desorbed and transferred to the ion source. A 3D-printed interface prevents evaporation of hydrogel micropatches assuring good reproducibility and sensitivity. MAPAs have been applied to follow dispersion of topical drugs applied to human skin in vivo and to porcine skin ex vivo, in the form of self-adhesive patches. Spatiotemporal characteristics of the drug dispersion process have been revealed using this non-invasive test. Differences between drug dispersion in vivo and ex vivo could be observed. We envision that MAPAs can be used to investigate spatiotemporal kinetics of various topical agents utilized in medical treatment. Copyright © 2015 John Wiley & Sons, Ltd.

Peringkasan Tweet Berdasarkan Trending Topic Twitter Dengan Pembobotan TF-IDF dan Single Linkage AngglomerativeHierarchical Clustering

Directory of Open Access Journals (Sweden)

Annisa Annisa

2016-10-01

Full Text Available Trending topic is a feature provided by twitter that informs something widely discussed by users in a particular time. The form of a trending topic is a hashtag and can be selected by clicking. However, the number of tweets for each trending topics can be very large, so it will be difficult if we want to know all the contents. So, in order to make easy when reading the topic, a small number of tweets can be selected as the main idea of the topic. In this study, we applied the Agglomerative Single Linkage Hierarchical Clustering by calculating the TF-IDF value for each word in advance. We used 100 trending topics, where each topic consists of 50 tweets in Indonesian. For testing, we provided 30 trending topics which consist of 2 until 9 sub-topics. The result is that each trending topics can be summarized into shorter text contains 2 until 9 tweets. We were able to summarize 1 trending topics exactly same as the topic summarized by human expert. However, the rest of topics corresponded partially with human expert.

Topical report review status

International Nuclear Information System (INIS)

1982-08-01

A Topical Report Review Status is scheduled to be published semi-annually. The primary purpose of this document is to provide periodic progress reports of on-going topical report reviews, to identify those topical reports for which the Nuclear Regulatory Commission (NRC) staff review has been completed and, to the extent practicable, to provide NRC management with sufficient information regarding the conduct of the topical report program to permit taking whatever actions deemed necessary or appropriate. This document is also intended to be a source of information to NRC Licensing Project Managers and other NRC personnel regarding the status of topical reports which may be referenced in applications for which they have responsibility. This status report is published primarily for internal NRC use in managing the topical report program, but is also used by NRC to advise the industry of report review status

Topical report review status

International Nuclear Information System (INIS)

1983-01-01

A Topical Report Review Status is scheduled to be published semi-annually. The primary purpose of this document is to provide periodic progress reports of on-going topical report reviews, to identify those topical reports for which the Nuclear Regulatory Commission (NRC) staff review has been completed and, to the extent practicable, to provide NRC management with sufficient information regarding the conduct of the topical report program to permit taking whatever actions deemed necessary or appropriate. This document is also intended to be a source of information to NRC Licensing Project Managers and other NRC personnel regarding the status of topical reports which may be referenced in applications for which they have responsibility. This status report is published primarily for internal NRC use in managing the topical report program, but is also used by NRC to advise the industry of report review status

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

Directory of Open Access Journals (Sweden)

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.

75 FR 26647 - Ophthalmic and Topical Dosage Form New Animal Drugs; Ivermectin Topical Solution

Science.gov (United States)

2010-05-12

.... FDA-2010-N-0002] Ophthalmic and Topical Dosage Form New Animal Drugs; Ivermectin Topical Solution... are treated with a topical solution of ivermectin. DATES: This rule is effective May 12, 2010. FOR... ANADA 200-340 for PRIVERMECTIN (ivermectin), a topical solution used on cattle to control infestations...

Women's Health Topics

Science.gov (United States)

... Information by Audience For Women Women's Health Topics Women's Health Topics Share Tweet Linkedin Pin it More sharing options Linkedin Pin it Email Print National Women's Health Week May 13 - 19, 2018 Join us ...

Tactile friction of topical formulations.

Science.gov (United States)

Skedung, L; Buraczewska-Norin, I; Dawood, N; Rutland, M W; Ringstad, L

2016-02-01

The tactile perception is essential for all types of topical formulations (cosmetic, pharmaceutical, medical device) and the possibility to predict the sensorial response by using instrumental methods instead of sensory testing would save time and cost at an early stage product development. Here, we report on an instrumental evaluation method using tactile friction measurements to estimate perceptual attributes of topical formulations. Friction was measured between an index finger and an artificial skin substrate after application of formulations using a force sensor. Both model formulations of liquid crystalline phase structures with significantly different tactile properties, as well as commercial pharmaceutical moisturizing creams being more tactile-similar, were investigated. Friction coefficients were calculated as the ratio of the friction force to the applied load. The structures of the model formulations and phase transitions as a result of water evaporation were identified using optical microscopy. The friction device could distinguish friction coefficients between the phase structures, as well as the commercial creams after spreading and absorption into the substrate. In addition, phase transitions resulting in alterations in the feel of the formulations could be detected. A correlation was established between skin hydration and friction coefficient, where hydrated skin gave rise to higher friction. Also a link between skin smoothening and finger friction was established for the commercial moisturizing creams, although further investigations are needed to analyse this and correlations with other sensorial attributes in more detail. The present investigation shows that tactile friction measurements have potential as an alternative or complement in the evaluation of perception of topical formulations. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

An Analysis of Research Topics within a Community : the Example of Knowledge Science

OpenAIRE

NIE, Kun; JI, Zhe; NAKAMORI, Yoshiteru

2007-01-01

This Paper presents a new approach how to analyze research topics within a given research community. Under the guidance of the I-system methodology, this paper conducts both top-down and bottom-up analysis. For the bottom-up analysis, similarity measurement and hierarchical clustering are applied to obtain a tree-like dendrogram structure of research topics; for the top-down analysis, the experts' knowledge is included. Then resulting from the iterative dialogue between the above two stages o...

Comparison of topical capsaicin and topical turpentine oil for treatment of painful diabetic neuropathy

International Nuclear Information System (INIS)

Musharraf, M.U.; Ahmed, Z.

2017-01-01

Background: Diabetes Mellitus is a pandemic of the modern era owing to our rapidly deteriorating lifestyle. Painful diabetic neuropathy is one of the costliest and disabling complications of diabetes mellitus. No single treatment exists to prevent or reverse neuropathic changes or to provide total pain relief. Topical Capsaicin and Turpentine Oil are found to be effective in treatment of painful diabetic neuropathy. Methods: Patients of either gender with ages between 18 and 70 years having painful diabetic neuropathy already taking one oral drug for painful neuropathy and treatment for diabetes mellitus and an HbA1C less than 8.5% were included while Pregnant or lactating mothers, patients with chronic liver disease and patients with renal insufficiency (creatinine >3.0 mg/dl) and peripheral arterial disease were excluded from study. Patients were randomly divided into two groups (A and B) using computer generated random number table. Group A was given topical application of capsaicin while Group B was given topical application of commercially available turpentine oil over painful site on feet. Results: 300 patients were equally divided in two groups. The patients in group A had a Visual Analog Pain Score of 7.91±5.10 at baseline and 5.10±1.343 after 3 months of treatment (p-value 0.0001). The patients in group B had a Visual Analog Pain Score of 7.83±1.012 at baseline and 5.20±1.187 after 3 months of treatment (p-value 0.0001). Chi Square test was applied to compare efficacy of both groups. It was noted that 71 (53%) had efficacy in group A and 63 (47%) had efficacy in the group B but the difference was not statistically significant. (p-value=0.399). Conclusion: It has been concluded that turpentine oil is effective in managing diabetic neuropathic pain similar to capsaicin cream.

Topical hydrocortisone, clobetasol propionate, and calcipotriol do not increase photocarcinogenesis induced by simulated solar irradiation in hairless mice

DEFF Research Database (Denmark)

Lerche, Catharina M; Philipsen, Peter A; Poulsen, Thomas

2010-01-01

. Few studies have assessed the effect of topical corticosteroids and topical vitamin D(3) derivatives on photocarcinogenesis induced by ultraviolet radiation. We investigated whether HCB, CP, or CAL can accelerate photocarcinogenesis using simulated solar radiation (SSR). HCB, CP, or CAL was applied...

Applied chemical engineering thermodynamics

CERN Document Server

Tassios, Dimitrios P

1993-01-01

Applied Chemical Engineering Thermodynamics provides the undergraduate and graduate student of chemical engineering with the basic knowledge, the methodology and the references he needs to apply it in industrial practice. Thus, in addition to the classical topics of the laws of thermodynamics,pure component and mixture thermodynamic properties as well as phase and chemical equilibria the reader will find: - history of thermodynamics - energy conservation - internmolecular forces and molecular thermodynamics - cubic equations of state - statistical mechanics. A great number of calculated problems with solutions and an appendix with numerous tables of numbers of practical importance are extremely helpful for applied calculations. The computer programs on the included disk help the student to become familiar with the typical methods used in industry for volumetric and vapor-liquid equilibria calculations.

Topics in Bayesian statistics and maximum entropy

International Nuclear Information System (INIS)

Mutihac, R.; Cicuttin, A.; Cerdeira, A.; Stanciulescu, C.

1998-12-01

Notions of Bayesian decision theory and maximum entropy methods are reviewed with particular emphasis on probabilistic inference and Bayesian modeling. The axiomatic approach is considered as the best justification of Bayesian analysis and maximum entropy principle applied in natural sciences. Particular emphasis is put on solving the inverse problem in digital image restoration and Bayesian modeling of neural networks. Further topics addressed briefly include language modeling, neutron scattering, multiuser detection and channel equalization in digital communications, genetic information, and Bayesian court decision-making. (author)

Human-competitive automatic topic indexing

CERN Document Server

Medelyan, Olena

2009-01-01

Topic indexing is the task of identifying the main topics covered by a document. These are useful for many purposes: as subject headings in libraries, as keywords in academic publications and as tags on the web. Knowing a document’s topics helps people judge its relevance quickly. However, assigning topics manually is labor intensive. This thesis shows how to generate them automatically in a way that competes with human performance. Three kinds of indexing are investigated: term assignment, a task commonly performed by librarians, who select topics from a controlled vocabulary; tagging, a popular activity of web users, who choose topics freely; and a new method of keyphrase extraction, where topics are equated to Wikipedia article names. A general two-stage algorithm is introduced that first selects candidate topics and then ranks them by significance based on their properties. These properties draw on statistical, semantic, domain-specific and encyclopedic knowledge. They are combined using a machine learn...

Topic Visualization and Survival Analysis

OpenAIRE

Wang, Ping Jr

2017-01-01

Latent semantic structure in a text collection is called a topic. In this thesis, we aim to visualize topics in the scientific literature and detect active or inactive research areas based on their lifetime. Topics were extracted from over 1 million abstracts from the arXiv.org database using Latent Dirichlet Allocation (LDA). Hellinger distance measures similarity between two topics. Topics are determined to be relevant if their pairwise distances are smaller than the threshold of Hellinger ...

Effect of topical application of melatonin cream 12.5% on cognitive parameters

DEFF Research Database (Denmark)

Scheuer, Cecilie; Pommergaard, Hans-Christian; Rosenberg, Jacob

2016-01-01

BACKGROUND: Skin cancer is an increasing problem in modern dermatology. Earlier studies have shown protective effects against ultraviolet radiation (UVR)-induced skin damage by topical treatment with melatonin. However, the potential sedative effects of full body topical application of melatonin...... have never been investigated. Objectives The aim of this study was to assess the degree of cognitive dysfunction when using melatonin cream as full body topical application. METHODS: In a randomized, placebo-controlled, double-blind crossover study in healthy volunteers, the degree of cognitive...... dysfunction when using cream containing 12.5% melatonin as full body application was assessed. A group of ten volunteers had melatonin cream 12.5% applied on 80% of their body surface area, and degree of cognitive dysfunction was assessed using a test battery consisting of Karolinska sleepiness scale (KSS...

