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Sample records for multiple drug resistant

  1. Dodecyltriphenylphosphonium inhibits multiple drug resistance in the yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Knorre, Dmitry A; Markova, Olga V; Smirnova, Ekaterina A; Karavaeva, Iuliia E; Sokolov, Svyatoslav S; Severin, Fedor F

    2014-08-08

    Multiple drug resistance pumps are potential drug targets. Here we asked whether the lipophilic cation dodecyltriphenylphosphonium (C12TPP) can interfere with their functioning. First, we found that suppression of ABC transporter gene PDR5 increases the toxicity of C12TPP in yeast. Second, C12TPP appeared to prevent the efflux of rhodamine 6G - a fluorescent substrate of Pdr5p. Moreover, C12TPP increased the cytostatic effects of some other known Pdr5p substrates. The chemical nature of C12TPP suggests that after Pdr5p-driven extrusion the molecules return to the plasma membrane and then into the cytosol, thus effectively competing with other substrates of the pump. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Mosaic Structure of a Multiple-Drug-Resistant, Conjugative Plasmid from Campylobacter jejuni

    National Research Council Canada - National Science Library

    Nirdnoy, Warawadee; Mason, Carl J; Guerry, Patricia

    2005-01-01

    ..., where it apparently integrated into the chromosome and expressed high-level resistance to multiple aminoglycoside antibiotics. This work provides new information about both the nature of drug resistance in C...

  3. Insulin resistance in drug naive patients with multiple sclerosis

    OpenAIRE

    Kostić Smiljana; Kolić Ivana; Raičević Ranko; Stojanović Zvezdana; Kostić Dejan; Dinčić Evica

    2017-01-01

    Background/Aim. Due to the fact that there is a relatively small number of data related to systemic insulin abnormalities in the multiple sclerosis (MS), the main objective of our study was to determine whether a dysbalance of glucose and insulin metabolism exist in patients with natural course of MS. Our hypothesis was that the metabolic disorder that characterizes state of the insulin resistance (IR) and reduced insulin sensitivity (IS) in untreated patie...

  4. Insulin resistance in drug naive patients with multiple sclerosis

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    Kostić Smiljana

    2017-01-01

    Full Text Available Background/Aim. Due to the fact that there is a relatively small number of data related to systemic insulin abnormalities in the multiple sclerosis (MS, the main objective of our study was to determine whether a dysbalance of glucose and insulin metabolism exist in patients with natural course of MS. Our hypothesis was that the metabolic disorder that characterizes state of the insulin resistance (IR and reduced insulin sensitivity (IS in untreated patients with MS could play a role in disease progression and degree of functional disability. Methods. The study included 31 patients with relapsing-remitting (RR MS and 14 healthy controls from the same geographic area matched by age, ethnicity and number of smokers. The glucose tolerance, IS, and IR were examined using an oral glucose tolerance test (OGTT and using basal plasma glucose and insulin levels. The functional disability and disease progression were evaluated by the Expanded Disability Status Scale (EDSS and Multiple Sclerosis Severity Score (MSSS. Results. The MS patients tolerated glucose equally well as the healthy controls. Basal concentrations of insulin were significantly higher in the MS group (p < 0.05, as well as insulin plasma level 30 min after oral glucose load (p < 0.01. The patients with MS had significantly higher values of homeostasis model assessment indexes of IR (HOMA-IR (p = 0.027; p = 0.028. The percentage of IS (HOMA2 %S and whole body IS index (ISI Matsuda showed significantly lower values in the MS patients than in the controls (p = 0.005; p = 0.001. The insulinogenic index in the first 30 min of OGTT was significantly higher in MS patients (p = 0.005. The measures of functional disability and MS progression did not correlate significantly with the investigated parameters of IR and IS indexes. Conclusion. This study demonstrates for the first time the existence of hyperinsulinemia, reduced insulin sensitivity and normal glucose tolerance that indicate the initial

  5. Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

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    Fei Tang

    2017-07-01

    Full Text Available Epilepsy is a common neurological disorder that affects over 70 million people worldwide. Despite the recent introduction of new antiseizure drugs (ASDs, about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Early identification of patients who will become refractory to ASDs could help direct such patients to appropriate non-pharmacological treatment, but the complexity in the temporal patterns of epilepsy could make such identification difficult. The target hypothesis and transporter hypothesis are the most cited theories trying to explain refractory epilepsy, but neither theory alone fully explains the neurobiological basis of pharmacoresistance. This review summarizes evidence for and against several major theories, including the pharmacokinetic hypothesis, neural network hypothesis, intrinsic severity hypothesis, gene variant hypothesis, target hypothesis, and transporter hypothesis. The discussion is mainly focused on the transporter hypothesis, where clinical and experimental data are discussed on multidrug transporter overexpression, substrate profiles of ASDs, mechanism of transporter upregulation, polymorphisms of transporters, and the use of transporter inhibitors. Finally, future perspectives are presented for the improvement of current hypotheses and the development of treatment strategies as guided by the current understanding of refractory epilepsy.

  6. Drug resistance in vectorborne parasites: multiple actors and scenarios for an evolutionary arms race.

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    Vanaerschot, Manu; Huijben, Silvie; Van den Broeck, Frederik; Dujardin, Jean-Claude

    2014-01-01

    Drug-resistant pathogens emerge faster than new drugs come out of drug discovery pipelines. Current and future drug options should therefore be better protected, requiring a clear understanding of the factors that contribute to the natural history of drug resistance. Although many of these factors are relatively well understood for most bacteria, this proves to be more complex for vectorborne parasites. In this review, we discuss considering three key models (Plasmodium, Leishmania and Schistosoma) how drug resistance can emerge, spread and persist. We demonstrate a multiplicity of scenarios, clearly resulting from the biological diversity of the different organisms, but also from the different modes of action of the drugs used, the specific within- and between-host ecology of the parasites, and environmental factors that may have direct or indirect effects. We conclude that integrated control of drug-resistant vectorborne parasites is not dependent upon chemotherapy only, but also requires a better insight into the ecology of these parasites and how their transmission can be impaired. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

  7. Antibacterial activity of combined medicinal plants extract against multiple drug resistant strains

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    Rafiqul Islam

    2015-06-01

    Full Text Available Objective: To find out the combined antibacterial efficacy of Aegle marmelos, Aphanamixis polystachya, Cuscuta reflexa and Aesclynomene indica against bacterial pathogens. Methods: Antibacterial potency of combined plant extracts has been tested against Bacillus subtilis IFO 3026, Sarcina lutea IFO 3232, Xanthomonas campestris IAM 1671, Escherichia coli IFO 3007, Klebsiella pneumoniae ATTC 10031, Proteus vulgaris MTCC 321 and Pseudomonas denitrificans KACC 32026 by disc diffusion assay. Commercially available standard antibiotic discs were also used to find out antibiotic resistance pattern of test organisms. Results: Among the test organisms, Escherichia coli, Proteus vulgaris, Klebsiella pneumoniae and Proteus denitrificans showed resistance against multiple commercially available antibiotics. On the other hand, these multiple drug resistant organisms showed susceptibility against combined plant extracts. Conclusions: These combined plants extracts showed synergistic antibacterial activity and could lead to new antibacterial drug designing.

  8. Multiple drug resistant carbapenemases producing Acinetobacter baumannii isolates harbours multiple R-plasmids

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    Rajagopalan Saranathan

    2014-01-01

    Full Text Available Background & objectives: The nosocomial human pathogen Acinetobacter baumannii has high propensity to develop resistance to antimicrobials and to become multidrug resistant (MDR, consequently complicating the treatment. This study was carried out to investigate the presence of resistant plasmids (R-plasmids among the clinical isolates of A. baumannii. In addition, the study was performed to check the presence of common β-lactamases encoding genes on these plasmids. Methods: A total of 55 clinical isolates of A. baumannii were included in the study and all were subjected to plasmid DNA isolation, followed by PCR to check the presence of resistance gene determinants such as blaOXA-23 , blaOXA-51, blaOXA-58 and blaIMP-1 on these plasmids that encode for oxacillinase (OXA and metallo-β-lactamase (MBL type of carbapenemases. Plasmid curing experiments were carried out on selected isolates using ethidium bromide and acridine orange as curing agents and the antibiotic resistance profiles were evaluated before and after curing. Results: All the isolates were identified as A. baumannii by 16SrDNA amplification and sequencing. Plasmid DNA isolated from these isolates showed the occurrence of multiple plasmids with size ranging from 500bp to ≥ 25 kb. The percentage of blaOXA-51 and blaOXA-23 on plasmids were found to be 78 and 42 per cent, respectively and 20 isolates (36% carried blaIMP-1 gene on plasmids. Significant difference was observed in the antibiograms of plasmid cured isolates when compared to their parental ones. The clinical isolates became susceptible to more than two antibiotic classes after curing of plasmids indicating plasmid borne resistance. Interpretation & conclusions: Our study determined the plasmid mediated resistance mechanisms and occurrence of different resistance genes on various plasmids isolated from MDR A. baumannii. The present findings showed the evidence for antibiotic resistance mediated through multiple plasmids in

  9. Drug Resistance

    Science.gov (United States)

    ... Drug-resistance testing is also recommended for all pregnant women with HIV before starting HIV medicines and also in some pregnant women already taking HIV medicines. Pregnant women will work with their health ...

  10. Significance of MDR1 and multiple drug resistance in refractory human epileptic brain

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    Dini Gabriele

    2004-10-01

    Full Text Available Abstract Background The multiple drug resistance protein (MDR1/P-glycoprotein is overexpressed in glia and blood-brain barrier (BBB endothelium in drug refractory human epileptic tissue. Since various antiepileptic drugs (AEDs can act as substrates for MDR1, the enhanced expression/function of this protein may increase their active extrusion from the brain, resulting in decreased responsiveness to AEDs. Methods Human drug resistant epileptic brain tissues were collected after surgical resection. Astrocyte cell cultures were established from these tissues, and commercially available normal human astrocytes were used as controls. Uptake of fluorescent doxorubicin and radioactive-labeled Phenytoin was measured in the two cell populations, and the effect of MDR1 blockers was evaluated. Frozen human epileptic brain tissue slices were double immunostained to locate MDR1 in neurons and glia. Other slices were exposed to toxic concentrations of Phenytoin to study cell viability in the presence or absence of a specific MDR1 blocker. Results MDR1 was overexpressed in blood vessels, astrocytes and neurons in human epileptic drug-resistant brain. In addition, MDR1-mediated cellular drug extrusion was increased in human 'epileptic' astrocytes compared to 'normal' ones. Concomitantly, cell viability in the presence of cytotoxic compounds was increased. Conclusions Overexpression of MDR1 in different cell types in drug-resistant epileptic human brain leads to functional alterations, not all of which are linked to drug pharmacokinetics. In particular, the modulation of glioneuronal MDR1 function in epileptic brain in the presence of toxic concentrations of xenobiotics may constitute a novel cytoprotective mechanism.

  11. Withanolide D Exhibits Similar Cytostatic Effect in Drug-Resistant and Drug-Sensitive Multiple Myeloma Cells

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    Mark E. Issa

    2017-09-01

    Full Text Available In spite of recent therapeutic advances, multiple myeloma (MM remains a malignancy with very low curability. This has been partly attributed to the existence of a drug-resistant subpopulation known as cancer stem cells (CSCs. MM-CSCs are equipped with the necessary tools that render them highly resistant to virtually all conventional therapies. In this study, the growth inhibitory effects of withanolide D (WND, a steroidal lactone isolated from Withania somnifera, on drug-sensitive tumoral plasma cells and drug-resistant MM cells have been investigated. In MTT/XTT assays, WND exhibited similar cytostatic effects between drug-resistant and drug-sensitive cell lines in the nM range. WND also induced cell death and apoptosis in MM-CSCs and RPMI 8226 cells, as examined by the calcein/ethidium homodimer and annexin V/propidium iodide stainings, respectively. To determine whether P-glycoprotein (P-gp efflux affected the cytostatic activity of WND, P-gp was inhibited with verapamil and results indicated that the WND cytostatic effect in MM-CSCs was independent of P-gp efflux. Furthermore, WND did not increase the accumulation of the fluorescent P-gp substrate rhodamine 123 in MM-CSCs, suggesting that WND may not inhibit P-gp at the tested relevant doses. Therefore, the WND-induced cytostatic effect may be independent of P-gp efflux. These findings warrant further investigation of WND in MM-CSC animal models.

  12. Transmissible Plasmids and Integrons Shift Escherichia coli Population Toward Larger Multiple Drug Resistance Numbers.

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    Suhartono, Suhartono; Savin, Mary C; Gbur, Edward E

    2018-04-01

    Transmissible plasmids and integrons may play important roles in the persistence and spread of antibiotic-resistant bacteria throughout aquatic environment by accumulating antibiotic resistance genes (ARG). Class 1 and class 2 integron (intI), mobilization (mob), sulfamethoxazole resistance (sul), and trimethoprim resistance (dfr) genes were PCR-amplified and confirmed through DNA sequencing following plasmid extraction from 139 antibiotic-resistant Escherichia coli. E. coli had previously been recovered from wastewater treatment plant effluent and receiving stream water in Northwest Arkansas and isolates had expressed resistance to one to six antibiotics. Almost half of the total isolates (47%) carried putatively transmissible plasmids with mob F12 gene as the most frequently detected mobilization gene. When two or three mob genes were detected per isolate, there was a significant shift in the population toward larger multiple drug resistance (MDR) number. Class 1 and/or 2 integrons were prevalent (46%), and the presence of integron significantly shifted the isolate population toward larger MDR number. More isolates carried single or coexistence of two or three sul genes (99.3%), and single or a combination up to five dfr genes (89.3%) than had exhibited in vitro resistance to the respective antibiotics. These findings indicate not only the role of the wastewater treatment effluent and the stream environment in coaccumulation of ARG with transmissible plasmids and integrons in multiple antibiotic-resistant E. coli populations but also suggest that density of sul and dfr resistance genes within an isolate may serve as a biomarker for mobile MDR in general.

  13. Drug resistance

    NARCIS (Netherlands)

    Gorter, J.A.; Potschka, H.; Noebels, J.L.; Avoli, M.; Rogawski, M.A.; Olsen, R.W.; Delgado-Escueta, A.V.

    2012-01-01

    Drug resistance remains to be one of the major challenges in epilepsy therapy. Identification of factors that contribute to therapeutic failure is crucial for future development of novel therapeutic strategies for difficult-to-treat epilepsies. Several clinical studies have shown that high seizure

  14. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia

    DEFF Research Database (Denmark)

    Göllner, Stefanie; Oellerich, Thomas; Agrawal-Singh, Shuchi

    2017-01-01

    In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction...

  15. The fitness of drug-resistant malaria parasites in a rodent model: multiplicity of infection

    OpenAIRE

    Huijben, Silvie; Sim, Derek G.; Nelson, William, A.; Read, Andrew F.

    2011-01-01

    Malaria infections normally consist of more than one clonally-replicating lineage. Within-host interactions between sensitive and resistant parasites can have profound effects on the evolution of drug resistance. Here, using the Plasmodium chabaudi mouse malaria model, we ask whether the costs and benefits of resistance are affected by the number of co-infecting strains competing with a resistant clone. We found strong competitive suppression of resistant parasites in untreated infections and...

  16. ANTIBACTERIAL ACTIVITY OF DRACONTOMELON DAO EXTRACTS ON METHICILLIN-RESISTANT S. AUREUS (MRSA) AND E. COLI MULTIPLE DRUG RESISTANCE (MDR).

    Science.gov (United States)

    Yuniati, Yuniati; Hasanah, Nurul; Ismail, Sjarif; Anitasari, Silvia; Paramita, Swandari

    2018-01-01

    Staphylococcus aureus , methicillin-resistant and Escherichia coli , multidrug-resistant included in the list of antibiotic-resistant priority pathogens from WHO. As multidrug-resistant bacteria problem is increasing, it is necessary to probe new sources for identifying antimicrobial compounds. Medicinal plants represent a rich source of antimicrobial agents. One of the potential plants for further examined as antibacterial is Dracontomelon dao (Blanco) Merr. & Rolfe. The present study designed to find the antibacterial activity of D. dao stem bark extracts on Methicillin-resistant S. aureus (MRSA) and E. coli Multiple Drug Resistance (MDR), followed by determined secondary metabolites with antibacterial activity and determined the value of MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration). D. dao stem bark extracted using 60% ethanol. Disc diffusion test methods used to find the antibacterial activity, following by microdilution methods to find the value of MIC and MBC. Secondary metabolites with antibacterial activity determined by bioautography using TLC (thin layer chromatography) methods. D. dao stem bark extracts are sensitive to MSSA, MRSA and E.coli MDR bacteria. The inhibition zone is 16.0 mm in MSSA, 11.7 mm in MRSA and 10.7 mm in E. coli MDR. The entire MBC/MIC ratios for MSSA, MRSA and E.coli MDR is lower than 4. The ratio showed bactericidal effects of D. dao stem bark extracts. In TLC results, colorless bands found to be secondary metabolites with antibacterial activity. D. dao stem bark extracts are potential to develop as antibacterial agent especially against MRSA and E. coli MDR strain.

  17. Characterization of the multiple drug resistance phenotype expressed by tumour cells following in vitro exposure to fractionated X-irradiation

    International Nuclear Information System (INIS)

    Hill, B.T.; McClean, S.; Hosking, L.; Shellard, S.; Dempke, W.; Whelan, R.

    1992-01-01

    The major clinical problem of the emergence of drug resistant tumor cell populations is recognized in patients previously treated with antitumor drugs and with radiotherapy. It is proposed that, although radiation-induced vascular fibrosis may limit drug delivery to the tumor, exposure to radiation may 'induce' or 'select for' drug resistance. This hypothesis was examined by establishing in vitro model systems to investigate the resistance phenotype of tumor cells following exposure to X-rays. Characteristically tumor cells surviving exposure to a series of fractions of X-irradiation are shown to have consistently expressed resistance to multiple drugs, including the Vinca alkaloids and the epipodophyllotoxins. Currently this research is aimed at determining whether distinctive resistance mechanisms operate depending on whether resistance results following drug or X-ray exposure. Initial results indicate that whilst some common mechanisms operate, drug resistant tumor cells identified following exposure to X-irradiation appear to exhibit a novel multidrug resistance phenotype. (author). 13 refs., 1 tab

  18. Multiple drug resistance patterns in various phylogenetic groups of uropathogenic E.coli isolated from Faisalabad region of Pakistan

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    Saira Bashir

    2011-12-01

    Full Text Available The objective of this work was the phylogenetic characterization of local clinical isolates of uropathogenic E. coli with respect to drug resistance. A total of 59 uropathogenic E. coli responsible for community acquired urinary tract infections were included in this study. A triplex PCR was employed to segregate each isolate into four different phylogenetic groups (A, B1, B2 and D. Drug resistance was evaluated by disc diffusion method. The drugs used were ampicillin, aztreonam, cefixime, cefoperazone, ceftriaxone, cephradine among β-lactam group; amikacin, gentamicin, and streptomycin among aminoglycosides; nalidixic acid and ciprofloxacin from quinolones; trimethoprim-sulfomethoxazole, and tetracycline. Among 59 uropathogenic E. coli isolates majority belonged to phylogenetic group B2 (50% where as 19% each belonged to groups A and B1, and 12% to group D. All the isolates were multiple drug resistant (MDR. Most effective drugs against Group A, B1, and B2 were gentamicin, amikacin and cefixime; ceftriaxone and quinolones; and ceftriaxone and amikacin, respectively. Group D isolates were found to be highly resistant to all drugs. Our results have shown emergence of MDR isolates among uropathogenic E. coli with dominance of phylogenetic group B2. However, it was found that group D isolates were though less frequent, more drug resistant as compared with group B2. Groups A and B1 were relatively uncommon. Amikacin, ceftriaxone and gentamicin were the most effective drugs in general.

  19. Multiple drug resistance protein (MDR-1, multidrug resistance-related protein (MRP and lung resistance protein (LRP gene expression in childhood acute lymphoblastic leukemia

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    Elvis Terci Valera

    Full Text Available CONTEXT: Despite the advances in the cure rate for acute lymphoblastic leukemia, approximately 25% of affected children suffer relapses. Expression of genes for the multiple drug resistance protein (MDR-1, multidrug resistance-related protein (MRP, and lung resistance protein (LRP may confer the phenotype of resistance to the treatment of neoplasias. OBJECTIVE: To analyze the expression of the MDR-1, MRP and LRP genes in children with a diagnosis of acute lymphoblastic leukemia via the semiquantitative reverse transcription polymerase chain reaction (RT-PCR, and to determine the correlation between expression and event-free survival and clinical and laboratory variables. DESIGN: A retrospective clinical study. SETTING: Laboratory of Pediatric Oncology, Department of Pediatrics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Brazil. METHODS: Bone marrow aspirates from 30 children with a diagnosis of acute lymphoblastic leukemia were assessed for the expression of messenger RNA for the MDR-1, MRP and LRP genes by semi-quantitative RT-PCR. RESULTS: In the three groups studied, only the increased expression of LRP was related to worsened event-free survival (p = 0.005. The presence of the common acute lymphoblastic leukemia antigen (CALLA was correlated with increased LRP expression (p = 0.009 and increased risk of relapse or death (p = 0.05. The relative risk of relapse or death was six times higher among children with high LRP expression upon diagnosis (p = 0.05, as confirmed by multivariate analysis of the three genes studied (p = 0.035. DISCUSSION: Cell resistance to drugs is a determinant of the response to chemotherapy and its detection via RT-PCR may be of clinical importance. CONCLUSIONS: Evaluation of the expression of genes for resistance to antineoplastic drugs in childhood acute lymphoblastic leukemia upon diagnosis, and particularly the expression of the LRP gene, may be of clinical relevance, and should be the

  20. Multiple drug resistance of Aeromonas hydrophila isolates from Chicken samples collected from Mhow and Indore city of Madhyapradesh

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    Kaskhedikar

    2009-02-01

    Full Text Available Fourteen antibacterial agents belonging to 9 different groups of antibiotics viz. aminoglycosides, cephalosporins, nitrofurantoin, fluroquinolones, chloramphenicol, sulphonamides, tetracyclines, penicillin and polymixin were used for in vitro sensitivity testing of Aeromonas hydrophila isolated from fifteen samples of chicken collected from retail shops in Mhow city. The sensitivity (100% was attributed to ciprofloxacin, cefuroxime, ceftriaxone, cephotaxime, chloramphenicol, gentamycin, kanamycin, nitrofurantoin, nalidixic acid and ofloxacin followed by oxytetracycline (50%. All the isolates were resistant to ampicillin and colistin antibiotics. That means, none of the isolates were found to be sensitive for penicillin and polymixin group of antibiotics. Multiple drug resistance was also observed in all A. hydrophila isolates. Out of total isolates, 100% were resistant to two antimicrobial drugs and 50% to three drugs. [Vet. World 2009; 2(1.000: 31-32

  1. Case Report of Urethritis in a Male Patient Infected with Two Different Isolates of Multiple Drug-Resistant Neisseria gonorrhoeae

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    Lamiaa Al-Madboly

    2017-11-01

    Full Text Available We report a brief description of a case suffering from bacterial urethritis, conjunctivitis, and arthritis, caused by two different isolates of multiple drug-resistant Neisseria gonorrhoeae. Initial diagnosis was dependent on the patient history, clinical findings, symptoms, and the bacteriological data. Polymerase chain reaction confirmed the identification of the pathogens. Random amplified polymorphic DNA revealed two different patterns. Susceptibility testing was performed using Kirby–Bauer disk diffusion method and the minimum inhibitory concentration was also determined. It revealed multiple drug resistance associated with β-lactamase production. Only gentamicin, rifampicin, and azithromycin were active against the test pathogens. A dual therapy was initiated using gentamicin as well as azithromycin to treat the possible co-infection with Chlamydia trachomatis. Complete recovery of the patient achieved with resolved symptoms a week later.

  2. Case Report of Urethritis in a Male Patient Infected with Two Different Isolates of Multiple Drug-Resistant Neisseria gonorrhoeae.

    Science.gov (United States)

    Al-Madboly, Lamiaa; Gheida, Shereen

    2017-01-01

    We report a brief description of a case suffering from bacterial urethritis, conjunctivitis, and arthritis, caused by two different isolates of multiple drug-resistant Neisseria gonorrhoeae . Initial diagnosis was dependent on the patient history, clinical findings, symptoms, and the bacteriological data. Polymerase chain reaction confirmed the identification of the pathogens. Random amplified polymorphic DNA revealed two different patterns. Susceptibility testing was performed using Kirby-Bauer disk diffusion method and the minimum inhibitory concentration was also determined. It revealed multiple drug resistance associated with β-lactamase production. Only gentamicin, rifampicin, and azithromycin were active against the test pathogens. A dual therapy was initiated using gentamicin as well as azithromycin to treat the possible co-infection with Chlamydia trachomatis . Complete recovery of the patient achieved with resolved symptoms a week later.

  3. The mathematics of random mutation and natural selection for multiple simultaneous selection pressures and the evolution of antimicrobial drug resistance.

    Science.gov (United States)

    Kleinman, Alan

    2016-12-20

    The random mutation and natural selection phenomenon act in a mathematically predictable behavior, which when understood leads to approaches to reduce and prevent the failure of the use of these selection pressures when treating infections and cancers. The underlying principle to impair the random mutation and natural selection phenomenon is to use combination therapy, which forces the population to evolve to multiple selection pressures simultaneously that invoke the multiplication rule of probabilities simultaneously as well. Recently, it has been seen that combination therapy for the treatment of malaria has failed to prevent the emergence of drug-resistant variants. Using this empirical example and the principles of probability theory, the derivation of the equations describing this treatment failure is carried out. These equations give guidance as to how to use combination therapy for the treatment of cancers and infectious diseases and prevent the emergence of drug resistance. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  4. Prevalence of multiple drug resistant Streptococcus suis in and around Guwahati, India

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    Mrinalee Devi

    2017-05-01

    , both the isolates were resistant to cefalexin, tetracycline, doxycycline HCL, and kanamycin. Altogether five different resistance patterns (multi-drug resistance were observed. Of the seven S. suis isolates, two isolates were susceptible to all the 17 antimicrobial agents, one isolate was resistant to four antimicrobial agents, two isolates to seven agents, one isolate to nine agents, and one isolate exhibited resistance to 14 antimicrobial agents. Conclusion: This study was conducted to determine the prevalence of S. suis in clinically healthy and diseased pigs and their antimicrobial susceptibility patterns. All the isolates were susceptible to gentamicin, amikacin and erythromycin, and most of them were resistant to cefalexin, tetracycline and streptomycin. Five different patterns of antimicrobial resistance (multi-drug resistance were observed.

  5. The effect of S1P receptor signaling pathway on the survival and drug resistance in multiple myeloma cells.

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    Fu, Di; Li, Yingchun; Li, Jia; Shi, Xiaoyan; Yang, Ronghui; Zhong, Yuan; Wang, Huihan; Liao, Aijun

    2017-01-01

    Multiple myeloma (MM) remains incurable by conventional chemotherapy. Sphingosine-1-phosphate (S1P) receptor-mediated signaling has been recently demonstrated to have critical roles in cell survival and drug resistance in a number of hematological malignancies. To dissect the roles of S1P receptor pathway in MM, we systematically examined cell viability and protein expression associated with cell survival and drug resistance in MM cell lines upon treatment with either pathway activator (S1P) or inhibitor (FTY720). Our results reveal that FTY720 inhibits cell proliferation by downregulating expression of target genes, while S1P has an opposite effect. Knocking down of S1P receptor S1P5R results in a reduction of cell survival-related gene expression; however, it does not have impacts on expression of drug resistance genes. These results suggest that S1P signaling plays a role in cell proliferation and drug resistance in MM, and targeting this pathway will provide a new therapeutic direction for MM management.

  6. NANOMEDICINE: will it offer possibilities to overcome multiple drug resistance in cancer?

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    Friberg, Sten; Nyström, Andreas M

    2016-03-09

    This review is written with the purpose to review the current nanomedicine literature and provide an outlook on the developments in utilizing nanoscale drug constructs in treatment of solid cancers as well as in the potential treatment of multi-drug resistant cancers. No specific design principles for this review have been utilized apart from our active choice to avoid results only based on in vitro studies. Few drugs based on nanotechnology have progressed to clinical trials, since most are based only on in vitro experiments which do not give the necessary data for the research to progress towards pre-clinical studies. The area of nanomedicine has indeed spark much attention and holds promise for improved future therapeutics in the treatment of solid cancers. However, despite much investment few targeted therapeutics have successfully progressed to early clinical trials, indicating yet again that the human body is complicated and that much more understanding of the fundamentals of receptor interactions, physics of nanomedical constructs and their circulation in the body is indeed needed. We believe that nanomedical therapeutics can allow for more efficient treatments of resistant cancers, and may well be a cornerstone for RNA based therapeutics in the future given their general need for shielding from the harsh environment in the blood stream.

  7. Mechanism of mercuric chloride resistance in microorganisms. I. Vaporization of a mercury compound from mercuric chloride by multiple drug resistant strains of Escherichia coli

    Energy Technology Data Exchange (ETDEWEB)

    Komura, I; Izaki, K

    1971-01-01

    Three strains of Escherichia coli possessing the multiple drug resistance were found to be resistant also to HgCl/sub 2/, though they were sensitive to other heavy metal ions such as nickel, cobalt, cadmium and zinc ions. Like the resistance to drugs such as chloramphenicol and tetracycline, the HgCl/sub 2/ resistance could be transferred from a resistant strain of E. coli to sensitive strains of E. coli and Aerobacter aerogenes. The resistant strains could grow in the presence of 0.02 mM HgCl/sub 2/, whereas a sensitive strain failed to grow in the presence of 0.01 mM HgCl/sub 2/. During cultivation in the presence of HgCl/sub 2/, the cells of resistant strain vaporized a form of radioactive mercury when incubated with /sup 203/HgCl/sub 2/, glucose and NaCl in phosphate buffer while the cells of sensitive strain showed no such activity. This phenomenon seemed to explain the HgCl/sub 2/ resistance of the resistant strains.

  8. THE EFFECT OF DIFFERENT TB DRUGS AND ANTIMICROBIAL AGENTS ON THE EFFICIENCY OF TREATMENT OF TUBERCULOSIS PATIENTS WITH MULTIPLE DRUG RESISTANCE

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    I. A. Vasilyeva

    2017-01-01

    Full Text Available Objective of the study: to study the effect of specific TB drugs and antimicrobial agents constituting chemotherapy regimens on the efficiency of treatment of tuberculosis patients with various patterns of multiple drug resistance.Subjects and Methods. 412 pulmonary tuberculosis patients with bacillary excretion and various patterns of multiple drug resistance were enrolled into the study (117 patients with MDR TB (non pre-XDR and non-XDR; 120 patients with pre-XDR TB and 175 with XDR TB. Patients in the subgroups were compatible regarding sex and age. The patients were prescribed regimens including 5-6 drugs in accordance with their drug resistance pattern. The time of sputum conversion (by culture versus the year of treatment was selected as a surrogate endpoint. The effect of specific TB drugs and antimicrobial agents on treatment efficiency was assessed through calculation of odds ratio (OR of achieving a surrogate endpoint in the patients receiving and not receiving a certain drug.Results. In the subgroup of pre-XDR TB, the following drugs demonstrated the valid increase of odds of sputum conversion: ethambutol (OR 11.8, pyrazinamide (OR 10.2, moxifloxacin (OR 7.8, capreomicin (OR 4.41. Sputum conversion was achieved in all 11 patients treated with bedaquiline.In the subgroup of XDR TB, the following drugs provided a positive effect on the achievement of sputum conversion: bedaquiline (OR 9.62, linezolid (OR 8.15, cycloserine (OR 7.88, pyrazinamide (OR 7.29, moxifloxacin (OR 7.08, and ethambutol (OR 6.69. Ofloxacin demonstrated a confident negative effect on achieving sputum conversion (95% CI 0.06-0.32. 