Plasmas applied atomic collision physics, v.2

CERN Document Server

Barnett, C F

1984-01-01

Applied Atomic Collision Physics, Volume 2: Plasmas covers topics on magnetically confined plasmas. The book starts by providing the history of fusion research and describing the various approaches in both magnetically and inertially confined plasmas. The text then gives a general discussion of the basic concepts and properties in confinement and heating of a plasma. The theory of atomic collisions that result in excited quantum states, particularly highly ionized impurity atoms; and diverse diagnostic topics such as emission spectra, laser scattering, electron cyclotron emission, particle bea

GeneTopics - interpretation of gene sets via literature-driven topic models

Science.gov (United States)

2013-01-01

Background Annotation of a set of genes is often accomplished through comparison to a library of labelled gene sets such as biological processes or canonical pathways. However, this approach might fail if the employed libraries are not up to date with the latest research, don't capture relevant biological themes or are curated at a different level of granularity than is required to appropriately analyze the input gene set. At the same time, the vast biomedical literature offers an unstructured repository of the latest research findings that can be tapped to provide thematic sub-groupings for any input gene set. Methods Our proposed method relies on a gene-specific text corpus and extracts commonalities between documents in an unsupervised manner using a topic model approach. We automatically determine the number of topics summarizing the corpus and calculate a gene relevancy score for each topic allowing us to eliminate non-specific topics. As a result we obtain a set of literature topics in which each topic is associated with a subset of the input genes providing directly interpretable keywords and corresponding documents for literature research. Results We validate our method based on labelled gene sets from the KEGG metabolic pathway collection and the genetic association database (GAD) and show that the approach is able to detect topics consistent with the labelled annotation. Furthermore, we discuss the results on three different types of experimentally derived gene sets, (1) differentially expressed genes from a cardiac hypertrophy experiment in mice, (2) altered transcript abundance in human pancreatic beta cells, and (3) genes implicated by GWA studies to be associated with metabolite levels in a healthy population. In all three cases, we are able to replicate findings from the original papers in a quick and semi-automated manner. Conclusions Our approach provides a novel way of automatically generating meaningful annotations for gene sets that are directly

Southern African Linguistics and Applied Language Studies

African Journals Online (AJOL)

... (e.g. syntax, phonology, semantics) and applied (e.g. sociolinguistic topics, ... Articles in languages other than English are accompanied by an extended English ... language ecologies post #RhodesMustFall at the University of the Free State ...

Preface to Special Topic: Acoustic Metamaterials and Metasurfaces

Science.gov (United States)

Assouar, Badreddine

2018-03-01

The advent of acoustic metamaterials in the beginning of 2000s and very recently of acoustic metasurfaces has created tremendous excitement and efforts in the field of materials science and physics by introducing and building real transformative research and dealing with unprecedented physics and applications. The acoustic/elastic metamaterials and metasurfaces, which can simply be described as designed artificial materials with unusual physical properties, form the core of the present Special Topic published by the Journal of Applied Physics.

Applied Genomics of Foodborne Pathogens

DEFF Research Database (Denmark)

and customized source of information designed for and accessible to microbiologists interested in applying cutting-edge genomics in food safety and public health research. This book fills this void with a well-selected collection of topics, case studies, and bioinformatics tools contributed by experts......This book provides a timely and thorough snapshot into the emerging and fast evolving area of applied genomics of foodborne pathogens. Driven by the drastic advance of whole genome shot gun sequencing (WGS) technologies, genomics applications are becoming increasingly valuable and even essential...... at the forefront of foodborne pathogen genomics research....

Pharmacokinetics of terbinafine in the rabbit ocular tissues after topical administration.

Science.gov (United States)

Sun, X G; Wang, Z X; Wang, Z Q; Deng, S J; Li, R; Luo, S Y; Wu, Y Y

2007-01-01

To determine the distribution of terbinafine in the cornea and aqueous humor after topical administration. A corn oil ointment of terbinafine 0.2% (resolved in sterile corn oil) was applied to the conjunctival sac of albino rabbits twice (with a 5-min interval). The concentration of terbinafine was determined with high-performance liquid chromatography (HPLC) 5, 15, 30, 60, 120 and 240 min after administration of terbinafine. After topical administration, the concentration of terbinafine increased gradually, reached a peak (1.39 microg/ml at 30 min in the cornea and 82.9 ng/ml at 30 min in aqueous humor, respectively) and then decreased. The concentration was 0.18 microg/g at 240 min in the cornea, but terbinafine could not be tested at 120 min in aqueous humor. Topical ophthalmic terbinafine 0.2% could penetrate into the cornea and aqueous humor at concentrations adequate for inhibition of fungus.

Topical versus systemic diclofenac in the treatment of temporo-mandibular joint dysfunction symptoms.

Science.gov (United States)

Di Rienzo Businco, L; Di Rienzo Businco, A; D'Emilia, M; Lauriello, M; Coen Tirelli, G

2004-10-01

The most frequent symptom of craniomandibular dysfunction is pain in the preauricular area or in the temporo-mandibular joint, usually localized at the level of the masticatory musculature. Patients sometimes also complain of reflect otalgia, headaches and facial pain. Osteoarthrosis is a frequent degenerative debilitating chronic disorder that can affect the temporomandibular joint. It causes pain and articular rigidity, a reduction in mobility, and radiological alterations are visible in stratigraphy. The aim of this study was to compare the efficacy of a topically applied non-steroid anti-inflammatory drug that has recently become commercially available (diclofenac sodium in a patented carrier containing dimethyl sulfoxide, that favours transcutaneous absorption) which is commonly used to alleviate pain in knee or elbow joints, versus oral diclofenac, in the treatment of symptoms of temporomandibular joint dysfunction. Dysfunction of the temporomandibular joint was diagnosed in 36 adult patients. The patients were randomized in two age- and gender -matched groups. Group A (18 patients) received oral diclofenac sodium administered after a meal in 50-mg tablets twice a day for 14 days. Group B (18 patients) received 16 mg/ml topical diclofenac (diclofenac topical solution, 10 drops 4 times a day for 14 days). All patients completed a questionnaire at the start and end of therapy. Patients were asked to quantify on a graded visual analogue scale and to reply to questions about the pain and tenderness of the temporomandibular joint and the functional limitation of mouth opening. Patients were also requested to report side-effects of the treatment. All patients showed relief from pain after treatment: the difference between the two groups was not significant (p > 0.05). Post-treatment, 16 patients of group A had epigastralgic symptoms. Three patients treated with topical diclofenac showed a modest irritation of the temporomandibular joint region, and disappeared

Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast.

Science.gov (United States)

Miller, Jessica A; Thompson, Patricia A; Hakim, Iman A; Lopez, Ana Maria; Thomson, Cynthia A; Chew, Wade; Hsu, Chiu-Hsieh; Chow, H-H Sherry

2012-10-01

Limonene, a major component in citrus oil, has demonstrated anti-cancer effects in preclinical mammary cancer models. However, the effective oral dose translates to a human dose that may not be feasible for chronic dosing. We proposed to evaluate topical application of limonene to the breast as an alternative dosing strategy. We conducted a mouse disposition study to determine whether limonene would be bio available in the mammary tissue after topical application. SKH-1 mice received topical or oral administration of limonene in the form of orange oil every day for 4 weeks. Plasma and mammary pads were collected 4 hrs after the final dosing. We also conducted an exploratory clinical study to evaluate the safety and feasibility of topically applied limonene in the form of orange oil to the breast. Healthy women were recruited to apply orange oil containing massage oil to their breasts daily for four weeks. Safety and feasibility were assessed by reported adverse events, clinical labs, and usage compliance. Pre and post-intervention nipple aspirate fluid (NAF) and plasma were collected for limonene concentration determination. The mouse disposition study showed that topical and oral orange oil administration resulted in similar mammary tissue disposition of limonene with no clinical signs of toxicity. In the clinical study, the topical application of limonene containing massage oil to the breast was found to be safe with high levels of usage compliance for daily application, although NAF and plasma limonene concentrations were not significantly changed after the massage oil application. Our studies showed that limonene is bio available in mammary tissue after topical orange oil application in mice and this novel route of administration to the breast is safe and feasible in healthy women.

Engaging Students in Applied Electromagnetics at the University of San Diego

Science.gov (United States)

Lumori, M. L. D.; Kim, E. M.

2010-01-01

Two possible topical approaches that have been applied to teaching an upper-division undergraduate electrical engineering applied electromagnetics course are presented. Each approach was applied to one of two offerings of the course, taught in different semesters. In either case, the course includes the study of electromagnetic theory and…

Incorporating Topic Assignment Constraint and Topic Correlation Limitation into Clinical Goal Discovering for Clinical Pathway Mining

Directory of Open Access Journals (Sweden)

Xiao Xu

2017-01-01

Full Text Available Clinical pathways are widely used around the world for providing quality medical treatment and controlling healthcare cost. However, the expert-designed clinical pathways can hardly deal with the variances among hospitals and patients. It calls for more dynamic and adaptive process, which is derived from various clinical data. Topic-based clinical pathway mining is an effective approach to discover a concise process model. Through this approach, the latent topics found by latent Dirichlet allocation (LDA represent the clinical goals. And process mining methods are used to extract the temporal relations between these topics. However, the topic quality is usually not desirable due to the low performance of the LDA in clinical data. In this paper, we incorporate topic assignment constraint and topic correlation limitation into the LDA to enhance the ability of discovering high-quality topics. Two real-world datasets are used to evaluate the proposed method. The results show that the topics discovered by our method are with higher coherence, informativeness, and coverage than the original LDA. These quality topics are suitable to represent the clinical goals. Also, we illustrate that our method is effective in generating a comprehensive topic-based clinical pathway model.

Applied longitudinal analysis

CERN Document Server

Fitzmaurice, Garrett M; Ware, James H

2012-01-01

Praise for the First Edition "". . . [this book] should be on the shelf of everyone interested in . . . longitudinal data analysis.""-Journal of the American Statistical Association   Features newly developed topics and applications of the analysis of longitudinal data Applied Longitudinal Analysis, Second Edition presents modern methods for analyzing data from longitudinal studies and now features the latest state-of-the-art techniques. The book emphasizes practical, rather than theoretical, aspects of methods for the analysis of diverse types of lo

Second Language Acquisition and Applied Linguistics.

Science.gov (United States)

Larsen-Freeman, Diane

2000-01-01

Discusses the second language acquisition (SLA) process and the differential success of second language learners. Examines the fundamental challenges that this characterization faces, and highlights the contributions SLA is capable of in the coming decade. Offers topics for a training and development of curriculum for future applied linguists from…

Complementary clinical effects of topical tightening treatment in conjunction with a radiofrequency procedure.

Science.gov (United States)

Goldberg, David J; Yatskayer, Margarita; Raab, Susana; Chen, Nannan; Krol, Yevgeniy; Oresajo, Christian

2014-10-01

Abstract Background: Skin laxity and cellulite on the buttocks and thighs are two common cosmetic concerns. Skin tightening with radiofrequency (RF) devices has become increasingly popular. The purpose of this study is to evaluate the efficacy and safety of a topical skin laxity tightening agent when used in combination with an RF device. A double-blinded, randomized clinical trial enrolled twenty females with mild-to-moderate skin laxity on the posterior thighs/buttocks. Each subject underwent two monthly treatments with an RF source (Alma Accent) to both legs. Subjects were then randomized to apply a topical agent (Skinceuticals Body Tightening Concentrate) twice daily to only one designated thigh/buttock throughout the eight-week duration of the study. All subjects were evaluated for improvement in lifting, skin tone, radiance, firmness/tightness, skin texture, and overall appearance based on photographic evaluation by blinded investigators at 12 weeks following the final RF treatment. A statistically significant improvement was found in the overall appearance on both sides treated with the RF device when compared to baseline. However, the area treated with the topical agent showed a statistically significantly greater degree of improvement than the side where no topical agent was applied. No adverse effects were reported. The use of a novel skin tightening agent used after RF procedures is both safe and effective for treatment of skin laxity on the buttocks and thighs. Combined therapy leads to a better result.

A UV-Independent Topical Small-Molecule Approach for Melanin Production in Human Skin

Directory of Open Access Journals (Sweden)

Nisma Mujahid

2017-06-01

Full Text Available The presence of dark melanin (eumelanin within human epidermis represents one of the strongest predictors of low skin cancer risk. Topical rescue of eumelanin synthesis, previously achieved in “redhaired” Mc1r-deficient mice, demonstrated significant protection against UV damage. However, application of a topical strategy for human skin pigmentation has not been achieved, largely due to the greater barrier function of human epidermis. Salt-inducible kinase (SIK has been demonstrated to regulate MITF, the master regulator of pigment gene expression, through its effects on CRTC and CREB activity. Here, we describe the development of small-molecule SIK inhibitors that were optimized for human skin penetration, resulting in MITF upregulation and induction of melanogenesis. When topically applied, pigment production was induced in Mc1r-deficient mice and normal human skin. These findings demonstrate a realistic pathway toward UV-independent topical modulation of human skin pigmentation, potentially impacting UV protection and skin cancer risk.

A UV-Independent Topical Small-Molecule Approach for Melanin Production in Human Skin.