  9. Antimicrobial (Drug) Resistance

    Science.gov (United States)

    ... with facebook share with twitter share with linkedin Antimicrobial (Drug) Resistance Go to Information for Researchers ► Credit: ... and infectious diseases. Why Is the Study of Antimicrobial (Drug) Resistance a Priority for NIAID? Over time, ...

  10. Hemibody irradiation. An effective second-line therapy in drug-resistance multiple myeloma

    International Nuclear Information System (INIS)

    Singer, C.R.; Tobias, J.S.; Giles, F.; Rudd, G.N.; Blackman, G.M.; Richards, J.D.

    1989-01-01

    The authors report the results of treatment of 41 patients with melphalan-resistant multiple myeloma using single half-body irradiation (HBI) or double half-body irradiation (DHBI). Patients were grouped using prognostic classification reported by the Medical Research Council. Patients in group I and II showed the best response to therapy with reduction in serum of urinary paraprotein and improvement in symptoms, most notably a marked reduction in bone pain. In these groups five patients have survived over 2 years after therapy. The therapeutic response appeared better in those patients who received DHBI as opposed to those whom treated with single HBI. Patients in group III did not achieve prolonged survival but effective relief of bone pain was a consistent finding in these patients also. Thus HBI represents an alternative to combination chemotherapy as second-line treatment of patients with melphalan-resistant multiple myeloma. A comparative study of HBI versus combination chemotherapy is now indicated to establish which therapeutic approach is most effective

  11. Immunohistochemical Estimates of Angiogenesis, Proliferative Activity, p53 Expression, and Multiple Drug Resistance Have No Prognostic Impact in Osteosarcoma: A Comparative Clinicopathological Investigation

    DEFF Research Database (Denmark)

    Sørensen, Flemming Brandt; Jensen, Kenneth; Vaeth, Michael

    2008-01-01

    Purpose. To investigate angiogenesis, multiple drug resistance (MDR) and proliferative activity as prognostic variables in patients suffering from osteosarcoma. Methods. Histologic biopsies from 117 patients treated in the period from 1972 through 1999 were immunohistologically investigated...

  12. Ursodeoxycholic acid pretreatment reduces oral bioavailability of the multiple drug resistance-associated protein 2 substrate baicalin in rats.

    Science.gov (United States)

    Wu, Tao; Li, Xi-Ping; Xu, Yan-Jiao; Du, Guang; Liu, Dong

    2013-11-01

    Baicalin is a major bioactive component of Scutellaria baicalensis and a substrate of multiple drug resistance-associated protein 2. Expression of multiple drug resistance-associated protein 2 is regulated by NF-E2-related factor 2. The aim of this study was to explore whether ursodeoxycholic acid, an NF-E2-related factor 2 activator, could influence the oral bioavailability of baicalin. A single dose of baicalin (200 mg/kg) was given orally to rats pretreated with ursodeoxycholic acid (75 mg/kg and 150 mg/kg, per day, intragastrically) or normal saline (per day, intragastrically) for six consecutive days. The plasma concentration of baicalin was measured with the HPLC method. The result indicated that the oral bioavailability of baicalin was significantly and dose-dependently reduced in rats pretreated with ursodeoxycholic acid. Compared with control rats, the mean area under concentration-time curve of baicalin was reduced from 13.25 ± 0.24 mg/L h to 7.62 ± 0.15 mg/L h and 4.97 ± 0.21 mg/L h, and the C(max) value was decreased from 1.31 ± 0.03 mg/L to 0.62 ± 0.05 mg/L and 0.36 ± 0.04 mg/L in rats pretreated with ursodeoxycholic acid at doses of 75 mg/kg and 150 mg/kg, respectively, for six consecutive days. Hence, ursodeoxycholic acid treatment reduced the oral bioavailability of baicalin in rats, probably due to the enhanced efflux of baicalin from the intestine and liver by multiple drug resistance-associated protein 2. Georg Thieme Verlag KG Stuttgart · New York.

  13. Molecular diagnostics of a single drug-resistant multiple myeloma case using targeted next-generation sequencing

    Directory of Open Access Journals (Sweden)

    Ikeda H

    2015-10-01

    Full Text Available Hiroshi Ikeda,1 Kazuya Ishiguro,1 Tetsuyuki Igarashi,1 Yuka Aoki,1 Toshiaki Hayashi,1 Tadao Ishida,1 Yasushi Sasaki,1,2 Takashi Tokino,2 Yasuhisa Shinomura1 1Department of Gastroenterology, Rheumatology and Clinical Immunology, 2Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan Abstract: A 69-year-old man was diagnosed with IgG λ-type multiple myeloma (MM, Stage II in October 2010. He was treated with one cycle of high-dose dexamethasone. After three cycles of bortezomib, the patient exhibited slow elevations in the free light-chain levels and developed a significant new increase of serum M protein. Bone marrow cytogenetic analysis revealed a complex karyotype characteristic of malignant plasma cells. To better understand the molecular pathogenesis of this patient, we sequenced for mutations in the entire coding regions of 409 cancer-related genes using a semiconductor-based sequencing platform. Sequencing analysis revealed eight nonsynonymous somatic mutations in addition to several copy number variants, including CCND1 and RB1. These alterations may play roles in the pathobiology of this disease. This targeted next-generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients. Keywords: multiple myeloma, drug resistance, genome-wide sequencing, semiconductor sequencer, target therapy

  14. Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by in Silico and in Vitro Analyses

    Directory of Open Access Journals (Sweden)

    Onat Kadioglu

    2018-04-01

    Full Text Available Drug resistance is one of the main reasons of chemotherapy failure. Therefore, overcoming drug resistance is an invaluable approach to identify novel anticancer drugs that have the potential to bypass or overcome resistance to established drugs and to substantially increase life span of cancer patients for effective chemotherapy. Oridonin is a cytotoxic diterpenoid isolated from Rabdosia rubescens with in vivo anticancer activity. In the present study, we evaluated the cytotoxicity of oridonin toward a panel of drug-resistant cancer cells overexpressing ABCB1, ABCG2, or ΔEGFR or with a knockout deletion of TP53. Interestingly, oridonin revealed lower degree of resistance than the control drug, doxorubicin. Molecular docking analyses pointed out that oridonin can interact with Akt/EGFR pathway proteins with comparable binding energies and similar docking poses as the known inhibitors. Molecular dynamics results validated the stable conformation of oridonin docking pose on Akt kinase domain. Western blot experiments clearly revealed dose-dependent downregulation of Akt and STAT3. Pharmacogenomics analyses pointed to a mRNA signature that predicted sensitivity and resistance to oridonin. In conclusion, oridonin bypasses major drug resistance mechanisms and targets Akt pathway and might be effective toward drug refractory tumors. The identification of oridonin-specific gene expressions may be useful for the development of personalized treatment approaches.

  15. Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells.

    Science.gov (United States)

    Pei, Xin-Yan; Dai, Yun; Felthousen, Jessica; Chen, Shuang; Takabatake, Yukie; Zhou, Liang; Youssefian, Leena E; Sanderson, Michael W; Bodie, Wesley W; Kramer, Lora B; Orlowski, Robert Z; Grant, Steven

    2014-01-01

    The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.

  16. Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells.

    Directory of Open Access Journals (Sweden)

    Xin-Yan Pei

    Full Text Available The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.

  17. Rationally engineered nanoparticles target multiple myeloma cells, overcome cell-adhesion-mediated drug resistance, and show enhanced efficacy in vivo

    International Nuclear Information System (INIS)

    Kiziltepe, T; Ashley, J D; Stefanick, J F; Qi, Y M; Alves, N J; Handlogten, M W; Suckow, M A; Navari, R M; Bilgicer, B

    2012-01-01

    In the continuing search for effective cancer treatments, we report the rational engineering of a multifunctional nanoparticle that combines traditional chemotherapy with cell targeting and anti-adhesion functionalities. Very late antigen-4 (VLA-4) mediated adhesion of multiple myeloma (MM) cells to bone marrow stroma confers MM cells with cell-adhesion-mediated drug resistance (CAM-DR). In our design, we used micellar nanoparticles as dynamic self-assembling scaffolds to present VLA-4-antagonist peptides and doxorubicin (Dox) conjugates, simultaneously, to selectively target MM cells and to overcome CAM-DR. Dox was conjugated to the nanoparticles through an acid-sensitive hydrazone bond. VLA-4-antagonist peptides were conjugated via a multifaceted synthetic procedure for generating precisely controlled number of targeting functionalities. The nanoparticles were efficiently internalized by MM cells and induced cytotoxicity. Mechanistic studies revealed that nanoparticles induced DNA double-strand breaks and apoptosis in MM cells. Importantly, multifunctional nanoparticles overcame CAM-DR, and were more efficacious than Dox when MM cells were cultured on fibronectin-coated plates. Finally, in a MM xenograft model, nanoparticles preferentially homed to MM tumors with ∼10 fold more drug accumulation and demonstrated dramatic tumor growth inhibition with a reduced overall systemic toxicity. Altogether, we demonstrate the disease driven engineering of a nanoparticle-based drug delivery system, enabling the model of an integrative approach in the treatment of MM

  18. Antimicrobial (Drug) Resistance Prevention

    Science.gov (United States)

    ... June 6, 2018 HIV Vaccine Elicits Antibodies in Animals that Neutralize Dozens of HIV Strains , June 4, 2018 ... Antimicrobial (Drug) Resistance > Understanding share with facebook share with twitter share ...

  19. Antibiotic Resistance, RAPD- PCR Typing of Multiple Drug Resistant Strains of Escherichia Coli From Urinary Tract Infection (UTI).

    Science.gov (United States)

    Marialouis, Xavier Alexander; Santhanam, Amutha

    2016-03-01

    Global spreading of multidrug resistant strains of Escherichia coli is responsible for Urinary Tract Infection (UTI) which is a major health problem in of concern. Among the gram negative bacteria, the major contributors for UTI belongs to the family Enterobacteriaceae, which includes E. coli, Klebsiella, Citrobacter and Proteus. However, E. coli accounts for the major cause of Urinary tract infections (UTIs) and accounts for 75% to 90% of UTI isolates. The main aim of this study is to analyse the phylogenetic grouping of clinical isolates of UTI E. coli. In this study nearly 58 E. coli strains were isolated and confirmed through microbiological, biochemical characterization. The urine samples were collected from outpatients having symptoms of UTI, irrespective of age and sex in Tamil Nadu, India. The isolates were subjected to analyse for ESBL and AmpC β-lactamase production. To understand its genetic correlation, molecular typing was carried out using RAPD-PCR method. Here we noted phenotypically twenty seven isolates were positive for ESBL and seven for AmpC β-lactamase production. However, among the ESBL isolates higher sensitivity was noted for Nitrofurantoin and Cefoxitin. It is worth to note that the prevalence of UTIs was more common among female and elderly male. Phylogenetic grouping revealed the presence of 24 isolates belonged to B2 group followed by 19 isolates to group A, eight isolates to group B1 and Seven isolates to group D. Phenotypically most of the strains were positive for ESBL and showed high sensitivity for Nitrofurantoin and cefoxitin.

  20. Control of hospital endemicity of multiple-drug-resistant Acinetobacter baumannii ST457 with directly observed hand hygiene.

    Science.gov (United States)

    Cheng, V C C; Chen, J H K; Poon, R W S; Lee, W M; So, S Y C; Wong, S C Y; Chau, P H; Yip, C C Y; Wong, S S Y; Chan, J F W; Hung, I F N; Ho, P L; Yuen, K Y

    2015-04-01

    An increasing endemicity of multiple-drug-resistant Acinetobacter baumannii (MRAB) ST457 was noted in Hong Kong. The epidemiology, risk factors, and infection control measures to prevent nosocomial transmission of this epidemic clone were analyzed. A total of 5,058 patients cultured positive with A. baumannii between 1 January 2004 and 30 June 2014 were included, of which 297 (5.9 %) had bacteremia. The first case of MRAB bacteremia emerged in 2009, with an incidence that increased from 0.27 (one case) in 2009 to 1.86 (14 cases) per 100,000 patient-days in 2013 (p hand hygiene in conscious patients immediately before receiving meals and medications in July 2013, the incidence of MRAB bacteremia reduced from its peak to 0.77 (one case) per 100,000 patient-days in the first 6 months of 2014 (p < 0.001). Patients from long-term care facilities for the elderly [odds ratio (OR) 18.6, confidence interval (CI) 2.1-162.4, p = 0.008] and history of carbapenem (OR 7.0, CI 1.7-28.0, p = 0.006) and beta-lactam/beta-lactamase use (OR 5.6, CI 1.1-28.7, p = 0.038) 90 days prior to admission were independent risk factors for MRAB bacteremia by logistic regression when compared with carbapenem-susceptible A. baumannii bacteremia.

  1. Kinetically Controlled Drug Resistance

    DEFF Research Database (Denmark)

    Sun, Xin E.; Hansen, Bjarne Gram; Hedstrom, Lizbeth

    2011-01-01

    The filamentous fungus Penicillium brevicompactum produces the immunosuppressive drug mycophenolic acid (MPA), which is a potent inhibitor of eukaryotic IMP dehydrogenases (IMPDHs). IMPDH catalyzes the conversion of IMP to XMP via a covalent enzyme intermediate, E-XMP*; MPA inhibits by trapping E...... of resistance is not apparent. Here, we show that, unlike MPA-sensitive IMPDHs, formation of E-XMP* is rate-limiting for both PbIMPDH-A and PbIMPDH-B. Therefore, MPA resistance derives from the failure to accumulate the drug-sensitive intermediate....

  2. Antibacterial effect of Allium sativum cloves and Zingiber officinale rhizomes against multiple-drug resistant clinical pathogens.

    Science.gov (United States)

    Karuppiah, Ponmurugan; Rajaram, Shyamkumar

    2012-08-01

    To evaluate the antibacterial properties of Allium sativum (garlic) cloves and Zingiber officinale (ginger) rhizomes against multi-drug resistant clinical pathogens causing nosocomial infection. The cloves of garlic and rhizomes of ginger were extracted with 95% (v/v) ethanol. The ethanolic extracts were subjected to antibacterial sensitivity test against clinical pathogens. Anti-bacterial potentials of the extracts of two crude garlic cloves and ginger rhizomes were tested against five gram negative and two gram positive multi-drug resistant bacteria isolates. All the bacterial isolates were susceptible to crude extracts of both plants extracts. Except Enterobacter sp. and Klebsiella sp., all other isolates were susceptible when subjected to ethanolic extracts of garlic and ginger. The highest inhibition zone was observed with garlic (19.45 mm) against Pseudomonas aeruginosa (P. aeruginosa). The minimal inhibitory concentration was as low as 67.00 µg/mL against P. aeruginosa. Natural spices of garlic and ginger possess effective anti-bacterial activity against multi-drug clinical pathogens and can be used for prevention of drug resistant microbial diseases and further evaluation is necessary.

  3. Drug Safety: Managing Multiple Drugs

    Science.gov (United States)

    ... This series is produced by Consumers Union and Consumer Reports Best Buy Drugs , a public information project sup- ported by grants from the Engelberg Foundation and the National Library of Medicine of ... Consumer and Prescriber Education Grant Program which is funded ...

  4. A treatment plant receiving waste water from multiple bulk drug manufacturers is a reservoir for highly multi-drug resistant integron-bearing bacteria.

    Directory of Open Access Journals (Sweden)

    Nachiket P Marathe

    Full Text Available The arenas and detailed mechanisms for transfer of antibiotic resistance genes between environmental bacteria and pathogens are largely unclear. Selection pressures from antibiotics in situations where environmental bacteria and human pathogens meet are expected to increase the risks for such gene transfer events. We hypothesize that waste-water treatment plants (WWTPs serving antibiotic manufacturing industries may provide such spawning grounds, given the high bacterial densities present there together with exceptionally strong and persistent selection pressures from the antibiotic-contaminated waste. Previous analyses of effluent from an Indian industrial WWTP that processes waste from bulk drug production revealed the presence of a range of drugs, including broad spectrum antibiotics at extremely high concentrations (mg/L range. In this study, we have characterized the antibiotic resistance profiles of 93 bacterial strains sampled at different stages of the treatment process from the WWTP against 39 antibiotics belonging to 12 different classes. A large majority (86% of the strains were resistant to 20 or more antibiotics. Although there were no classically-recognized human pathogens among the 93 isolated strains, opportunistic pathogens such as Ochrobactrum intermedium, Providencia rettgeri, vancomycin resistant Enterococci (VRE, Aerococcus sp. and Citrobacter freundii were found to be highly resistant. One of the O. intermedium strains (ER1 was resistant to 36 antibiotics, while P. rettgeri (OSR3 was resistant to 35 antibiotics. Class 1 and 2 integrons were detected in 74/93 (80% strains each, and 88/93 (95% strains harbored at least one type of integron. The qPCR analysis of community DNA also showed an unprecedented high prevalence of integrons, suggesting that the bacteria living under such high selective pressure have an appreciable potential for genetic exchange of resistance genes via mobile gene cassettes. The present study provides

  5. Drugs Approved for Multiple Myeloma

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for multiple myeloma and other plasma cell neoplasms. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

  6. Mechanisms of drug resistance in cancer cells

    International Nuclear Information System (INIS)

    Iqbal, M.P.

    2003-01-01

    Development of drug resist chemotherapy. For the past several years, investigators have been striving hard to unravel mechanisms of drug resistance in cancer cells. Using different experimental models of cancer, some of the major mechanisms of drug resistance identified in mammalian cells include: (a) Altered transport of the drug (decreased influx of the drug; increased efflux of the drug (role of P-glycoprotein; role of polyglutamation; role of multiple drug resistance associated protein)), (b) Increase in total amount of target enzyme/protein (gene amplification), (c) alteration in the target enzyme/protein (low affinity enzyme), (d) Elevation of cellular glutathione, (e) Inhibition of drug-induced apoptosis (mutation in p53 tumor suppressor gene; increased expression of bcl-xl gene). (author)

  7. Drug Reactions - Multiple Languages

    Science.gov (United States)

    ... PDF Drug Interactions - HIV medicines, part 6 - English MP3 Drug Interactions - HIV medicines, part 6 - 简体中文 (Chinese, Simplified (Mandarin dialect)) MP3 Drug Interactions - HIV medicines, part 6 - English MP4 ...

  8. Virulence characteristics and genetic affinities of multiple drug resistant uropathogenic Escherichia coli from a semi urban locality in India.

    Directory of Open Access Journals (Sweden)

    Savita Jadhav

    Full Text Available Extraintestinal pathogenic Escherichia coli (ExPEC are of significant health concern. The emergence of drug resistant E. coli with high virulence potential is alarming. Lack of sufficient data on transmission dynamics, virulence spectrum and antimicrobial resistance of certain pathogens such as the uropathogenic E. coli (UPEC from countries with high infection burden, such as India, hinders the infection control and management efforts. In this study, we extensively genotyped and phenotyped a collection of 150 UPEC obtained from patients belonging to a semi-urban, industrialized setting near Pune, India. The isolates representing different clinical categories were analyzed in comparison with 50 commensal E. coli isolates from India as well as 50 ExPEC strains from Germany. Virulent strains were identified based on hemolysis, haemagglutination, cell surface hydrophobicity, serum bactericidal activity as well as with the help of O serotyping. We generated antimicrobial resistance profiles for all the clinical isolates and carried out phylogenetic analysis based on repetitive extragenic palindromic (rep-PCR. E. coli from urinary tract infection cases expressed higher percentages of type I (45% and P fimbriae (40% when compared to fecal isolates (25% and 8% respectively. Hemolytic group comprised of 60% of UPEC and only 2% of E. coli from feces. Additionally, we found that serum resistance and cell surface hydrophobicity were not significantly (p = 0.16/p = 0.51 associated with UPEC from clinical cases. Moreover, clinical isolates exhibited highest resistance against amoxicillin (67.3% and least against nitrofurantoin (57.3%. We also observed that 31.3% of UPEC were extended-spectrum beta-lactamase (ESBL producers belonging to serotype O25, of which four were also positive for O25b subgroup that is linked to B2-O25b-ST131-CTX-M-15 virulent/multiresistant type. Furthermore, isolates from India and Germany (as well as global sources were found to be

  9. Multiple Introduction and Naturally Occuring Drug Resistance of HCV among HIV-Infected Intravenous Drug Users in Yunnan: An Origin of China's HIV/HCV Epidemics.

    Directory of Open Access Journals (Sweden)

    Min Chen

    Full Text Available The human immunodeficiency virus 1 (HIV-1 epidemic in China historically stemmed from intravenous drug users (IDUs in Yunnan. Due to a shared transmission route, hepatitis C virus (HCV/HIV-1 co-infection is common. Here, we investigated HCV genetic characteristics and baseline drug resistance among HIV-infected IDUs in Yunnan.Blood samples of 432 HIV-1/HCV co-infected IDUs were collected from January to June 2014 in six prefectures of Yunnan Province. Partial E1E2 and NS5B genes were sequenced. Phylogenetic, evolutionary and genotypic drug resistance analyses were performed.Among the 293 specimens successfully genotyped, seven subtypes were identified, including subtypes 3b (37.9%, 111/293, 3a (21.8%, 64/293, 6n (14.0%, 41/293, 1b (10.6%, 31/293, 1a (8.2%, 24/293, 6a (5.1%, 15/293 and 6u (2.4%, 7/293. The distribution of HCV subtypes was mostly related to geographic location. Subtypes 3b, 3a, and 6n were detected in all six prefectures, however, the other four subtypes were detected only in parts of the six prefectures. Phylogeographic analyses indicated that 6n, 1a and 6u originated in the western prefecture (Dehong and spread eastward and showed genetic relatedness with those detected in Burmese. However, 6a originated in the southeast prefectures (Honghe and Wenshan bordering Vietnam and was transmitted westward. These subtypes exhibited different evolutionary rates (between 4.35×10-4 and 2.38×10-3 substitutions site-1 year-1 and times of most recent common ancestor (tMRCA, between 1790.3 and 1994.6, suggesting that HCV was multiply introduced into Yunnan. Naturally occurring resistance-associated mutations (C316N, A421V, C445F, I482L, V494A, and V499A to NS5B polymerase inhibitors were detected in direct-acting antivirals (DAAs-naïve IDUs.This work reveals the temporal-spatial distribution of HCV subtypes and baseline HCV drug resistance among HIV-infected IDUs in Yunnan. The findings enhance our understanding of the characteristics and

  10. Combined phylogeny and neighborhood analysis of the evolution of the ABC transporters conferring multiple drug resistance in hemiascomycete yeasts

    Directory of Open Access Journals (Sweden)

    Goffeau André

    2009-10-01

    Full Text Available Abstract Background Pleiotropic Drug Resistant transporters (PDR are members of the ATP-Binding Cassette (ABC subfamily which export antifungals and other xenobiotics in fungi and plants. This subfamily of transmembrane transporters has nine known members in Saccharomyces cerevisiae. We have analyzed the complex evolution of the pleiotropic drug resistance proteins (Pdrp subfamily where gene duplications and deletions occur independently in individual genomes. This study was carried out on 62 Pdrp from nine hemiascomycetous species, seven of which span 6 of the 14 clades of the Saccharomyces complex while the two others species, Debaryomyces hansenii and Yarrowia lipolytica, are further apart from an evolutive point of view. Results Combined phylogenetic and neighborhood analyses enabled us to identify five Pdrp clusters in the Saccharomyces complex. Three of them comprise orthologs of the Pdrp sensu stricto, Pdr5p, Pdr10p, Pdr12p, Pdr15p, Snq2p and YNR070wp. The evolutive pathway of the orthologs of Snq2 and YNR070w is particularly complex due to a tandem gene array in Eremothecium gossypii, Kluyveromyces lactis and Saccharomyces (Lachancea kluyveri. This pathway and different cases of duplications and deletions were clarified by using a neighborhood analysis based on synteny. For the two distant species, Yarrowia lipolytica and Debaryomyces hansenii, no neighborhood evidence is available for these clusters and many homologs of Pdr5 and Pdr15 are phylogenetically assigned to species-based clusters. Two other clusters comprise the orthologs of the sensu lato Pdrp, Aus1p/Pdr11p and YOL075cp respectively. The evolutionary pathway of these clusters is simpler. Nevertheless, orthologs of these genes are missing in some species. Conclusion Numerous duplications were traced among the Hemiascomycetous Pdrp studied. The role of the Whole Genome Duplication (WGD is sorted out and our analyses confirm the common ancestrality of Pdr5p and Pdr15p. A tandem

  11. Combined phylogeny and neighborhood analysis of the evolution of the ABC transporters conferring multiple drug resistance in hemiascomycete yeasts.

    Science.gov (United States)

    Seret, Marie-Line; Diffels, Julie F; Goffeau, André; Baret, Philippe V

    2009-10-01

    Pleiotropic Drug Resistant transporters (PDR) are members of the ATP-Binding Cassette (ABC) subfamily which export antifungals and other xenobiotics in fungi and plants. This subfamily of transmembrane transporters has nine known members in Saccharomyces cerevisiae. We have analyzed the complex evolution of the pleiotropic drug resistance proteins (Pdrp) subfamily where gene duplications and deletions occur independently in individual genomes. This study was carried out on 62 Pdrp from nine hemiascomycetous species, seven of which span 6 of the 14 clades of the Saccharomyces complex while the two others species, Debaryomyces hansenii and Yarrowia lipolytica, are further apart from an evolutive point of view. Combined phylogenetic and neighborhood analyses enabled us to identify five Pdrp clusters in the Saccharomyces complex. Three of them comprise orthologs of the Pdrp sensu stricto, Pdr5p, Pdr10p, Pdr12p, Pdr15p, Snq2p and YNR070wp. The evolutive pathway of the orthologs of Snq2 and YNR070w is particularly complex due to a tandem gene array in Eremothecium gossypii, Kluyveromyces lactis and Saccharomyces (Lachancea) kluyveri. This pathway and different cases of duplications and deletions were clarified by using a neighborhood analysis based on synteny. For the two distant species, Yarrowia lipolytica and Debaryomyces hansenii, no neighborhood evidence is available for these clusters and many homologs of Pdr5 and Pdr15 are phylogenetically assigned to species-based clusters. Two other clusters comprise the orthologs of the sensu lato Pdrp, Aus1p/Pdr11p and YOL075cp respectively. The evolutionary pathway of these clusters is simpler. Nevertheless, orthologs of these genes are missing in some species. Numerous duplications were traced among the Hemiascomycetous Pdrp studied. The role of the Whole Genome Duplication (WGD) is sorted out and our analyses confirm the common ancestrality of Pdr5p and Pdr15p. A tandem gene array is observed in Eremothecium gossypii. One

  12. A new system for parallel drug screening against multiple-resistant HIV mutants based on lentiviral self-inactivating (SIN vectors and multi-colour analyses

    Directory of Open Access Journals (Sweden)

    Prokofjeva Maria M

    2013-01-01

    Full Text Available Abstract Background Despite progress in the development of combined antiretroviral therapies (cART, HIV infection remains a significant challenge for human health. Current problems of cART include multi-drug-resistant virus variants, long-term toxicity and enormous treatment costs. Therefore, the identification of novel effective drugs is urgently needed. Methods We developed a straightforward screening approach for simultaneously evaluating the sensitivity of multiple HIV gag-pol mutants to antiviral drugs in one assay. Our technique is based on multi-colour lentiviral self-inactivating (SIN LeGO vector technology. Results We demonstrated the successful use of this approach for screening compounds against up to four HIV gag-pol variants (wild-type and three mutants simultaneously. Importantly, the technique was adapted to Biosafety Level 1 conditions by utilising ecotropic pseudotypes. This allowed upscaling to a large-scale screening protocol exploited by pharmaceutical companies in a successful proof-of-concept experiment. Conclusions The technology developed here facilitates fast screening for anti-HIV activity of individual agents from large compound libraries. Although drugs targeting gag-pol variants were used here, our approach permits screening compounds that target several different, key cellular and viral functions of the HIV life-cycle. The modular principle of the method also allows the easy exchange of various mutations in HIV sequences. In conclusion, the methodology presented here provides a valuable new approach for the identification of novel anti-HIV drugs.

  13. Drug-resistant spinal tuberculosis

    Directory of Open Access Journals (Sweden)

    Anil K Jain

    2018-01-01

    Full Text Available Drug-resistant spinal tuberculosis (TB is an emerging health problem in both developing and developed countries. In this review article, we aim to define management protocols for suspicion, diagnosis, and treatment of such patients. Spinal TB is a deep-seated paucibacillary lesion, and the demonstration of acid-fast bacilli on Ziehl-Neelsen staining is possible only in 10%–30% of cases. Drug resistance is suspected in patients showing the failure of clinicoradiological improvement or appearance of a fresh lesion of osteoarticular TB while on anti tubercular therapy (ATT for a minimum period of 5 months. The conventional culture of Mycobacterium tuberculosis remains the gold standard for both bacteriological diagnosis and drug sensitivity testing (DST; however, the high turn around time of 2–6 weeks for detection with added 3 weeks for DST is a major limitation. To overcome this problem, rapid culture methods and molecular methods have been introduced. From a public health perspective, reducing the period between diagnosis and treatment initiation has direct benefits for both the patient and the community. For all patients of drug-resistant spinal TB, a complete Drug-O-Gram should be prepared which includes details of all drugs, their doses, and duration. Patients with confirmed multidrug-resistant TB strains should receive a regimen with at least five effective drugs, including pyrazinamide and one injectable. Patients with resistance to additional antitubercular drugs should receive individualized ATT as per their DST results.

  14. Enterococcus spp. Resistant to Multiple Antimicrobial Drugs and Determination of Fecal Contamination Levels in Mangrove Oysters (Crassostrea rhizophorae

    Directory of Open Access Journals (Sweden)

    Cynthia Annes Rubião

    2017-08-01

    Full Text Available ABSTRACT The aim of this study was to determine and compare the Most Probable Number (MPN of Total Coliforms (TC, Escherichia coli and Enterococcus spp. and to characterize the antimicrobial resistance profiles of Enterococcus spp. isolated from oysters collected in the Barra de Guaratiba Mangrove, Rio de Janeiro, Brazil. The enumeration of E. coli has been used to indicate fecal contamination and hygienic-sanitary conditions of bivalve molluscs. Enterococci are capable to transfer several antimicrobial resistance genes to pathogenic bacteria, including those from Gram-negative group. The oysters were bought from local fishermen and a total of 123 individuals were analyzed. The TC, E. coli and Enterococcus spp. MPN mean were 26,300/100 g, 3,260/100 g and 2,820/100 g, respectively. The only correlation found was between TC and E. coli. Two strains of Enterococcus spp. were resistant to three different antimicrobial categories, including a high level resistance to streptomycin. One strain presented intermediate resistance to vancomycin. The E. coli levels exceeded the limits established by international legislation. This microbiological contamination in oysters reflects the water pollution and indicates a probable contamination of other seafood species from this mangrove, which can represent a risk for consumers and a threat to the environment and public health.