Science.gov (United States)

Mujahid, Nisma; Liang, Yanke; Murakami, Ryo; Choi, Hwan Geun; Dobry, Allison S; Wang, Jinhua; Suita, Yusuke; Weng, Qing Yu; Allouche, Jennifer; Kemeny, Lajos V; Hermann, Andrea L; Roider, Elisabeth M; Gray, Nathanael S; Fisher, David E

2017-06-13

The presence of dark melanin (eumelanin) within human epidermis represents one of the strongest predictors of low skin cancer risk. Topical rescue of eumelanin synthesis, previously achieved in "redhaired" Mc1r-deficient mice, demonstrated significant protection against UV damage. However, application of a topical strategy for human skin pigmentation has not been achieved, largely due to the greater barrier function of human epidermis. Salt-inducible kinase (SIK) has been demonstrated to regulate MITF, the master regulator of pigment gene expression, through its effects on CRTC and CREB activity. Here, we describe the development of small-molecule SIK inhibitors that were optimized for human skin penetration, resulting in MITF upregulation and induction of melanogenesis. When topically applied, pigment production was induced in Mc1r-deficient mice and normal human skin. These findings demonstrate a realistic pathway toward UV-independent topical modulation of human skin pigmentation, potentially impacting UV protection and skin cancer risk. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Anti-inflammatory effect of topical administration of tofacitinib on corneal inflammation.

Science.gov (United States)

Sakimoto, Tohru; Ishimori, Akiko

2016-04-01

We evaluated an anti-inflammatory effect of topical administration of tofacitinib, janus kinase (JAK) blocker, on corneal inflammation. Topical instillation of either tofacitinib or PBS was applied after wounding BALB/c mice corneas with alkali burn. Topical instillation was performed until day 14 after injury and injured eye was analyzed. The vascularized area in the alkali burned cornea was significantly reduced in the tofacitinib group compared with that in the PBS group. The immunoreactivity of Gr-1, F4/80, IFN-γ, and phosphorylated STAT(signal transducer and activator of transcription)1 in corneal stroma was diminished significantly in the tofacitinib group. Using laser capture microdissection system and quantitative PCR array analysis, the expression levels of CXCL9, CXCL5, CCL7, CCL2, MMP(matrix metalloproteinase)-9, and STAT1 in corneal stroma were down-regulated in the tofacitinib group. In in vitro study, human fibroblast pretreated by IFN-γ showed phosphorylation of STAT1, and this phosphorylation was down-regulated by adding tofacitinib to the culture medium. These results indicate the topical application of JAK inhibitor causes down-regulation of JAK- or IFN-γ-related molecules. Therefore, we deduce that application of JAK inhibitor for topical instillation may contribute to the treatment of corneal inflammation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Health Topic XML File Description

Science.gov (United States)

... this page: https://medlineplus.gov/xmldescription.html Health Topic XML File Description: MedlinePlus To use the sharing ... information categories assigned. Example of a Full Health Topic Record A record for a MedlinePlus health topic ...

Application of Topic Map on Knowledge Organization

Directory of Open Access Journals (Sweden)

Sou-shan Wu

2003-06-01

Full Text Available Knowledge management (KM has received much attention from both academics and practitioners in the past few years. Following the KM trend, many organizations have built their own knowledge repositories or data warehouses. However, information or knowledge is still scattered everywhere without being properly managed. The rapid growth of the Internet accelerates the creation of unstructured and unclassified information and causes the explosion of information overload. The effort of browsing information through general-purpose search engines turns out to be tedious and painstaking. Hence, an effective technology to solve this information retrieval problem is much needed. The purpose of this research is to explore the application of text mining technique in organizing knowledge stored in unstructured natural language text documents. Major components of text mining techniques required for topic map in particular will be presented in detail.Two sets of unstructured documents are utilized to demonstrate the usage of SOM for topic categorization. The first set of documents is a collection of speeches given by Y.C. Wang, Chairman of the Taiwan Plastics Group, and the other is the collection of all laws and regulations related to securities and future markets in Taiwan. We also try to apply text mining to these two sets of documents to generate their respective topic maps, thus revealing the differences between organizing explicit and tacit knowledge as well as the difficulties associated with tacit knowledge.[Article content in Chinese

Selected Topics on Mass Transport in Gas-solid Interactions

DEFF Research Database (Denmark)

Somers, Marcel A.J.

2004-01-01

The present article is a short review containing examples of the role of mass transport in the solid state during gas-solid interactions. Examples are taken from the authors' research on the interaction of carbon and/or nitrogen with iron-based metals. Topics dealt with are diffusion-controlled d......The present article is a short review containing examples of the role of mass transport in the solid state during gas-solid interactions. Examples are taken from the authors' research on the interaction of carbon and/or nitrogen with iron-based metals. Topics dealt with are diffusion...... on the kinetics of phenomena in the solid state. Various experimental techniques were applied to investigate these phenomena; it is however beyond the scope of the present article to treat experimental conditions in detail. The interested reader is referred to the original work for in depth discussions...

Applied probability and stochastic processes

CERN Document Server

Sumita, Ushio

1999-01-01

Applied Probability and Stochastic Processes is an edited work written in honor of Julien Keilson. This volume has attracted a host of scholars in applied probability, who have made major contributions to the field, and have written survey and state-of-the-art papers on a variety of applied probability topics, including, but not limited to: perturbation method, time reversible Markov chains, Poisson processes, Brownian techniques, Bayesian probability, optimal quality control, Markov decision processes, random matrices, queueing theory and a variety of applications of stochastic processes. The book has a mixture of theoretical, algorithmic, and application chapters providing examples of the cutting-edge work that Professor Keilson has done or influenced over the course of his highly-productive and energetic career in applied probability and stochastic processes. The book will be of interest to academic researchers, students, and industrial practitioners who seek to use the mathematics of applied probability i...

Applied programs at Brookhaven National Laboratory

Energy Technology Data Exchange (ETDEWEB)

1991-09-01

This document overviews the areas of current research at Brookhaven National Laboratory. Technology transfer and the user facilities are discussed. Current topics are presented in the areas of applied physics, chemical science, material science, energy efficiency and conservation, environmental health and mathematics, biosystems and process science, oceanography, and nuclear energy. (GHH)

Identifying Topics in Microblogs Using Wikipedia.

Science.gov (United States)

Yıldırım, Ahmet; Üsküdarlı, Suzan; Özgür, Arzucan

2016-01-01

Twitter is an extremely high volume platform for user generated contributions regarding any topic. The wealth of content created at real-time in massive quantities calls for automated approaches to identify the topics of the contributions. Such topics can be utilized in numerous ways, such as public opinion mining, marketing, entertainment, and disaster management. Towards this end, approaches to relate single or partial posts to knowledge base items have been proposed. However, in microblogging systems like Twitter, topics emerge from the culmination of a large number of contributions. Therefore, identifying topics based on collections of posts, where individual posts contribute to some aspect of the greater topic is necessary. Models, such as Latent Dirichlet Allocation (LDA), propose algorithms for relating collections of posts to sets of keywords that represent underlying topics. In these approaches, figuring out what the specific topic(s) the keyword sets represent remains as a separate task. Another issue in topic detection is the scope, which is often limited to specific domain, such as health. This work proposes an approach for identifying domain-independent specific topics related to sets of posts. In this approach, individual posts are processed and then aggregated to identify key tokens, which are then mapped to specific topics. Wikipedia article titles are selected to represent topics, since they are up to date, user-generated, sophisticated articles that span topics of human interest. This paper describes the proposed approach, a prototype implementation, and a case study based on data gathered during the heavily contributed periods corresponding to the four US election debates in 2012. The manually evaluated results (0.96 precision) and other observations from the study are discussed in detail.

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.

Nigeria Journal of Pure and Applied Physics: Editorial Policies

African Journals Online (AJOL)

Focus and Scope. Nigeria Journal of Pure and Applied Physics publishes papers of the highest quality and significance in specific areas of physics, pure and applied, as listed below. The journal content reflects core physics disciplines, but is also open to a broad range of topics whose central theme falls within the bounds ...

Applied logistic regression

CERN Document Server

Hosmer, David W; Sturdivant, Rodney X

2013-01-01

 A new edition of the definitive guide to logistic regression modeling for health science and other applications This thoroughly expanded Third Edition provides an easily accessible introduction to the logistic regression (LR) model and highlights the power of this model by examining the relationship between a dichotomous outcome and a set of covariables. Applied Logistic Regression, Third Edition emphasizes applications in the health sciences and handpicks topics that best suit the use of modern statistical software. The book provides readers with state-of-

Comparison of Clustering Algorithms for the Identification of Topics on Twitter

Directory of Open Access Journals (Sweden)

Marjori N. M. Klinczak

2016-05-01

Full Text Available Topic Identification in Social Networks has become an important task when dealing with event detection, particularly when global communities are affected. In order to attack this problem, text processing techniques and machine learning algorithms have been extensively used. In this paper we compare four clustering algorithms – k-means, k-medoids, DBSCAN and NMF (Non-negative Matrix Factorization – in order to detect topics related to textual messages obtained from Twitter. The algorithms were applied to a database initially composed by tweets having hashtags related to the recent Nepal earthquake as initial context. Obtained results suggest that the NMF clustering algorithm presents superior results, providing simpler clusters that are also easier to interpret.

Regulatory Information By Topic

Science.gov (United States)

EPA develops and enforces regulations that span many environmental topics, from acid rain reduction to wetlands restoration. Each topic listed below may include related laws and regulations, compliance enforcement information, policies guidance

Potentiation of ALA-PDT antitumor activity in mice using topical DMXAA

Science.gov (United States)

Marrero, Allison; Sunar, Ulas; Sands, Theresa; Oseroff, Allan; Bellnier, David

2009-06-01

Photodynamic treatment of subcutaneously implanted Colon 26 tumors in BALB/c mice using the aminolevulinic acid (ALA)-induced photosensitizer protoporphyrin IX (PpIX) was shown to be enhanced by the addition of the vascular disrupting agent 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA; Novartis ASA404). DMXAA increases vascular permeability and decreases blood flow in both murine and human tumors. Sufficiently high parenteral DMXAA doses can lead to tumor collapse and necrosis. We have previously reported marked enhancement of antitumor activity when PDT, using either Photofrin or HPPH, is combined with low-dose intraperitoneal DMXAA. We now describe the first attempt to combine topically-applied DMXAA with PDT. For this, DMXAA was applied two hours before PpIX-activating light delivery. PDT with ALA-PDT alone (ALA 20%; 80 J/cm2 delivered at 75 mW/cm2) caused a 39% decrease in tumor volume compared to unirradiated controls. Addition of topical DMXAA to ALA-PDT resulted in a 74% reduction in tumor volume. Diffuse correlation spectroscopy (DCS), a non-invasive blood flow imaging method, is being used to understand the mechanism of this effect and to aid in the proper design of the therapy. For instance, our most recent DCS data suggests that the 2-hour interval between the DMXAA and light applications may not be optimum. This preliminary study suggests a potential role for topical DMXAA in combination with PDT for dermatologic tumors.

Identifying Topics in Microblogs Using Wikipedia.

Directory of Open Access Journals (Sweden)

Ahmet Yıldırım

Full Text Available Twitter is an extremely high volume platform for user generated contributions regarding any topic. The wealth of content created at real-time in massive quantities calls for automated approaches to identify the topics of the contributions. Such topics can be utilized in numerous ways, such as public opinion mining, marketing, entertainment, and disaster management. Towards this end, approaches to relate single or partial posts to knowledge base items have been proposed. However, in microblogging systems like Twitter, topics emerge from the culmination of a large number of contributions. Therefore, identifying topics based on collections of posts, where individual posts contribute to some aspect of the greater topic is necessary. Models, such as Latent Dirichlet Allocation (LDA, propose algorithms for relating collections of posts to sets of keywords that represent underlying topics. In these approaches, figuring out what the specific topic(s the keyword sets represent remains as a separate task. Another issue in topic detection is the scope, which is often limited to specific domain, such as health. This work proposes an approach for identifying domain-independent specific topics related to sets of posts. In this approach, individual posts are processed and then aggregated to identify key tokens, which are then mapped to specific topics. Wikipedia article titles are selected to represent topics, since they are up to date, user-generated, sophisticated articles that span topics of human interest. This paper describes the proposed approach, a prototype implementation, and a case study based on data gathered during the heavily contributed periods corresponding to the four US election debates in 2012. The manually evaluated results (0.96 precision and other observations from the study are discussed in detail.

Applied mathematics for science and engineering

CERN Document Server

Glasgow, Larry A

2014-01-01

Prepare students for success in using applied mathematics for engineering practice and post-graduate studies moves from one mathematical method to the next sustaining reader interest and easing the application of the techniques Uses different examples from chemical, civil, mechanical and various other engineering fields Based on a decade's worth of the authors lecture notes detailing the topic of applied mathematics for scientists and engineers Concisely writing with numerous examples provided including historical perspectives as well as a solutions manual for academic adopters

A First Course in Applied Mathematics

CERN Document Server

Rebaza, Jorge

2012-01-01

Explore real-world applications of selected mathematical theory, concepts, and methods Exploring related methods that can be utilized in various fields of practice from science and engineering to business, A First Course in Applied Mathematics details how applied mathematics involves predictions, interpretations, analysis, and mathematical modeling to solve real-world problems. Written at a level that is accessible to readers from a wide range of scientific and engineering fields, the book masterfully blends standard topics with modern areas of application and provides the needed foundation

Differential Topic Models.

Science.gov (United States)

Chen, Changyou; Buntine, Wray; Ding, Nan; Xie, Lexing; Du, Lan

2015-02-01

In applications we may want to compare different document collections: they could have shared content but also different and unique aspects in particular collections. This task has been called comparative text mining or cross-collection modeling. We present a differential topic model for this application that models both topic differences and similarities. For this we use hierarchical Bayesian nonparametric models. Moreover, we found it was important to properly model power-law phenomena in topic-word distributions and thus we used the full Pitman-Yor process rather than just a Dirichlet process. Furthermore, we propose the transformed Pitman-Yor process (TPYP) to incorporate prior knowledge such as vocabulary variations in different collections into the model. To deal with the non-conjugate issue between model prior and likelihood in the TPYP, we thus propose an efficient sampling algorithm using a data augmentation technique based on the multinomial theorem. Experimental results show the model discovers interesting aspects of different collections. We also show the proposed MCMC based algorithm achieves a dramatically reduced test perplexity compared to some existing topic models. Finally, we show our model outperforms the state-of-the-art for document classification/ideology prediction on a number of text collections.

Topic modeling for cluster analysis of large biological and medical datasets.

Science.gov (United States)

Zhao, Weizhong; Zou, Wen; Chen, James J

2014-01-01

The big data moniker is nowhere better deserved than to describe the ever-increasing prodigiousness and complexity of biological and medical datasets. New methods are needed to generate and test hypotheses, foster biological interpretation, and build validated predictors. Although multivariate techniques such as cluster analysis may allow researchers to identify groups, or clusters, of related variables, the accuracies and effectiveness of traditional clustering methods diminish for large and hyper dimensional datasets. Topic modeling is an active research field in machine learning and has been mainly used as an analytical tool to structure large textual corpora for data mining. Its ability to reduce high dimensionality to a small number of latent variables makes it suitable as a means for clustering or overcoming clustering difficulties in large biological and medical datasets. In this study, three topic model-derived clustering methods, highest probable topic assignment, feature selection and feature extraction, are proposed and tested on the cluster analysis of three large datasets: Salmonella pulsed-field gel electrophoresis (PFGE) dataset, lung cancer dataset, and breast cancer dataset, which represent various types of large biological or medical datasets. All three various methods are shown to improve the efficacy/effectiveness of clustering results on the three datasets in comparison to traditional methods. A preferable cluster analysis method emerged for each of the three datasets on the basis of replicating known biological truths. Topic modeling could be advantageously applied to the large datasets of biological or medical research. The three proposed topic model-derived clustering methods, highest probable topic assignment, feature selection and feature extraction, yield clustering improvements for the three different data types. Clusters more efficaciously represent truthful groupings and subgroupings in the data than traditional methods, suggesting

Active-learning Strategies for Legal Topics and Substance Abuse in a Pharmacy Curriculum.

Science.gov (United States)

Steinhardt, Sarah J; Clark, John E; Kelly, William N; Hill, Angela M

2017-02-25

Objective. To implement active-learning strategies to engage students in learning, applying, and teaching legal and substance abuse topics. Design. Medication Safety course student groups created films on a National Patient Safety Goal (NPSG) using a movie genre and presented them in film festival format. Pharmacogenomics course student groups taught ethical, legal, and social implications (ELSI) topics through presentation of short stories about comic book characters with genetic mutations. Students in the Drugs of Abuse course composed and performed dances depicting the mechanism of action of a drug in an in-class rave dance format. Assessment. Course evaluations revealed student engagement with subject material and enjoyment of the creative applications, critical thinking, and collaborative aspects of the activities. Students performed well on examination questions and graded assignments. Conclusion. These active-learning strategies facilitated students' abilities to learn, apply, and teach material in medication safety, pharmacogenomics, and substance abuse courses.

Analyses of Research Topics in the Field of Informetrics Based on the Method of Topic Modeling

OpenAIRE

Sung-Chien Lin

2014-01-01

In this study, we used the approach of topic modeling to uncover the possible structure of research topics in the field of Informetrics, to explore the distribution of the topics over years, and to compare the core journals. In order to infer the structure of the topics in the field, the data of the papers published in the Journal of Informetricsand Scientometrics during 2007 to 2013 are retrieved from the database of the Web of Science as input of the approach of topic modeling. The results ...

Analyses of Research Topics in the Field of Informetrics Based on the Method of Topic Modeling

Directory of Open Access Journals (Sweden)

Sung-Chien Lin

2014-07-01

Full Text Available In this study, we used the approach of topic modeling to uncover the possible structure of research topics in the field of Informetrics, to explore the distribution of the topics over years, and to compare the core journals. In order to infer the structure of the topics in the field, the data of the papers published in the Journal of Informetricsand Scientometrics during 2007 to 2013 are retrieved from the database of the Web of Science as input of the approach of topic modeling. The results of this study show that when the number of topics was set to 10, the topic model has the smallest perplexity. Although data scopes and analysis methodsare different to previous studies, the generating topics of this study are consistent with those results produced by analyses of experts. Empirical case studies and measurements of bibliometric indicators were concerned important in every year during the whole analytic period, and the field was increasing stability. Both the two core journals broadly paid more attention to all of the topics in the field of Informetrics. The Journal of Informetricsput particular emphasis on construction and applications ofbibliometric indicators and Scientometrics focused on the evaluation and the factors of productivity of countries, institutions, domains, and journals.

Topical treatments of skin pain: a general review with a focus on hidradenitis suppurativa with topical agents.

Science.gov (United States)

Scheinfeld, Noah

2014-07-15

Hidradenitis Supprurativa (HS) is a painful chronic follicular disease. Few papers have addressed pain control for this debilitating condition. Possible topical agents include tricyclic antidepressants, opioids, anticonvulsants, NSAIDs, NMDA receptor antagonists, local anesthetics and other agents. The first line agents for the topical treatment of the cutaneous pain of HS are diclonefac gel 1% and liposomal xylocaine 4% and 5% cream or 5% ointment. The chief advantage of topical xylocaine is that is quick acting i.e. immediate however with a limited duration of effect 1-2 hours. The use of topical ketamine, which blocks n-methyl-D-aspartate receptors in a non-competitive fashion, might be a useful tool for the treatment of HS pain. Topical doxepin, which available in a 5% commercially preparation (Zonalon®) , makes patients drowsy and is not useful for controlling the pain of HS . Doxepin is available in a 3% or 3.3% concentration (which causes less drowsiness) from compounding pharmacies and can be used in compounded analgesic preparations with positive effect. Topical doxepin is preferred over use of topical amitriptyline because topical doxepin is more effective. Nevertheless, topical amitriptyline increase of the tactile and mechanical nociceptive thresholds and can be used for topical pain control in compound mixture of analgesics . Gabapentin and pregablin can also be used compounded with other agents in topical analgesic preparations with positive topical anesthetic effect. Capsaicin is not useful for topical treatment of the pain of HS. Sometimes compounded of anesthetics medications such as ketamine 10%, bupivacaine 1%, diclofenac 3%, doxepin 3% or 3.3%, and gabapentin 6% can extend the duration of effect so that medication only needs to be used 2 or 3 times a day. Still in my experience the easiest to get and most patient requested agent is topical diclonefac 1% gel.

Developing topic-specific search filters for PubMed with click-through data.

Science.gov (United States)

Li, J; Lu, Z

2013-01-01

Search filters have been developed and demonstrated for better information access to the immense and ever-growing body of publications in the biomedical domain. However, to date the number of filters remains quite limited because the current filter development methods require significant human efforts in manual document review and filter term selection. In this regard, we aim to investigate automatic methods for generating search filters. We present an automated method to develop topic-specific filters on the basis of users' search logs in PubMed. Specifically, for a given topic, we first detect its relevant user queries and then include their corresponding clicked articles to serve as the topic-relevant document set accordingly. Next, we statistically identify informative terms that best represent the topic-relevant document set using a background set composed of topic irrelevant articles. Lastly, the selected representative terms are combined with Boolean operators and evaluated on benchmark datasets to derive the final filter with the best performance. We applied our method to develop filters for four clinical topics: nephrology, diabetes, pregnancy, and depression. For the nephrology filter, our method obtained performance comparable to the state of the art (sensitivity of 91.3%, specificity of 98.7%, precision of 94.6%, and accuracy of 97.2%). Similarly, high-performing results (over 90% in all measures) were obtained for the other three search filters. Based on PubMed click-through data, we successfully developed a high-performance method for generating topic-specific search filters that is significantly more efficient than existing manual methods. All data sets (topic-relevant and irrelevant document sets) used in this study and a demonstration system are publicly available at http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/downloads/CQ_filter/

Dermal carotenoid level and kinetics after topical and systemic administration of antioxidants: enrichment strategies in a controlled in vivo study.

Science.gov (United States)

Darvin, Maxim E; Fluhr, Joachim W; Schanzer, Sabine; Richter, Heike; Patzelt, Alexa; Meinke, Martina C; Zastrow, Leonhard; Golz, Karin; Doucet, Olivier; Sterry, Wolfram; Lademann, Juergen

2011-10-01

High doses of sun-emitted UV-radiation induce reactive oxygen species (ROS) as major pro-oxidants thus inducing premature skin aging. The best prevention of the destructive action of free radicals in human skin is textile coverings, topical sunscreens and the development of a high antioxidative protective network. The effects of topical, systemic and combined application of antioxidants (AO) were investigated on human skin in vivo. Topical application of creams and systemic incorporation of tablets both containing AO was investigated in vivo by resonance Raman spectroscopy. Topical, systemic and combined AO-treatments induced a statistically significant increase of AO levels in human skin while placebo did not show any changes. The highest accumulation was induced by the combination of topical and systemic AO. Carotenoid-tablets combined with placebo-cream induced less carotenoid accumulation than carotenoid-tablets alone. Carotenoid levelling after the end of treatment lasted for around 2 weeks following the topical application of AOs, and up to 5 weeks after systemic administration, depending on the BMI of volunteers. Topically applied AO are stored in the SC for a short time only due to the rapid AO-depletion by desquamation, textile contact, washing and environmental stress. In contrast to topical application, the systemically applied carotenoids are stored in the body fat tissue and slowly released onto the skin surface with sweat and sebum. The combined topical and systemic application of AO represents an optimal form of protection of the AO-network. Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Topical steroid-damaged skin

Directory of Open Access Journals (Sweden)

Anil Abraham

2014-01-01

Full Text Available Topical steroids, commonly used for a wide range of skin disorders, are associated with side effects both systemic and cutaneous. This article aims at bringing awareness among practitioners, about the cutaneous side effects of easily available, over the counter, topical steroids. This makes it important for us as dermatologists to weigh the usefulness of topical steroids versus their side effects, and to make an informed decision regarding their use in each individual based on other factors such as age, site involved and type of skin disorder.

Mental Mechanisms for Topics Identification

Directory of Open Access Journals (Sweden)

Louis Massey

2014-01-01

Full Text Available Topics identification (TI is the process that consists in determining the main themes present in natural language documents. The current TI modeling paradigm aims at acquiring semantic information from statistic properties of large text datasets. We investigate the mental mechanisms responsible for the identification of topics in a single document given existing knowledge. Our main hypothesis is that topics are the result of accumulated neural activation of loosely organized information stored in long-term memory (LTM. We experimentally tested our hypothesis with a computational model that simulates LTM activation. The model assumes activation decay as an unavoidable phenomenon originating from the bioelectric nature of neural systems. Since decay should negatively affect the quality of topics, the model predicts the presence of short-term memory (STM to keep the focus of attention on a few words, with the expected outcome of restoring quality to a baseline level. Our experiments measured topics quality of over 300 documents with various decay rates and STM capacity. Our results showed that accumulated activation of loosely organized information was an effective mental computational commodity to identify topics. It was furthermore confirmed that rapid decay is detrimental to topics quality but that limited capacity STM restores quality to a baseline level, even exceeding it slightly.

THE Port: Hackathon at CERN | Apply now!