  15. Mechanism of mercuric chloride resistance in microorganisms. II. NADPH-dependent reduction of mercuric chloride and vaporization of mercury from mercuric chloride by a multiple drug resistant strain of Escherichia coli

    Energy Technology Data Exchange (ETDEWEB)

    Komura, I; Funaba, T; Izaki, K

    1971-01-01

    The activity to vaporize a /sup 203/Hg compound from /sup 203/HgCl/sub 2/ was demonstrated in crude cell-free extracts of a strain of Escherichia coli W2252, which had acquired the multiple drug resistance. NADPH was essential for the vaporization, while NADH had only a slight stimulating effect and NADP/sup +/ had no effect. The oxidation of NADPH dependent on HgCl/sub 2/ was also demonstrated in the crude extracts, but the HgCl/sub 2/-dependent NADH oxidation could be demonstrated only when a partially purified enzyme preparation was used. The rate of NADH oxidation was much slower than that of NADPH oxidation. It was concluded that NADPH, and to a lesser extent NADH, act as electron donors for the enzymatic reduction of HgCl/sub 2/ and the vaporization occurs after this reduction. This reduction and subsequent vaporization seem to provide a mechanism of resistance to HgCl/sub 2/ in E. coli strains having the multiple drug resistance. 15 references, 4 figures, 4 tables.

  16. Prevalence of Multiple Drug Resistant Clinical Isolates of Extended-Spectrum Beta-Lactamase Producing Enterobacteriaceae in Southeast Iran

    Directory of Open Access Journals (Sweden)

    Shahla Mansouri

    2010-06-01

    Full Text Available AbstractBackground: Multidrug resistance and production of extendedspectrum β-lactamases (ESBLs by enteric gramnegativerods in hospitals and community continue to beworsened. We aimed to characterize the multidrug resistanceand determine the prevalence of ESBL production by clinicalisolates of Enterobacteriaceae in southeast Iran.Methods: Gram-negative bacteria isolated from clinical samplesof hospital inpatients and outpatients from three hospitalsin southeast Iran were tested for susceptibility to 10commonly used antimicrobials. For 500 isolates whichshowed resistance to ≥3 antibiotics from different classes,minimum inhibitory concentration, and prevalence of ESBLproduction were determined by agar dilution and double discsynergy method respectively. The isolated bacterial specieswere compared in respect of antibacterial resistance, ESBLproduction, patients' gender, hospital ward, and type ofspecimen.Results: The most frequent resistance was to trimethoprim/sulfamethoxazole, amoxicillin, and tetracycline. Imipenemwith 99.8% and ceftizoxime with 83% susceptibility were themost active agents. A total of 53.8% of isolates expressedESBL production. Escherichia coli and Klebsiella pneumoniaewere most common in outpatients, and inpatients samplesrespectively. Higher rate of resistance to most antibacterialagents and ESBL production was found in samples ofinpatients.Conclusion: The present study showed high prevalence ofESBL-producing Enterobacteriaceae especially in the patientsadmitted to hospital. Infection control strategy with continuousresistance surveillance is essential to monitor in vitro susceptibilityto antibacterial agents currently used in clinicalpractice. Determination of the type of involved ESBL enzymesis important for a better antimicrobial control and empiricaltherapy of critically ill patients in hospitals.Iran J Med Sci 2010; 35(2: 101-108.

  17. Effects of Silver Nanoparticles on Multiple Drug-Resistant Strains of Staphylococcus aureus and Pseudomonas aeruginosa from Mastitis-Infected Goats: An Alternative Approach for Antimicrobial Therapy

    Directory of Open Access Journals (Sweden)

    Yu-Guo Yuan

    2017-03-01

    Full Text Available Recently, silver nanoparticles (AgNPs have been widely used in various applications as antimicrobial agents, anticancer, diagnostics, biomarkers, cell labels, and drug delivery systems for the treatment of various diseases. Microorganisms generally acquire resistance to antibiotics through the course of antibacterial therapy. Multi-drug resistance (MDR has become a growing problem in the treatment of infectious diseases, and the widespread use of broad-spectrum antibiotics has resulted in the development of antibiotic resistance by numerous human and animal bacterial pathogens. As a result, an increasing number of microorganisms are resistant to multiple antibiotics causing continuing economic losses in dairy farming. Therefore, there is an urgent need for the development of alternative, cost-effective, and efficient antimicrobial agents that overcome antimicrobial resistance. Here, AgNPs synthesized using the bio-molecule quercetin were characterized using various analytical techniques. The synthesized AgNPs were highly spherical in shape and had an average size of 11 nm. We evaluated the efficacy of synthesized AgNPs against two MDR pathogenic bacteria, namely, Pseudomonas aeruginosa and Staphylococcus aureus, which were isolated from milk samples produced by mastitis-infected goats. The minimum inhibitory concentrations (MICs of AgNPs against P. aeruginosa and S. aureus were found to be 1 and 2 μg/mL, respectively. Our findings suggest that AgNPs exert antibacterial effects in a dose- and time-dependent manner. Results from the present study demonstrate that the antibacterial activity of AgNPs is due to the generation of reactive oxygen species (ROS, malondialdehyde (MDA, and leakage of proteins and sugars in bacterial cells. Results of the present study showed that AgNP-treated bacteria had significantly lower lactate dehydrogenase activity (LDH and lower adenosine triphosphate (ATP levels compared to the control. Furthermore, Ag

  18. Enterococcus spp. Resistant to Multiple Antimicrobial Drugs and Determination of Fecal Contamination Levels in Mangrove Oysters (Crassostrea rhizophorae)

    OpenAIRE

    Rubião, Cynthia Annes; Franco, Robson Maia; Mesquita, Eliana de Fátima Marques de; Miguel, Marco Antonio Lemos; Cabral, Claudius Couto; Fonseca, Ana Beatriz Monteiro

    2017-01-01

    ABSTRACT The aim of this study was to determine and compare the Most Probable Number (MPN) of Total Coliforms (TC), Escherichia coli and Enterococcus spp. and to characterize the antimicrobial resistance profiles of Enterococcus spp. isolated from oysters collected in the Barra de Guaratiba Mangrove, Rio de Janeiro, Brazil. The enumeration of E. coli has been used to indicate fecal contamination and hygienic-sanitary conditions of bivalve molluscs. Enterococci are capable to transfer several ...

  19. MICROBIAL LOAD AND MULTIPLE DRUG RESISTANCE OF PATHOGENIC BACTERIA ISOLATED FROM FEACES AND BODY SURFACES OF COCKROACHES IN AN URBAN AREA OF SOUTHWESTERN NIGERIA

    Directory of Open Access Journals (Sweden)

    Monsuru Adebayo Adeleke

    2012-06-01

    Full Text Available This study investigates the microbial load and antibiotic susceptibility pattern of pathogenic bacteria isolated from the faeces and body surfaces of cockroaches in Osogbo, Southwestern Nigeria. The cockroaches collected from residential areas and hospital vicinities were screened for microbial load and antibiotic susceptibility pattern using standard protocols. A total of twenty- three microorganisms namely Klebsiella aerogenes, Bacillius cereus, Proteus spp, Staphyloccocus aureus, S. saprophyticus, Enteroccocus faecalis, Staphylococus epididermis, E. coli, Listeria monoctogene, Proteus mirabilis, Citrobacter species, Pseudomonas aeruginosa, Psuedomonas species, Seretia mensence, Candida albicans, Candida spp., Aspergilius spp., A. flavus, A. fumigates, Mucor species and Penicilium species were isolated. The microbial load of the microorganisms was significantly higher in the isolates from hospital as compared with the residential area (p<0.05 with the exception of Canidida species, Mucor and Penicillium which had higher or equal microbial load at the residential areas. All the pathogenic bacteria isolated had multiple resistance to antibiotics most importantly, Ampicillin, Augumentin, Amoxicillin and Septrin (30μg. Efforts geared towards controlling the insects will be indispensable in curbing the wide spread of multi-drug resistant pathogens in the study area.

  20. Computational Studies of Drug Resistance

    DEFF Research Database (Denmark)

    da Silva Martins, João Miguel

    Drug resistance has been an increasing problem in patient treatment and drug development. Starting in the last century and becoming a major worry in the medical and scienti c communities in the early part of the current millennium, major research must be performed to address the issues of viral...... is of the utmost importance in developing better and less resistance-inducing drugs. A drug's in uence can be characterized in many diff erent ways, however, and the approaches I take in this work re ect those same different in uences. This is what I try to achieve in this work, through seemingly unrelated...... approaches that come together in the study of drug's and their in uence on proteins and vice-versa. In part I, I aim to understand through combined theoretical ensemble analysis and free energy calculations the e ects mutations have over the binding anity and function of the M2 proton channel. This research...

  1. Drug-resistant tuberculosis

    African Journals Online (AJOL)

    statistics show that almost half a million new ... testing for second-line drugs, no international consensus has been reached about .... Given the high background rates of TB and MDR-TB in several countries, regimens are often constructed ...

  2. [Polymorphisms of the multiple drug resistance gene (MDR1) in Mapuche, Mestizo and Maori populations in Chile].

    Science.gov (United States)

    Wielandt, Ana María; Vollrath, Valeska; Chianale, José

    2004-09-01

    There are significant differences in drug responses among different ethnic groups. The multidrug transporter P-gp, encoded by the MDR1 gene, plays a key role in determining drug bioavailability, and an association between a polymorphism in exon 26 (C3435T) and lower P-gp expression has been found. The co-segregation of this polymorphism with the polymorphism in exon 12 (C1236T) and in exon 21 (G2677T/A) determines several MDR1 haplotypes in humans. To characterize the polymorphisms of exons 26, 21 and 12 of the MDR1 gene in different Chilean populations. Using a polymerase chain reaction and restriction fragment length polymorphism technique, we studied the allelic frequencies and the distribution of MDR1 haplotypes in 3 Chilean populations: Mestizo (n=104), Mapuche (n=96, living in the National Reservation of the Huapi Island, Ranico Lake) and Maori (n=52, living in Eastern Island). The frequency of the normal MDR1*1 haplotype, without mutations, was lower in Mapuches than in Mestizos or Maoris (p0.0.5), but lower than the frequencies reported in Caucasians or Asians (p<0.05). We found significant differences in the frequencies of genetic polymorphisms of the MDR1 gene in Chilean populations, related to the ethnic origins of our ancestors.

  3. Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma.

    Directory of Open Access Journals (Sweden)

    Martin Bøgsted

    Full Text Available In a conceptual study of drug resistance we have used a preclinical model of malignant B-cell lines by combining drug induced growth inhibition and gene expression profiling. In the current report a melphalan resistance profile of 19 genes were weighted by microarray data from the MRC Myeloma IX trial and time to progression following high dose melphalan, to generate an individual melphalan resistance index. The resistance index was subsequently validated in the HOVON65/GMMG-HD4 trial data set to prove the concept. Biologically, the assigned resistance indices were differentially distributed among translocations and cyclin D expression classes. Clinically, the 25% most melphalan resistant, the intermediate 50% and the 25% most sensitive patients had a median progression free survival of 18, 32 and 28 months, respectively (log-rank P-value  = 0.05. Furthermore, the median overall survival was 45 months for the resistant group and not reached for the intermediate and sensitive groups (log-rank P-value  = 0.003 following 38 months median observation. In a multivariate analysis, correcting for age, sex and ISS-staging, we found a high resistance index to be an independent variable associated with inferior progression free survival and overall survival. This study provides clinical proof of concept to use in vitro drug screen for identification of melphalan resistance gene signatures for future functional analysis.

  4. Mesenchymal change and drug resistance in neuroblastoma.

    Science.gov (United States)

    Naiditch, Jessica A; Jie, Chunfa; Lautz, Timothy B; Yu, Songtao; Clark, Sandra; Voronov, Dimitry; Chu, Fei; Madonna, Mary Beth

    2015-01-01

    Metastatic initiation has many phenotypic similarities to epithelial-to-mesenchymal transition, including loss of cell-cell adhesion, increased invasiveness, and increased cell mobility. We have previously demonstrated that drug resistance is associated with a metastatic phenotype in neuroblastoma (NB). The purpose of this project was to determine if the development of doxorubicin resistance is associated with characteristics of mesenchymal change in human NB cells. Total RNA was isolated from wild type (WT) and doxorubicin-resistant (DoxR) human NB cell lines (SK-N-SH and SK-N-BE(2)C) and analyzed using the Illumina Human HT-12 version 4 Expression BeadChip. Differentially expressed genes (DEGs) were identified. Volcano plots and heat maps were generated. Genes of interest with a fold change in expression >1.5 and an adjusted P change via multiple pathways in the transition to a drug-resistant state. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. High Prevalence of Multiple Drug Resistance among ESBLs-Producing Klebsiella pneumoniae Isolated from Hospitalized Patients in Isfahan, Iran

    Directory of Open Access Journals (Sweden)

    Zahra Tahanasab

    2017-02-01

    Full Text Available Background:   This study was to evaluate the prevalence of CTX-Mand TEM type ESBLs-producing K. pneumoniae and determination of MDR, XDR, and PDR phenotypes of these isolates as well as find out the genetic relationship and molecular typing of these isolates using phenotypic and genotypic methods.Methods:   Non-repetitive 96 K. pneumonia isolates were isolated from hospitalized patients in Al-Zahra hospital of Isfahan, Iran. The antibiotic susceptibility test was assessed for 20 antibiotics using Kirby-Bauer disk diffusion method. The frequency of ESBL-producing isolates was determined by phenotypic confirmatory test. All ESBLs-producing isolates were assessed for blaTEM and blaCTX-M genes using PCR method. Molecular typing was performed by enterobacterial repetitive intergenic consensus sequence-based PCR (ERIC-PCR.Results:  Among 96 isolates, 58 isolates (60.4% were ESBL-producers. In this study, 85.7% and 30.3% of ESBL-producing isolates showed MDR and XDR phenotypes, respectively. No PDR isolate was found. PCR amplification on ESBL-producing isolates showed that 47 (81% isolates were carried blaTEM gene, while blaCTX-M was detected in all isolates (100%. ERIC-PCR typing was characterized the high genetic similarity among ESBL-producing K. pneumonia isolates and revealed 32 band pattern for the isolates. Conclusion:  This study showed high prevalence of important ESBL genes (blaCTX-M and blaTEM genes among the K. pneumoniae isolated from in-patients. Constant following of ESBLs, also identification of their types, in bacteria isolated from hospitalized patients has an important clinical impact. It can provide valuable information for the choice of appropriate antibacterial therapy and decrease of antibiotic resistance.

  6. Community-based management of multiple drug resistant tuberculosis in a tertiary hospital in Tanzania: a best practice implementation project.

    Science.gov (United States)

    Jelly, Isaya; Peters, Micah D J

    2017-12-01

    The World Health Organization (WHO) has prioritized collaboration with communities in its 2016 "End TB" implementation strategy. Acknowledging the difficulties that some communities face in gaining access to health facilities due to barriers such as stigma, discrimination, healthcare expenditure, transport and income loss, partnering with communities in the roll-out of community-based TB management activities is vital. The aim of this project was to make a contribution to promoting evidence-based practice with regards to the community-based management of multidrug-resistant tuberculosis (MDR-TB) at Kibong'oto National Infectious Disease Hospital, Tanzania, and thereby supporting improvements in patient outcomes and resource utilization. The project utilized the Joanna Briggs Institute Practical Application of Clinical Evidence System (JBI PACES) program to facilitate the collection of pre- and post-audit data. The Getting Research into Practice (GRiP) module was also used to analyze the potential barriers and for designing the final action plan. This project was conducted in three phases over a three-month period at the MDR-TB unit in a referral hospital in Northern Tanzania. The project showed that there were significant improvements in compliance rates in staff education and documentation of patients' suitability and preferences in receiving community-based care for MDR-TB. The compliance rate of criterion 2, which was already 100% at baseline, was slightly lower at follow-up. The project achieved significant improvements in the delivery of evidence-based practice with regards to community-based management of MDR-TB.

  7. Lysosomes as mediators of drug resistance in cancer.

    Science.gov (United States)

    Zhitomirsky, Benny; Assaraf, Yehuda G

    2016-01-01

    Drug resistance remains a leading cause of chemotherapeutic treatment failure and cancer-related mortality. While some mechanisms of anticancer drug resistance have been well characterized, multiple mechanisms remain elusive. In this respect, passive ion trapping-based lysosomal sequestration of multiple hydrophobic weak-base chemotherapeutic agents was found to reduce the accessibility of these drugs to their target sites, resulting in a markedly reduced cytotoxic effect and drug resistance. Recently we have demonstrated that lysosomal sequestration of hydrophobic weak base drugs triggers TFEB-mediated lysosomal biogenesis resulting in an enlarged lysosomal compartment, capable of enhanced drug sequestration. This study further showed that cancer cells with an increased number of drug-accumulating lysosomes are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. In addition to passive drug sequestration of hydrophobic weak base chemotherapeutics, other mechanisms of lysosome-mediated drug resistance have also been reported; these include active lysosomal drug sequestration mediated by ATP-driven transporters from the ABC superfamily, and a role for lysosomal copper transporters in cancer resistance to platinum-based chemotherapeutics. Furthermore, lysosomal exocytosis was suggested as a mechanism to facilitate the clearance of chemotherapeutics which highly accumulated in lysosomes, thus providing an additional line of resistance, supplementing the organelle entrapment of chemotherapeutics away from their target sites. Along with these mechanisms of lysosome-mediated drug resistance, several approaches were recently developed for the overcoming of drug resistance or exploiting lysosomal drug sequestration, including lysosomal photodestruction and drug-induced lysosomal membrane permeabilization. In this review we explore the current literature addressing the role of lysosomes in mediating cancer drug

  8. Extensively Drug-Resistant TB

    Centers for Disease Control (CDC) Podcasts

    2016-12-16

    Dr. Charlotte Kvasnovsky, a surgery resident and Ph.D. candidate in biostatistics, discusses various types of drug resistance in TB patients in South Africa.  Created: 12/16/2016 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 12/16/2016.

  9. Initial drug resistance in India

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Initial drug resistance in India. There is gradual increase in primary MDR all over India : Pondi= Pondicherry 1985; Bangalore =1986; Jaipur = 1991; Jaipur =2000. Overall the MDR is less than 3% (TRC studies).

  10. Overview of drug-resistant tuberculosis worldwide

    Directory of Open Access Journals (Sweden)

    Ali A Velayati

    2016-01-01

    Full Text Available Even in the 21st century, we are losing the battle against eradication of tuberculosis (TB. In 2015, 9.6 million people were estimated to have fallen ill with TB, of which 1.5 million people died. This is the real situation despite the well-structured treatment programs and availability of effective treatment options since the 1950s. The high mortality rate has been associated with other risk factors, such as the HIV epidemic, underlying diseases, and decline of socioeconomic standards. Furthermore, the problem of drug resistance that was recognized in the early days of the chemotherapeutic era raises serious concerns. Although resistance to a single agent is the most common type, resistance to multiple agents is less frequent but of greater concern. The World Health Organization estimated approximately 5% of all new TB cases involved multidrug-resistant (MDR-TB. The estimation for MDR-TB is 3.3% for new cases, and 20.5% for previously treated cases. Failure to identify and appropriately treat MDR-TB patients has led to more dangerous forms of resistant TB. Based on World Health Organization reports, 5% of global TB cases are now considered to be extensively drug resistant (XDR, defined as MDR with additional resistance to both fluoroquinolones and at least one second-line injectable drug. XDR-TB had been reported by 105 countries by 2015. An estimated 9.7% of people with MDR-TB have XDR-TB. More recently, another dangerous form of TB bacillus was identified, which was named totally drug resistant (TDR-TB or extremely drug resistant TB. These strains were resistant to all first- and second-line anti-TB drugs. Collectively, it is accepted that 2% of MDR-TB strains turn to be TDR-TB. This number, however, may not reflect the real situation, as many laboratories in endemic TB countries do not have proper facilities and updated protocols to detect the XDR or TDR-TB strains. Nevertheless, existing data emphasize the need for additional control

  11. Mechanisms of Candida biofilm drug resistance

    Science.gov (United States)

    Taff, Heather T; Mitchell, Kaitlin F; Edward, Jessica A; Andes, David R

    2013-01-01

    Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, β-glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases. PMID:24059922

  12. La resistencia a múltiples fármacos: una amenaza para el control de la tuberculosis Multiple drug resistance: a threat for tuberculosis control

    Directory of Open Access Journals (Sweden)

    Ernesto Montoro Cardoso

    2004-07-01

    Full Text Available Drug-resistant tuberculosis (TB was reported soon after the introduction of streptomycin, although it did not receive major attention until recently. It was not considered a major issue in the industrialized world until outbreaks of multidrug-resistant TB (MDR-TB were reported among HIV infected people. Administration of standard short-course chemotherapy (SSCC with first-line drugs under directly observed therapy (DOT is the cornerstone of modern TB control. Unfortunately, data available on the treatment outcome of MDR-TB cases under routine programmatic conditions suggest that patients with MDR-TB respond poorly to SSCC with first-line drugs. Since 1994, the World Health Organization and the International Union Against Tuberculosis and Lung Disease (IUATLD have conducted anti-TB drug resistance surveys through a network of subregional laboratories and researchers. Drug resistance was present in almost all settings surveyed, and prevalence varied widely across regions. High prevalence of MDR-TB is widespread in the Russian Federation and areas of the former Soviet Union (Estonia, Kazakhstan, Latvia, and Lithuania as well as Israel, Liaoning and Henan Provinces in China, and Ecuador. The Global Project has surveyed areas representing over one third of notified TB cases. However, enormous gaps still exist in the most crucial areas. The most effective strategy to prevent the emergence of drug resistance is through implementation of the directly observed treatment short (DOTS strategy. Effective implementation of the DOTS strategy saves lives through decreased TB transmission, decreased risk of emergence of drug- resistance, and decreased risk for individual TB patients of treatment failure, TB relapse, and death. The World Bank recognizes the DOTS strategy as one of the most cost-effective health interventions, and recommends that effective TB treatment be a part of the essential clinical services package available in primary health care settings

  13. Study on drug resistance of mycobacterium tuberculosis in patients with pulmonary tuberculosis by drug resistance gene detecting

    International Nuclear Information System (INIS)

    Wang Wei; Li Hongmin; Wu Xueqiong; Wang Ansheng; Ye Yixiu; Wang Zhongyuan; Liu Jinwei; Chen Hongbing; Lin Minggui; Wang Jinhe; Li Sumei; Jiang Ping; Feng Bai; Chen Dongjing

    2004-01-01

    To investigate drug resistance of mycobacterium tuberculosis in different age group, compare detecting effect of two methods and evaluate their the clinical application value, all of the strains of mycobacterium tuberculosis were tested for resistance to RFP, INH SM PZA and EMB by the absolute concentration method on Lowenstein-Jensen medium and the mutation of the rpoB, katG, rpsL, pncA and embB resistance genes in M. tuberculosis was tested by PCR-SSCP. In youth, middle and old age group, the rate of acquired drug resistance was 89.2%, 85.3% and 67.6% respectively, the gene mutation rate was 76.2%, 81.3% and 63.2% respectively. The rate of acquired drug resistance and multiple drug resistance in youth group was much higher than those in other groups. The gene mutation was correlated with drug resistance level of mycobacterium tuberculosis. The gene mutation rate was higher in strains isolated from high concentration resistance than those in strains isolated from low concentration resistance. The more irregular treatment was longer, the rate of drug resistance was higher. Acquired drug resistance varies in different age group. It suggested that surveillance of drug resistence in different age group should be taken seriously, especially in youth group. PCR - SSCP is a sensitive and specific method for rapid detecting rpoB, katG, rpsL, pncA and embB genes mutations of MTB. (authors)

  14. DRUG RESISTANCE IN HELICOBACTER PYLORI

    Directory of Open Access Journals (Sweden)

    Júlia Silveira VIANNA

    Full Text Available ABSTRACT Background Helicobacter pylori has a worldwide distribution and is associated with the pathogenesis of various diseases of the digestive system. Treatment to eradicate this microorganism involves the use of a combination of antimicrobials, such as amoxicillin, metronidazole, clarithromycin, and levofloxacin, combined with proton pump inhibitors. Although the current therapy is effective, a high rate of treatment failure has been observed, mainly because of the acquisition of point mutations, one of the major resistance mechanisms developed by H. pylori. This phenomenon is related to frequent and/or inappropriate use of antibiotics. Conclusion This review reported an overview of the resistance to the main drugs used in the treatment of H. pylori, confirming the hypothesis that antibacterial resistance is a highly local phenomenon and genetic characteristics of a given population can influence which therapy is the most appropriate.

  15. Potential of berberine to enhance antimicrobial activity of commonly used antibiotics for dairy cow mastitis caused by multiple drug-resistant Staphylococcus epidermidis infection.

    Science.gov (United States)

    Zhou, X; Yang, C; Li, Y; Liu, X; Wang, Y

    2015-08-19

    Berberine is a plant alkaloid with antimicrobial activity against a variety of microorganisms. In this study, the antimicrobial properties of berberine against multi-drug resistant field isolates of Staphylococcus epidermidis were investigated using berberine alone or in combination with a commonly used antibiotics in veterinary clinics, including penicillin, lincomycin, and amoxicillin. The results indicated that the minimum inhibitory concentrations of berberine, penicillin, lincomycin, and amoxicillin against field S. epidermidis isolates were 2-512, 0.8-213, 0.4-1024, and 0.4-256 mg/mL, respectively. Furthermore, the synergistic effects of antimicrobial activity against these multi-drug resistant isolates were observed when the berberine was combined with penicillin, lincomycin, or amoxicillin; no antagonistic effect of the combination was detected in any of the clinical isolates. These observations were further confirmed using a time-killing assay, in which a combination of 2 agents yielded a greater than 2.03-2.44 log10 decrease in colony-forming unit/mL compared with each agent alone. These findings suggest that berberine is a promising compound for preventing and treating multi-drug resistant S. epidermidis infected mastitis in dairy cows either alone or in combination with other commonly used antibiotics, such as penicillin, lincomycin, and amoxicillin.

  16. Occurrence of extended-spectrum and AmpC β-lactamases in multiple drug resistant Salmonella isolates from clinical samples in Lagos, Nigeria

    Directory of Open Access Journals (Sweden)

    Akinyemi KO

    2017-01-01

    Full Text Available KO Akinyemi,1 Bamidele Abiodun Iwalokun,2 Akeeb O Bola Oyefolu,1 CO Fakorede1 1Department of Microbiology, Lagos State University, Ojo, 2Molecular Biology and Biotechnology Division, Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria Purpose: Salmonella spp. are important foodborne pathogens exhibiting increasing resistance to antimicrobial drugs. Resistance to broad-spectrum β-lactams, mediated by extended-spectrum β-lactamase (ESBL and AmpC β-lactamase enzymes is fast spreading and has had negative impacts on the clinical outcomes, particularly on third-generation cephalosporins. This study investigated the carriage of AmpC gene among multidrug-resistant Salmonella spp. from Lagos, Nigeria. Methods: Forty Salmonella spp. from clinical samples (S. typhi = 13; S. typhimurium = 10; S. enteritidis = 8; S. choleraesuis = 5; S. paratyphi = 4 were subjected to in vitro susceptibility test by disk diffusion methods. Isolates that were resistant to cefoxitin and third-generation cephalosporins were screened for ESBL (Double Disk Synergy Test Method and AmpC enzyme (AmpC disk test production. Detection of AmpC fox gene was carried out by polymerase chain reaction. Results: Thirty-two (80% of the Salmonella isolates were cefoxitin resistant. Plasmid-mediated AmpC β-lactamase and ESBL enzymes were recorded in 10/40 (25% and 16/40 (40% of the Salmonella isolates, respectively. Specifically, 16/40 (40% of the Salmonella isolates possessed 380 bp AmpC fox gene, with the highest occurrence found in S. typhi strains (43.8% followed by S. typhimurium (25%. There was no AmpC fox gene detected in S. paratyphi strains. Interestingly, coproduction of enzymes occurred in some of the isolates, raising fears of resistance to a multitude of antibiotics in the treatment of bacterial infections. Conclusion: Emergence of AmpC β-lactamase–producing Salmonella isolates in our environment was recorded for the first time, raising concern on increased

  17. Multidrug resistant to extensively drug resistant tuberculosis: What is ...

    Indian Academy of Sciences (India)

    Prakash

    The modern, ... World Health Organization is based on a four-drug regimen ... Better management and control of tuberculosis specially drug resistant TB by experienced and qualified .... a comprehensive approach including the major DOTS.

  18. Tumor Heterogeneity and Drug Resistance

    International Nuclear Information System (INIS)

    Kucerova, L.; Skolekova, S.; Kozovska, Z.

    2015-01-01

    New generation of sequencing methodologies revealed unexpected complexity and genomic alterations linked with the tumor subtypes. This diversity exists across the tumor types, histologic tumor subtypes and subsets of the tumor cells within the same tumor. This phenomenon is termed tumor heterogeneity. Regardless of its origin and mechanisms of development it has a major impact in the clinical setting. Genetic, phenotypic and expression pattern diversity of tumors plays critical role in the selection of suitable treatment and also in the prognosis prediction. Intratumoral heterogeneity plays a key role in the intrinsic and acquired chemoresistance to cytotoxic and targeted therapies. In this review we focus on the mechanisms of intratumoral and inter tumoral heterogeneity and their relationship to the drug resistance. Understanding of the mechanisms and spatiotemporal dynamics of tumor heterogeneity development before and during the therapy is important for the ability to design individual treatment protocols suitable in the given molecular context. (author)

  19. Drug-resistant tuberculosis in Sindh

    International Nuclear Information System (INIS)

    Almani, S.A.; Memon, N.M.; Qureshi, A.F.

    2002-01-01

    Objective: To assess the prevalence of primary and secondary drug resistance amongst the clinical isolates of M.tuberculosis, to identify risk factors and how to overcome this problem. Design: A case series of 50 indoor patients with sputum smear-positive pulmonary tuberculosis. Place and duration of Study: Department of Medicine, Liaquat University of Medical and Health Sciences Jamshoro, Sindh, (Pakistan) from January 1999 to December 2000. Patients and methods: Four first line anti-tuberculous drugs rifampicine, ethambutol and streptomycin were tested for sensitivity pattern. Results: Twelve (26.66%) were sensitive to all four drugs, 12(26.66%) were resistant to one drug, 14 (31.11%) were resistant to two drugs, 2 (4.44%) were resistant to three drugs, and 5(11.11%) were resistant to all four drugs. Resistance to isoniazid was the most common in 27 cases (60%) with primary resistance in 6(13.33%) and secondary resistance in 21(46.66%), followed by resistance to streptomycin in 17 cases (37.77%) with primary resistance in 5(11.11%) and secondary resistance in 12 (26.66%). Resistance to ethambutol in 10 cases (22.22%) and rifampicine in 11 (24.44%) and all cases were secondary. Similarly multi-drugs resistance (MRD) TB was found in 11(24.44%) isolates. Conclusion: This study showed high prevalence of drug resistance among clinical isolates of M. tuberculosis. Their is a need to establish centers at number of places with adequate facilities for susceptibility testing so that the resistant pattern could be ascertained and treatment regimens tailored accordingly. (author)

  20. Clinical Management of HIV Drug Resistance

    Science.gov (United States)

    Cortez, Karoll J.; Maldarelli, Frank

    2011-01-01

    Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy. PMID:21994737

  1. Antimicrobial Activities of Methanol, Ethanol and Supercritical CO2 Extracts of Philippine Piper betle L. on Clinical Isolates of Gram Positive and Gram Negative Bacteria with Transferable Multiple Drug Resistance.

    Directory of Open Access Journals (Sweden)

    Demetrio L Valle

    Full Text Available Piper betle L. has traditionally been used in alternative medicine in different countries for various therapeutic purposes, including as an anti-infective agent. However, studies reported in the literature are mainly on its activities on drug susceptible bacterial strains. This study determined the antimicrobial activities of its ethanol, methanol, and supercritical CO2 extracts on clinical isolates of multiple drug resistant bacteria which have been identified by the Infectious Disease Society of America as among the currently more challenging strains in clinical management. Assay methods included the standard disc diffusion method and the broth microdilution method for the determination of the minimum inhibitory concentration (MIC and the minimum bactericidal concentrations (MBC of the extracts for the test microorganisms. This study revealed the bactericidal activities of all the P. betle leaf crude extracts on methicillin-resistant Staphylococcus aureus (MRSA, vancomycin-resistant Enterococcus (VRE, extended spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and metallo-β-lactamase-producing Pseudomonas aeruginosa and Acinetobacter baumannii, with minimum bactericidal concentrations that ranged from 19μg/ml to 1250 μg/ml. The extracts proved to be more potent against the Gram positive MRSA and VRE than for the Gram negative test bacteria. VRE isolates were more susceptible to all the extracts than the MRSA isolates. Generally, the ethanol extracts proved to be more potent than the methanol extracts and supercritical CO2 extracts as shown by their lower MICs for both the Gram positive and Gram negative MDRs. MTT cytotoxicity assay showed that the highest concentration (100 μg/ml of P. betle ethanol extract tested was not toxic to normal human dermal fibroblasts (HDFn. Data from the study firmly established P. betle as an alternative source of anti-infectives against multiple drug resistant

  2. Antimicrobial Activities of Methanol, Ethanol and Supercritical CO2 Extracts of Philippine Piper betle L. on Clinical Isolates of Gram Positive and Gram Negative Bacteria with Transferable Multiple Drug Resistance.

    Science.gov (United States)

    Valle, Demetrio L; Cabrera, Esperanza C; Puzon, Juliana Janet M; Rivera, Windell L

    2016-01-01

    Piper betle L. has traditionally been used in alternative medicine in different countries for various therapeutic purposes, including as an anti-infective agent. However, studies reported in the literature are mainly on its activities on drug susceptible bacterial strains. This study determined the antimicrobial activities of its ethanol, methanol, and supercritical CO2 extracts on clinical isolates of multiple drug resistant bacteria which have been identified by the Infectious Disease Society of America as among the currently more challenging strains in clinical management. Assay methods included the standard disc diffusion method and the broth microdilution method for the determination of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentrations (MBC) of the extracts for the test microorganisms. This study revealed the bactericidal activities of all the P. betle leaf crude extracts on methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), extended spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and metallo-β-lactamase-producing Pseudomonas aeruginosa and Acinetobacter baumannii, with minimum bactericidal concentrations that ranged from 19μg/ml to 1250 μg/ml. The extracts proved to be more potent against the Gram positive MRSA and VRE than for the Gram negative test bacteria. VRE isolates were more susceptible to all the extracts than the MRSA isolates. Generally, the ethanol extracts proved to be more potent than the methanol extracts and supercritical CO2 extracts as shown by their lower MICs for both the Gram positive and Gram negative MDRs. MTT cytotoxicity assay showed that the highest concentration (100 μg/ml) of P. betle ethanol extract tested was not toxic to normal human dermal fibroblasts (HDFn). Data from the study firmly established P. betle as an alternative source of anti-infectives against multiple drug resistant bacteria.

  3. Multi drug resistance tuberculosis: pattern seen in last 13 years

    International Nuclear Information System (INIS)

    Iqbal, R.; Shabbir, I.; Munir, K.; Tabassum, M.N.; Khan, S.U.; Khan, M.Z.U.

    2011-01-01

    Background: Drug resistance in tuberculosis is a serious problem throughout the world especially, after the emergence of multi drug resistant TB strains. Objectives: To estimate drug resistance in TB patients and compare it with previous studies to see the changing trends. Materials and Methods: The PMRC Research Centre receives sputum samples from all the leading hospitals of Lahore. This retrospective analysis was done from 1996 to 2008 on the multi drug resistant TB strains that were seen during these years. Five first lines anti tuberculosis drugs were tested on Lowenstein Jensen medium using standard proportion method. Results: A total of 2661 confirmed isolates of Mycobacterium tuberculosis were seen over the past 13 years. Of the total, 2182 were pulmonary and 479 were extra pulmonary specimens. The patients comprised of those with and without history of previous treatment. These specimens were subjected to drug susceptibility testing. Almost half of the patient had some resistance; multiple drug resistance was seen in 12.3% and 23.0% cases without and with history of previous treatment respectively. Overall resistance to rifampicin was 26.4%, isoniazid 24.1% streptomycin 21.6% ethambutol 13.4% and pyrazinamide 28.4% respectively. Statistically significant difference was seen between primary and acquired resistance. When compared with the reports from previous studies from the same area, there was a trend of gradual increase of drug resistance. Conclusions Resistance to anti tuberculosis drugs is high. Policy message. TB Control Program should start 'DOTS Plus' schemes for which drug susceptibility testing facilities should be available for correctly managing the patients. (author)

  4. Multi drug resistance tuberculosis: pattern seen in last 13 years

    Energy Technology Data Exchange (ETDEWEB)

    Iqbal, R; Shabbir, I; Munir, K [King Edward Medical University Hospital, Lahore (Pakistan). Dept. of Research Centre; Tabassum, M N; Khan, S U; Khan, M Z.U. [King Edward Medical University Hospital, Lahore (Pakistan). Dept. of Chest Medicine

    2011-01-15

    Background: Drug resistance in tuberculosis is a serious problem throughout the world especially, after the emergence of multi drug resistant TB strains. Objectives: To estimate drug resistance in TB patients and compare it with previous studies to see the changing trends. Materials and Methods: The PMRC Research Centre receives sputum samples from all the leading hospitals of Lahore. This retrospective analysis was done from 1996 to 2008 on the multi drug resistant TB strains that were seen during these years. Five first lines anti tuberculosis drugs were tested on Lowenstein Jensen medium using standard proportion method. Results: A total of 2661 confirmed isolates of Mycobacterium tuberculosis were seen over the past 13 years. Of the total, 2182 were pulmonary and 479 were extra pulmonary specimens. The patients comprised of those with and without history of previous treatment. These specimens were subjected to drug susceptibility testing. Almost half of the patient had some resistance; multiple drug resistance was seen in 12.3% and 23.0% cases without and with history of previous treatment respectively. Overall resistance to rifampicin was 26.4%, isoniazid 24.1% streptomycin 21.6% ethambutol 13.4% and pyrazinamide 28.4% respectively. Statistically significant difference was seen between primary and acquired resistance. When compared with the reports from previous studies from the same area, there was a trend of gradual increase of drug resistance. Conclusions Resistance to anti tuberculosis drugs is high. Policy message. TB Control Program should start 'DOTS Plus' schemes for which drug susceptibility testing facilities should be available for correctly managing the patients. (author)

  5. Preventing drug resistance in severe influenza

    Science.gov (United States)

    Dobrovolny, Hana; Deecke, Lucas

    2015-03-01

    Severe, long-lasting influenza infections are often caused by new strains of influenza. The long duration of these infections leads to an increased opportunity for the emergence of drug resistant mutants. This is particularly problematic for new strains of influenza since there is often no vaccine, so drug treatment is the first line of defense. One strategy for trying to minimize drug resistance is to apply periodic treatment. During treatment the wild-type virus decreases, but resistant virus might increase; when there is no treatment, wild-type virus will hopefully out-compete the resistant virus, driving down the number of resistant virus. We combine a mathematical model of severe influenza with a model of drug resistance to study emergence of drug resistance during a long-lasting infection. We apply periodic treatment with two types of antivirals: neuraminidase inhibitors, which block release of virions; and adamantanes, which block replication of virions. We compare the efficacy of the two drugs in reducing emergence of drug resistant mutants and examine the effect of treatment frequency on the emergence of drug resistant mutants.

  6. Combined antiretroviral and anti- tuberculosis drug resistance ...

    African Journals Online (AJOL)

    these epidemics, many challenges remain.[3] Antiretroviral and anti-TB drug resistance pose considerable threats to the control of these epidemics.[4,5]. The breakdown in HIV/TB control within prisons is another emerging threat.[6,7] We describe one of the first reports of combined antiretroviral and anti-TB drug resistance ...

  7. Drug Resistance of Mycobacterium tuberculosis Complex among ...

    African Journals Online (AJOL)

    BACKGROUND: In Burkina Faso, there is no recent data about the level of drug resistance in Mycobacterium tuberculosis strains among newly diagnosed tuberculosis cases. OBJECTIVE: To provide an update of the primary drug resistance of mycobacterium tuberculosis among patients in Burkina faso. METHODS: ...

  8. Emergence of Extensively Drug Resistant Tuberculosis

    Centers for Disease Control (CDC) Podcasts

    Extensively drug-resistant tuberculosis (XDR TB) outbreaks have been reported in South Africa, and strains have been identified on 6 continents. Dr. Peter Cegielski, team leader for drug-resistant TB with the Division of Tuberculosis Elimination at CDC, comments on a multinational team's report on this emerging global public health threat.

  9. [Change in drug resistance of Staphylococcus aureus].

    Science.gov (United States)

    Lin, Yan; Liu, Yan; Luo, Yan-Ping; Liu, Chang-Ting

    2013-11-01

    To analyze the change in drug resistance of Staphylococcus aureus (SAU) in the PLA general hospital from January 2008 to December 2012, and to provide solid evidence to support the rational use of antibiotics for clinical applications. The SAU strains isolated from clinical samples in the hospital were collected and subjected to the Kirby-Bauer disk diffusion test. The results were assessed based on the 2002 American National Committee for Clinical Laboratory Standards (NCCLS) guidelines. SAU strains were mainly isolated from sputum, urine, blood and wound excreta and distributed in penology, neurology wards, orthopedics and surgery ICU wards. Except for glycopeptide drugs, methicillin-resistant Staphylococcus aureus (MRSA) had a higher drug resistance rate than those of the other drugs and had significantly more resistance than methicillin-sensitive Staphylococcus aureus (MSSA) (P resistance, we discovered a gradual increase in drug resistance to fourteen test drugs during the last five years. Drug resistance rate of SAU stayed at a higher level over the last five years; moreover, the detection ratio of MRSA keeps rising year by year. It is crucial for physicians to use antibiotics rationally and monitor the change in drug resistance in a dynamic way.

  10. Antimicrobial Drugs in Fighting against Antimicrobial Resistance

    OpenAIRE

    Cheng, Guyue; Dai, Menghong; Ahmed, Saeed; Hao, Haihong; Wang, Xu; Yuan, Zonghui

    2016-01-01

    The outbreak of antimicrobial resistance, together with the lack of newly developed antimicrobial drugs, represents an alarming signal for both human and animal healthcare worldwide. Selection of rational dosage regimens for traditional antimicrobial drugs based on pharmacokinetic/pharmacodynamic principles as well as development of novel antimicrobials targeting new bacterial targets or resistance mechanisms are key approaches in tackling AMR. In addition to the cellular level resistance (i....

  11. [New drugs in the treatment of multiple myeloma].

    Science.gov (United States)

    Oriol, Albert; Motlló, Cristina

    2014-09-15

    Progress in the treatment of multiple myeloma in the last decade has been able to delay, but ultimately not to prevent, the development of resistances and most patients still die of the disease or its related complications. New drugs have been developed including new alkylating agents, proteasome inhibitors and immunomodulators but also monoclonal antibodies and drugs with new mechanisms of action. Hopefully, this new generation of targeted agents will improve the results of the initial therapy, avoid relapses and development of resistances and provide better and less toxic options for the relapsed and refractory patient. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

  12. Plasmodium falciparum drug resistance in Angola.

    Science.gov (United States)

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-02-09

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information on malaria drug resistance in Angola, is reviewed and discussed. The review aims to inform but also to encourage future research studies that monitor and update the information on anti-malarial drug efficacy and prevalence of molecular markers of drug resistance, key fields in the context and objectives of elimination.

  13. Life cycle synchronization is a viral drug resistance mechanism.

    Directory of Open Access Journals (Sweden)

    Iulia A Neagu

    2018-02-01

    Full Text Available Viral infections are one of the major causes of death worldwide, with HIV infection alone resulting in over 1.2 million casualties per year. Antiviral drugs are now being administered for a variety of viral infections, including HIV, hepatitis B and C, and influenza. These therapies target a specific phase of the virus's life cycle, yet their ultimate success depends on a variety of factors, such as adherence to a prescribed regimen and the emergence of viral drug resistance. The epidemiology and evolution of drug resistance have been extensively characterized, and it is generally assumed that drug resistance arises from mutations that alter the virus's susceptibility to the direct action of the drug. In this paper, we consider the possibility that a virus population can evolve towards synchronizing its life cycle with the pattern of drug therapy. The periodicity of the drug treatment could then allow for a virus strain whose life cycle length is a multiple of the dosing interval to replicate only when the concentration of the drug is lowest. This process, referred to as "drug tolerance by synchronization", could allow the virus population to maximize its overall fitness without having to alter drug binding or complete its life cycle in the drug's presence. We use mathematical models and stochastic simulations to show that life cycle synchronization can indeed be a mechanism of viral drug tolerance. We show that this effect is more likely to occur when the variability in both viral life cycle and drug dose timing are low. More generally, we find that in the presence of periodic drug levels, time-averaged calculations of viral fitness do not accurately predict drug levels needed to eradicate infection, even if there is no synchronization. We derive an analytical expression for viral fitness that is sufficient to explain the drug-pattern-dependent survival of strains with any life cycle length. We discuss the implications of these findings for

  14. Pseudomonas aeruginosa: freqüência de resistência a múltiplos fármacos e resistência cruzada entre antimicrobianos no Recife/PE Pseudomonas aeruginosa: frequency of resistance to multiple drugs and cross-resistance between antimicrobials in Recife/PE

    Directory of Open Access Journals (Sweden)

    Eduardo Andrada Pessoa de Figueiredo

    2007-12-01

    OBJECTIVES: The frequency of multiple-antibiotic resistant bacteria has been increasing in recent years. Among the gram-negative bacteria Pseudomonas aeruginosa (P. aeruginosa shows a great propensity for the development of multidrug resistance mechanisms. The objective of this study was to identify the profile of susceptibility to antibiotics, the frequency of multidrug resistance and the cross-resistance between drugs of P. aeruginosa strains in two tertiary hospitals in Recife, Pernambuco. METHODS: The study was carried out between September 2004 and January 2006. The antimicrobial susceptibility testing was performed in 304 strains of P. aeruginosa by the disc diffusion method in accordance with National Committee for Clinical and Laboratory Standards (NCCLS guidelines. RESULTS: The most frequent materials were urine (26.7% and respiratory tract secretion (26.1% The antibiotics tested and their respective susceptibilities were as follows: piperacillin-tazobactam (66.2%; aztreonam (59.8%; amikacin (59.4%; meropenem (58.2%; imipenem (57.7%; ciprofloxacin (49.7%; gentamicin and cefepime (48.6%; ceftazidime (30% and cefotaxime (6.8%. A high prevalence of multi-resistance was detected. Half (49.7% the strains showed resistance to three or more antibiotics and 28% were resistant to six antimicrobials or more. Also, cross-resistance between the beta-lactams (carbapenems and piperacilin/tazobactam and aminoglicosides and quinolones was between 22.9% and 38.1%. These drugs are commonly combined in the treatment of severe infections caused by Pseudomonas, which reflects the difficulty in choosing the appropriate option for combination therapy. CONCLUSIONS: The frequency of multidrug-resistant strains of P. aeruginosa in this study was similar to other hospitals in Brazil and higher than in other countries. In order to reduce the frequency of these multiresistant clones, epidemiologic surveillance and the rational use of antibiotic protocols need to be urgently implemented.

  15. Emergence of Extensively Drug Resistant Tuberculosis

    Centers for Disease Control (CDC) Podcasts

    2007-03-01

    Extensively drug-resistant tuberculosis (XDR TB) outbreaks have been reported in South Africa, and strains have been identified on 6 continents. Dr. Peter Cegielski, team leader for drug-resistant TB with the Division of Tuberculosis Elimination at CDC, comments on a multinational team's report on this emerging global public health threat.  Created: 3/1/2007 by Emerging Infectious Diseases.   Date Released: 3/26/2007.

  16. HIV resistance testing and detected drug resistance in Europe

    DEFF Research Database (Denmark)

    Schultze, Anna; Phillips, Andrew N; Paredes, Roger

    2015-01-01

    to Southern Europe. CONCLUSIONS: Despite a concurrent decline in virological failure and testing, drug resistance was commonly detected. This suggests a selective approach to resistance testing. The regional differences identified indicate that policy aiming to minimize the emergence of resistance......OBJECTIVES: To describe regional differences and trends in resistance testing among individuals experiencing virological failure and the prevalence of detected resistance among those individuals who had a genotypic resistance test done following virological failure. DESIGN: Multinational cohort...... study. METHODS: Individuals in EuroSIDA with virological failure (>1 RNA measurement >500 on ART after >6 months on ART) after 1997 were included. Adjusted odds ratios (aORs) for resistance testing following virological failure and aORs for the detection of resistance among those who had a test were...

  17. Drug resistance in the mouse cancer clinic

    NARCIS (Netherlands)

    Rottenberg, Sven; Borst, Piet

    2012-01-01

    Drug resistance is one of the most pressing problems in treating cancer patients today. Local and regional disease can usually be adequately treated, but patients eventually die from distant metastases that have become resistant to all available chemotherapy. Although work on cultured tumor cell

  18. Malaria epidemic and drug resistance, Djibouti.

    Science.gov (United States)

    Rogier, Christophe; Pradines, Bruno; Bogreau, H; Koeck, Jean-Louis; Kamil, Mohamed-Ali; Mercereau-Puijalon, Odile

    2005-02-01

    Analysis of Plasmodium falciparum isolates collected before, during, and after a 1999 malaria epidemic in Djibouti shows that, despite a high prevalence of resistance to chloroquine, the epidemic cannot be attributed to a sudden increase in drug resistance of local parasite populations.

  19. Impact of treatment heterogeneity on drug resistance and supply chain costs.

    Science.gov (United States)

    Spiliotopoulou, Eirini; Boni, Maciej F; Yadav, Prashant

    2013-09-01

    The efficacy of scarce drugs for many infectious diseases is threatened by the emergence and spread of resistance. Multiple studies show that available drugs should be used in a socially optimal way to contain drug resistance. This paper studies the tradeoff between risk of drug resistance and operational costs when using multiple drugs for a specific disease. Using a model for disease transmission and resistance spread, we show that treatment with multiple drugs, on a population level, results in better resistance-related health outcomes, but more interestingly, the marginal benefit decreases as the number of drugs used increases. We compare this benefit with the corresponding change in procurement and safety stock holding costs that result from higher drug variety in the supply chain. Using a large-scale simulation based on malaria transmission dynamics, we show that disease prevalence seems to be a less important factor when deciding the optimal width of drug assortment, compared to the duration of one episode of the disease and the price of the drug(s) used. Our analysis shows that under a wide variety of scenarios for disease prevalence and drug cost, it is optimal to simultaneously deploy multiple drugs in the population. If the drug price is high, large volume purchasing discounts are available, and disease prevalence is high, it may be optimal to use only one drug. Our model lends insights to policy makers into the socially optimal size of drug assortment for a given context.

  20. Streptococcus pneumoniae Drugs Resistance in Acute Rhinosinusitis

    Directory of Open Access Journals (Sweden)

    Chong Jie Hao

    2016-03-01

    Full Text Available Background: Acute rhinosinusitis that usually caused by Streptococcus pneumoniae becomes the reason why patients seek for medical care. Drugs resistance in Streptococcus pneumoniae is increasing worldwide. This study was conducted to determine drugs resistance of Streptococcus pneumonia from acute rhinosinusitis in Dr. Hasan Sadikin General Hospital. Methods: A descriptive laboratory study was conducted in June–October 2014 at the Laboratory of Microbiology Faculty of Medicine Universitas Padjadjaran. The sample was taken using nasopharyngeal swabbing from 100 acute rhinosinusitis patients in Dr. Hasan Sadikin General Hospital and planted on tryptic soy agar containing 5% sheep blood and 5 μg/ml of gentamicin sulphate and then incubated in 5% CO2 incubator at 37°C for 24 hours. The identification of Streptococcus pneumonia was performed by optochin test. The susceptibility test against Streptococcus pneumoniae was done using disk diffusion method.The antibiotic disks were trimethoprim-sulfamethoxazole, oxacillin, levofloxacin, azithromycin, and doxycycline. Results: Out of 100 samples, 8 of them were tested positive for Streptococcus pneumoniae. Three of Streptococcus pneumoniae isolates died with unknown reason after it were stored at -80 .The drugs resistance test showed the resistance of Streptococcus pneumonia to oxacillin, azithromycin and trimethoprim were 6, whereas levofloxacin and doxycycline are 4. Conclusions: Streptococcus pneumonia drugs resistance in acute rhinosinusitis shows the resistance of Streptococcus pneumoniae to oxacillin, azithromycin and trimethoprim are 6, whereas the resistance to levofloxacin and doxycycline are 4.

  1. Antimicrobial Drug Resistance and Gonorrhea

    Centers for Disease Control (CDC) Podcasts

    2017-12-26

    Dr. Robert Kirkcaldy, a medical officer at CDC, discusses his article on antimicrobial resistance and gonorrhea.  Created: 12/26/2017 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 12/26/2017.

  2. Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

    International Nuclear Information System (INIS)

    Hembruff, Stacey L; Laberge, Monique L; Villeneuve, David J; Guo, Baoqing; Veitch, Zachary; Cecchetto, Melanie; Parissenti, Amadeo M

    2008-01-01

    Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7 DOX-2 ), epirubicin (MCF-7 EPI ), paclitaxel (MCF-7 TAX-2 ), or docetaxel (MCF-7 TXT ). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of

  3. Functional miRNAs in breast cancer drug resistance

    Directory of Open Access Journals (Sweden)

    Hu WZ

    2018-03-01

    Full Text Available Weizi Hu,1–3,* Chunli Tan,1–3,* Yunjie He,4 Guangqin Zhang,2 Yong Xu,3,5 Jinhai Tang1 1Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 3Nanjing Medical University Affiliated Cancer Hospital, 4The First Clinical School of Nanjing Medical University, 5Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: Owing to improved early surveillance and advanced therapy strategies, the current death rate due to breast cancer has decreased; nevertheless, drug resistance and relapse remain obstacles on the path to successful systematic treatment. Multiple mechanisms responsible for drug resistance have been elucidated, and miRNAs seem to play a major part in almost every aspect of cancer progression, including tumorigenesis, metastasis, and drug resistance. In recent years, exosomes have emerged as novel modes of intercellular signaling vehicles, initiating cell–cell communication through their fusion with target cell membranes, delivering functional molecules including miRNAs and proteins. This review particularly focuses on enumerating functional miRNAs involved in breast cancer drug resistance as well as their targets and related mechanisms. Subsequently, we discuss the prospects and challenges of miRNA function in drug resistance and highlight valuable approaches for the investigation of the role of exosomal miRNAs in breast cancer progression and drug resistance. Keywords: microRNA, exosome, breast cancer, drug resistance

  4. Radiosensitivity of drug-resistant human tumour xenografts

    International Nuclear Information System (INIS)

    Mattern, J.; Bak, M. Jr.; Volm, M.; Hoever, K.H.

    1989-01-01

    The radiosensitivity of three drug-resistant sublines of a human epidermoid lung carcinoma growing as xenografts in nude mice was investigated. Drug resistance to vincristine, actinomycin D and cisplatin was developed in vivo by repeated drug treatment. It was found that all three drug-resistant tumour lines were not cross-resistant to irradiation. (orig.) [de

  5. Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer

    International Nuclear Information System (INIS)

    Kangaspeska, Sara; Hultsch, Susanne; Jaiswal, Alok; Edgren, Henrik; Mpindi, John-Patrick; Eldfors, Samuli; Brück, Oscar; Aittokallio, Tero; Kallioniemi, Olli

    2016-01-01

    The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains. Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance. We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred. This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns. The online version of this article (doi:10.1186/s12885-016-2452-5) contains supplementary material, which is available to authorized users

  6. Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer.

    Science.gov (United States)

    Kangaspeska, Sara; Hultsch, Susanne; Jaiswal, Alok; Edgren, Henrik; Mpindi, John-Patrick; Eldfors, Samuli; Brück, Oscar; Aittokallio, Tero; Kallioniemi, Olli

    2016-07-04

    The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains. Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance. We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred. This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns.

  7. HIV Genetic Diversity and Drug Resistance

    Science.gov (United States)

    Santos, André F.; Soares, Marcelo A.

    2010-01-01

    Most of the current knowledge on antiretroviral (ARV) drug development and resistance is based on the study of subtype B of HIV-1, which only accounts for 10% of the worldwide HIV infections. Cumulative evidence has emerged that different HIV types, groups and subtypes harbor distinct biological properties, including the response and susceptibility to ARV. Recent laboratory and clinical data highlighting such disparities are summarized in this review. Variations in drug susceptibility, in the emergence and selection of specific drug resistance mutations, in viral replicative capacity and in the dynamics of resistance acquisition under ARV selective pressure are discussed. Clinical responses to ARV therapy and associated confounding factors are also analyzed in the context of infections by distinct HIV genetic variants. PMID:21994646

  8. Drug-resistant tuberculosis: emerging treatment options

    Directory of Open Access Journals (Sweden)

    Adhvaryu MR

    2011-12-01

    Full Text Available Meghna Adhvaryu1, Bhasker Vakharia21Department of Biotechnology, SRK Institute of Computer Education and Applied Sciences, 2R&D, Bhuma Research in Ayurvedic and Herbal Medicine, Surat, Gujarat, IndiaAbstract: Multidrug-resistant tuberculosis has emerged worldwide, with an increasing incidence due to failure of implementation of apparently effective first-line antituberculous therapy as well as primary infection with drug-resistant strains. Failure of current therapy is attributed to a long duration of treatment leading to nonadherence and irregular therapy, lack of patient education about the disease, poverty, irregular supply by care providers, drug–drug interactions in patients coinfected with human immunodeficiency virus (HIV, inadequate regulations causing market overlap and irresponsible drug usage in the private sector, and lack of research, with no addition of new drugs in the last four decades. Present standards of care for the treatment of drug-susceptible tuberculosis, multidrug-resistant tuberculosis, tuberculosis-HIV coinfection, and latent tuberculosis infection are all unsatisfactory. Since 2000, the World Health Organization (WHO has focused on drug development for tuberculosis, as well as research in all relevant aspects to discover new regimens by 2015 and to eliminate tuberculosis as a public health concern by 2050. As a result, some 20 promising compounds from 14 groups of drugs have been discovered. Twelve candidates from eight classes are currently being evaluated in clinical trials. Ongoing research should prioritize identification of novel targets and newer application of existing drugs, discovery of multitargeted drugs from natural compounds, strengthening host factors by immunopotentiation with herbal immunomodulators, as well as protective vaccines before and after exposure, consideration of surgical measures when indicated, development of tools for rapid diagnosis, early identification of resistant strains, and

  9. The Prevalence of acrA and acrB Genes Among Multiple-Drug Resistant Uropathogenic Escherichia coli Isolated From Patients With UTI in Milad Hospital, Tehran

    Directory of Open Access Journals (Sweden)

    Maleki

    2016-09-01

    Full Text Available Background Urinary tract infection (UTI is one of the most common infectious diseases and nosocomial infections worldwide, and uropathogenic Escherichia coli is the primary cause of UTI. Due to increased antibiotic resistance and the emergence of multidrug resistant (MDR UPEC clones, the treatment of UTI is difficult. The occurrence of MDR in E. coli has been attributed to the AcrAB-TolC complex of efflux pumps. Objectives The aim of this study was to complete a frequency evaluation of acrA and acrB genes among UPEC MDR strains isolated from patients with UTI who were admitted to Milad hospital in Tehran. Methods For 123 UPEC strains that were isolated and diagnosed from the urine samples of patients using biochemical tests, antibiotic susceptibility was carried out using the disc diffusion method according to CLSI guidelines. Isolates that were resistant to at least one antimicrobial agent in three or more of the categories were considered to be MDR. The presence and frequency of acrA and acrB genes was determined using PCR. Results The rates of antibiotic resistance to ampicillin, cefalotin, tetracycline, cefazolin, ceftriaxone, ceftizoxime, ceftazidime, ciprofloxacin, and cotrimoxazole were 82.9%, 78.1%, 61.1%, 49.5%, 38.2%, 30.2%, 26.1%, 42.2%, and 60.1%, respectively. The isolates were most sensitive to nitrofurantoin (95.9%, gentamicin (77.2%, and amikacin (71.5%. A total of 78% of the isolates were MDR. The frequency of the acrA gene was 82.90%, the acrB gene was 95.90% and acrA + acrB was 95.90%. There was no significant difference between acrA and acrB frequency relating to bacterial antibiotic resistance. Conclusions Our results showed that ways to control the treatment of UTI for the prevention of MDR occurrence should be sought. For a better study of efflux pumps, a comprehensive and detailed study regarding the presence of efflux pumps gees is required.

  10. Total hip prosthesis complication, periprosthetic infection with external fistulizing due to Enterobacter cloacae complex multiple drugs resistance: A clinical case report

    Directory of Open Access Journals (Sweden)

    V. Amorese

    2017-01-01

    Conclusion: The patient was hospitalized in our facility and 2 months later she underwent another operation to remove the antibiotic spacer and to place a new total hip arthroprosthesis. Multiple swabs showed the complete healing from the infection, which was confirmed a couple of months later.

  11. Economic implications of resistance to antimalarial drugs.

    Science.gov (United States)

    Phillips, M; Phillips-Howard, P A

    1996-09-01

    The widespread evolution of drug resistance in malarial parasites has seriously hampered efforts to control this debilitating disease. Chloroquine, the mainstay of malaria treatment for many decades, is now proving largely ineffective in many parts of the world, particularly against the most severe form of malaria--falciparum. Alternative drugs have been developed, but they are frequently less safe and are all between 50 and 700% more expensive than chloroquine. Choice of drug clearly has important budgetary implications and national malaria control programmes need to weigh up the costs and benefits in deciding whether to change to more effective but more expensive drugs. The growth in drug resistance also has implications for the choice of diagnostic tool. Clinical diagnosis of malaria is relatively cheap, but less specific than some technological approaches. As more expensive drugs are employed, the cost of wasted treatment on suspected cases who do not in fact have malaria rises and the more worthwhile it becomes to invest in more specific diagnostic techniques. This paper presents an economic framework for analysing the various malaria drug and diagnostic tool options available. It discusses the nature of the key factors that need to be considered when making choices of malaria treatment (including treatment costs, drug resistance, the costs of treatment failure and compliance) and diagnosis (including diagnosis cost and accuracy, and the often overlooked costs associated with delayed treatment), and uses some simple equations to illustrate the impact of these on the relative cost effectiveness of the alternatives being considered. On the basis of some simplifying assumptions and illustrative calculations, it appears that in many countries more effective drugs and more specific and rapid diagnostic approaches will be worth adopting even although they imply additional expense.

  12. Drug resistance patterns in pulmonary tuberculosis

    International Nuclear Information System (INIS)

    Khoharo, H.K.; Shaikh, I.A.

    2011-01-01

    Objective: To determine the resistance patterns of mycobacterium tuberculosis (MTB) isolates among category I and II patients of pulmonary tuberculosis. Methods: This cross sectional study was conducted at the Department of Medicine, Liaquat University of Medical and Health Sciences Jamshoro, from November 2008 to September 2009. Patients were divided into category I and II. The sputa were collected, stained with Ziehl-Nielsen (Z-N) staining and ultimately inoculated on Lowenstein-Jensen (L-J) media for six weeks. Out of 890 pulmonary tuberculosis (PTB) patients, the growth was obtained in 285 cases. The Drug sensitivity testing (DST) for Isoniazid (INH), Rifampicin (RIF), Ethambutol (EMB) Pyrazinamide (PZA) and Streptomycin (SM) were performed. The data was analyzed on SPSS 10.0. A p-value of <0.05 was taken as significant. Result: Out of 285 cases, 176 (61.75%) were male and 109 (38.24%) female. The mean age was 37 +- 19.90 years. The DST showed drug sensitive and drug resistant isolates in 80 (28.05%) and 205 (71.92%) cases respectively (p=0.001). The drug resistant tuberculosis (DR-TB) rates for individual drugs; INH, RIF, EMB, PZA and SM were 51,22%, 15.4%, 13.33%, 9%12, and 3.85% respectively (p=0.03). The MDR-TB isolates were detected in 120 (42.10%) cases, including 5 (5.88%) in category I and 115 (57.50%) in category II patients (p=0.0001). Conclusion: Drug resistant and multidrug resistant tuberculosis was observed mainly in category II patients. However, primary MDR was also observed in category I patients and reflects dissemination of MDR cases within the community. (author)

  13. characterization of drug resistant pseudomonas aeruginosa and ...