CERN Multimedia

THE Port team

2014-01-01

Are you innovative and like to share your ideas with other enthusiasts? Would you like to apply your knowledge and skills to humanitarian problems? Are you motivated to work on issues beneficial to society?   Apply to our problem-solving workshop - also known as hackathon / makeathon - taking place at CERN from 31 October to 2 November. You will work in interdisciplinary teams on topics inspired by other NGOs like ICRC, UN Development Programme, UNOSAT and UNITAR. Example topics are: Virtual tower camera for air fields The conflict zone humanitarian demarcation certificate The 10$ inflatable fridge for field operations Wearable sign language interpreter Can mobile communication data reveal election fraud? Tracking and demarcation system for dogs in rescue and de-mining operations   The 4 teams of 7 hand-picked innovators will be assembled 6 weeks ahead of the event to give time for preparation as some hardware might be needed. In this time they c...

THE Port: Hackathon at CERN | Apply now!

CERN Multimedia

THE Port team

2014-01-01

Are you innovative and do you like to share your ideas with other enthusiasts? Would you like to apply your knowledge and skills to humanitarian problems? Are you motivated to work on issues beneficial to society?   Apply for our problem-solving workshop - also known as a hackathon / makeathon - taking place at CERN from 31 October to 2 November. You will work in interdisciplinary teams on topics inspired by other NGOs such as the ICRC, UN Development Programme, UNOSAT and UNITAR. Example topics are: Virtual tower camera for air fields The conflict zone humanitarian demarcation certificate The $10 inflatable fridge for field operations Wearable sign language interpreter Can mobile communication data reveal election fraud? Tracking and demarcation system for dogs in rescue and de-mining operations   The four teams of seven hand-picked innovators will be assembled six weeks ahead of the event to give time for preparation as some hardware m...

Pilot Study of Topical Copper Chlorophyllin Complex in Subjects With Facial Acne and Large Pores.

Science.gov (United States)

Stephens, Thomas J; McCook, John P; Herndon, James H

2015-06-01

Acne vulgaris is one of the most common skin diseases treated by dermatologists. Salts of copper chlorophyllin complex are semi-synthetic naturally-derived compounds with antioxidant, anti-inflammatory and wound healing activity that have not been previously tested topically in the treatment of acne-prone skin with enlarged pores. This single-center pilot study was conducted to assess the efficacy and safety of a liposomal dispersion of topically applied sodium copper chlorophyllin complex in subjects with mild-moderate acne and large, visible pores over a course of 3 weeks. Subjects were supplied with the test product, a topical gel containing a liposomal dispersion of sodium copper chlorophyllin complex (0.1%) with directions to apply a small amount to the facial area twice daily. Clinical assessments were performed at screening/baseline and at week 3. VISIA readings were taken and self-assessment questionnaires were conducted. 10 subjects were enrolled and completed the 3-week study. All clinical efficacy parameters showed statistically significant improvements over baseline at week 3. The study product was well tolerated. Subject questionnaires showed the test product was highly rated. In this pilot study, a topical formulation containing a liposomal dispersion of sodium copper chlorophyllin complex was shown to be clinically effective and well tolerated for the treatment of mild-moderate acne and large, visible pores when used for 3 weeks.

Topical bioavailability of diclofenac from locally-acting, dermatological formulations.

Science.gov (United States)

Cordery, S F; Pensado, A; Chiu, W S; Shehab, M Z; Bunge, A L; Delgado-Charro, M B; Guy, R H

2017-08-30

Assessment of the bioavailability of topically applied drugs designed to act within or beneath the skin is a challenging objective. A number of different, but potentially complementary, techniques are under evaluation. The objective of this work was to evaluate in vitro skin penetration and stratum corneum tape-stripping in vivo as tools with which to measure topical diclofenac bioavailability from three approved and commercialized products (two gels and one solution). Drug uptake into, and its subsequent clearance from, the stratum corneum of human volunteers was used to estimate the input rate of diclofenac into the viable skin layers. This flux was compared to that measured across excised porcine skin in conventional diffusion cells. Both techniques clearly demonstrated (a) the superiority in terms of drug delivery from the solution, and (b) that the two gels performed similarly. There was qualitative and, importantly, quantitative agreement between the in vitro and in vivo measurements of drug flux into and beyond the viable skin. Evidence is therefore presented to support an in vivo - in vitro correlation between methods to assess topical drug bioavailability. The potential value of the stratum corneum tape-stripping technique to quantify drug delivery into (epi)dermal and subcutaneous tissue beneath the barrier is demonstrated. Copyright © 2017 Elsevier B.V. All rights reserved.

Traditional Persian topical medications for gastrointestinal diseases

Directory of Open Access Journals (Sweden)

Laleh Dehghani Tafti

2017-03-01

Full Text Available Drug delivery across the skin is used for several millennia to ease gastrointestinal (GI ailments in Traditional Persian Medicine (TPM. TPM topical remedies are generally being applied on the stomach, lower abdomen, lower back and liver to alleviate GI illnesses such as dyspepsia, gastritis, GI ulcers, inflammatory bowel disease, intestinal worms and infections. The aim of the present study is to survey the topical GI remedies and plant species used as ingredients for these remedies in TPM. In addition, pharmacological activities of the mentioned plants have been discussed. For this, we searched major TPM textbooks to find plants used to cure GI problems in topical use. Additionally, scientific databases were searched to obtain pharmacological data supporting the use of TPM plants in GI diseases. Rosa × damascena, Pistacia lentiscus, Malus domestica, Olea europaea and Artemisia absinthium are among the most frequently mentioned ingredients of TPM remedies. β-asarone, amygdalin, boswellic acids, guggulsterone, crocin, crocetin, isomasticadienolic acid, and cyclotides are the most important phytochemicals present in TPM plants with GI-protective activities. Pharmacological studies demonstrated GI activities for TPM plants supporting their extensive traditional use. These plants play pivotal role in alleviating GI disorders through exhibiting numerous activities including antispasmodic, anti-ulcer, anti-secretory, anti-colitis, anti-diarrheal, antibacterial and anthelmintic properties. Several mechanisms underlie these activities including the alleviation of oxidative stress, exhibiting cytoprotective activity, down-regulation of the inflammatory cytokines, suppression of the cellular signaling pathways of inflammatory responses, improving re-epithelialization and angiogenesis, down-regulation of anti-angiogenic factors, blocking activity of acetylcholine, etc.

Quality assurance program description. Topical report SDQAPD-1

International Nuclear Information System (INIS)

1975-01-01

The topical report presented describes the SDG and E QA Program that is applied to the design, procurement, construction, and preoperational testing of nuclear power plants. The QA plan describes the SDG and E organizational structure for quality assurance; identifies the functions, duties, and responsibilities of key departments and individuals; describes interrelationships and interfaces among internal groups and external organizations; delineates program requirements, and prescribes methods of implementation. SDG and E Procedures and Directives provide detailed direction for accomplishment of program requirements in consonance with the methods specified in the QA Plan

Uncovering the Topic Landscape of Product-Service System Research: from Sustainability to Value Creation

Directory of Open Access Journals (Sweden)

Hakyeon Lee

2018-03-01

Full Text Available As the product-service system (PSS is considered a promising business model that can create more value for customers, PSS research has enjoyed remarkable growth in its volume and coverage over the last decade. This study aims to delineate the thematic landscape of PSS research by identifying latent topics from a large amount of scholarly data. Ten topics of PSS research are identified by applying the Latent Dirichlet Allocation (LDA model to 1229 PSS publications published between 2000 and 2016. The ten PSS topics are briefly reviewed to provide an overview of what has previously been studied in PSS research. We also investigate which topics rise or fall in popularity by identifying hot and cold topics of PSS research. It is observed that the focus of discussions on the benefits of PSS has shifted from sustainability to value creation. Also, increasing attention has been paid to more practical topics such as PSS implementation. The areas of subspecialty of the top ten PSS journals are also examined to explore the interdisciplinary nature of PSS research and thematic differences across disciplines. The findings of this study can provide rich implications for both academia and practice in the field of PSS.

77 FR 55863 - NASA Advisory Council; Science Committee; Earth Science Subcommittee; Applied Sciences Advisory...

Science.gov (United States)

2012-09-11

... Committee; Earth Science Subcommittee; Applied Sciences Advisory Group Meeting AGENCY: National Aeronautics... the Applied Science Advisory Group. This Subcommittee reports to the Earth Science Subcommittee... following topics: --Applied Sciences Program Update --Earth Science Data Latency Study Preliminary Update...

The Optical Society's 2016 topical meeting on optical interference coatings: introduction.

Science.gov (United States)

Ristau, Detlev; Li, Li; Sargent, Robert; Sytchkova, Anna

2017-02-01

This feature issue of Applied Optics is dedicated to the 13th Topical Meeting on Optical Interference Coatings, which was held June 19-24, 2016, in Tucson, Arizona, USA. The conference, taking place every three years, is a focal point for global technical interchange in the field of optical interference coatings and provides premier opportunities for people working in the field to present their new advances in research and development. Papers presented at the meeting covered a broad range of topics, including fundamental research on coating design theory, new materials, and deposition and characterization technologies, as well as the vast and growing number of applications in electronic displays, communication, optical instruments, high power and ultra-fast lasers, solar cells, space missions, gravitational wave detection, and many others.

Learning to Apply Models of Materials While Explaining Their Properties

Science.gov (United States)

Karpin, Tiia; Juuti, Kalle; Lavonen, Jari

2014-01-01

Background: Applying structural models is important to chemistry education at the upper secondary level, but it is considered one of the most difficult topics to learn. Purpose: This study analyses to what extent in designed lessons students learned to apply structural models in explaining the properties and behaviours of various materials.…

Topical Treatment of Degenerative Knee Osteoarthritis.

Science.gov (United States)

Meng, Zengdong; Huang, Rongzhong

2018-01-01

This article reviews topical management strategies for degenerative osteoarthritis (OA) of the knee. A search of Pubmed, Embase and the Cochrane library using MeSH terms including "topical," "treatment," "knee" and "osteoarthritis" was carried out. Original research and review articles on the effectiveness and safety, recommendations from international published guidelines and acceptability studies of topical preparations were included. Current topical treatments included for the management of knee OA include topical nonsteroidal anti-inflammatory drugs, capsaicin, salicylates and physical treatments such as hot or cold therapy. Current treatment guidelines recommend topical nonsteroidal anti-inflammatory drugs as an alternative and even first-line therapy for OA management, especially among elderly patients. Guidelines on other topical treatments vary, from recommendations against their use, to in favor as alternative or simultaneous therapy, especially for patients with contraindications to other analgesics. Although often well-tolerated and preferred by many patients, clinical care still lags in the adoption of topical treatments. Aspects of efficacy, safety and patient quality of life data require further research. Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Correlated Topic Vector for Scene Classification.

Science.gov (United States)

Wei, Pengxu; Qin, Fei; Wan, Fang; Zhu, Yi; Jiao, Jianbin; Ye, Qixiang

2017-07-01

Scene images usually involve semantic correlations, particularly when considering large-scale image data sets. This paper proposes a novel generative image representation, correlated topic vector, to model such semantic correlations. Oriented from the correlated topic model, correlated topic vector intends to naturally utilize the correlations among topics, which are seldom considered in the conventional feature encoding, e.g., Fisher vector, but do exist in scene images. It is expected that the involvement of correlations can increase the discriminative capability of the learned generative model and consequently improve the recognition accuracy. Incorporated with the Fisher kernel method, correlated topic vector inherits the advantages of Fisher vector. The contributions to the topics of visual words have been further employed by incorporating the Fisher kernel framework to indicate the differences among scenes. Combined with the deep convolutional neural network (CNN) features and Gibbs sampling solution, correlated topic vector shows great potential when processing large-scale and complex scene image data sets. Experiments on two scene image data sets demonstrate that correlated topic vector improves significantly the deep CNN features, and outperforms existing Fisher kernel-based features.

Topical treatment of psoriasis: questionnaire results on topical therapy accessibility and influence of body surface area on usage.

Science.gov (United States)

Iversen, L; Lange, M M; Bissonette, R; Carvalho, A V E; van de Kerkhof, P C; Kirby, B; Kleyn, C E; Lynde, C W; van der Walt, J M; Wu, J J

2017-07-01

Topical treatment of mild to moderate psoriasis is first-line treatment and exhibits varying degrees of success across patient groups. Key factors influencing treatment success are physician topical treatment choice (high efficacy, low adverse events) and strict patient adherence. Currently, no formalized, international consensus guidelines exist to direct optimal topical treatment, although many countries have national guidelines. To describe and analyse cross-regional variations in the use and access of psoriasis topical therapies. The study was conducted as an observational cross-sectional study. A survey was distributed to dermatologists from the International Psoriasis Council (IPC) to assess topical therapy accessibility in 26 countries and to understand how body surface area (BSA) categories guide clinical decisions on topical use. Variation in the availability of tars, topical retinoids, dithranol and balneotherapy was reported. The vast majority of respondents (100% and 88.4%) used topical therapy as first-line monotherapy in situations with BSA 10%, the number of respondents who prescribe topical therapy decreased considerably. In addition, combination therapy of a topical drug and a systemic drug was frequently reported when BSA measured >10%. This physician survey provides new evidence on topical access and the influence of disease severity on topical usage in an effort to improve treatment strategies on a global level. © 2017 European Academy of Dermatology and Venereology.