    African Journals Online (AJOL)

    Abstract: Lizards as well as some other reptiles have been known to carry pathogenic bacteria organisms as well as drug resistant pathogens. Despite the fact that they remain asymptomatic in many cases, they nevertheless play significant roles in the epidemiology of these pathogens through their dissemination to the ...

  14. Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus.

    Science.gov (United States)

    Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Conery, Annie L; Kim, Wooseong; Jayamani, Elamparithi; Kwon, Bumsup; Ausubel, Frederick M; Mylonakis, Eleftherios

    2015-01-01

    Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA) approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC): 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs). The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively), but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections.

  15. Population mobility, globalization, and antimicrobial drug resistance.

    Science.gov (United States)

    MacPherson, Douglas W; Gushulak, Brian D; Baine, William B; Bala, Shukal; Gubbins, Paul O; Holtom, Paul; Segarra-Newnham, Marisel

    2009-11-01

    Population mobility is a main factor in globalization of public health threats and risks, specifically distribution of antimicrobial drug-resistant organisms. Drug resistance is a major risk in healthcare settings and is emerging as a problem in community-acquired infections. Traditional health policy approaches have focused on diseases of global public health significance such as tuberculosis, yellow fever, and cholera; however, new diseases and resistant organisms challenge existing approaches. Clinical implications and health policy challenges associated with movement of persons across barriers permeable to products, pathogens, and toxins (e.g., geopolitical borders, patient care environments) are complex. Outcomes are complicated by high numbers of persons who move across disparate and diverse settings of disease threat and risk. Existing policies and processes lack design and capacity to prevent or mitigate adverse health outcomes. We propose an approach to global public health risk management that integrates population factors with effective and timely application of policies and processes.

  16. Drug resistance in Mexico: results from the National Survey on Drug-Resistant Tuberculosis.

    Science.gov (United States)

    Bojorquez-Chapela, I; Bäcker, C E; Orejel, I; López, A; Díaz-Quiñonez, A; Hernández-Serrato, M I; Balandrano, S; Romero, M; Téllez-Rojo Solís, M M; Castellanos, M; Alpuche, C; Hernández-Ávila, M; López-Gatell, H

    2013-04-01

    To present estimations obtained from a population-level survey conducted in Mexico of prevalence rates of mono-, poly- and multidrug-resistant strains among newly diagnosed cases of pulmonary tuberculosis (TB), as well as the main factors associated with multidrug resistance (combined resistance to isoniazid and rifampicin). Study data came from the National Survey on TB Drug Resistance (ENTB-2008), a nationally representative survey conducted during 2008-2009 in nine states with a stratified cluster sampling design. Samples were obtained for all newly diagnosed cases of pulmonary TB in selected sites. Drug susceptibility testing (DST) was performed for anti-tuberculosis drugs. DST results were obtained for 75% of the cases. Of these, 82.2% (95%CI 79.5-84.7) were susceptible to all drugs. The prevalence of multidrug-resistant TB (MDR-TB) was estimated at 2.8% (95%CI 1.9-4.0). MDR-TB was associated with previous treatment (OR 3.3, 95%CI 1.1-9.4). The prevalence of drug resistance is relatively low in Mexico. ENTB-2008 can be used as a baseline for future follow-up of drug resistance.

  17. Determination of the Antimicrobial Effects of Hydro-Alcoholic Extract of Cannabis Sativa on Multiple Drug Resistant Bacteria Isolated from Nosocomial Infections

    Directory of Open Access Journals (Sweden)

    Hossein Sarmadyan

    2014-02-01

    Full Text Available Background: The science of identification and employment of medicinal plants dates back to the early days of man on earth. Cannabis (hashish is the most common illegal substance used in the United States and was subjected to extensive research as a powerful local disinfecting agent for mouth cavity and skin and an anti-tubercular agent in 1950. Methods: Clinical strains were isolated from hospitalized patients in Vali-e-Asr Hospital of Arak. The hydro-alcoholic extract of cannabis (5 g was prepared following liquid-liquid method and drying in 45˚C. The antimicrobial properties of the extract were determined through disk diffusion and determination of MIC (Minimum Inhibitory Concentration. Results: First, the sensitivity of bacteria was detected based on disk diffusion method and the zone of inhibition was obtained for MRSA (12 mm, S.aureus 25923 (14 mm, E. coli ESBL+: (10 mm, and Klebsiella pneumoniae (7 mm. Disk diffusion for Pseudomonas and Acinetobacter demonstrated no inhibitory zones. Through Broth dilution method, MIC of cannabis extract on the bacteria was determined: E.coli 25922: 50µg/ml, E.coli ESBL+:100 µg/ml, S.aureus 25923:25 µg/ml, MRSA: 50 µg/ml, Pseudomona aeroginosaESBL+> 100 µg/ml, Pseudomonas: 100 µg/ml, Klebsiella pneumoniae: 100 µg/ml, and Acinetobacter baumannii> 1000. Conclusion: The maximum anti-microbial effect of the hydro-alcoholic extract of cannabis was seen for gram positive cocci, especially S. aureus, whereas non-fermentative gram negatives presented resistance to the extract. This extract had intermediate effect on Enterobacteriacae family. Cannabis components extracted through chemical analysis can perhaps be effective in treatment of nosocomial infections.

  18. Supermolecular drug challenge to overcome drug resistance in cancer cells.

    Science.gov (United States)

    Onishi, Yasuhiko; Eshita, Yuki; Ji, Rui-Cheng; Kobayashi, Takashi; Onishi, Masayasu; Mizuno, Masaaki; Yoshida, Jun; Kubota, Naoji

    2018-06-04

    Overcoming multidrug resistance (MDR) of cancer cells can be accomplished using drug delivery systems in large-molecular-weight ATP-binding cassette transporters before entry into phagolysosomes and by particle-cell-surface interactions. However, these hypotheses do not address the intratumoral heterogeneity in cancer. Anti-MDR must be related to alterations of drug targets, expression of detoxification, as well as altered proliferation. In this study, it is shown that the excellent efficacy and sustainability of anti-MDR is due to a stable ES complex because of the allosteric facilities of artificial enzymes when they are used as supramolecular complexes. The allosteric effect of supermolecular drugs can be explained by the induced-fit model and can provide stable feedback control systems through the loop transfer function of the Hill equation. Copyright © 2018 Elsevier Ltd. All rights reserved.

  19. Antituberculosis drug resistance patterns in adults with tuberculous meningitis

    DEFF Research Database (Denmark)

    Senbayrak, Seniha; Ozkutuk, Nuri; Erdem, Hakan

    2015-01-01

    BACKGROUND: Tuberculous meningitis (TBM) caused by Mycobacterium tuberculosis resistant to antituberculosis drugs is an increasingly common clinical problem. This study aimed to evaluate drug resistance profiles of TBM isolates in adult patients in nine European countries involving 32 centers...

  20. Telomerase and drug resistance in cancer

    OpenAIRE

    Lipinska, Natalia; Romaniuk, Aleksandra; Paszel-Jaworska, Anna; Toton, Ewa; Kopczynski, Przemyslaw; Rubis, Blazej

    2017-01-01

    It is well known that a decreased expression or inhibited activity of telomerase in cancer cells is accompanied by an increased sensitivity to some drugs (e.g., doxorubicin, cisplatin, or 5-fluorouracil). However, the mechanism of the resistance resulting from telomerase alteration remains elusive. There are theories claiming that it might be associated with telomere shortening, genome instability, hTERT translocation, mitochondria functioning modulation, or even alterations in ABC family gen...

  1. Multi-drug resistant Ewingella Americana

    International Nuclear Information System (INIS)

    Bukhari, Syed Z.; Ashshi, Ahmad M.; Hussain, Waleed M.; Fatani, Mohammad I.

    2008-01-01

    We report a case of pneumonia due to multi-drug resistant Ewingella Americana in a young patient admitted in the Intensive Care Unit of Hera General Hospital, Makkah, Saudi Arabia with severe head injury in a road traffic accident. He was an Indonesian pilgrim who had traveled to the Kingdom of Saudi Arabia to perform Hajj in December 2007. Ewingella Americana was identified to be the pathogen of pneumonia with clinical signs and symptoms along with positive radiological findings. (author)

  2. Emerging drugs for primary progressive multiple sclerosis.

    Science.gov (United States)

    Narayan, Ram Narendra; Forsthuber, Thomas; Stüve, Olaf

    2018-04-24

    The identification of effective therapies for progressive forms of multiple sclerosis (MS) has remains a priority and challenge for the global MS community. Despite a few proposed mechanisms, a more complete understanding of the mechanisms involved in the pathogenesis of these MS phenotypes, animal models that incorporate these pathogenic characteristics, novel trial designs, drug repurposing strategies, and new models of collaboration between clinical and basic science personnel may be required in identifying effective therapies. Areas covered: Here, we review the current knowledge on putative pathogenic mechanisms in primary progressive MS (PPMS). Also, the rationale and outcomes of key phase II or III trial initiatives in PPMS are summarized. Future perspectives are outlined. Expert opinion: The recent approval of ocrelizumab is a major milestone forward in the therapy of PPMS. One reason for success of this drug is appropriate patient selection. The ultimate goal in PPMS therapy should be the reversal of disability, and the arrest of disease progression. Our current understanding of PPMS suggests that a combination of immune-modulatory, myelin-restorative, and neuro-regenerative therapies particularly early in the disease course would be a reasonable strategy. Finally, selection of appropriate patients, selection of appropriate outcomes and monitoring therapy is again crucial for success of therapeutic strategies.

  3. Neurological autoantibodies in drug-resistant epilepsy of unknown cause.

    Science.gov (United States)

    Tecellioglu, Mehmet; Kamisli, Ozden; Kamisli, Suat; Yucel, Fatma Ebru; Ozcan, Cemal

    2018-03-09

    Autoimmune epilepsy is a rarely diagnosed condition. Recognition of the underlying autoimmune condition is important, as these patients can be resistant to antiepileptic drugs. To determine the autoimmune and oncological antibodies in adult drug-resistant epilepsy of unknown cause and identify the clinical, radiological, and EEG findings associated with these antibodies according to data in the literature. Eighty-two patients with drug-resistant epilepsy of unknown cause were prospectively identified. Clinical features were recorded. The levels of anti-voltage-gated potassium channel complex (anti-VGKCc), anti-thyroid peroxidase (anti-TPO), anti-nuclear antibody (ANA), anti-glutamic acid decarboxylase (anti-GAD), anti-phospholipid IgG and IgM, anti-cardiolipin IgG and IgM, and onconeural antibodies were determined. Serum antibody positivity suggesting the potential role of autoimmunity in the aetiology was present in 17 patients with resistant epilepsy (22.0%). Multiple antibodies were found in two patients (2.6%). One of these patients (1.3%) had anti-VGKCc and ANA, whereas another (1.3%) had anti-VGKCc and anti-TPO. A single antibody was present in 15 patients (19.5%). Of the 77 patients finally included in the study, 4 had anti-TPO (5.2%), 1 had anti-GAD (1.3%), 4 had anti-VGKCc (5.2%) 8 had ANA (10.3%), and 2 had onconeural antibodies (2.6%) (1 patient had anti-Yo and 1 had anti-MA2/TA). The other antibodies investigated were not detected. EEG abnormality (focal), focal seizure incidence, and frequent seizures were more common in antibody-positive patients. Autoimmune factors may be aetiologically relevant in patients with drug-resistant epilepsy of unknown cause, especially if focal seizures are present together with focal EEG abnormality and frequent seizures.

  4. Malaria medicines to address drug resistance and support malaria elimination efforts.

    Science.gov (United States)

    Achan, Jane; Mwesigwa, Julia; Edwin, Chinagozi Precious; D'alessandro, Umberto

    2018-01-01

    Antimalarial drugs are essential weapons to fight malaria and have been used effectively since the 17 th century. However, P.falciparum resistance has been reported to almost all available antimalarial drugs, including artemisinin derivatives, raising concerns that this could jeopardize malaria elimination. Areas covered: In this article, we present a historical perspective of antimalarial drug resistance, review current evidence of resistance to available antimalarial drugs and discuss possible mitigating strategies to address this challenge. Expert commentary: The historical approach to drug resistance has been to change the national treatment policy to an alternative treatment. However, alternatives to artemisinin-based combination treatment are currently extremely limited. Innovative approaches utilizing available schizonticidal drugs such as triple combination therapies or multiple first line treatments could delay the emergence and spread of drug resistance. Transmission blocking drugs like primaquine may play a key role if given to a substantial proportion of malaria infected persons. Deploying antimalarial medicines in mass drug administration or mass screening and treatment campaigns could also contribute to containment efforts by eliminating resistant parasites in some settings. Ultimately, response to drug resistance should also include further investment in the development of new antimalarial drugs.

  5. Active control of multiple resistive wall modes

    International Nuclear Information System (INIS)

    Brunsell, P. R.; Yadikin, D.; Gregoratto, D.; Paccagnella, R.; Liu, Y. Q.; Bolzonella, T.; Cecconello, M.; Drake, J. R.; Kuldkepp, M.; Manduchi, G.; Marchiori, G.; Marrelli, L.; Partin, P.; Menmuir, S.; Ortolani, S.; Rachlew, E.; Spizzo, S.; Zanca, P.

    2005-01-01

    Active magnetic feedback suppression of resistive wall modes is of common interest for several fusion concepts relying on close conducting walls for stabilization of ideal magnetohydrodynamic (MHD) modes. In the advanced tokamak without plasma rotation the kink mode is not completely stabilized, but rather converted into an unstable resistive wall mode (RWM) with a growth time comparable to the wall magnetic flux penetration time. The reversed field pinch (RFP) is similar to the advanced tokamak in the sense that it uses a conducting wall for kink mode stabilization. Also both configurations are susceptible to resonant field error amplification of marginally stable modes. However, the RFP has a different RWM spectrum and, in general, a range of modes is unstable. Hence, the requirement for simultaneous feedback stabilization of multiple independent RWMs arises for the RFP configuration. Recent experiments on RWM feedback stabilization, performed in the RFP device EXTRAP T2R [1], are presented. The experimental results obtained are the first demonstration of simultaneous feedback control of multiple independent RWMs [2]. Using an array of active magnetic coils, a reproducible suppression of several RWMs is achieved for the duration of the discharge, 3-5 wall times, through feedback action. An array with 64 active saddle coils at 4 poloidal times 16 toroidal positions is used. The important issues of side band generation by the active coil array and the accompanying coupling of different unstable modes through the feedback action are addressed in this study. Open loop control experiments have been carried out to quantitatively study resonant field error amplification. (Author)

  6. Detection of low frequency multi-drug resistance and novel putative maribavir resistance in immunocompromised paediatric patients with cytomegalovirus

    Directory of Open Access Journals (Sweden)

    Charlotte Jane Houldcroft

    2016-09-01

    Full Text Available Human cytomegalovirus (HCMV is a significant pathogen in immunocompromised individuals, with the potential to cause fatal pneumonitis and colitis, as well as increasing the risk of organ rejection in transplant patients. With the advent of new anti-HCMV drugs there is therefore considerable interest in using virus sequence data to monitor emerging resistance to antiviral drugs in HCMV viraemia and disease, including the identification of putative new mutations. We used target-enrichment to deep sequence HCMV DNA from 11 immunosuppressed paediatric patients receiving single or combination anti-HCMV treatment, serially sampled over 1-27 weeks. Changes in consensus sequence and resistance mutations were analysed for three ORFs targeted by anti-HCMV drugs and the frequencies of drug resistance mutations monitored. Targeted-enriched sequencing of clinical material detected mutations occurring at frequencies of 2%. Seven patients showed no evidence of drug resistance mutations. Four patients developed drug resistance mutations a mean of 16 weeks after starting treatment. In two patients, multiple resistance mutations accumulated at frequencies of 20% or less, including putative maribavir and ganciclovir resistance mutations P522Q (UL54 and C480F (UL97. In one patient, resistance was detected 14 days earlier than by PCR. Phylogenetic analysis suggested recombination or superinfection in one patient. Deep sequencing of HCMV enriched from clinical samples excluded resistance in 7 of eleven subjects and identified resistance mutations earlier than conventional PCR-based resistance testing in 2 patients. Detection of multiple low level resistance mutations was associated with poor outcome.

  7. Gene expression analysis of two extensively drug-resistant tuberculosis isolates show that two-component response systems enhance drug resistance.

    Science.gov (United States)

    Yu, Guohua; Cui, Zhenling; Sun, Xian; Peng, Jinfu; Jiang, Jun; Wu, Wei; Huang, Wenhua; Chu, Kaili; Zhang, Lu; Ge, Baoxue; Li, Yao

    2015-05-01

    Global analysis of expression profiles using DNA microarrays was performed between a reference strain H37Rv and two clinical extensively drug-resistant isolates in response to three anti-tuberculosis drug exposures (isoniazid, capreomycin, and rifampicin). A deep analysis was then conducted using a combination of genome sequences of the resistant isolates, resistance information, and related public microarray data. Certain known resistance-associated gene sets were significantly overrepresented in upregulated genes in the resistant isolates relative to that observed in H37Rv, which suggested a link between resistance and expression levels of particular genes. In addition, isoniazid and capreomycin response genes, but not rifampicin, either obtained from published works or our data, were highly consistent with the differentially expressed genes of resistant isolates compared to those of H37Rv, indicating a strong association between drug resistance of the isolates and genes differentially regulated by isoniazid and capreomycin exposures. Based on these results, 92 genes of the studied isolates were identified as candidate resistance genes, 10 of which are known resistance-related genes. Regulatory network analysis of candidate resistance genes using published networks and literature mining showed that three two-component regulatory systems and regulator CRP play significant roles in the resistance of the isolates by mediating the production of essential envelope components. Finally, drug sensitivity testing indicated strong correlations between expression levels of these regulatory genes and sensitivity to multiple anti-tuberculosis drugs in Mycobacterium tuberculosis. These findings may provide novel insights into the mechanism underlying the emergence and development of drug resistance in resistant tuberculosis isolates and useful clues for further studies on this issue. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Frequency of Natural Resistance within NS5a Replication Complex Domain in Hepatitis C Genotypes 1a, 1b: Possible Implication of Subtype-Specific Resistance Selection in Multiple Direct Acting Antivirals Drugs Combination Treatment

    Directory of Open Access Journals (Sweden)

    Sabrina Bagaglio

    2016-03-01

    Full Text Available Different HCV subtypes may naturally harbor different resistance selection to anti-NS5a inhibitors. 2761 sequences retrieved from the Los Alamos HCV database were analyzed in the NS5a domain 1, the target of NS5a inhibitors. The NS5a resistance-associated polymorphisms (RAPs were more frequently detected in HCV G1b compared to G1a. The prevalence of polymorphisms associated with cross-resistance to compounds in clinical use (daclatasvir, DCV, ledipasvir, LDV, ombitasvir, and OMV or scheduled to come into clinical use in the near future (IDX719, elbasvir, and ELV was higher in G1b compared to G1a (37/1552 (2.4% in 1b sequences and 15/1209 (1.2% in 1a isolates, p = 0.040. Interestingly, on the basis of the genotype-specific resistance pattern, 95 (6.1% G1b sequences had L31M RAP to DCV/IDX719, while 6 sequences of G1a (0.5% harbored L31M RAP, conferring resistance to DCV/LDV/IDX719/ELV (p < 0.0001. Finally, 28 (2.3% G1a and none of G1b isolates harbored M28V RAP to OMV (p < 0.0001. In conclusion, the pattern of subtype-specific resistance selection in the naturally occurring strains may guide the treatment option in association with direct acting antivirals (DAAs targeting different regions, particularly in patients that are difficult to cure, such as those with advanced liver disease or individuals who have failed previous DAAs.

  9. Treatment results of patients with multiple and extensive drug resistance registered in 2012 in the Russian Federation and in the world

    Directory of Open Access Journals (Sweden)

    S. A. Sterlikov

    2016-01-01

    Full Text Available The chemotherapy results have been analyzed in tuberculosis patients suffering from multiple drug resistance registered for treatment in the Russian Federation in 2011-2012 compared with the treatment outcomes of MDR patients registered for treatment in the world, BRICS and countries of the former Soviet Union in 2011. Treatment outcomes of XDR TB patients have been analyzed for the first time. Chemotherapy efficiency in MDR TB patients in the Russian Federation in the cohort of 2011 made 37.1%, and in the cohort of 2012 made 39.1%, which significantly lower than in the world in general (47.5%, in BRICS and countries of the former Soviet Union; this low treatment efficiency is mostly due to treatment failures (18.3% and those died (19.1%. The treatment efficiency of XDR TB patients registered for treatment in the Russian Federation in 2012 made 26.2% versus 22.0% in the cohort of 2011. Considering the significant financial costs spent on the treatment, the chemotherapy efficiency of M/XDR TB patients in the Russian Federation is too low to improve the epidemic situation and some additional measures are to be taken for its improvement.

  10. Prediction of resistance development against drug combinations by collateral responses to component drugs

    DEFF Research Database (Denmark)

    Munck, Christian; Gumpert, Heidi; Nilsson Wallin, Annika

    2014-01-01

    the genomes of all evolved E. coli lineages, we identified the mutational events that drive the differences in drug resistance levels and found that the degree of resistance development against drug combinations can be understood in terms of collateral sensitivity and resistance that occurred during...... adaptation to the component drugs. Then, using engineered E. coli strains, we confirmed that drug resistance mutations that imposed collateral sensitivity were suppressed in a drug pair growth environment. These results provide a framework for rationally selecting drug combinations that limit resistance......Resistance arises quickly during chemotherapeutic selection and is particularly problematic during long-term treatment regimens such as those for tuberculosis, HIV infections, or cancer. Although drug combination therapy reduces the evolution of drug resistance, drug pairs vary in their ability...

  11. HIV protease drug resistance and its impact on inhibitor design.

    Science.gov (United States)

    Ala, P J; Rodgers, J D; Chang, C H

    1999-07-01

    The primary cause of resistance to the currently available HIV protease inhibitors is the accumulation of multiple mutations in the viral protease. So far more than 20 substitutions have been observed in the active site, dimer interface, surface loops and flaps of the homodimer. While many mutations reduce the protease's affinity for inhibitors, others appear to enhance its catalytic efficiency. This high degree of genetic flexibility has made the protease an elusive drug target. The design of the next generation of HIV protease inhibitors will be discussed in light of the current structural information.

  12. Distribution of multiple antibiotic resistant Vibrio spp across Palk Bay

    Digital Repository Service at National Institute of Oceanography (India)

    Sneha, K.G.; Anas, A.; Jayalakshmy, K.V.; Jasmin, C.; VipinDas, P.V.; Pai, S.S.; Pappu, S.; Nair, M.; Muraleedharan, K.R.; Sudheesh, K.; Nair, S.

    Presence of multiple antibiotic resistant microorganisms in marine systems is increasingly a focus of concern as they pose potential health risk to humans and animals. The present study reports the distribution, diversity, antibiotic resistance...

  13. Predicted levels of HIV drug resistance

    DEFF Research Database (Denmark)

    Cambiano, Valentina; Bertagnolio, Silvia; Jordan, Michael R

    2014-01-01

    -term effects. METHODS: The previously validated HIV Synthesis model was calibrated to South Africa. Resistance was modeled at the level of single mutations, transmission potential, persistence, and effect on drug activity. RESULTS: We estimate 652 000 people (90% uncertainty range: 543 000-744 000) are living...... are maintained, in 20 years' time HIV incidence is projected to have declined by 22% (95% confidence interval, CI -23 to -21%), and the number of people carrying NNRTI resistance to be 2.9-fold higher. If enhancements in diagnosis and retention in care occur, and ART is initiated at CD4 cell count less than 500......  cells/μl, HIV incidence is projected to decline by 36% (95% CI: -37 to -36%) and the number of people with NNRTI resistance to be 4.1-fold higher than currently. Prevalence of people with viral load more than 500  copies/ml carrying NRMV is not projected to differ markedly according to future ART...

  14. Young Women's Experiences of Resisting Invitations to Use Illicit Drugs

    Science.gov (United States)

    Koehn, Corinne V.; O'Neill, Linda K.

    2011-01-01

    Ten young women were interviewed regarding their experiences of resisting invitations to use illicit drugs. Hermeneutic phenomenology was used to gather and analyze information. One key theme was the motivations that inspired women to refuse drug offers. Young women resisted drug invitations because of their desires to be authentic, protect their…

  15. Prevalence of drug resistant tuberculosis in Arsi Zone, Ethiopia ...

    African Journals Online (AJOL)

    Background: Wide spread of occurrence of multi-drug resistance tuberculosis is becoming a major challenge to effective tuberculosis control. Thus, it is imperative to monitor the sensitivity of anti-TB drugs regularly. Objective: To determine the prevalence resistance to anti-TB drugs in a well established control program area ...

  16. GEAR: A database of Genomic Elements Associated with drug Resistance

    Science.gov (United States)

    Wang, Yin-Ying; Chen, Wei-Hua; Xiao, Pei-Pei; Xie, Wen-Bin; Luo, Qibin; Bork, Peer; Zhao, Xing-Ming

    2017-01-01

    Drug resistance is becoming a serious problem that leads to the failure of standard treatments, which is generally developed because of genetic mutations of certain molecules. Here, we present GEAR (A database of Genomic Elements Associated with drug Resistance) that aims to provide comprehensive information about genomic elements (including genes, single-nucleotide polymorphisms and microRNAs) that are responsible for drug resistance. Right now, GEAR contains 1631 associations between 201 human drugs and 758 genes, 106 associations between 29 human drugs and 66 miRNAs, and 44 associations between 17 human drugs and 22 SNPs. These relationships are firstly extracted from primary literature with text mining and then manually curated. The drug resistome deposited in GEAR provides insights into the genetic factors underlying drug resistance. In addition, new indications and potential drug combinations can be identified based on the resistome. The GEAR database can be freely accessed through http://gear.comp-sysbio.org. PMID:28294141

  17. A Structural View on Medicinal Chemistry Strategies against Drug Resistance.

    Science.gov (United States)

    Agnello, Stefano; Brand, Michael; Chellat, Mathieu F; Gazzola, Silvia; Riedl, Rainer

    2018-05-30

    The natural phenomenon of drug resistance represents a generic impairment that hampers the benefits of drugs in all major clinical indications. Antibacterials and antifungals are affected as well as compounds for the treatment of cancer, viral infections or parasitic diseases. Despite the very diverse set of biological targets and organisms involved in the development of drug resistance, underlying molecular processes have been identified to understand the emergence of resistance and to overcome this detrimental mechanism. Detailed structural information of the root causes for drug resistance is nowadays frequently available to design next generation drugs anticipated to suffer less from resistance. This knowledge-based approach is a prerequisite in the fight against the inevitable occurrence of drug resistance to secure the achievements of medicinal chemistry in the future. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Fluorometric assay for phenotypic differentiation of drug-resistant HIV mutants

    OpenAIRE

    Zhu, Qinchang; Yu, Zhiqiang; Kabashima, Tsutomu; Yin, Sheng; Dragusha, Shpend; El-Mahdy, Ahmed F. M.; Ejupi, Valon; Shibata, Takayuki; Kai, Masaaki

    2015-01-01

    Convenient drug-resistance testing of viral mutants is indispensable to effective treatment of viral infection. We developed a novel fluorometric assay for phenotypic differentiation of drug-resistant mutants of human immunodeficiency virus-I protease (HIV-PR) which uses enzymatic and peptide-specific fluorescence (FL) reactions and high-performance liquid chromatography (HPLC) of three HIV-PR substrates. This assay protocol enables use of non-purified enzyme sources and multiple substrates f...

  19. 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

  20. Multi-drug resistance and molecular pattern of erythromycin and ...

    African Journals Online (AJOL)

    The appearance and dissemination of penicillin resistant and macrolide resistant Streptococcus pneumoniae strains has caused increasing concern worldwide. The aim of this study was to survey drug resistance and genetic characteristics of macrolide and penicillin resistance in S. pneumoniae. This is a cross-sectional ...

  1. Engineered reversal of drug resistance in cancer cells--metastases suppressor factors as change agents.

    Science.gov (United States)

    Yadav, Vinod Kumar; Kumar, Akinchan; Mann, Anita; Aggarwal, Suruchi; Kumar, Maneesh; Roy, Sumitabho Deb; Pore, Subrata Kumar; Banerjee, Rajkumar; Mahesh Kumar, Jerald; Thakur, Ram Krishna; Chowdhury, Shantanu

    2014-01-01

    Building molecular correlates of drug resistance in cancer and exploiting them for therapeutic intervention remains a pressing clinical need. To identify factors that impact drug resistance herein we built a model that couples inherent cell-based response toward drugs with transcriptomes of resistant/sensitive cells. To test this model, we focused on a group of genes called metastasis suppressor genes (MSGs) that influence aggressiveness and metastatic potential of cancers. Interestingly, modeling of 84 000 drug response transcriptome combinations predicted multiple MSGs to be associated with resistance of different cell types and drugs. As a case study, on inducing MSG levels in a drug resistant breast cancer line resistance to anticancer drugs caerulomycin, camptothecin and topotecan decreased by more than 50-60%, in both culture conditions and also in tumors generated in mice, in contrast to control un-induced cells. To our knowledge, this is the first demonstration of engineered reversal of drug resistance in cancer cells based on a model that exploits inherent cellular response profiles.

  2. Induced multiple disease resistance in wheat

    International Nuclear Information System (INIS)

    Borojevic, K.; Worland, A.J.

    1990-01-01

    Full text: The existence of genes suppressing resistance to leaf rust, stem rust and yellow rust in hexaploid wheat has been suggested. If such genes are deleted or inactivated, a more resistant variety may be obtained. In mutant lines of the wheat variety San Pastore, selected after treatment with 20,000 rad of gamma-rays, resistance to leaf rust, yellow rust, stem rust, and to some extent to Erysiphe graminis was determined. The mutants responded to infection by producing necrotic flecks in the presence of high level of disease inoculum. Similar flecks develop under stress condition. It is likely that the mother variety San Pastore carries genes for resistance which are masked by suppressor genes. Irradiation inactivates suppressors so that resistance genes which were previously masked are expressed. The first results of monosomic analysis indicate that chromosomes of groups 4 and 5 or possibly 7 may be critical for expression of resistance in the mutant lines. (author)

  3. Effect of radiation decontamination on drug-resistant bacteria

    International Nuclear Information System (INIS)

    Ito, Hitoshi

    2006-01-01

    More than 80% of food poisoning bacteria such as Salmonella are reported as antibiotic-resistant to at least one type antibiotic, and more than 50% as resistant to two or more. For the decontamination of food poisoning bacteria in foods, radiation resistibility on drug-resistant bacteria were investigated compared with drug-sensitive bacteria. Possibility on induction of drug-resistant mutation by radiation treatment was also investigated. For these studies, type strains of Escherichia coli S2, Salmonella enteritidis YK-2 and Staphylococcus aureus H12 were used to induce drug-resistant strains with penicillin G. From the study of radiation sensitivity on the drug-resistant strain induced from E. coli S2, D 10 value was obtained to be 0.20 kGy compared with 0.25 kGy at parent strain. On S. enteritidis YK-2, D 10 value was obtained to be 0.14 kGy at drug-resistant strain compared with 0.16 kGy at parent strain. D 10 value was also obtained to be 0.15 kGy at drug-resistant strain compared with 0.21 kGy at parent strain of St. aureus H12. Many isolates of E. coli 157:H7 or other type of E. coli from meats such as beef were resistant to penicillin G, and looked to be no relationship on radiation resistivities between drug-resistant strains and sensitive strains. On the study of radiation sensitivity on E. coli S2 at plate agars containing antibiotics, higher survival fractions were obtained at higher doses compared with normal plate agar. The reason of higher survival fractions at higher doses on plate agar containing antibiotics should be recovery of high rate of injured cells by the relay of cell division, and drug-resistant strains by mutation are hardly induced by irradiation. (author)

  4. Multiple antibiotics resistant among environmental isolates of ...

    African Journals Online (AJOL)

    In this study we assessed the functionality of integrons, melanin-like pigment and biofilm formation on multidrug resistance among environmental isolates of Stenotrophomonas maltophilia. Marked resistances were noted against aztreonam (60%), cefepime (68%), ceftazidime (77%), ciprofloxacin (72%), gentamicin (65%), ...

  5. Distribution of red blood cell antigens in drug-resistant and drug ...

    African Journals Online (AJOL)

    sofo

    Frequency distribution of ABO, Rh-Hr, MN, Kell blood group system antigens were studied in 277 TB patients (151-drug-sensitive and 126 drug-resistant) of pulmonary tuberculosis to know whether there was any association between them, and also between drug resistance and sensitiveness. They were compared with 485 ...

  6. Multi-drug resistant tuberculosis in Tanzania: Initial description of ...

    African Journals Online (AJOL)

    Background: Drug resistant Tuberculosis is well documented worldwide and is associated with increasing morbidity and mortality complicating Tuberculosis control with increasing costs of managing the disease. Broad. Objective: To describe clinical and laboratory characteristics of multi-drug resistant Tuberculosis ...

  7. Drug-resistance in chronic tuberculosis cases in Southern Nigeria ...

    African Journals Online (AJOL)

    Nigeria has a high burden of tuberculosis but the drug resistant situationwas previously unknown. This report evaluates the firstline drug resistance and associated factors among chronic tuberculosis cases from the tuberculosis control programme in South south and South east zones ofNigeria. Descriptive study of chronic ...

  8. Tuberculosis drug resistance in the Western Cape | Weyer | South ...

    African Journals Online (AJOL)

    Objectives: Drug resistance is a serious problem in the treatment of tuberculosis and a threat to successful tuberculosis control programmes. Local health workers have expressed concern that the increasing tuberculosis epidemic in the Western Cape is partly attributable to drug resistance. The aim of this study was to ...

  9. Multi drug resistant tuberculosis: a challenge in the management of ...

    African Journals Online (AJOL)

    Multi drug resistant tuberculosis (MDR-TB) will not usually respond to short course chemotherapy. Unless the individual infected with this bug is treated appropriately, they can continue spreading resistant strains in the community and further fuel the tuberculosis epidemic. Diagnosis requires drug sensitivity testing and the ...

  10. Adaptation and evolution of drug-resistant Mycobacterium tuberculosis

    NARCIS (Netherlands)

    Bergval, I.L.

    2013-01-01

    Many studies have been conducted on drug resistance and the evolution of Mycobacterium tuberculosis. Notwithstanding, many molecular mechanisms facilitating the emergence, adaptation and spread of drug-resistant tuberculosis have yet to be discovered. This thesis reports studies of the adaptive

  11. Multiple genetic resistances in Capsicum spp.

    Science.gov (United States)

    Bento, C S; de Souza, A G; Sudré, C P; Pimenta, S; Rodrigues, R

    2017-09-27

    This study aimed to identify Capsicum genotypes with resistance to bacterial spot (BS), anthracnose and Pepper yellow mosaic virus (PepYMV). Fifty-four genotypes of Capsicum spp were evaluated. Resistance reaction against BS was evaluated using three replicates, testing hypersensitivity and quantitative resistance in leaves. After evaluation, inoculated leaves were detached from the plants, being then cultivated until reproductive stage for evaluations anthracnose resistance in immature and mature fruit, totalizing 18 fruits per genotype. For PepYMV resistance was performed with five replications. Each genotype reaction was evaluated by a scoring scale, using the area under the disease progress curve for each pathosystem, and incubation period for the three systems. The latent period was evaluated only for the pathosystem Capsicum-Colletotrichum gloeosporioides. Means were grouped by the Scott-Knott test. Measures of dissimilarity matrix among the genotypes were obtained by Gower's algorithm and the grouping was obtained by the UPGMA clustering method. The accessions belonging to the Capsicum frutescens were the most susceptible to the three diseases. At least one genotype of Capsicum baccatum var. pendulum, Capsicum annuum, and Capsicum chinense showed resistance potential to BS and PepYMV, for use in breeding programs. The accession UENF 1381 (C. annuum) was resistant to the three pathogens.

  12. Drug resistance in leishmaniasis: current drug-delivery systems and future perspectives.

    Science.gov (United States)

    Yasinzai, Masoom; Khan, Momin; Nadhman, Akhtar; Shahnaz, Gul

    2013-10-01

    Leishmaniasis is a complex of diseases with numerous clinical manifestations for instance harshness from skin lesions to severe disfigurement and chronic systemic infection in the liver and spleen. So far, the most classical leishmaniasis therapy, despite its documented toxicities, remains pentavalent antimonial compounds. The arvailable therapeutic modalities for leishmaniasis are overwhelmed with resistance to leishmaniasis therapy. Mechanisms of classical drug resistance are often related with the lower drug uptake, increased efflux, the faster drug metabolism, drug target modifications and over-expression of drug transporters. The high prevalence of leishmaniasis and the appearance of resistance to classical drugs reveal the demand to develop and explore novel, less toxic, low cost and more promising therapeutic modalities. The review describes the mechanisms of classical drug resistance and potential drug targets in Leishmania infection. Moreover, current drug-delivery systems and future perspectives towards Leishmaniasis treatment are also covered.

  13. Early antiretroviral therapy and potent second-line drugs could decrease HIV incidence of drug resistance.

    Science.gov (United States)

    Shen, Mingwang; Xiao, Yanni; Rong, Libin; Meyers, Lauren Ancel; Bellan, Steven E

    2017-06-28

    Early initiation of antiretroviral therapy (ART) reduces the risk of drug-sensitive HIV transmission but may increase the transmission of drug-resistant HIV. We used a mathematical model to estimate the long-term population-level benefits of ART and determine the scenarios under which earlier ART (treatment at 1 year post-infection, on average) could decrease simultaneously both total and drug-resistant HIV incidence (new infections). We constructed an infection-age-structured mathematical model that tracked the transmission rates over the course of infection and modelled the patients' life expectancy as a function of ART initiation timing. We fitted this model to the annual AIDS incidence and death data directly, and to resistance data and demographic data indirectly among men who have sex with men (MSM) in San Francisco. Using counterfactual scenarios, we assessed the impact on total and drug-resistant HIV incidence of ART initiation timing, frequency of acquired drug resistance, and second-line drug effectiveness (defined as the combination of resistance monitoring, biomedical drug efficacy and adherence). Earlier ART initiation could decrease the number of both total and drug-resistant HIV incidence when second-line drug effectiveness is sufficiently high (greater than 80%), but increase the proportion of new infections that are drug resistant. Thus, resistance may paradoxically appear to be increasing while actually decreasing. © 2017 The Author(s).

  14. Repurposing and Revival of the Drugs: A New Approach to Combat the Drug Resistant Tuberculosis

    Directory of Open Access Journals (Sweden)

    Divakar Sharma

    2017-12-01

    Full Text Available Emergence of drug resistant tuberculosis like multi drug resistant tuberculosis (MDR-TB, extensively drug-resistant tuberculosis (XDR-TB and totally drug resistant tuberculosis (TDR-TB has created a new challenge to fight against these bad bugs of Mycobacterium tuberculosis. Repurposing and revival of the drugs are the new trends/options to combat these worsen situations of tuberculosis in the antibiotics resistance era or in the situation of global emergency. Bactericidal and synergistic effect of repurposed/revived drugs along with the latest drugs bedaquiline and delamanid used in the treatment of MDR-TB, XDR-TB, and TDR-TB might be the choice for future promising combinatorial chemotherapy against these bad bugs.

  15. Quantifying the Determinants of Evolutionary Dynamics Leading to Drug Resistance.

    Directory of Open Access Journals (Sweden)

    Guillaume Chevereau

    Full Text Available The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome-wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the "morbidostat", a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations-an almost paradoxical behavior since this drug causes DNA damage and increases the mutation

  16. Shigella Antimicrobial Drug Resistance Mechanisms, 2004-2014.

    Science.gov (United States)

    Nüesch-Inderbinen, Magdalena; Heini, Nicole; Zurfluh, Katrin; Althaus, Denise; Hächler, Herbert; Stephan, Roger

    2016-06-01

    To determine antimicrobial drug resistance mechanisms of Shigella spp., we analyzed 344 isolates collected in Switzerland during 2004-2014. Overall, 78.5% of isolates were multidrug resistant; 10.5% were ciprofloxacin resistant; and 2% harbored mph(A), a plasmid-mediated gene that confers reduced susceptibility to azithromycin, a last-resort antimicrobial agent for shigellosis.

  17. Cancer stem cells and drug resistance: the potential of nanomedicine

    Science.gov (United States)

    Vinogradov, Serguei; Wei, Xin

    2012-01-01

    Properties of the small group of cancer cells called tumor-initiating or cancer stem cells (CSCs) involved in drug resistance, metastasis and relapse of cancers can significantly affect tumor therapy. Importantly, tumor drug resistance seems to be closely related to many intrinsic or acquired properties of CSCs, such as quiescence, specific morphology, DNA repair ability and overexpression of antiapoptotic proteins, drug efflux transporters and detoxifying enzymes. The specific microenvironment (niche) and hypoxic stability provide additional protection against anticancer therapy for CSCs. Thus, CSC-focused therapy is destined to form the core of any effective anticancer strategy. Nanomedicine has great potential in the development of CSC-targeting drugs, controlled drug delivery and release, and the design of novel gene-specific drugs and diagnostic modalities. This review is focused on tumor drug resistance-related properties of CSCs and describes current nanomedicine approaches, which could form the basis of novel combination therapies for eliminating metastatic and CSCs. PMID:22471722

  18. Enhanced Transmission of Drug-Resistant Parasites to Mosquitoes following Drug Treatment in Rodent Malaria

    OpenAIRE

    Bell, Andrew S.; Huijben, Silvie; Paaijmans, Krijn P.; Sim, Derek G.; Chan, Brian H. K.; Nelson, William A.; Read, Andrew F.

    2012-01-01

    The evolution of drug resistant Plasmodium parasites is a major challenge to effective malaria control. In theory, competitive interactions between sensitive parasites and resistant parasites within infections are a major determinant of the rate at which parasite evolution undermines drug efficacy. Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it. Here we report that for the murine model Plasm...

  19. MODELING OF TARGETED DRUG DELIVERY PART II. MULTIPLE DRUG ADMINISTRATION

    Directory of Open Access Journals (Sweden)

    A. V. Zaborovskiy

    2017-01-01

    Full Text Available In oncology practice, despite significant advances in early cancer detection, surgery, radiotherapy, laser therapy, targeted therapy, etc., chemotherapy is unlikely to lose its relevance in the near future. In this context, the development of new antitumor agents is one of the most important problems of cancer research. In spite of the importance of searching for new compounds with antitumor activity, the possibilities of the “old” agents have not been fully exhausted. Targeted delivery of antitumor agents can give them a “second life”. When developing new targeted drugs and their further introduction into clinical practice, the change in their pharmacodynamics and pharmacokinetics plays a special role. The paper describes a pharmacokinetic model of the targeted drug delivery. The conditions under which it is meaningful to search for a delivery vehicle for the active substance were described. Primary screening of antitumor agents was undertaken to modify them for the targeted delivery based on underlying assumptions of the model.

  20. ORIGINAL ARTICLE MULTIPLE ANTIBIOTIC RESISTANCE (MAR ...

    African Journals Online (AJOL)

    boaz

    ABSRACT. Background/Objectives: Pseudomonas and Klebsiella infections are important nosocomial infections because of the attendant significant morbidity, mortality and socio-economic impact. These infections are difficult to treat due to the innate and acquired resistance mediated by the organisms' genome and other ...

  1. Diversity and evolution of drug resistance mechanisms in Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Al-Saeedi M

    2017-10-01

    Full Text Available Mashael Al-Saeedi, Sahal Al-Hajoj Department of Infection and Immunity, Mycobacteriology Research Section, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia Abstract: Despite the efficacy of antibiotics to protect humankind against many deadly pathogens, such as Mycobacterium tuberculosis, nothing can prevent the emergence of drug-resistant strains. Several mechanisms facilitate drug resistance in M. tuberculosis including compensatory evolution, epistasis, clonal interference, cell wall integrity, efflux pumps, and target mimicry. In this study, we present recent findings relevant to these mechanisms, which can enable the discovery of new drug targets and subsequent development of novel drugs for treatment of drug-resistant M. tuberculosis. Keywords: Mycobacterium tuberculosis, antibiotic resistance, compensatory evolution, epistasis, efflux pumps, fitness cost

  2. Drug-resistant gram-negative uropathogens: A review.

    Science.gov (United States)

    Khoshnood, Saeed; Heidary, Mohsen; Mirnejad, Reza; Bahramian, Aghil; Sedighi, Mansour; Mirzaei, Habibollah

    2017-10-01

    Urinary tract infection(UTI) caused by Gram-negative bacteria is the second most common infectious presentation in community medical practice. Approximately 150 million people are diagnosed with UTI each year worldwide. Drug resistance in Gram-negative uropathogens is a major global concern which can lead to poor clinical outcomes including treatment failure, development of bacteremia, requirement for intravenous therapy, hospitalization, and extended length of hospital stay. The mechanisms of drug resistance in these bacteria are important due to they are often not identified by routine susceptibility tests and have an exceptional potential for outbreaks. Treatment of UTIs depends on the access to effective drugs, which is now threatened by antibiotic resistant Gram-negative uropathogens. Although several effective antibiotics with activity against highly resistant Gram-negatives are available, there is not a unique antibiotic with activity against the high variety of resistance. Therefore, antimicrobial susceptibility tests, correlation between clinicians and laboratories, development of more rapid diagnostic methods, and continuous monitoring of drug resistance are urgent priorities. In this review, we will discuss about the current global status of drug-resistant Gram-negative uropathogens and their mechanisms of drug resistance to provide new insights into their treatment options. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. Fitness of Leishmania donovani parasites resistant to drug combinations.

    Directory of Open Access Journals (Sweden)

    Raquel García-Hernández

    2015-04-01

    Full Text Available Drug resistance represents one of the main problems for the use of chemotherapy to treat leishmaniasis. Additionally, it could provide some advantages to Leishmania parasites, such as a higher capacity to survive in stress conditions. In this work, in mixed populations of Leishmania donovani parasites, we have analyzed whether experimentally resistant lines to one or two combined anti-leishmanial drugs better support the stress conditions than a susceptible line expressing luciferase (Luc line. In the absence of stress, none of the Leishmania lines showed growth advantage relative to the other when mixed at a 1:1 parasite ratio. However, when promastigotes from resistant lines and the Luc line were mixed and exposed to different stresses, we observed that the resistant lines are more tolerant of different stress conditions: nutrient starvation and heat shock-pH stress. Further to this, we observed that intracellular amastigotes from resistant lines present a higher capacity to survive inside the macrophages than those of the control line. These results suggest that resistant parasites acquire an overall fitness increase and that resistance to drug combinations presents significant differences in their fitness capacity versus single-drug resistant parasites, particularly in intracellular amastigotes. These results contribute to the assessment of the possible impact of drug resistance on leishmaniasis control programs.

  4. Surveillance of drug resistance for tuberculosis control: why and how?

    Science.gov (United States)

    Chaulet, P; Boulahbal, F; Grosset, J

    1995-12-01

    The resistance of Mycobacterium tuberculosis to antibiotics, which reflects the quality of the chemotherapy applied in the community, is one of the elements of epidemiological surveillance used in national tuberculosis programmes. Measurement of drug resistance poses problems for biologists in standardization of laboratory methods and quality control. The definition of rates of acquired and primary drug resistance also necessitates standardization in the methods used to collect information transmitted by clinicians. Finally, the significance of the rates calculated depends on the choice of the patients sample on which sensitivity tests have been performed. National surveys of drug resistance therefore require multidisciplinary participation in order to select the only useful indicators: rates of primary resistance and of acquired resistance. These indicators, gathered in representative groups of patients over a long period, are a measurement of the impact of modern chemotherapy regimens on bacterial ecology.

  5. [Morphological signs of inflammatory activity in different clinical forms of drug-resistant pulmonary tuberculosis].

    Science.gov (United States)

    Elipashev, A A; Nikolsky, V O; Shprykov, A S

    to determine whether the activity of tuberculous inflammation is associated with different clinical forms of drug-resistant pulmonary tuberculosis. The material taken from 310 patients operated on in 2010-2015 were retrospectively examined. The patients underwent economical lung resections of limited extent (typical and atypical ones of up to 3 segments) for circumscribed forms of tuberculosis with bacterial excretion. A study group consisted of 161 (51.9%) patients with drug-resistant variants of pulmonary tuberculosis. A control group included 149 (48.1%) patients with preserved susceptibility of Mycobacterium tuberculosis to anti-TB drugs. The activity of specific changes in tuberculosis was morphologically evaluated in accordance with the classification proposed by B.M. Ariel in 1998. The highest activity of fourth-to-fifth degree specific inflammation, including that outside the primary involvement focus, was obtained in the drug-resistant pulmonary tuberculosis group due to the predominance of patients with cavernous and fibrous-cavernous tuberculosis versus those in whom the susceptibility to chemotherapeutic agents was preserved. A macroscopic study showed that the primary lesion focus had a median size in one-half of the all the examinees; but large tuberculomas, caverns, and fibrous caverns over 4 cm in diameter were multiple and detected in the drug-resistant pulmonary tuberculosis group. Multidrug resistance was observed in more than 60% of the patients with fibrous-cavernous pulmonary tuberculosis, extensive drug resistance was seen in those with cavernous tuberculosis, which is an aggravating factor. The data obtained from the morphological study of the intraoperative material can specify the clinical form of tuberculosis and evaluate the efficiency of preoperative specific therapy. The highest activity of specific inflammation was observed in patients with multiple drug-resistant pulmonary tuberculosis, the prevalence of third-to-fourth degree

  6. Multiple insect resistance in 59 commmerical corn hybrids - 2017

    Science.gov (United States)

    Commercial corn hybrids were screened for ear- and kernel-feeding insect resistance under field conditions at Tifton, GA. Nine hybrids were rated Very Good (VG), the highest rating for multiple insect resistance in 2017 (see following table). Thirteen were Good (G), 19 were Fair (F), and 13 were Poo...

  7. DNA origami as a carrier for circumvention of drug resistance.

    Science.gov (United States)

    Jiang, Qiao; Song, Chen; Nangreave, Jeanette; Liu, Xiaowei; Lin, Lin; Qiu, Dengli; Wang, Zhen-Gang; Zou, Guozhang; Liang, Xingjie; Yan, Hao; Ding, Baoquan

    2012-08-15

    Although a multitude of promising anti-cancer drugs have been developed over the past 50 years, effective delivery of the drugs to diseased cells remains a challenge. Recently, nanoparticles have been used as drug delivery vehicles due to their high delivery efficiencies and the possibility to circumvent cellular drug resistance. However, the lack of biocompatibility and inability to engineer spatially addressable surfaces for multi-functional activity remains an obstacle to their widespread use. Here we present a novel drug carrier system based on self-assembled, spatially addressable DNA origami nanostructures that confronts these limitations. Doxorubicin, a well-known anti-cancer drug, was non-covalently attached to DNA origami nanostructures through intercalation. A high level of drug loading efficiency was achieved, and the complex exhibited prominent cytotoxicity not only to regular human breast adenocarcinoma cancer cells (MCF 7), but more importantly to doxorubicin-resistant cancer cells, inducing a remarkable reversal of phenotype resistance. With the DNA origami drug delivery vehicles, the cellular internalization of doxorubicin was increased, which contributed to the significant enhancement of cell-killing activity to doxorubicin-resistant MCF 7 cells. Presumably, the activity of doxorubicin-loaded DNA origami inhibits lysosomal acidification, resulting in cellular redistribution of the drug to action sites. Our results suggest that DNA origami has immense potential as an efficient, biocompatible drug carrier and delivery vehicle in the treatment of cancer.

  8. Mathematical modeling and computational prediction of cancer drug resistance.

    Science.gov (United States)

    Sun, Xiaoqiang; Hu, Bin

    2017-06-23

    Diverse forms of resistance to anticancer drugs can lead to the failure of chemotherapy. Drug resistance is one of the most intractable issues for successfully treating cancer in current clinical practice. Effective clinical approaches that could counter drug resistance by restoring the sensitivity of tumors to the targeted agents are urgently needed. As numerous experimental results on resistance mechanisms have been obtained and a mass of high-throughput data has been accumulated, mathematical modeling and computational predictions using systematic and quantitative approaches have become increasingly important, as they can potentially provide deeper insights into resistance mechanisms, generate novel hypotheses or suggest promising treatment strategies for future testing. In this review, we first briefly summarize the current progress of experimentally revealed resistance mechanisms of targeted therapy, including genetic mechanisms, epigenetic mechanisms, posttranslational mechanisms, cellular mechanisms, microenvironmental mechanisms and pharmacokinetic mechanisms. Subsequently, we list several currently available databases and Web-based tools related to drug sensitivity and resistance. Then, we focus primarily on introducing some state-of-the-art computational methods used in drug resistance studies, including mechanism-based mathematical modeling approaches (e.g. molecular dynamics simulation, kinetic model of molecular networks, ordinary differential equation model of cellular dynamics, stochastic model, partial differential equation model, agent-based model, pharmacokinetic-pharmacodynamic model, etc.) and data-driven prediction methods (e.g. omics data-based conventional screening approach for node biomarkers, static network approach for edge biomarkers and module biomarkers, dynamic network approach for dynamic network biomarkers and dynamic module network biomarkers, etc.). Finally, we discuss several further questions and future directions for the use of

  9. Drug-Resistant Bacteria: On the Edge of a Crisis | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... drug-resistant bacteria research program. Why are certain bacteria becoming more resistant to drugs? There is a ... a national, even global crisis of drug-resistant bacteria. Why is that? The more we see this ...

  10. Antimicrobial resistance determinant microarray for analysis of multi-drug resistant isolates

    Science.gov (United States)

    Taitt, Chris Rowe; Leski, Tomasz; Stenger, David; Vora, Gary J.; House, Brent; Nicklasson, Matilda; Pimentel, Guillermo; Zurawski, Daniel V.; Kirkup, Benjamin C.; Craft, David; Waterman, Paige E.; Lesho, Emil P.; Bangurae, Umaru; Ansumana, Rashid

    2012-06-01

    The prevalence of multidrug-resistant infections in personnel wounded in Iraq and Afghanistan has made it challenging for physicians to choose effective therapeutics in a timely fashion. To address the challenge of identifying the potential for drug resistance, we have developed the Antimicrobial Resistance Determinant Microarray (ARDM) to provide DNAbased analysis for over 250 resistance genes covering 12 classes of antibiotics. Over 70 drug-resistant bacteria from different geographic regions have been analyzed on ARDM, with significant differences in patterns of resistance identified: genes for resistance to sulfonamides, trimethoprim, chloramphenicol, rifampin, and macrolide-lincosamidesulfonamide drugs were more frequently identified in isolates from sources in Iraq/Afghanistan. Of particular concern was the presence of genes responsible for resistance to many of the last-resort antibiotics used to treat war traumaassociated infections.

  11. Molecular chess? Hallmarks of anti-cancer drug resistance.

    Science.gov (United States)

    Cree, Ian A; Charlton, Peter

    2017-01-05

    The development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years. Resistance to anti-cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as (1) alteration of drug targets, (2) expression of drug pumps, (3) expression of detoxification mechanisms, (4) reduced susceptibility to apoptosis, (5) increased ability to repair DNA damage, and (6) altered proliferation. It is clear, however, that changes in stroma and tumour microenvironment, and local immunity can also contribute to the development of resistance. Cancer cells can and do use several of these mechanisms at one time, and there is considerable heterogeneity between tumours, necessitating an individualised approach to cancer treatment. As tumours are heterogeneous, positive selection of a drug-resistant population could help drive resistance, although acquired resistance cannot simply be viewed as overgrowth of a resistant cancer cell population. The development of such resistance mechanisms can be predicted from pre-existing genomic and proteomic profiles, and there are increasingly sophisticated methods to measure and then tackle these mechanisms in patients. The oncologist is now required to be at least one step ahead of the cancer, a process that can be likened to 'molecular chess'. Thus, as well as an increasing role for predictive biomarkers to clinically stratify patients, it is becoming clear that personalised strategies are required to obtain best results.

  12. Fluorometric assay for phenotypic differentiation of drug-resistant HIV mutants

    Science.gov (United States)

    Zhu, Qinchang; Yu, Zhiqiang; Kabashima, Tsutomu; Yin, Sheng; Dragusha, Shpend; El-Mahdy, Ahmed F. M.; Ejupi, Valon; Shibata, Takayuki; Kai, Masaaki

    2015-01-01

    Convenient drug-resistance testing of viral mutants is indispensable to effective treatment of viral infection. We developed a novel fluorometric assay for phenotypic differentiation of drug-resistant mutants of human immunodeficiency virus-I protease (HIV-PR) which uses enzymatic and peptide-specific fluorescence (FL) reactions and high-performance liquid chromatography (HPLC) of three HIV-PR substrates. This assay protocol enables use of non-purified enzyme sources and multiple substrates for the enzymatic reaction. In this study, susceptibility of HIV mutations to drugs was evaluated by selective formation of three FL products after the enzymatic HIV-PR reaction. This proof-of-concept study indicates that the present HPLC-FL method could be an alternative to current phenotypic assays for the evaluation of HIV drug resistance. PMID:25988960

  13. Aggressive chemotherapy and the selection of drug resistant pathogens.

    Directory of Open Access Journals (Sweden)

    Silvie Huijben

    2013-09-01

    Full Text Available Drug resistant pathogens are one of the key public health challenges of the 21st century. There is a widespread belief that resistance is best managed by using drugs to rapidly eliminate target pathogens from patients so as to minimize the probability that pathogens acquire resistance de novo. Yet strong drug pressure imposes intense selection in favor of resistance through alleviation of competition with wild-type populations. Aggressive chemotherapy thus generates opposing evolutionary forces which together determine the rate of drug resistance emergence. Identifying treatment regimens which best retard resistance evolution while maximizing health gains and minimizing disease transmission requires empirical analysis of resistance evolution in vivo in conjunction with measures of clinical outcomes and infectiousness. Using rodent malaria in laboratory mice, we found that less aggressive chemotherapeutic regimens substantially reduced the probability of onward transmission of resistance (by >150-fold, without compromising health outcomes. Our experiments suggest that there may be cases where resistance evolution can be managed more effectively with treatment regimens other than those which reduce pathogen burdens as fast as possible.

  14. mtct regimen choice, drug resistance and the treatment of hiv

    African Journals Online (AJOL)

    risk of transmission is highest during labour and delivery, ... will have a major impact on controlling perinatally acquired HIV infection. ... could result in the development of drug resistance with potential .... dosing, pharmacokinetics and safety.

  15. Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

    Institute of Scientific and Technical Information of China (English)

    REBECCA L DUNNE; LINDA A DUNN; PETER UPCROFT; PETER J O'DONOGHUE; JACQUELINE A UPCROFT

    2003-01-01

    Trichomoniasis is the most common, sexually transmitted infection. It is caused by the flagellated protozoan parasite Trichomonas vaginalis. Symptoms include vaginitis and infections have been associated with preterm delivery, low birth weight and increased infant mortality, as well as predisposing to HIV/AIDS and cervical cancer. Trichomoniasis has the highest prevalence and incidence of any sexually transmitted infection. The 5-nitroimidazole drugs, of which metronidazole is the most prescribed, are the only approved,effective drugs to treat trichomoniasis. Resistance against metronidazole is frequently reported and crossresistance among the family of 5-nitroimidazole drugs is common, leaving no alternative for treatment, with some cases remaining unresolved. The mechanism of metronidazole resistance in T. vaginalis from treatment failures is not well understood, unlike resistance which is developed in the laboratory under increasing metronidazole pressure. In the latter situation, hydrogenosomal function which is involved in activation of the prodrug, metronidazole, is down-regulated. Reversion to sensitivity is incomplete after removal of drug pressure in the highly resistant parasites while clinically resistant strains, so far analysed, maintain their resistance levels in the absence of drug pressure. Although anaerobic resistance has been regarded as a laboratory induced phenomenon, it clearly has been demonstrated in clinical isolates. Pursuit of both approaches will allow dissection of the underlying mechanisms. Many alternative drugs and treatments have been tested in vivo in cases of refractory trichomoniasis, as well as in vitro with some successes including the broad spectrum anti-parasitic drug nitazoxanide. Drug resistance incidence in T. vaginalis appears to be on the increase and improved surveillance of treatment failures is urged.

  16. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

    Science.gov (United States)

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-12-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

  17. Reaching consensus on drug resistance conferring mutations (Part 1

    Directory of Open Access Journals (Sweden)

    Daniela M Cirillo

    2016-01-01

    A user-friendly interface designed for nonexpert or expert operability.A standardized and validated analysis pipeline for variant analyses of M. tuberculosis next-generation sequencing (NGS data.Access to data beyond the published literature with dynamic and iterative updates of new data generated by global surveillance and clinical trials.A well-developed legal structure to ensure intellectual property rights and data ownership remain with contributors.A structured data-sharing architecture to restrict access to sensitive or unpublished data sets.Metadata standardization using CDISC: supports global, platform-independent data standards that enable information system interoperability.An emphasis on data quality and rigorous, expert curation with multiple quality control checks for whole-genome sequencing and other metadata.Validation of NGS analysis output by an expert committee with grading of resistance conferring mutations based on rigorous statistical standards.Regulatory-compliant analysis pipeline and database architecture. Successful execution of such an extensive database platform requires substantial collaboration from scientists investigating the genetic basis for drug resistance worldwide, and from developers with expertise in database design and implementation.

  18. Monitoring of drug resistance amplification and attenuation with the use of tetracycline-resistant bacteria during wastewater treatment

    Science.gov (United States)

    Harnisz, Monika; Korzeniewska, Ewa; Niestępski, Sebastian; Osińska, Adriana; Nalepa, Beata

    2017-11-01

    The objective of this study was to monitor changes (amplification or attenuation) in antibiotic resistance during wastewater treatment based on the ecology of tetracycline-resistant bacteria. The untreated and treated wastewater were collected in four seasons. Number of tetracycline-(TETR) and oxytetracycline-resistant (OTCR) bacteria, their qualitative composition, minimum inhibitory concentrations (MICs), sensitivity to other antibiotics, and the presence of tet (A, B, C, D, E) resistance genes were determined. TETR and OTCR counts in untreated wastewater were 100 to 1000 higher than in treated effluent. OTCR bacterial counts were higher than TETR populations in both untreated and treated wastewater. TETR isolates were not dominated by a single bacterial genus or species, whereas Aeromonas hydrophila and Aeromonas sobria were the most common in OTCR isolates. The treatment process attenuated the drug resistance of TETR bacteria and amplified the resistance of OTCR bacteria. In both microbial groups, the frequency of tet(A) gene increased in effluent in comparison with untreated wastewater. Our results also indicate that treated wastewater is a reservoir of multiple drug-resistant bacteria as well as resistance determinants which may pose a health hazard for humans and animals when released to the natural environment.