2nd Applied Electromagnetic International Conference

CERN Document Server

Sulaiman, Hamzah; Othman, Mohd; Aziz, Mohamad; Malek, Mohd

2017-01-01

In this book, experts from academia and industry present the latest advances in scientific theory relating to applied electromagnetics and examine current and emerging applications particularly within the fields of electronics, communications, and computer technology. The book is based on presentations delivered at APPEIC 2015, the 2nd Applied Electromagnetic International Conference, held in Krabi, Thailand in December 2015. The conference provided an ideal platform for researchers and specialists to deliver both theoretically and practically oriented contributions on a wide range of topics relevant to the theme of nurturing applied electromagnetics for human technology. Many novel aspects were addressed, and the contributions selected for this book highlight the relevance of advances in applied electromagnetics to a variety of industrial engineering problems and identify exciting future directions for research.

1st Applied Electromagnetic International Conference

CERN Document Server

Othman, Mohd; Aziz, Mohamad; Malek, Mohd

2015-01-01

In this book, experts from academia and industry present the latest advances in scientific theory relating to applied electromagnetics and examine current and emerging applications particularly within the fields of electronics, communications, and computer technology. The book is based on presentations delivered at APPEIC 2014, the 1st Applied Electromagnetic International Conference, held in Bandung, Indonesia in December 2014. The conference provided an ideal platform for researchers and specialists to deliver both theoretically and practically oriented contributions on a wide range of topics relevant to the theme of nurturing applied electromagnetics for human technology. Many novel aspects were addressed, and the contributions selected for this book highlight the relevance of advances in applied electromagnetics to a variety of industrial engineering problems and identify exciting future directions for research.

Applied Behavior Analysis in Autism Spectrum Disorders: Recent Developments, Strengths, and Pitfalls

Science.gov (United States)

Matson, Johnny L.; Turygin, Nicole C.; Beighley, Jennifer; Rieske, Robert; Tureck, Kimberly; Matson, Michael L.

2012-01-01

Autism has become one of the most heavily researched topics in the field of mental health and education. While genetics has been the most studied of all topics, applied behavior analysis (ABA) has also received a great deal of attention, and has arguably yielded the most promising results of any research area to date. The current paper provides a…

[Otomycosis and topical application of thimerosal: study of 152 cases].

Science.gov (United States)

Tisner, J; Millán, J; Rivas, P; Adiego, I; Castellote, A; Valles, H

1995-01-01

To evaluate the effectiveness of the topical application of Timerosal (merthilate tintura) in mycosis involving the external auditory canal. The study includes 152 patients with the clinical, otoscopic and microscopic diagnosis of otomycosis. Results were assessed 72 hours and 10 days after the application. Bacteriological study was performed in 83 patients, finding Aspergilly niger in 54.0% of the cases, Candida albicans in 25.4%, Aspergillus fumigatus in 15.8% and Penicillium in 4.8%. Improvement at 72 h. was found in 66.4% and at 10 days in 93.4% of the patients. Bacteriological contamination was found in 6.6% of the total. In most of the patients, the otomycosis healed after cleaning of the external auditory canal and topical application of timerosal. This method is easy to apply, fast, effective, of low cost and few side effects.

An Evaluation of Applying Knowledge Base to Academic Information Service

OpenAIRE

Seok-Hyoung Lee; Hwan-Min Kim; Ho-Seop Choe

2013-01-01

Through a series of precise text handling processes, including automatic extraction of information from documents with knowledge from various fields, recognition of entity names, detection of core topics, analysis of the relations between the extracted information and topics, and automatic inference of new knowledge, the most efficient knowledge base of the relevant field is created, and plans to apply these to the information knowledge management and service are the core requirements necessa...

[TOPICS-MDS: a versatile resource for generating scientific and social knowledge for elderly care].

Science.gov (United States)

van den Brink, Danielle; Lutomski, Jennifer E; Qin, Li; den Elzen, Wendy P J; Kempen, Gertrudis I J M; Krabbe, Paul F M; Steyerberg, Ewout W; Muntinga, Maaike; Moll van Charante, Eric P; Bleijenberg, Nienke; Olde Rikkert, Marcel G M; Melis, René J F

2015-04-01

Developed as part of the National Care for the Elderly Programme (NPO), TOPICS-MDS is a uniform, national database on the health and wellbeing of the older persons and caregivers who participated in NPO-funded projects. TOPICS-MDS Consortium has gained extensive experience in constructing a standardized questionnaire to collect relevant health care data on quality of life, health services utilization, and informal care use. A proactive approach has been undertaken not only to ensure the standardization and validation of instruments but also the infrastructure for external data requests. Efforts have been made to promote scientifically and socially responsible use of TOPICS-MDS; data has been available for secondary use since early 2014. Through this data sharing initiative, researchers can explore health issues in a broader framework which may have not been possible within individual NPO projects; this broader framework is highly relevant for influencing health policy. In this article, we provide an overview of the development and on-going progress of TOPICS-MDS. We further describe how information derived from TOPICS-MDS can be applied to facilitate future scientific innovations and public health initiatives to improve care for frail older persons and their caregivers.

Topics in quantum field theory and cosmology

International Nuclear Information System (INIS)

Brandenberger, R.H.

1983-01-01

This thesis contains a study of topics in quantum field theory and cosmology in the context of the new inflationary universe scenario. It presents a review of the quantum field theory methods used in the new cosmological models. The following chapters are a detailed study of energy density fluctuations in the early universe. Hawking radiation is derived as the source of initial perturbations in two complementary ways. The following section presents a new gauge invariant framework to study the growth of fluctuations outside the horizon. This framework is applied to the new inflationary universe in the final chapter. The introduction gives a brief outline of the new cosmological models

Topical botulinum toxin.

Science.gov (United States)

Collins, Ashley; Nasir, Adnan

2010-03-01

Nanotechnology is a rapidly growing discipline that capitalizes on the unique properties of matter engineered on the nanoscale. Vehicles incorporating nanotechnology have led to great strides in drug delivery, allowing for increased active ingredient stability, bioavailability, and site-specific targeting. Botulinum toxin has historically been used for the correction of neurological and neuromuscular disorders, such as torticollis, blepharospasm, and strabismus. Recent dermatological indications have been for the management of axillary hyperhydrosis and facial rhytides. Traditional methods of botulinum toxin delivery have been needle-based. These have been associated with increased pain and cost. Newer methods of botulinum toxin formulation have yielded topical preparations that are bioactive in small pilot clinical studies. While there are some risks associated with topical delivery, the refinement and standardization of delivery systems and techniques for the topical administration of botulinum toxin using nanotechnology is anticipated in the near future.

Topical methotrexate pretreatment enhances the therapeutic effect of topical 5-aminolevulinic acid-mediated photodynamic therapy on hamster buccal pouch precancers.

Science.gov (United States)

Yang, Deng-Fu; Lee, Jeng-Woei; Chen, Hsin-Ming; Hsu, Yih-Chih

2014-09-01

Topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is effective for treatment of human oral precancerous lesions. This animal study aimed to assess whether topical methotrexate (MTX) pretreatment could enhance the therapeutic effect of topical ALA-PDT on hamster buccal pouch precancerous lesions. Twenty hamster buccal pouch precancerous lesions were treated with either topical ALA-PDT with topical MTX pretreatment (topical MTX-ALA-PDT group, n = 10) or topical ALA-PDT alone (topical ALA-PDT group, n = 10). The intracellular protoporphyrin IX (PpIX) level in another 12 precancerous lesions (n = 6 for either the topical MTX-ALA or topical ALA group) was monitored by fluorescence spectroscopy. The intracellular PpIX reached its peak level in precancerous lesions 6.5 hours and 2.5 hours after topical ALA application for the topical MTX-ALA group (5.63-fold higher in the lesion than in the normal mucosa) and topical ALA group (2.42-fold higher in the lesion than in the normal mucosa), respectively. The complete response rate of precancerous lesions was 80% for the topical MTX-ALA-PDT group and 70% for the topical ALA-PDT group. In addition, the topical MTX-ALA-PDT group required a significantly lower mean treatment number (2.1 ± 0.6) to achieve complete response than the topical ALA-PDT group (4.4 ± 1.3, p topical MTX-ALA-PDT group had a lower recurrence rate (12.5%) than the topical ALA-PDT group (28.6%). We conclude that topical MTX-pretreatment can increase intracellular PpIX production in hamster buccal pouch precancerous lesions and significantly improves the outcomes of the precancerous lesions treated with topical ALA-PDT. Copyright © 2014. Published by Elsevier B.V.

Machine Learning-Based Classification of 38 Years of Spine-Related Literature Into 100 Research Topics.

Science.gov (United States)

Sing, David C; Metz, Lionel N; Dudli, Stefan

2017-06-01

Retrospective review. To identify the top 100 spine research topics. Recent advances in "machine learning," or computers learning without explicit instructions, have yielded broad technological advances. Topic modeling algorithms can be applied to large volumes of text to discover quantifiable themes and trends. Abstracts were extracted from the National Library of Medicine PubMed database from five prominent peer-reviewed spine journals (European Spine Journal [ESJ], The Spine Journal [SpineJ], Spine, Journal of Spinal Disorders and Techniques [JSDT], Journal of Neurosurgery: Spine [JNS]). Each abstract was entered into a latent Dirichlet allocation model specified to discover 100 topics, resulting in each abstract being assigned a probability of belonging in a topic. Topics were named using the five most frequently appearing terms within that topic. Significance of increasing ("hot") or decreasing ("cold") topic popularity over time was evaluated with simple linear regression. From 1978 to 2015, 25,805 spine-related research articles were extracted and classified into 100 topics. Top two most published topics included "clinical, surgeons, guidelines, information, care" (n = 496 articles) and "pain, back, low, treatment, chronic" (424). Top two hot trends included "disc, cervical, replacement, level, arthroplasty" (+0.05%/yr, P < 0.001), and "minimally, invasive, approach, technique" (+0.05%/yr, P < 0.001). By journal, the most published topics were ESJ-"operative, surgery, postoperative, underwent, preoperative"; SpineJ-"clinical, surgeons, guidelines, information, care"; Spine-"pain, back, low, treatment, chronic"; JNS- "tumor, lesions, rare, present, diagnosis"; JSDT-"cervical, anterior, plate, fusion, ACDF." Topics discovered through latent Dirichlet allocation modeling represent unbiased meaningful themes relevant to spine care. Topic dynamics can provide historical context and direction for future research for aspiring investigators and trainees

Linear algebra and matrices topics for a second course

CERN Document Server

Shapiro, Helene

2015-01-01

Linear algebra and matrix theory are fundamental tools for almost every area of mathematics, both pure and applied. This book combines coverage of core topics with an introduction to some areas in which linear algebra plays a key role, for example, block designs, directed graphs, error correcting codes, and linear dynamical systems. Notable features include a discussion of the Weyr characteristic and Weyr canonical forms, and their relationship to the better-known Jordan canonical form; the use of block cyclic matrices and directed graphs to prove Frobenius's theorem on the structure of the eigenvalues of a nonnegative, irreducible matrix; and the inclusion of such combinatorial topics as BIBDs, Hadamard matrices, and strongly regular graphs. Also included are McCoy's theorem about matrices with property P, the Bruck-Ryser-Chowla theorem on the existence of block designs, and an introduction to Markov chains. This book is intended for those who are familiar with the linear algebra covered in a typical first c...

Applied partial differential equations

CERN Document Server

Logan, J David

2015-01-01

This text presents the standard material usually covered in a one-semester, undergraduate course on boundary value problems and PDEs.  Emphasis is placed on motivation, concepts, methods, and interpretation, rather than on formal theory. The concise treatment of the subject is maintained in this third edition covering all the major ideas: the wave equation, the diffusion equation, the Laplace equation, and the advection equation on bounded and unbounded domains. Methods include eigenfunction expansions, integral transforms, and characteristics. In this third edition, text remains intimately tied to applications in heat transfer, wave motion, biological systems, and a variety other topics in pure and applied science. The text offers flexibility to instructors who, for example, may wish to insert topics from biology or numerical methods at any time in the course. The exposition is presented in a friendly, easy-to-read, style, with mathematical ideas motivated from physical problems. Many exercises and worked e...