  19. Molecular basis of antifungal drug resistance in yeasts

    DEFF Research Database (Denmark)

    Morio, Florent; Jensen, Rasmus Hare; Le Pape, Patrice

    2017-01-01

    Besides inherent differences in in vitro susceptibilities, clinically-relevant yeast species may acquire resistance upon exposure to most antifungal drugs used in the clinic. In recent years, major fundamental research studies have been conducted to improve our understanding of the molecular basis...... of antifungal resistance. This topic is of major interest as antifungal resistance in yeast is clearly evolving and is correlated with clinical failure. This minireview is an overview of the most recent findings about key molecular mechanisms evolving in human pathogenic yeasts, particularly Candida spp......., in the context of antifungal drug resistance. Also included are the methods currently available for in vitro antifungal susceptibility testing and for molecular detection of mutations associated with resistance. Finally, the genetic drivers of antifungal resistance are discussed in light of the spectra...

  20. Competitive release of drug resistance following drug treatment of mixed Plasmodium chabaudi infections.

    Science.gov (United States)

    de Roode, Jacobus C; Culleton, Richard; Bell, Andrew S; Read, Andrew F

    2004-09-14

    Malaria infections are often genetically diverse, potentially leading to competition between co-infecting strains. Such competition is of key importance in the spread of drug resistance. The effects of drug treatment on within-host competition were studied using the rodent malaria Plasmodium chabaudi. Mice were infected simultaneously with a drug-resistant and a drug-sensitive clone and were then either drug-treated or left untreated. Transmission was assessed by feeding mice to Anopheles stephensi mosquitoes. In the absence of drugs, the sensitive clone competitively suppressed the resistant clone; this resulted in lower asexual parasite densities and also reduced transmission to the mosquito vector. Drug treatment, however, allowed the resistant clone to fill the ecological space emptied by the removal of the sensitive clone, allowing it to transmit as well as it would have done in the absence of competition. These results show that under drug pressure, resistant strains can have two advantages: (1) they survive better than sensitive strains and (2) they can exploit the opportunities presented by the removal of their competitors. When mixed infections are common, such effects could increase the spread of drug resistance.

  1. Plasmid Conjugation in E. coli and Drug Resistance | Igwe ...

    African Journals Online (AJOL)

    This study aimed at determining the antibiotics susceptibility pattern of E. coli isolates claimed to be multidrug resistance using disc diffusion method. It also determined the presence of transferable resistance plasmids through conjugation and evaluated the medical significance of plasmid encoding E. coli and drug ...

  2. Antiretroviral drug resistance: A guide for the southern African clinician

    African Journals Online (AJOL)

    Both private and public sector see a bewildering clinical array of patients taking failing antiretroviral (ARV) regimens. We intend this article to provide a practical guide to help clinicians understand and manage ARV drug resistance in an African context. ARV resistance is a rapidly evolving field, requiring expertise in dealing ...

  3. Options for modulation of drug resistance in ovarian cancer

    NARCIS (Netherlands)

    Arts, HJG; Van der Zee, AGJ; De Jong, S; De Vries, EGE

    2000-01-01

    The objective of this paper is to present an update of mechanisms responsible for drug resistance in ovarian cancer and the possible therapeutic options to modulate this resistance using literature review with emphasis on data acquired in studies comprising ovarian tumor samples. The classic

  4. Characterization of drug resistant Enterobacter species isolated from ...

    African Journals Online (AJOL)

    Enterobacter species are emerging clinical pathogens and they play important roles in the dissemination of drug resistant traits within the food chain due to their intrinsic abilities for resistance to commonly used antibiotics such as cephalosporins. Two Enterobacter cloacae and one Enterobacter hormaechei characterized in ...

  5. Drug Resistant Hypertension - No SIMPLE Way Out

    OpenAIRE

    Janusz Skrzypecki; Marcin Ufnal

    2015-01-01

    Hypertension poses growing challenge for health policy-makers and doctors worldwide. Recently published results of Symplicity-III trial (HTN-3), the first blinded, randomized, multicenter study on the efficacy of renal denervation for the treatment of resistant hypertension did not show a significant reduction of BP in patients with resistant hypertension 6 months after renal-artery denervation, as compared with controls. In this paper we review clinical and experimental studies on renal dene...

  6. Multi drug resistance and β-lactamase production by Klebsiella ...

    African Journals Online (AJOL)

    SERVER

    2007-08-06

    Aug 6, 2007 ... *Corresponding author. E-mail: gnsimha123@rediffmail.com. (Rice, 1999). plasmid that can be easily spread from one organisms to another (Sirot, 1995) these enzymes are capable of inactivating a variety of β-lactam drugs (Rice,. 1999). The ESBL producing organisms often show multi- drug resistant as ...

  7. Towards an understanding of drug resistance in malaria

    DEFF Research Database (Denmark)

    Lemcke, T; Christensen, I T; Jørgensen, Flemming Steen

    1999-01-01

    and structural differences. Based on this analysis the molecular consequences of point mutations known to be involved in drug resistance were discussed. The significance of the most important point mutation causing resistance, S108N, could be explained by the model, whereas the point mutations associated...... with enhanced resistance, N51I and C59R, seem to have a more indirect effect on inhibitor binding....

  8. Research Highlights: Helping Adolescents Resist Drugs

    National Research Council Canada - National Science Library

    2000-01-01

    Project ALERT departs boldly from prevention models of the 196Os and 197Os, which emphasized informing adolescents about the long-term consequences of drug use or building their decisionmaking skills...

  9. Rational polypharmacology: systematically identifying and engaging multiple drug targets to promote axon growth

    Science.gov (United States)

    Al-Ali, Hassan; Lee, Do-Hun; Danzi, Matt C.; Nassif, Houssam; Gautam, Prson; Wennerberg, Krister; Zuercher, Bill; Drewry, David H.; Lee, Jae K.; Lemmon, Vance P.; Bixby, John L.

    2016-01-01

    Mammalian Central Nervous System (CNS) neurons regrow their axons poorly following injury, resulting in irreversible functional losses. Identifying therapeutics that encourage CNS axon repair has been difficult, in part because multiple etiologies underlie this regenerative failure. This suggests a particular need for drugs that engage multiple molecular targets. Although multi-target drugs are generally more effective than highly selective alternatives, we lack systematic methods for discovering such drugs. Target-based screening is an efficient technique for identifying potent modulators of individual targets. In contrast, phenotypic screening can identify drugs with multiple targets; however, these targets remain unknown. To address this gap, we combined the two drug discovery approaches using machine learning and information theory. We screened compounds in a phenotypic assay with primary CNS neurons and also in a panel of kinase enzyme assays. We used learning algorithms to relate the compounds’ kinase inhibition profiles to their influence on neurite outgrowth. This allowed us to identify kinases that may serve as targets for promoting neurite outgrowth, as well as others whose targeting should be avoided. We found that compounds that inhibit multiple targets (polypharmacology) promote robust neurite outgrowth in vitro. One compound with exemplary polypharmacology, was found to promote axon growth in a rodent spinal cord injury model. A more general applicability of our approach is suggested by its ability to deconvolve known targets for a breast cancer cell line, as well as targets recently shown to mediate drug resistance. PMID:26056718

  10. A study on Prevalence of Drug Resistance in Drug Default ...

    African Journals Online (AJOL)

    ), and particularly multidrug-resistant TB (MDR-TB), has become a significant public health problem in a number of countries and an obstacle to effective global TB control. Method: This is a prospective randomized cross sectional study to ...

  11. Drug-resistant tuberculosis in two children in Greece: report of the first extensively drug-resistant case.

    Science.gov (United States)

    Katragkou, Aspasia; Antachopoulos, Charalampos; Hatziagorou, Elpis; Sdougka, Maria; Roilides, Emmanuel; Tsanakas, John

    2013-04-01

    Extensively drug-resistant (XDR) tuberculosis (TB) represents a serious and growing problem in both endemic and non-endemic countries. We describe a 2.5-year-old girl with XDR-pulmonary TB and an 18-month-old boy with pre-XDR-central nervous system TB. Patients received individualized treatment with second-line anti-TB agents based on genotypic and phenotypic drug susceptibility testing results. Both children achieved culture conversion 3 months and 1 month after treatment initiation, respectively. The child with XDR-pulmonary TB showed evidence of cure while treatment adverse events were managed without treatment interruption. The child with pre-XDR-central nervous system TB after 6-month hospitalization with multiple infectious complications had a dismal end due to hepatic insufficiency possibly related to anti-TB treatment. This is the first report of children with pre-XDR and XDR TB in Greece, emphasizing the public health dimensions and management complexity of XDR TB.

  12. Absence of association between major vault protein (MVP) gene polymorphisms and drug resistance in Chinese Han patients with partial epilepsy.

    Science.gov (United States)

    Zhou, Luo; Zhang, Mengqi; Long, Hongyu; Long, Lili; Xie, Yuanyuan; Liu, Zhaoqian; Kang, Jin; Chen, Qihua; Feng, Li; Xiao, Bo

    2015-11-15

    Drug resistance in epilepsy is common despite many antiepileptic drugs (AEDs) available for treatment. The development of drug resistant epilepsy may be a result of multiple factors. Several previous studies reported that the major vault protein (MVP) was significantly increased in epileptogenic brain tissues resected from patients with partial-onset seizures, indicating the possible involvement of MVP in drug resistance. In this article, we aimed to identify the association between single nucleotide polymorphisms (SNPs) of MVP gene and drug resistance of partial epilepsy in a Chinese Han population. A total of 510 patients with partial-onset seizures and 206 healthy controls were recruited. Among the patients, 222 were drug resistant and 288 were responsive. The selection of tagging SNPs was based on the Hapmap database and Haploview software and the genotyping was conducted on the Sequenom MassARRAY iPLEX platform. For the selected loci rs12149746, rs9938630 and rs4788186 in the MVP gene, there was no significant difference in allele or genotype distribution between the drug resistant and responsive groups, or between all of the patients and healthy controls. Linkage disequilibrium between any two loci was detected but there was no significant difference in haplotype frequency between the drug resistant and responsive groups. Our results suggest that MVP genetic polymorphisms and haplotypes may not be associated with drug resistance of partial epilepsy in the Chinese Han population. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Challenges of drug resistance in the management of pancreatic cancer.

    LENUS (Irish Health Repository)

    Sheikh, Rizwan

    2012-02-01

    The current treatment of choice for metastatic pancreatic cancer involves single-agent gemcitabine or a combination of gemcitabine with capecitabine or erlotinib (a tyrosine kinase inhibitor). Only 25–30% of patients respond to this treatment and patients who do respond initially ultimately exhibit disease progression. Median survival for pancreatic cancer patients has reached a plateau due to inherent and acquired resistance to these agents. Key molecular factors implicated in this resistance include: deficiencies in drug uptake, alteration of drug targets, activation of DNA repair pathways, resistance to apoptosis and the contribution of the tumor microenvironment. Moreover, for newer agents including tyrosine kinase inhibitors, overexpression of signaling proteins, mutations in kinase domains, activation of alternative pathways, mutations of genes downstream of the target and\\/or amplification of the target represent key challenges for treatment efficacy. Here we will review the contribution of known mechanisms and markers of resistance to key pancreatic cancer drug treatments.

  14. Genetic Indicators of Drug Resistance in the Highly Repetitive Genome of Trichomonas vaginalis.

    Science.gov (United States)

    Bradic, Martina; Warring, Sally D; Tooley, Grace E; Scheid, Paul; Secor, William E; Land, Kirkwood M; Huang, Po-Jung; Chen, Ting-Wen; Lee, Chi-Ching; Tang, Petrus; Sullivan, Steven A; Carlton, Jane M

    2017-06-01

    Trichomonas vaginalis, the most common nonviral sexually transmitted parasite, causes ∼283 million trichomoniasis infections annually and is associated with pregnancy complications and increased risk of HIV-1 acquisition. The antimicrobial drug metronidazole is used for treatment, but in a fraction of clinical cases, the parasites can become resistant to this drug. We undertook sequencing of multiple clinical isolates and lab derived lines to identify genetic markers and mechanisms of metronidazole resistance. Reduced representation genome sequencing of ∼100 T. vaginalis clinical isolates identified 3,923 SNP markers and presence of a bipartite population structure. Linkage disequilibrium was found to decay rapidly, suggesting genome-wide recombination and the feasibility of genetic association studies in the parasite. We identified 72 SNPs associated with metronidazole resistance, and a comparison of SNPs within several lab-derived resistant lines revealed an overlap with the clinically resistant isolates. We identified SNPs in genes for which no function has yet been assigned, as well as in functionally-characterized genes relevant to drug resistance (e.g., pyruvate:ferredoxin oxidoreductase). Transcription profiles of resistant strains showed common changes in genes involved in drug activation (e.g., flavin reductase), accumulation (e.g., multidrug resistance pump), and detoxification (e.g., nitroreductase). Finally, we identified convergent genetic changes in lab-derived resistant lines of Tritrichomonas foetus, a distantly related species that causes venereal disease in cattle. Shared genetic changes within and between T. vaginalis and Tr. foetus parasites suggest conservation of the pathways through which adaptation has occurred. These findings extend our knowledge of drug resistance in the parasite, providing a panel of markers that can be used as a diagnostic tool. © The Author 2017. Published by Oxford University Press on behalf of the Society for

  15. Drug Resistant Hypertension - No SIMPLE Way Out

    Directory of Open Access Journals (Sweden)

    Janusz Skrzypecki

    2015-02-01

    Full Text Available Hypertension poses growing challenge for health policy-makers and doctors worldwide. Recently published results of Symplicity-III trial (HTN-3, the first blinded, randomized, multicenter study on the efficacy of renal denervation for the treatment of resistant hypertension did not show a significant reduction of BP in patients with resistant hypertension 6 months after renal-artery denervation, as compared with controls. In this paper we review clinical and experimental studies on renal denervation. In order to identify causes of inconsistent results in renal denervation studies we look at basic science support for renal denervation and at designs of clinical trials.

  16. Genome Analysis of the First Extensively Drug-Resistant (XDR Mycobacterium tuberculosis in Malaysia Provides Insights into the Genetic Basis of Its Biology and Drug Resistance.

    Directory of Open Access Journals (Sweden)

    Chee Sian Kuan

    Full Text Available The outbreak of extensively drug-resistant tuberculosis (XDR-TB has become an increasing problem in many TB-burdened countries. The underlying drug resistance mechanisms, including the genetic variation favored by selective pressure in the resistant population, are partially understood. Recently, the first case of XDR-TB was reported in Malaysia. However, the detailed genotype family and mechanisms of the formation of multiple drugs resistance are unknown. We sequenced the whole genome of the UM 1072388579 strain with a 2-kb insert-size library and combined with that from previously sequenced 500-bp-insert paired-end reads to produce an improved sequence with maximal sequencing coverage across the genome. In silico spoligotyping and phylogenetic analyses demonstrated that UM 1072388579 strain belongs to an ancestral-like, non-Beijing clade of East Asia lineage. This is supported by the presence of a number of lineage-specific markers, including fadD28, embA, nuoD and pks7. Polymorphism analysis showed that the drug-susceptibility profile is correlated with the pattern of resistance mutations. Mutations in drug-efflux pumps and the cell wall biogenesis pathway such as mmpL, pks and fadD genes may play an important role in survival and adaptation of this strain to its surrounding environment. In this work, fifty-seven putative promoter SNPs were identified. Among them, we identified a novel SNP located at -4 T allele of TetR/acrR promoter as an informative marker to recognize strains of East Asian lineage. Our work indicates that the UM 1072388579 harbors both classical and uncommon SNPs that allow it to escape from inhibition by many antibiotics. This study provides a strong foundation to dissect the biology and underlying resistance mechanisms of the first reported XDR M. tuberculosis in Malaysia.

  17. Quantification of Markers of Antimalarial Drug Resistance ...

    African Journals Online (AJOL)

    MALISA DR

    2012-08-28

    Aug 28, 2012 ... vivo method for the detection of resistance, and has the potential to guide public health policy in a timely manner. .... signal such that the greater the intensity the greater the parasite .... was carried out by light box illumination, while the phophoimager ..... weakness of underestimation of SNPs/haplotypes.

  18. Insulin resistance induced by antiretroviral drugs: Current ...

    African Journals Online (AJOL)

    Treatment with highly active antiretroviral therapy (HAART) has improved the prognosis of patients with AIDS, but it has also increased the incidence of various metabolic disorders, in particular insulin resistance accompanied by dyslipidaemia, hyperglycaemia and lipodystrophy. This is often accompanied by frank type 2 ...

  19. Drug efflux proteins in multidrug resistant bacteria

    NARCIS (Netherlands)

    vanVeen, HW; Konings, WN

    Bacteria contain an array of transport proteins in their cytoplasmic membrane. Many of these proteins play an important role in conferring resistance to toxic compounds. The multidrug efflux systems encountered in prokaryotic cells are very similar to those observed in eukaryotic cells. Therefore, a

  20. Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review

    Directory of Open Access Journals (Sweden)

    Olliaro P

    2004-01-01

    Full Text Available The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent

  1. Establishing Drug Resistance in Microorganisms by Mass Spectrometry

    Science.gov (United States)

    Demirev, Plamen A.; Hagan, Nathan S.; Antoine, Miquel D.; Lin, Jeffrey S.; Feldman, Andrew B.

    2013-08-01

    A rapid method to determine drug resistance in bacteria based on mass spectrometry is presented. In it, a mass spectrum of an intact microorganism grown in drug-containing stable isotope-labeled media is compared with a mass spectrum of the intact microorganism grown in non-labeled media without the drug present. Drug resistance is determined by predicting characteristic mass shifts of one or more microorganism biomarkers using bioinformatics algorithms. Observing such characteristic mass shifts indicates that the microorganism is viable even in the presence of the drug, thus incorporating the isotopic label into characteristic biomarker molecules. The performance of the method is illustrated on the example of intact E. coli, grown in control (unlabeled) and 13C-labeled media, and analyzed by MALDI TOF MS. Algorithms for data analysis are presented as well.

  2. Antifolate drug resistance: Novel mutations and haplotype ...

    Indian Academy of Sciences (India)

    N P Sarmah

    2017-09-27

    Sep 27, 2017 ... distribution in dhps and dhfr from Northeast India ... The findings of this study strongly discourage the use SP as a partner drug in ACT. ... led to critical hindrances in controlling of Plasmodium fal- ciparum (Pf) malaria in this part of India. ..... alignment editor and analysis programme for Windows95/98/. NT.

  3. Profiling evolutionary landscapes underlying drug resistance

    DEFF Research Database (Denmark)

    Hickman, Rachel

    bacterial communities i.e. biofilms or dormant metabolic states. Antibiotic drugs are currently our best medicine to treat (against) bacterial pathogens due to antibiotics unique properties of being small molecules that are soluble and act systemically. These qualities allow for many modern medical...

  4. Efflux Pump-mediated Drug Resistance in Burkholderia

    Directory of Open Access Journals (Sweden)

    Nicole L Podnecky

    2015-04-01

    Full Text Available Several members of the genus Burkholderia are prominent pathogens. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. Virtually all Burkholderia species are also resistant to polymyxin, prohibiting use of drugs like colistin that are available for treatment of infections caused by most other drug resistant Gram-negative bacteria. Despite clinical significance and antibiotic resistance of Burkholderia species, characterization of efflux pumps lags behind other non-enteric Gram-negative pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa. Although efflux pumps have been described in several Burkholderia species, they have been best studied in B. cenocepacia and B. pseudomallei. As in other non-enteric Gram-negatives, efflux pumps of the resistance nodulation cell division (RND family are the clinically most significant efflux systems in these two species. Several efflux pumps were described in B. cenocepacia, which when expressed confer resistance to clinically significant antibiotics, including aminoglycosides, chloramphenicol, fluoroquinolones, and tetracyclines. Three RND pumps have been characterized in B. pseudomallei, two of which confer either intrinsic or acquired resistance to aminoglycosides, macrolides, chloramphenicol, fluoroquinolones, tetracyclines, trimethoprim, and in some instances trimethoprim+sulfamethoxazole. Several strains of the host-adapted B. mallei, a clone of B. pseudomallei, lack AmrAB-OprA and are therefore aminoglycoside and macrolide susceptible. B. thailandensis is closely related to B. pseudomallei, but non-pathogenic to humans. Its pump repertoire and ensuing drug resistance profile parallels that of B. pseudomallei. An efflux pump in B. vietnamiensis plays a significant role in acquired aminoglycoside resistance. Summarily, efflux pumps are significant players in Burkholderia drug resistance.

  5. Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria.

    Directory of Open Access Journals (Sweden)

    Richard J Pearce

    2009-04-01

    Full Text Available Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps gene and mapped their contemporary distribution.We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations.Resistant dhps has emerged independently in multiple sites in Africa during the past 10-20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns.

  6. In vivo selection of resistant E. coli after ingestion of milk with added drug residues.

    Directory of Open Access Journals (Sweden)

    Richard Van Vleck Pereira

    Full Text Available Antimicrobial resistance represents a major global threat to modern medicine. In vitro studies have shown that very low concentrations of drugs, as frequently identified in the environment, and in foods and water for human and animal consumption, can select for resistant bacteria. However, limited information is currently available on the in vivo impact of ingested drug residues. The objective of our study was to evaluate the effect of feeding preweaned calves milk containing antimicrobial drug residues (below the minimum inhibitory concentration, similar to concentrations detected in milk commonly fed to dairy calves, on selection of resistant fecal E. coli in calves from birth to weaning. At birth, thirty calves were randomly assigned to a controlled feeding trial where: 15 calves were fed raw milk with no drug residues (NR, and 15 calves were fed raw milk with drug residues (DR by adding ceftiofur, penicillin, ampicillin, and oxytetracycline at final concentrations in the milk of 0.1, 0.005, 0.01, and 0.3 µg/ml, respectively. Fecal samples were rectally collected from each calf once a week starting at birth prior to the first feeding in the trial (pre-treatment until 6 weeks of age. A significantly greater proportion of E. coli resistant to ampicillin, cefoxitin, ceftiofur, streptomycin and tetracycline was observed in DR calves when compared to NR calves. Additionally, isolates from DR calves had a significant decrease in susceptibility to ceftriaxone and ceftiofur when compared to isolates from NR calves. A greater proportion of E. coli isolates from calves in the DR group were resistant to 3 or more antimicrobial drugs when compared to calves in the ND group. These findings highlight the role that low concentrations of antimicrobial drugs have on the evolution and selection of resistance to multiple antimicrobial drugs in vivo.

  7. Extensively Drug-Resistant Tuberculosis: Principles of Resistance, Diagnosis, and Management.

    Science.gov (United States)

    Wilson, John W; Tsukayama, Dean T

    2016-04-01

    Extensively drug-resistant (XDR) tuberculosis (TB) is an unfortunate by-product of mankind's medical and pharmaceutical ingenuity during the past 60 years. Although new drug developments have enabled TB to be more readily curable, inappropriate TB management has led to the emergence of drug-resistant disease. Extensively drug-resistant TB describes Mycobacterium tuberculosis that is collectively resistant to isoniazid, rifampin, a fluoroquinolone, and an injectable agent. It proliferates when established case management and infection control procedures are not followed. Optimized treatment outcomes necessitate time-sensitive diagnoses, along with expanded combinations and prolonged durations of antimicrobial drug therapy. The challenges to public health institutions are immense and most noteworthy in underresourced communities and in patients coinfected with human immunodeficiency virus. A comprehensive and multidisciplinary case management approach is required to optimize outcomes. We review the principles of TB drug resistance and the risk factors, diagnosis, and managerial approaches for extensively drug-resistant TB. Treatment outcomes, cost, and unresolved medical issues are also discussed. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  8. Nanoparticles: Alternatives Against Drug-Resistant Pathogenic Microbes

    Directory of Open Access Journals (Sweden)

    Gudepalya Renukaiah Rudramurthy

    2016-06-01

    Full Text Available Antimicrobial substances may be synthetic, semisynthetic, or of natural origin (i.e., from plants and animals. Antimicrobials are considered “miracle drugs” and can determine if an infected patient/animal recovers or dies. However, the misuse of antimicrobials has led to the development of multi-drug-resistant bacteria, which is one of the greatest challenges for healthcare practitioners and is a significant global threat. The major concern with the development of antimicrobial resistance is the spread of resistant organisms. The replacement of conventional antimicrobials by new technology to counteract antimicrobial resistance is ongoing. Nanotechnology-driven innovations provide hope for patients and practitioners in overcoming the problem of drug resistance. Nanomaterials have tremendous potential in both the medical and veterinary fields. Several nanostructures comprising metallic particles have been developed to counteract microbial pathogens. The effectiveness of nanoparticles (NPs depends on the interaction between the microorganism and the NPs. The development of effective nanomaterials requires in-depth knowledge of the physicochemical properties of NPs and the biological aspects of microorganisms. However, the risks associated with using NPs in healthcare need to be addressed. The present review highlights the antimicrobial effects of various nanomaterials and their potential advantages, drawbacks, or side effects. In addition, this comprehensive information may be useful in the discovery of broad-spectrum antimicrobial drugs for use against multi-drug-resistant microbial pathogens in the near future.

  9. 75 FR 69591 - Medicaid Program; Withdrawal of Determination of Average Manufacturer Price, Multiple Source Drug...

    Science.gov (United States)

    2010-11-15

    ..., Multiple Source Drug Definition, and Upper Limits for Multiple Source Drugs AGENCY: Centers for Medicare... withdrawing the definition of ``multiple source drug'' as it was revised in the ``Medicaid Program; Multiple Source Drug Definition'' final rule published in the October 7, 2008 Federal Register. DATES: Effective...

  10. Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance.

    Science.gov (United States)

    Khdair, Ayman; Chen, Di; Patil, Yogesh; Ma, Linan; Dou, Q Ping; Shekhar, Malathy P V; Panyam, Jayanth

    2010-01-25

    Tumor drug resistance significantly limits the success of chemotherapy in the clinic. Tumor cells utilize multiple mechanisms to prevent the accumulation of anticancer drugs at their intracellular site of action. In this study, we investigated the anticancer efficacy of doxorubicin in combination with photodynamic therapy using methylene blue in a drug-resistant mouse tumor model. Surfactant-polymer hybrid nanoparticles formulated using an anionic surfactant, Aerosol-OT (AOT), and a naturally occurring polysaccharide polymer, sodium alginate, were used for synchronized delivery of the two drugs. Balb/c mice bearing syngeneic JC tumors (mammary adenocarcinoma) were used as a drug-resistant tumor model. Nanoparticle-mediated combination therapy significantly inhibited tumor growth and improved animal survival. Nanoparticle-mediated combination treatment resulted in enhanced tumor accumulation of both doxorubicin and methylene blue, significant inhibition of tumor cell proliferation, and increased induction of apoptosis. These data suggest that nanoparticle-mediated combination chemotherapy and photodynamic therapy using doxorubicin and methylene blue has significant therapeutic potential against drug-resistant tumors. Copyright 2009 Elsevier B.V. All rights reserved.

  11. An investigation of classification algorithms for predicting HIV drug resistance without genotype resistance testing

    CSIR Research Space (South Africa)

    Brandt, P

    2014-01-01

    Full Text Available is limited in low-resource settings. In this paper we investigate machine learning techniques for drug resistance prediction from routine treatment and laboratory data to help clinicians select patients for confirmatory genotype testing. The techniques...

  12. Breeding cassava for multiple pest resistance in Africa | Mahungu ...

    African Journals Online (AJOL)

    The green spider mite and cassava mealybug are by far the most economically important arthropod pests. The long growing period and diverse agroecologies in which cassava cultivars are grown expose them to one or more of these problems and the losses can be devastating. Multiple pest resistance helps to ensure ...

  13. Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies

    Directory of Open Access Journals (Sweden)

    Dondorp Arjen M

    2008-11-01

    Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with

  14. mTOR Signaling Confers Resistance to Targeted Cancer Drugs.

    Science.gov (United States)

    Guri, Yakir; Hall, Michael N

    2016-11-01

    Cancer is a complex disease and a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that target cancer-specific signaling pathways. However, the clinical benefits of such drugs are at best transient due to tumors displaying intrinsic or adaptive resistance. The underlying compensatory pathways that allow cancer cells to circumvent a drug blockade are poorly understood. We review here recent studies suggesting that mammalian TOR (mTOR) signaling is a major compensatory pathway conferring resistance to many cancer drugs. mTOR-mediated resistance can be cell-autonomous or non-cell-autonomous. These findings suggest that mTOR signaling should be monitored routinely in tumors and that an mTOR inhibitor should be considered as a co-therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Prevalence of genotypic HIV-1 drug resistance in Thailand, 2002

    Directory of Open Access Journals (Sweden)

    Watitpun Chotip

    2003-03-01

    Full Text Available Abstract Background The prices of reverse transcriptase (RT inhibitors in Thailand have been reduced since December 1, 2001. It is expected that reduction in the price of these inhibitors may influence the drug resistance mutation pattern of HIV-1 among infected people. This study reports the frequency of HIV-1 genetic mutation associated with drug resistance in antiretroviral-treated patients from Thailand. Methods Genotypic resistance testing was performed on samples collected in 2002 from 88 HIV-1 infected individuals. Automated DNA sequencing was used to genotype the HIV-1 polymerase gene isolated from patients' plasma. Results Resistance to protease inhibitors, nucleoside and non-nucleoside reverse transcriptase inhibitors were found in 10 (12%, 42 (48% and 19 (21% patients, respectively. The most common drug resistance mutations in the protease gene were at codon 82 (8%, 90 (7% and 54 (6%, whereas resistant mutations at codon 215 (45%, 67 (40%, 41 (38% and 184 (27% were commonly found in the RT gene. This finding indicates that genotypic resistance to nucleoside reverse transcriptase inhibitors was prevalent in 2002. The frequency of resistant mutations corresponding to non-nucleoside reverse transcriptase inhibitors was three times higher-, while resistant mutation corresponding to protease inhibitors was two times lower than those frequencies determined in 2001. Conclusion This study shows that the frequencies of RT inhibitor resistance mutations have been increased after the reduction in the price of RT inhibitors since December 2001. We believe that this was an important factor that influenced the mutation patterns of HIV-1 protease and RT genes in Thailand.

  16. Enhanced transmission of drug-resistant parasites to mosquitoes following drug treatment in rodent malaria.

    Directory of Open Access Journals (Sweden)

    Andrew S Bell

    Full Text Available The evolution of drug resistant Plasmodium parasites is a major challenge to effective malaria control. In theory, competitive interactions between sensitive parasites and resistant parasites within infections are a major determinant of the rate at which parasite evolution undermines drug efficacy. Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it. Here we report that for the murine model Plasmodium chabaudi, co-infection with drug-sensitive parasites can prevent the transmission of initially rare resistant parasites to mosquitoes. Removal of drug-sensitive parasites following chemotherapy enabled resistant parasites to transmit to mosquitoes as successfully as sensitive parasites in the absence of treatment. We also show that the genetic composition of gametocyte populations in host venous blood accurately reflects the genetic composition of gametocytes taken up by mosquitoes. Our data demonstrate that, at least for this mouse model, aggressive chemotherapy leads to very effective transmission of highly resistant parasites that are present in an infection, the very parasites which undermine the long term efficacy of front-line drugs.