Convective transport of highly plasma protein bound drugs facilitates direct penetration into deep tissues after topical application

Science.gov (United States)

Dancik, Yuri; Anissimov, Yuri G; Jepps, Owen G; Roberts, Michael S

2012-01-01

AIMS To relate the varying dermal, subcutaneous and muscle microdialysate concentrations found in man after topical application to the nature of the drug applied and to the underlying physiology. METHODS We developed a physiologically based pharmacokinetic model in which transport to deeper tissues was determined by tissue diffusion, blood, lymphatic and intersitial flow transport and drug properties. The model was applied to interpret published human microdialysis data, estimated in vitro dermal diffusion and protein binding affinity of drugs that have been previously applied topically in vivo and measured in deep cutaneous tissues over time. RESULTS Deeper tissue microdialysis concentrations for various drugs in vivo vary widely. Here, we show that carriage by the blood to the deeper tissues below topical application sites facilitates the transport of highly plasma protein bound drugs that penetrate the skin, leading to rapid and significant concentrations in those tissues. Hence, the fractional concentration for the highly plasma protein bound diclofenac in deeper tissues is 0.79 times that in a probe 4.5 mm below a superficial probe whereas the corresponding fractional concentration for the poorly protein bound nicotine is 0.02. Their corresponding estimated in vivo lag times for appearance of the drugs in the deeper probes were 1.1 min for diclofenac and 30 min for nicotine. CONCLUSIONS Poorly plasma protein bound drugs are mainly transported to deeper tissues after topical application by tissue diffusion whereas the transport of highly plasma protein bound drugs is additionally facilitated by convective blood, lymphatic and interstitial transport to deep tissues. PMID:21999217

Systemic component of protoporphyrin IX production in nude mouse skin upon topical application of aminolevulinic acid depends on the application conditions

NARCIS (Netherlands)

van den Akker, Johanna T. H. M.; Iani, Vladimir; Star, Willem M.; Sterenborg, Henricus J. C. M.; Moan, Johan

2002-01-01

Topical application of 5-aminolevulinic acid (ALA) for protoporphyrin IX (PpIX)-based photodynamic therapy of skin cancer is generally considered not to induce systemic side effects because PpIX is supposed to be formed locally. However, earlier studies with topically applied ALA have revealed that

Recent advances in topical anesthesia

Science.gov (United States)

2016-01-01

Topical anesthetics act on the peripheral nerves and reduce the sensation of pain at the site of application. In dentistry, they are used to control local pain caused by needling, placement of orthodontic bands, the vomiting reflex, oral mucositis, and rubber-dam clamp placement. Traditional topical anesthetics contain lidocaine or benzocaine as active ingredients and are used in the form of solutions, creams, gels, and sprays. Eutectic mixtures of local anesthesia cream, a mixture of various topical anesthetics, has been reported to be more potent than other anesthetics. Recently, new products with modified ingredients and application methods have been introduced into the market. These products may be used for mild pain during periodontal treatment, such as scaling. Dentists should be aware that topical anesthetics, although rare, might induce allergic reactions or side effects as a result of an overdose. Topical anesthetics are useful aids during dental treatment, as they reduce dental phobia, especially in children, by mitigating discomfort and pain. PMID:28879311

Discriminative Relational Topic Models.

Science.gov (United States)

Chen, Ning; Zhu, Jun; Xia, Fei; Zhang, Bo

2015-05-01

Relational topic models (RTMs) provide a probabilistic generative process to describe both the link structure and document contents for document networks, and they have shown promise on predicting network structures and discovering latent topic representations. However, existing RTMs have limitations in both the restricted model expressiveness and incapability of dealing with imbalanced network data. To expand the scope and improve the inference accuracy of RTMs, this paper presents three extensions: 1) unlike the common link likelihood with a diagonal weight matrix that allows the-same-topic interactions only, we generalize it to use a full weight matrix that captures all pairwise topic interactions and is applicable to asymmetric networks; 2) instead of doing standard Bayesian inference, we perform regularized Bayesian inference (RegBayes) with a regularization parameter to deal with the imbalanced link structure issue in real networks and improve the discriminative ability of learned latent representations; and 3) instead of doing variational approximation with strict mean-field assumptions, we present collapsed Gibbs sampling algorithms for the generalized relational topic models by exploring data augmentation without making restricting assumptions. Under the generic RegBayes framework, we carefully investigate two popular discriminative loss functions, namely, the logistic log-loss and the max-margin hinge loss. Experimental results on several real network datasets demonstrate the significance of these extensions on improving prediction performance.

Topical Retinol Restores Type I Collagen Production in Photoaged Forearm Skin within Four Weeks

Directory of Open Access Journals (Sweden)

Min Sun

2016-09-01

Full Text Available Production of type I collagen (COL1, the major structural protein of the skin, declines during aging, leading to skin thinning and becoming fragile, which increases the risk of bruising and wound healing disorders in the elderly. Topical treatments that can restore COL1 synthesis and ultimately COL1 content in aged skin hold promise to improve skin health. Much effort has been spent on developing agents that can safely and effectively enhance COL1 synthesis in aged skin. However, how fast and to what extent COL1 production in aged skin can be enhanced by a topical treatment remains unclear. Herein, we investigated a four-week topical retinol (ROL treatment. A one-day occlusion of ROL (0.4% or vehicle was applied on photoaged forearms of elderly (>65 years old subjects once a week for four weeks. Vehicle was also applied on forearms of young (23–33 years subjects in the same manner. Skin samples were obtained one week after the last treatment and analyzed for COL1 synthesis. We found that the ROL treatment increased the level of COL1 mRNA (2.3-fold and proCOL1 protein (1.8-fold in photoaged forearms to levels similar to that of young forearms within four weeks. Our study proves the concept that reduced COL1 production in aged skin can be readily restored. In addition, our study provides an evidence-based foundation for developing COL1-enhancing topical agents, and establishes a reliable and practical efficacy test for evaluating such agents.

The effect of microneedles on the skin permeability and antitumor activity of topical 5-fluorouracil

Directory of Open Access Journals (Sweden)

Youssef W. Naguib

2014-02-01

Full Text Available Topical 5-fluorouracil (5-FU is approved for the treatment of superficial basal cell carcinoma and actinic keratosis. However, 5-FU suffers from poor skin permeation. Microneedles have been successfully applied to improve the skin permeability of small and large molecules, and even nanoparticles, by creating micron-sized pores in the stratum corneum layer of the skin. In this report, the feasibility of using microneedles to increase the skin permeability of 5-FU was tested. Using full thickness mouse skin mounted on Franz diffusion apparatus, it was shown that the flux of 5-FU through the skin was increased by up to 4.5-fold when the skin was pretreated with microneedles (500 μm in length, 50 μm in base diameter. In a mouse model with B16-F10 mouse melanoma cells implanted in the subcutaneous space, the antitumor activity of a commercially available 5-FU topical cream (5% was significantly enhanced when the cream was applied on a skin area that was pretreated with microneedles, as compared to when the cream was simply applied on a skin area, underneath which the tumor cells were implanted, and without pretreatment of the skin with microneedles. Fluorouracil is not approved for melanoma therapy, but the clinical efficacy of topical 5-FU against tumors such as basal cell carcinoma may be improved by integrating microneedle technology into the therapy.

Topical anesthesia

Directory of Open Access Journals (Sweden)

Mritunjay Kumar

2015-01-01

Full Text Available Topical anesthetics are being widely used in numerous medical and surgical sub-specialties such as anesthesia, ophthalmology, otorhinolaryngology, dentistry, urology, and aesthetic surgery. They cause superficial loss of pain sensation after direct application. Their delivery and effectiveness can be enhanced by using free bases; by increasing the drug concentration, lowering the melting point; by using physical and chemical permeation enhancers and lipid delivery vesicles. Various topical anesthetic agents available for use are eutectic mixture of local anesthetics, ELA-max, lidocaine, epinephrine, tetracaine, bupivanor, 4% tetracaine, benzocaine, proparacaine, Betacaine-LA, topicaine, lidoderm, S-caine patch™ and local anesthetic peel. While using them, careful attention must be paid to their pharmacology, area and duration of application, age and weight of the patients and possible side-effects.

Applied mathematics

International Nuclear Information System (INIS)

Nedelec, J.C.

1988-01-01

The 1988 progress report of the Applied Mathematics center (Polytechnic School, France), is presented. The research fields of the Center are the scientific calculus, the probabilities and statistics and the video image synthesis. The research topics developed are: the analysis of numerical methods, the mathematical analysis of the physics and mechanics fundamental models, the numerical solution of complex models related to the industrial problems, the stochastic calculus and the brownian movement, the stochastic partial differential equations, the identification of the adaptive filtering parameters, the discrete element systems, statistics, the stochastic control and the development, the image synthesis techniques for education and research programs. The published papers, the congress communications and the thesis are listed [fr

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.

Problematic topic transitions in dysarthric conversation.

Science.gov (United States)

Bloch, Steven; Saldert, Charlotta; Ferm, Ulrika

2015-01-01

This study examined the nature of topic transition problems associated with acquired progressive dysarthric speech in the everyday conversation of people with motor neurone disease. Using conversation analytic methods, a video collection of five naturally occurring problematic topic transitions was identified, transcribed and analysed. These were extracted from a main collection of over 200 other-initiated repair sequences and a sub-set of 15 problematic topic transition sequences. The sequences were analysed with reference to how the participants both identified and resolved the problems. Analysis revealed that topic transition by people with dysarthria can prove problematic. Conversation partners may find transitions problematic not only because of speech intelligibility but also because of a sequential disjuncture between the dysarthric speech turn and whatever topic has come prior. In addition the treatment of problematic topic transition as a complaint reveals the potential vulnerability of people with dysarthria to judgements of competence. These findings have implications for how dysarthria is conceptualized and how specific actions in conversation, such as topic transition, might be suitable targets for clinical intervention.

76 FR 81806 - Ophthalmic and Topical Dosage Form New Animal Drugs; Ivermectin Topical Solution

Science.gov (United States)

2011-12-29

.... FDA-2011-N-0003] Ophthalmic and Topical Dosage Form New Animal Drugs; Ivermectin Topical Solution... solution of ivermectin. DATES: This rule is effective December 29, 2011. FOR FURTHER INFORMATION CONTACT... ANADA 200-318 for [[Page 81807

Issue on applied human bioclimatology in memory of Henrique Andrade

OpenAIRE

Alcoforado, Maria João

2014-01-01

This issue of Finisterra is dedicated mostly to human bioclimatology and urbanclimatology, as these were the main research topics of our late colleague HenriqueAndrade, to whom this issue is dedicated. Furthermore, these topics are of currentinterest and can be of use for applied purposes.Henrique passed away last year (January 9th 2013) and a short note on his lifehas already been published in this Journal (Finisterra, XLVIII, 95:9-13, availableonline). He taught at the Geography Department ...

Topical methotrexate pretreatment enhances the therapeutic effect of topical 5-aminolevulinic acid-mediated photodynamic therapy on hamster buccal pouch precancers

OpenAIRE

Deng-Fu Yang; Jeng-Woei Lee; Hsin-Ming Chen; Yih-Chih Hsu

2014-01-01

Topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is effective for treatment of human oral precancerous lesions. This animal study aimed to assess whether topical methotrexate (MTX) pretreatment could enhance the therapeutic effect of topical ALA-PDT on hamster buccal pouch precancerous lesions. Methods: Twenty hamster buccal pouch precancerous lesions were treated with either topical ALA-PDT with topical MTX pretreatment (topical MTX-ALA-PDT group, n = 10) or topical A...

Topical immunomodulators in dermatology

Directory of Open Access Journals (Sweden)

Khandpur Sujay

2004-04-01

Full Text Available Topical immunomodulators are agents that regulate the local immune response of the skin. They are now emerging as the therapy of choice for several immune-mediated dermatoses such as atopic dermatitis, contact allergic dermatitis, alopecia areata, psoriasis, vitiligo, connective tissue disorders such as morphea and lupus erythematosus, disorders of keratinization and several benign and malignant skin tumours, because of their comparable efficacy, ease of application and greater safety than their systemic counterparts. They can be used on a domiciliary basis for longer periods without aggressive monitoring. In this article, we have discussed the mechanism of action, common indications and side-effects of the commonly used topical immunomodulators, excluding topical steroids. Moreover, newer agents, which are still in the experimental stages, have also been described. A MEDLINE search was undertaken using the key words "topical immunomodulators, dermatology" and related articles were also searched. In addition, a manual search for many Indian articles, which are not indexed, was also carried out. Wherever possible, the full article was reviewed. If the full article could not be traced, the abstract was used.

Recent Advances In Topical Therapy In Dermatology

Directory of Open Access Journals (Sweden)

Mohan Thappa Devinder

2003-01-01

Full Text Available With changing times various newer topical agents are introduced in the field of dermatology. Tacrolimus and pimecrolimus are immunisuppressants, which are effective topically and are tried in the management of atopic dermatitis as well as other disorders including allergic contact dermatitis, atrophic lichen planus, pyoderma gangrenosum. Imiquimod, an immune response modifier, is presently in use for genital warts but has potentials as anti- tumour agent and in various other dermatological conditions when used topically. Tazarotene is a newer addition to the list of topical reginoids, which is effective in psoriasis and has better effect in combination with calcipotriene, phototherapy and topical costicosteroids. Tazarotene and adapelene are also effective in inflammatory acne. Calcipotriol, a vitamin D analogue has been introduced as a topical agent in the treatment of psoriasis. Steroid components are also developed recently which will be devoid of the side effects but having adequate anti-inflammatory effect. Topical photodynamic therapy has also a wide range of use in dermatology. Newer topical agents including cidofovir, capsaicin, topical sensitizers, topical antifungal agents for onychomycosis are also of use in clinical practice. Other promising developments include skin substitutes and growth factors for wound care.

Topic Modeling of Hierarchical Corpora /

OpenAIRE

Kim, Do-kyum

2014-01-01

The sizes of modern digital libraries have grown beyond our capacity to comprehend manually. Thus we need new tools to help us in organizing and browsing large corpora of text that do not require manually examining each document. To this end, machine learning researchers have developed topic models, statistical learning algorithms for automatic comprehension of large collections of text. Topic models provide both global and local views of a corpus; they discover topics that run through the co...

Credibility improves topical blog post retrieval

NARCIS (Netherlands)

Weerkamp, W.; de Rijke, M.

2008-01-01

Topical blog post retrieval is the task of ranking blog posts with respect to their relevance for a given topic. To improve topical blog post retrieval we incorporate textual credibility indicators in the retrieval process. We consider two groups of indicators: post level (determined using

Feline penile erection induced by topical glans penis application of combination alprostadil and SEPA (Topiglan).

Science.gov (United States)

Usta, M F; Sanabria, J; Bivalacqua, T J; Hellstrom, W J G; Sanabriav, J

2004-02-01

The objective of this study was to evaluate the efficacy of topically applied prostaglandin E1 (PGE(1))+5% SEPA (soft enhancement of percutaneous absorption) on the glans penis in a feline erection model. Erectile response after glans penis administration of PGE(1)+5% SEPA cream (Topiglan, MacroChem Co., Lexington, MA, USA) was compared to the erectile response after intracavernosal administration of the triple-drug combination (1.65 mg papaverine, 25 microg phentolamine, and 0.5 microg PGE(1)). The placebo cream and increasing concentrations (0.25%, 2.5 mg/ml; 0.5%, 5 mg/ml; and 1%, 10 mg/ml) of PGE(1)+5% SEPA were applied in a total volume of 0.1 ml via a plastic needle-less syringe. The control triple-drug combination was administrated intracavernosally via a 30-gauge needle at the completion of each experiment to serve as a control reference. With each application of placebo, PGE(1)+SEPA, and the triple-drug combination, changes in intracavernosal pressure and systemic blood pressure were continuously monitored. Topical application of PGE(1)+SEPA induced increases in intracavernosal pressure in a dose-dependent manner, with minimal effects on systemic blood pressure. The increases obtained with 1% PGE(1) Topiglan cream were similar to the intracavernosal pressure values elicited by the standard intracavernosal triple-drug combination. These data demonstrate that topical glans penis application of PGE(1)+SEPA can induce an erectile response in cats with minimal systemic adverse effects. Oral pharmacological agents are the first-line treatment for male ED. Studies investigating the effectiveness of noninvasive modalities such as topical therapy should continue, because these agents have the potential to avoid the systemic effects commonly seen with oral therapies. Additionally, topical therapy may also benefit patients who are unresponsive to oral agents or have explicit contraindications. Topical PGE(1) application to the glans penis may become an important

Topic prominence in Chinese EFL learners’ interlanguage

Directory of Open Access Journals (Sweden)

Shaopeng Li

2014-01-01

Full Text Available The present study aims to investigate the general characteristics of topicprominent typological interlanguage development of Chinese learners of English in terms of acquiring subject-prominent English structures from a discourse perspective. Topic structures mainly appear in Chinese discourse in the form of topic chains (Wang, 2002; 2004. The research target are the topic chain, which is the main topic-prominent structure in Chinese discourse, and zero anaphora, which is the most common topic anaphora in the topic chain. Two important findings emerged from the present study. First, the characteristics of Chinese topic chains are transferrable to the interlanguage of Chinese EFL learners, thus resulting in overgeneralization of the zero anaphora. Second, the interlanguage discourse of Chinese EFL learners reflects a change of the second language acquisition process from topic-prominence to subject-prominence, thus lending support to the discourse transfer hypothesis.

Onychopharmacokinetics of terbinafine hydrochloride penetration from a novel topical formulation into the human nail in vitro.

Science.gov (United States)

Hui, Xiaoying; Lindahl, Åke; Lamel, Sonia; Maibach, Howard I

2013-09-01

This study determined the onychopharmacokinetics, nail absorption, distribution, and penetration of [¹⁴C]-terbinafine HCl in a new topical formulation into/through the human finger nail using the in vitro finite dose model. This study determined the penetration rate of terbinafine HCl from multiple doses of topical formulation applied daily for 14 days. Results showed that the total dose recovery (mass balance) was almost 100%. The concentration of terbinafine HCl in the deeper nail plate (ventral/intermediate layers) and the cotton-pad nail bed samples after the 14-day treatment were 613 ± 145 and (±S.D.) and 27 ± 1.2 µg/cm³ (or 1.9 ± 0.6 µg/cm³ daily) on average, respectively. In comparison with nail concentration data from the literature for other topical terbinatine formulations, our results show that higher amounts of terbinafine HCl reached the deep nail plate and/or the nail bed after a 14-day topical treatment with this topical formulation in vitro.

Fixed drug eruption: topical provocation and subsequent phenomena

Energy Technology Data Exchange (ETDEWEB)

Mahboob, A; Haroon, T S [Shaikh Zayed FPGMI, Lahore (Pakistan). Dept. of Dermatology; Haroon, T S [King Edward Medical Univ., Lahore (Pakistan). Dept. of Dematology; Iqbal, Z; Iqbal, F [Shaikh Zayed FPGMI, Lahore (Pakistan). Dept. of Medicine

2006-12-15

To determine the usefulness of topical provocation in detecting the incriminated drug causing fixed eruption. Three hundred and five, clinically diagnosed cases of Fixed Drug Eruption (FDE) of either gender and of any age were subjected to topical provocation with different drugs by using concentration of 1% (n=203), 2% (n=210) and 5% (n=235) in white soft paraffin. Drug ointment of one strength was applied one at a time on normal skin of flexor surface of right or left forearm. The effects of tests on involved and uninvolved skin were observed for 48 hours. The changes in lesions like erythema, hyperpigmentation, itching, burning or appearance of new lesion were considered a positive response. In case of no change, the patients (n=5) were subjected to oral provocation test, by giving half to full therapeutic dose of the suspected drug depending upon the severity of the initial attack. A patient who exhibited see-sawing phenomenon with 5% metamizole TPT was given oral challenge with same drug. Control topical tests were repeated in equal number of normal persons with various drug ointments and in patients of FDE with white soft paraffin on normal and affected skin. One hundred and thirty-seven patients were males and one hundred and sixty-eight patients were females. Maximum number of patients belonged to third decade. With 1% drug preparations 12 out of 316, with 2% drug preparations 28 out of 422 and with 5% drug preparations, 312 out of 523 TPTs were positive. The comparison revealed a highly significant association (Chi-square 448.1 and p<0.000) among various strengths of preparations and positive response. Sulphamethoxazole was found to be the most commonly incriminated cause of FDE applied in 5% concentration yielded sensitivity rate of 91% compared to 4% with lower concentrations. Positive patch test was also observed with oxytetracycline. Five patients who were given oral provocation with different drugs were found to be positive to tinidazole, dapsone

Fixed drug eruption: topical provocation and subsequent phenomena

International Nuclear Information System (INIS)

Mahboob, A.; Haroon, T.S.; Haroon, T.S.; Iqbal, Z.; Iqbal, F.

2006-01-01

To determine the usefulness of topical provocation in detecting the incriminated drug causing fixed eruption. Three hundred and five, clinically diagnosed cases of Fixed Drug Eruption (FDE) of either gender and of any age were subjected to topical provocation with different drugs by using concentration of 1% (n=203), 2% (n=210) and 5% (n=235) in white soft paraffin. Drug ointment of one strength was applied one at a time on normal skin of flexor surface of right or left forearm. The effects of tests on involved and uninvolved skin were observed for 48 hours. The changes in lesions like erythema, hyperpigmentation, itching, burning or appearance of new lesion were considered a positive response. In case of no change, the patients (n=5) were subjected to oral provocation test, by giving half to full therapeutic dose of the suspected drug depending upon the severity of the initial attack. A patient who exhibited see-sawing phenomenon with 5% metamizole TPT was given oral challenge with same drug. Control topical tests were repeated in equal number of normal persons with various drug ointments and in patients of FDE with white soft paraffin on normal and affected skin. One hundred and thirty-seven patients were males and one hundred and sixty-eight patients were females. Maximum number of patients belonged to third decade. With 1% drug preparations 12 out of 316, with 2% drug preparations 28 out of 422 and with 5% drug preparations, 312 out of 523 TPTs were positive. The comparison revealed a highly significant association (Chi-square 448.1 and p<0.000) among various strengths of preparations and positive response. Sulphamethoxazole was found to be the most commonly incriminated cause of FDE applied in 5% concentration yielded sensitivity rate of 91% compared to 4% with lower concentrations. Positive patch test was also observed with oxytetracycline. Five patients who were given oral provocation with different drugs were found to be positive to tinidazole, dapsone

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

Topical report review status: Volume 10

International Nuclear Information System (INIS)

1996-03-01

This report provides industry with procedures for submitting topical reports, guidance on how the U.S. Nuclear Regulatory Commission (NRC) processes and responds to topical report submittals, and an accounting, with review schedules, of all topical reports currently accepted for review by the NRC. This report is published annually

[Topical haemotherapy as treatment for necrotic angiodermatitis: a pilot study].

Science.gov (United States)

Courivaud, D; Ségard, M; Darras, S; Carpentier, O; Thomas, P

2005-03-01

Necrotic angiodermatitis is a variety of leg ulcer, characterized by very painful and rapidly spreading lesions. Healing takes time, a mean of 4 to 11 months. Current treatment is difficult and rarely satisfactory. Only early skin grafts lead to rapid sedation of pain and stop the lesion from extending. However, this technique, performed during a progressive phase, enhances the risk of losing a certain number of grafts. We wanted to confirm the efficacy of local auto-haemo-therapy proposed in 2 non-controlled studies. Eleven patients with necrotic angiodermatitis were included in our non-controlled prospective study. The topical hemotherapy was applied three times a week for one month, with initial hospitalization for 15 days. The criteria of assessment were: evolution of pain, surface of the ulcer, colorimetric scale and the date of disappearance of the purple halo. Ten patients were relieved by the treatment, with progressive withdrawal of the analgesics. The progression of the lesion had stopped and the purple halo had disappeared in general by D6 (range: 2 to 21 days). The percentage of granulation tissue with regard to the surface of the ulcer was of 45.4 p. 100 on D0, 80 p. 100 on D14 and 85 p. 100 on D28. Topical hemotherapy applied during the initial phase of treatment would reduce the pain and prepare the lesion for a secondary skin graft.

Anesthesia with topical lidocaine hydrochloride gauzes in acute traumatic wounds in triage, a pilot study

NARCIS (Netherlands)

Ridderikhof, Milan L.; Leenders, Noukje; Goddijn, Helma; Schep, Niels W.; Lirk, Philipp; Goslings, J. Carel; Hollmann, Markus W.

2016-01-01

Topical application of lidocaine in wounds has been studied in combination with vasoconstrictive additives, but the effect without these additives is unknown. The objective was to examine use of lidocaine-soaked gauzes without vasoconstrictive agents, in traumatic wounds in adult patients, applied

Chiropractic: MedlinePlus Health Topic

Science.gov (United States)

... for back pain (Medical Encyclopedia) Also in Spanish Topic Image MedlinePlus Email Updates Get Chiropractic updates by ... ENCYCLOPEDIA Chiropractic care for back pain Related Health Topics Back Pain Complementary and Integrative Medicine National Institutes ...

Diets: MedlinePlus Health Topic

Science.gov (United States)

... Spanish Mediterranean diet (Medical Encyclopedia) Also in Spanish Topic Image MedlinePlus Email Updates Get Diets updates by ... foods Diet-busting foods Mediterranean diet Related Health Topics Child Nutrition DASH Eating Plan Diabetic Diet Nutrition ...