  17. CHANGES IN THE PREVALENCE OF DRUG RESISTANT TUBERCULOSIS

    Directory of Open Access Journals (Sweden)

    V. B. Galkin

    2017-01-01

    Full Text Available The tendency of tuberculosis prevalence reduction observed in the Russian Federation is mostly related to the cases without multiple drug resistance (MDR. In general the number of MDR TB cases still tends to be increasing in the Russian Federation. Confident long-term reduction is registered only in the Central and North-Western Districts with relatively low level of MDR TB prevalence. From 2017 MDR TB patients are expected to prevail in the structure of the sputum positive cases which surely provides negative impact on the treatment efficiency and epidemic trends. The system of dispensary follow-up allows evaluating the annual number of MDT TB cases and following the ways of its increase and reduction. Taking MDR TB sources on and off the register is less intensive compared to the same flows of non-MDR infectious cases. The number of MDR TB sources is increasing mostly due new tuberculosis cases however acquired MDR TB makes significant contribution to the growth of MDR TB sources number. The increase in the ratio of respiratory MDR TB patients with sputum conversion to those died reflects the success in the improvement of the treatment strategy of MDR TB patients.

  18. Salvage Therapy of Multiple Myeloma: The New Generation Drugs

    Directory of Open Access Journals (Sweden)

    Alessandra Romano

    2014-01-01

    Full Text Available During the past decade, overall results of treatment of multiple myeloma (MM have been improved and survival curves are now significantly better with respect to those obtained with historical treatment. These improvements are linked to a deeper knowledge of the biology of disease and to the introduction in clinical practice of drugs with different mechanism of action such as proteasome inhibitors and immunomodulatory drugs (IMiDs. However, MM remains in most cases an incurable disease. For patients who relapse after treatment with novel agents, the prognosis is dismal and new drugs and therapeutic strategies are required for continued disease control. In this review, we summarize new insights in salvage therapy for relapsed/refractory MM as emerging from recent clinical trials exploring the activity of bendamustine, new generation proteasome inhibitors, novel IMiDs, monoclonal antibodies, and drugs interfering with growth pathways.

  19. Salvage Therapy of Multiple Myeloma: The New Generation Drugs

    Science.gov (United States)

    Romano, Alessandra; Conticello, Concetta; Di Raimondo, Cosimo; Schinocca, Elena; La Fauci, Alessia; Parrinello, Nunziatina Laura; Chiarenza, Annalisa

    2014-01-01

    During the past decade, overall results of treatment of multiple myeloma (MM) have been improved and survival curves are now significantly better with respect to those obtained with historical treatment. These improvements are linked to a deeper knowledge of the biology of disease and to the introduction in clinical practice of drugs with different mechanism of action such as proteasome inhibitors and immunomodulatory drugs (IMiDs). However, MM remains in most cases an incurable disease. For patients who relapse after treatment with novel agents, the prognosis is dismal and new drugs and therapeutic strategies are required for continued disease control. In this review, we summarize new insights in salvage therapy for relapsed/refractory MM as emerging from recent clinical trials exploring the activity of bendamustine, new generation proteasome inhibitors, novel IMiDs, monoclonal antibodies, and drugs interfering with growth pathways. PMID:24967371

  20. Raman spectroscopy differentiates between sensitive and resistant multiple myeloma cell lines

    Science.gov (United States)

    Franco, Domenico; Trusso, Sebastiano; Fazio, Enza; Allegra, Alessandro; Musolino, Caterina; Speciale, Antonio; Cimino, Francesco; Saija, Antonella; Neri, Fortunato; Nicolò, Marco S.; Guglielmino, Salvatore P. P.

    2017-12-01

    Current methods for identifying neoplastic cells and discerning them from their normal counterparts are often nonspecific and biologically perturbing. Here, we show that single-cell micro-Raman spectroscopy can be used to discriminate between resistant and sensitive multiple myeloma cell lines based on their highly reproducible biomolecular spectral signatures. In order to demonstrate robustness of the proposed approach, we used two different cell lines of multiple myeloma, namely MM.1S and U266B1, and their counterparts MM.1R and U266/BTZ-R subtypes, resistant to dexamethasone and bortezomib, respectively. Then, micro-Raman spectroscopy provides an easily accurate and noninvasive method for cancer detection for both research and clinical environments. Characteristic peaks, mostly due to different DNA/RNA ratio, nucleic acids, lipids and protein concentrations, allow for discerning the sensitive and resistant subtypes. We also explored principal component analysis (PCA) for resistant cell identification and classification. Sensitive and resistant cells form distinct clusters that can be defined using just two principal components. The identification of drug-resistant cells by confocal micro-Raman spectroscopy is thus proposed as a clinical tool to assess the development of resistance to glucocorticoids and proteasome inhibitors in myeloma cells.

  1. What is the mechanism for persistent coexistence of drug-susceptible and drug-resistant strains of Streptococcus pneumoniae?

    Science.gov (United States)

    Colijn, Caroline; Cohen, Ted; Fraser, Christophe; Hanage, William; Goldstein, Edward; Givon-Lavi, Noga; Dagan, Ron; Lipsitch, Marc

    2010-01-01

    The rise of antimicrobial resistance in many pathogens presents a major challenge to the treatment and control of infectious diseases. Furthermore, the observation that drug-resistant strains have risen to substantial prevalence but have not replaced drug-susceptible strains despite continuing (and even growing) selective pressure by antimicrobial use presents an important problem for those who study the dynamics of infectious diseases. While simple competition models predict the exclusion of one strain in favour of whichever is ‘fitter’, or has a higher reproduction number, we argue that in the case of Streptococcus pneumoniae there has been persistent coexistence of drug-sensitive and drug-resistant strains, with neither approaching 100 per cent prevalence. We have previously proposed that models seeking to understand the origins of coexistence should not incorporate implicit mechanisms that build in stable coexistence ‘for free’. Here, we construct a series of such ‘structurally neutral’ models that incorporate various features of bacterial spread and host heterogeneity that have been proposed as mechanisms that may promote coexistence. We ask to what extent coexistence is a typical outcome in each. We find that while coexistence is possible in each of the models we consider, it is relatively rare, with two exceptions: (i) allowing simultaneous dual transmission of sensitive and resistant strains lets coexistence become a typical outcome, as does (ii) modelling each strain as competing more strongly with itself than with the other strain, i.e. self-immunity greater than cross-immunity. We conclude that while treatment and contact heterogeneity can promote coexistence to some extent, the in-host interactions between strains, particularly the interplay between coinfection, multiple infection and immunity, play a crucial role in the long-term population dynamics of pathogens with drug resistance. PMID:19940002

  2. Dynamic optical tweezers based assay for monitoring early drug resistance

    International Nuclear Information System (INIS)

    Wu, Xiaojing; Zhu, Siwei; Feng, Jie; Zhang, Yuquan; Min, Changjun; Yuan, X-C

    2013-01-01

    In this letter, a dynamic optical tweezers based assay is proposed and investigated for monitoring early drug resistance with Pemetrexed-resistant non-small cell lung cancer (NSCLC) cell lines. The validity and stability of the method are verified experimentally in terms of the physical parameters of the optical tweezers system. The results demonstrate that the proposed technique is more convenient and faster than traditional techniques when the capability of detecting small variations of the response of cells to a drug is maintained. (letter)

  3. Multi drug resistance to cancer chemotherapy: Genes involved and blockers

    International Nuclear Information System (INIS)

    Sayed-Ahmed, Mohamed M.

    2007-01-01

    During the last three decades, important and considerable research efforts had been performed to investigate the mechanism through which cancer cells overcome the cytotoxic effects of a variety of chemotherapeutic drugs. Most of the previously published work has been focused on the resistance of tumor cells to those anticancer drugs of natural source. Multidrug resistance (MDR) is a cellular cross-resistance to a broad spectrum of natural products used in cancer chemotherapy and is believed to be the major cause of the therapeutic failures of the drugs belonging to different naturally obtained or semisynthetic groups including vinca alkaloids, taxans, epipodophyllotoxins and certain antibiotics. This phenomenon results from overexpression of four MDR genes and their corresponding proteins that act as membrane-bound ATP consuming pumps. These proteins mediate the efflux of many structurally and functionally unrelated anticancer drugs of natural source. MDR may be intrinsic or acquired following exposure to chemotherapy. The existence of intrinsically resistant tumor cell clone before and following chemotherapeutic treatment has been associated with a worse final outcome because of increased incidence of distant metasis. In view of irreplaceability of natural product anticancer drugs as effective chemotherapeutic agents, and in view of MDR as a major obstacle to successful chemotherapy, this review is aimed to highlight the genes involved in MDR, classical MDR blockers and gene therapy approaches to overcome MDR. (author)

  4. "A'ole" Drugs! Cultural Practices and Drug Resistance of Rural Hawai'ian Youths

    Science.gov (United States)

    Po'A-Kekuawela, Ka'Ohinani; Okamoto, Scott K.; Nebre, La Risa H.; Helm, Susana; Chin, Coralee I. H.

    2009-01-01

    This qualitative study examined how Native Hawai'ian youths from rural communities utilized cultural practices to promote drug resistance and/or abstinence. Forty-seven students from five different middle schools participated in gender-specific focus groups that focused on the cultural and environmental contexts of drug use for Native Hawai'ian…

  5. Characterization of p38 MAPK isoforms for drug resistance study using systems biology approach.

    Science.gov (United States)

    Peng, Huiming; Peng, Tao; Wen, Jianguo; Engler, David A; Matsunami, Risë K; Su, Jing; Zhang, Le; Chang, Chung-Che Jeff; Zhou, Xiaobo

    2014-07-01

    p38 mitogen-activated protein kinase activation plays an important role in resistance to chemotherapeutic cytotoxic drugs in treating multiple myeloma (MM). However, how the p38 mitogen-activated protein kinase signaling pathway is involved in drug resistance, in particular the roles that the various p38 isoforms play, remains largely unknown. To explore the underlying mechanisms, we developed a novel systems biology approach by integrating liquid chromatography-mass spectrometry and reverse phase protein array data from human MM cell lines with computational pathway models in which the unknown parameters were inferred using a proposed novel algorithm called modularized factor graph. New mechanisms predicted by our models suggest that combined activation of various p38 isoforms may result in drug resistance in MM via regulating the related pathways including extracellular signal-regulated kinase (ERK) pathway and NFкB pathway. ERK pathway regulating cell growth is synergistically regulated by p38δ isoform, whereas nuclear factor kappa B (NFкB) pathway regulating cell apoptosis is synergistically regulated by p38α isoform. This finding that p38δ isoform promotes the phosphorylation of ERK1/2 in MM cells treated with bortezomib was validated by western blotting. Based on the predicted mechanisms, we further screened drug combinations in silico and found that a promising drug combination targeting ERK1/2 and NFκB might reduce the effects of drug resistance in MM cells. This study provides a framework of a systems biology approach to studying drug resistance and drug combination selection. RPPA experimental Data and Matlab source codes of modularized factor graph for parameter estimation are freely available online at http://ctsb.is.wfubmc.edu/publications/modularized-factor-graph.php. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Hepatitis C Virus and Antiviral Drug Resistance.

    Science.gov (United States)

    Kim, Seungtaek; Han, Kwang-Hyub; Ahn, Sang Hoon

    2016-11-15

    Since its discovery in 1989, hepatitis C virus (HCV) has been intensively investigated to understand its biology and develop effective antiviral therapies. The efforts of the previous 25 years have resulted in a better understanding of the virus, and this was facilitated by the development of in vitro cell culture systems for HCV replication. Antiviral treatments and sustained virological responses have also improved from the early interferon monotherapy to the current all-oral regimens using direct-acting antivirals. However, antiviral resistance has become a critical issue in the treatment of chronic hepatitis C, similar to other chronic viral infections, and retreatment options following treatment failure have become important questions. Despite the clinical challenges in the management of chronic hepatitis C, substantial progress has been made in understanding HCV, which may facilitate the investigation of other closely related flaviviruses and lead to the development of antiviral agents against these human pathogens.

  7. Detection of multi-drug resistant Escherichia coli in the urban waterways of Milwaukee, WI

    Directory of Open Access Journals (Sweden)

    Anthony D. Kappell

    2015-04-01

    Full Text Available Urban waterways represent a natural reservoir of antibiotic resistance which may provide a source of transferable genetic elements to human commensal bacteria and pathogens. The objective of this study was to evaluate antibiotic resistance of Escherichia coli isolated from the urban waterways of Milwaukee, WI compared to those from Milwaukee sewage and a clinical setting in Milwaukee. Antibiotics covering 10 different families were utilized to determine the phenotypic antibiotic resistance for all 259 E. coli isolates. All obtained isolates were determined to be multi-drug resistant. The E. coli isolates were also screened for the presence of the genetic determinants of resistance including ermB (macrolide resistance, tet(M (tetracycline resistance, and β-lactamases (blaOXA, blaSHV, and blaPSE. E. coli from urban waterways showed a greater incidence of antibiotic resistance to 8 of 17 antibiotics tested compared to human derived sources. These E. coli isolates also demonstrated a greater incidence of resistance to higher numbers of antibiotics compared to the human derived isolates. The urban waterways demonstrated a greater abundance of isolates with co-occurrence of antibiotic resistance than human derived sources. When screened for 5 different antibiotic resistance genes conferring macrolide, tetracycline, and β-lactam resistance, clinical E. coli isolates were more likely to harbor ermB and blaOXA than isolates from urban waterway. These results indicate that Milwaukee’s urban waterways may select for a greater incidence of multiple antibiotic resistance organisms and likely harbor a different antibiotic resistance gene pool than clinical sources. The implications of this study are significant to understanding the presence of resistance in urban freshwater environments by supporting the idea that sediment from urban waterways serves as a reservoir of antibiotic resistance.

  8. Epigenetic Modulation of the Biophysical Properties of Drug-Resistant Cell Lipids to Restore Drug Transport and Endocytic Functions

    OpenAIRE

    Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

    2012-01-01

    In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g....

  9. Effect and Safety of Shihogyejitang for Drug Resistant Childhood Epilepsy

    Directory of Open Access Journals (Sweden)

    Jinsoo Lee

    2016-01-01

    Full Text Available Objective. Herbal medicine has been widely used to treat drug resistant epilepsy. Shihogyejitang (SGT has been commonly used to treat epilepsy. We investigated the effect and safety of SGT in children with drug resistant epilepsy. Design. We reviewed medical records of 54 patients with epilepsy, who failed to respond to at least two antiepileptic drugs and have been treated with SGT between April 2006 and June 2014 at the Department of Pediatric Neurology, I-Tomato Hospital, Korea. Effect was measured by the response rate, seizure-free rate, and retention rate at six months. We also checked adverse events, change in antiepileptic drugs use, and the variables related to the outcome. Results. Intent-to-treat analysis showed that, after six months, 44.4% showed a >50% seizure reduction, 24.1% including seizure-free, respectively, and 53.7% remained on SGT. Two adverse events were reported, mild skin rash and fever. Focal seizure type presented significantly more positive responses when compared with other seizure types at six months (p=0.0284, Fisher’s exact test. Conclusion. SGT is an effective treatment with excellent tolerability for drug resistant epilepsy patients. Our data provide evidence that SGT may be used as alternative treatment option when antiepileptic drug does not work in epilepsy children.

  10. Having multiple sexual partners among Iranian Injection Drug Users

    Directory of Open Access Journals (Sweden)

    Shervin eAssari

    2014-10-01

    Full Text Available Background: Transmission of HIV from intra-venous drug users (IDUs to the community occurs predominantly through high-risk sexual behaviors. Limited information exists regarding the high-risk sexual behaviors of IDUs in Iran. Aim. The aim of this study was to determine the prevalence and factors associated with having multiple sexual partners among Iranian IDUs. Methods. This is a national survey on drug-dependent adults. Participants were sampled from medical centers, prisons, and streets of capitals of 29 provinces in Iran, between May 2007 and February 2008. We analyzed data of 1,416 current IDUs. Socio-demographics and drug use characteristics were entered into a binary logistic regression model to determine predictors of having multiple sexual partners. Results. Having multiple sexual partners in the past or at the time of survey was reported by 56.4% of Iranian IDUs. Multivariate analysis showed that the likelihood of having multiple sexual partners in IDUs decreased by being married (odds ratio [OR], 0.38; P < .001 and increased by female gender (OR, 13.44; P = .02, having illegal income (OR, 1.72; P = .003, higher monthly family income (OR, 1.01; P = .003, pleasure, curiosity, and recreation as cause of first drug use (OR, 1.37; P = .04, ruins as usual place for injection (OR, 1.89; P = .001, and history of syringe sharing (OR, 1.50; P = .02. Conclusions. Having multiple sexual partners was reported by majority of Iranian IDUs, and this was linked to socio-demographics, initiation data, and other risk behaviors. This information should be considered in prevention efforts to reduce sexual transmission of HIV infection in Iran.

  11. A Multiple Indicators Multiple Causes (MIMIC) model of internal barriers to drug treatment in China.

    Science.gov (United States)

    Qi, Chang; Kelly, Brian C; Liao, Yanhui; He, Haoyu; Luo, Tao; Deng, Huiqiong; Liu, Tieqiao; Hao, Wei; Wang, Jichuan

    2015-03-01

    Although evidence exists for distinct barriers to drug abuse treatment (BDATs), investigations of their inter-relationships and the effect of individual characteristics on the barrier factors have been sparse, especially in China. A Multiple Indicators Multiple Causes (MIMIC) model is applied for this target. A sample of 262 drug users were recruited from three drug rehabilitation centers in Hunan Province, China. We applied a MIMIC approach to investigate the effect of gender, age, marital status, education, primary substance use, duration of primary drug use, and drug treatment experience on the internal barrier factors: absence of problem (AP), negative social support (NSS), fear of treatment (FT), and privacy concerns (PC). Drug users of various characteristics were found to report different internal barrier factors. Younger participants were more likely to report NSS (-0.19, p=0.038) and PC (-0.31, p<0.001). Compared to other drug users, ice users were more likely to report AP (0.44, p<0.001) and NSS (0.25, p=0.010). Drug treatment experiences related to AP (0.20, p=0.012). In addition, differential item functioning (DIF) occurred in three items when participant from groups with different duration of drug use, ice use, or marital status. Individual characteristics had significant effects on internal barriers to drug treatment. On this basis, BDAT perceived by different individuals could be assessed before tactics were utilized to successfully remove perceived barriers to drug treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. Multiple Drug Transport Pathways through Human P-Glycoprotein.

    Science.gov (United States)

    McCormick, James W; Vogel, Pia D; Wise, John G

    2015-07-21

    P-Glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell. Because of the broad range of substrates transported by P-gp, overexpression of P-gp causes multidrug resistance. We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11-12 Å through the plane of the membrane as P-gp progressed through a catalytic cycle. Methylpyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane. The specific side-chain interactions with drugs within each pathway seemed to be, at least in part, stochastic. The docking and transport properties of a P-gp inhibitor, tariquidar, were also studied. A mechanism of inhibition by tariquidar that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp is presented.

  13. Multiple Drug Transport Pathways through human P-Glycoprotein(†)

    Science.gov (United States)

    McCormick, James W.; Vogel, Pia D.; Wise, John G.

    2015-01-01

    P-glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell. Because of the broad range of substrates transported by P-gp, overexpression of P-gp causes multidrug resistance. We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11 to 12 Å through the plane of the membrane as P-gp progressed through a catalytic cycle. Methyl-pyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane. The specific side-chain interactions with drugs within each pathway seemed to be, at least in part, stochastic. The docking and transport properties of a P-gp inhibitor, tariquidar, were also studied. A mechanism of inhibition by tariquidar is presented that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp. PMID:26125482

  14. Influence of multidrug resistance and drug transport proteins on chemotherapy drug metabolism.

    Science.gov (United States)

    Joyce, Helena; McCann, Andrew; Clynes, Martin; Larkin, Annemarie

    2015-05-01

    Chemotherapy involving the use of anticancer drugs remains an important strategy in the overall management of patients with metastatic cancer. Acquisition of multidrug resistance remains a major impediment to successful chemotherapy. Drug transporters in cell membranes and intracellular drug metabolizing enzymes contribute to the resistance phenotype and determine the pharmacokinetics of anticancer drugs in the body. ATP-binding cassette (ABC) transporters mediate the transport of endogenous metabolites and xenobiotics including cytotoxic drugs out of cells. Solute carrier (SLC) transporters mediate the influx of cytotoxic drugs into cells. This review focuses on the substrate interaction of these transporters, on their biology and what role they play together with drug metabolizing enzymes in eliminating therapeutic drugs from cells. The majority of anticancer drugs are substrates for the ABC transporter and SLC transporter families. Together, these proteins have the ability to control the influx and the efflux of structurally unrelated chemotherapeutic drugs, thereby modulating the intracellular drug concentration. These interactions have important clinical implications for chemotherapy because ultimately they determine therapeutic efficacy, disease progression/relapse and the success or failure of patient treatment.

  15. Genotypes of Mycobacterium tuberculosis in patients at risk of drug resistance in Bolivia.

    Science.gov (United States)

    Monteserin, Johana; Camacho, Mirtha; Barrera, Lucía; Palomino, Juan Carlos; Ritacco, Viviana; Martin, Anandi

    2013-07-01

    Bolivia ranks among the 10 Latin American countries with the highest rates of tuberculosis (TB) and multidrug resistant (MDR) TB. In view of this, and of the lacking information on the population structure of Mycobacterium tuberculosis in the country, we explored genotype associations with drug resistance and clustering by analyzing isolates collected in 2010 from 100 consecutive TB patients at risk of drug resistance in seven of the nine departments in which Bolivia is divided. Fourteen isolates were MDR, 29 had other drug resistance profiles, and 57 were pansusceptible. Spoligotype family distribution was: Haarlem 39.4%, LAM 26.3%, T 22.2%, S 2.0%, X 1.0%, orphan 9.1%, with very low intra-family diversity and absence of Beijing genotypes. We found 66 different MIRU-VNTR patterns; the most frequent corresponded to Multiple Locus Variable Analysis (MLVA) MtbC15 patterns 860, 372 and 873. Twelve clusters, each with identical MIRU-VNTR and spoligotypes, gathered 35 patients. We found no association of genotype with drug resistant or MDR-TB. Clustering associated with SIT 50 and the H3 subfamily to which it belongs (pBolivia. However, results should be taken cautiously because the sample is small and includes a particular subset of M. tuberculosis population. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Emerging drug -resistance and guidelines for treatment of malaria

    International Nuclear Information System (INIS)

    Khan, M.A.; Smego Jr, R.A.; Razi, S.T.; Beg, M.A.

    2004-01-01

    The increasing prevalence of multi-resistant Plasmodium falciparum malaria worldwide is a serious public health threat to the global control of malaria, especially in poor countries like Pakistan. In many countries chloroquine-resistance is a huge problem, accounting for more than 90% of malaria cases. In Pakistan, resistance to chloroquine is on the rise and reported in up to 16- 62% of Plasmodium falciparum. Four to 25% of Plasmodium falciparum also reported to be resistant to sulfadoxine-pyrimethamine and several cases of delayed parasite clearance have been observed in patients with Plasmodium falciparum malaria treated with quinine. In this article we have introduced the concept of artemisinin- based combination therapy (ACT) and emphasize the use of empiric combination therapy for all patients with Plasmodium falciparum malaria to prevent development of drug resistance and to obtain additive and synergistic killing of parasite. (author)

  17. Drug-resistant tuberculosis in Mumbai, India: An agenda for operations research

    Science.gov (United States)

    Mistry, Nerges; Tolani, Monica; Osrin, David

    2012-01-01

    Operations research (OR) is well established in India and is also a prominent feature of the global and local agendas for tuberculosis (TB) control. India accounts for a quarter of the global burden of TB and of new cases. Multidrug-resistant TB is a significant problem in Mumbai, India’s most populous city, and there have been recent reports of totally resistant TB. Much thought has been given to the role of OR in addressing programmatic challenges, by both international partnerships and India’s Revised National TB Control Programme. We attempt to summarize the major challenges to TB control in Mumbai, with an emphasis on drug resistance. Specific challenges include diagnosis of TB and defining cure, detecting drug resistant TB, multiple sources of health care in the private, public and informal sectors, co-infection with human immunodeficiency virus (HIV) and a concurrent epidemic of non-communicable diseases, suboptimal prescribing practices, and infection control. We propose a local agenda for OR: modeling the effects of newer technologies, active case detection, and changes in timing of activities, and mapping hotspots and contact networks; modeling the effects of drug control, changing the balance of ambulatory and inpatient care, and adverse drug reactions; modeling the effects of integration of TB and HIV diagnosis and management, and preventive drug therapy; and modeling the effects of initiatives to improve infection control. PMID:24501697

  18. Pattern of secondary acquired drug resistance to antituberculosis drug in Mumbai, India--1991-1995.

    Science.gov (United States)

    Chowgule, R V; Deodhar, L

    1998-01-01

    A retrospective observational study was conducted to find out whether secondary acquired drug resistance to isoniazid and ethambutol is high and to rifamycin and pyrazinamide is low, as is commonly believed in India. There were 2033 patients, whose sputum samples (6099) were reviewed from a specimen registry of the microbiology laboratory for the years 1991 to 1995. Of these, 521 (25.6%) patients [335 males and 186 females; age ranged from 11 to 75 years] had sputum positive culture and sensitivity for acid-fast bacilli (AFB). The drug resistance patterns in our study were: isoniazid (H) 15%, rifamycin (R) 66.8%, pyrazinamide (Z) 72.2%, ethambutol (E) 8.4%, streptomycin (S) 53.6%, cycloserine (C) 39.2% kanamycin (K) 25.1% and ethionamide (Eth) 65.3%. The resistance to streptomycin showed a significant fall over a year while there was a rise in resistance to cycloserine and kanamycin which is significant. The rate of secondary acquired resistance of isoniazid and ethambutol was low, and the rate of secondary acquired resistance to rifamycin and pyrazinamide was high, which is contarary to the common belief regarding these drugs in India. This implies that isoniazid is still a valuable drug in the treatment of multidrug resistance in India.

  19. Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

    Science.gov (United States)

    Upcroft, Peter; Upcroft, Jacqueline A.

    2001-01-01

    The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E. histolytica can form abscesses and invade other organs, where it can be fatal if left untreated. T. vaginalis infection is a sexually transmitted infection causing vaginitis and acute inflammatory disease of the genital mucosa. T. vaginalis has also been reported in the urinary tract, fallopian tubes, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respiratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mortality as well as predisposing to human immunodeficiency virus infection, AIDS, and cervical cancer. All three organisms lack mitochondria and are susceptible to the nitroimidazole metronidazole because of similar low-redox-potential anaerobic metabolic pathways. Resistance to metronidazole and other drugs has been observed clinically and in the laboratory. Laboratory studies have identified the enzyme that activates metronidazole, pyruvate:ferredoxin oxidoreductase, to its nitroso form and distinct mechanisms of decreasing drug susceptibility that are induced in each organism. Although the nitroimidazoles have been the drug family of choice for treating the anaerobic protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been demonstrated for each agent, and the mechanism of resistance has been investigated. Metronidazole resistance in T. vaginalis is well documented, and the principal mechanisms have been defined. Bypass metabolism, such as alternative oxidoreductases, have been discovered in both organisms. Aerobic versus anaerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazole resistance in E. histolytica have recently

  20. Ribonucleotide reductase as a drug target against drug resistance Mycobacterium leprae: A molecular docking study.

    Science.gov (United States)

    Mohanty, Partha Sarathi; Bansal, Avi Kumar; Naaz, Farah; Gupta, Umesh Datta; Dwivedi, Vivek Dhar; Yadava, Umesh

    2018-06-01

    Leprosy is a chronic infection of skin and nerve caused by Mycobacterium leprae. The treatment is based on standard multi drug therapy consisting of dapsone, rifampicin and clofazamine. The use of rifampicin alone or with dapsone led to the emergence of rifampicin-resistant Mycobacterium leprae strains. The emergence of drug-resistant leprosy put a hurdle in the leprosy eradication programme. The present study aimed to predict the molecular model of ribonucleotide reductase (RNR), the enzyme responsible for biosynthesis of nucleotides, to screen new drugs for treatment of drug-resistant leprosy. The study was conducted by retrieving RNR of M. leprae from GenBank. A molecular 3D model of M. leprae was predicted using homology modelling and validated. A total of 325 characters were included in the analysis. The predicted 3D model of RNR showed that the ϕ and φ angles of 251 (96.9%) residues were positioned in the most favoured regions. It was also conferred that 18 α-helices, 6 β turns, 2 γ turns and 48 helix-helix interactions contributed to the predicted 3D structure. Virtual screening of Food and Drug Administration approved drug molecules recovered 1829 drugs of which three molecules, viz., lincomycin, novobiocin and telithromycin, were taken for the docking study. It was observed that the selected drug molecules had a strong affinity towards the modelled protein RNR. This was evident from the binding energy of the drug molecules towards the modelled protein RNR (-6.10, -6.25 and -7.10). Three FDA-approved drugs, viz., lincomycin, novobiocin and telithromycin, could be taken for further clinical studies to find their efficacy against drug resistant leprosy. Copyright © 2018 Elsevier B.V. All rights reserved.

  1. Mycobacterium tuberculosis drug-resistance in previously treated ...

    African Journals Online (AJOL)

    Corresponding to: Professor Lassana Sangaré, Department of Bacteriology and Virology, University Hospital Centre. Yalgado Ouedraogo, 03 BP 7022 Ouagadougou 03, Burkina Faso. E-mail: sangarel@hotmail.com. Abstract. Background: Tuberculosis drug-resistance becomes common in sub-Saharan Africa; however, ...

  2. Diversity of Urinary Tract Pathogens and Drug Resistant Isolates of ...

    African Journals Online (AJOL)

    Purpose: This paper was mainly aimed to investigate drug resistance of the various urinary tract infection (UTI) pathogens from patients of different gender and age groups of Pakistanis. Method: For these purposes, urine samples of 109 patients were analyzed. Samples were screened on CLED agar. Antimicrobial ...

  3. Beijing/W genotype Mycobacterium tuberculosis and drug resistance.

    NARCIS (Netherlands)

    Glynn, Judith R; Kremer, Kristin; Borgdorff, Martien W; Rodriguez, Mar Pujades; Soolingen, Dick van

    2006-01-01

    Beijing/W genotype Mycobacterium tuberculosis is widespread, may be increasing, and may have a predilection for drug resistance. Individual-level data on >29,000 patients from 49 studies in 35 countries were combined to assess the Beijing genotype's prevalence worldwide, trends over time and with

  4. National anti-tuberculosis drug resistance study in Tanzania

    NARCIS (Netherlands)

    Chonde, T. M.; Basra, D.; Mfinanga, S. G. M.; Range, N.; Lwilla, F.; Shirima, R. P.; van Deun, A.; Zignol, M.; Cobelens, F. G.; Egwaga, S. M.; van Leth, F.

    2010-01-01

    OBJECTIVE: To assess the prevalence of anti-tuberculosis drug resistance in a national representative sample of tuberculosis (TB) patients in Tanzania according to recommended methodology. DESIGN: Cluster survey, with 40 clusters sampled proportional to size, of notified TB patients from all

  5. Drug-resistant tuberculosis: time for visionary political leadership.

    Science.gov (United States)

    Abubakar, Ibrahim; Zignol, Matteo; Falzon, Dennis; Raviglione, Mario; Ditiu, Lucica; Masham, Susan; Adetifa, Ifedayo; Ford, Nathan; Cox, Helen; Lawn, Stephen D; Marais, Ben J; McHugh, Timothy D; Mwaba, Peter; Bates, Matthew; Lipman, Marc; Zijenah, Lynn; Logan, Simon; McNerney, Ruth; Zumla, Adam; Sarda, Krishna; Nahid, Payam; Hoelscher, Michael; Pletschette, Michel; Memish, Ziad A; Kim, Peter; Hafner, Richard; Cole, Stewart; Migliori, Giovanni Battista; Maeurer, Markus; Schito, Marco; Zumla, Alimuddin

    2013-06-01

    Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630 000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans. Copyright © 2013 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd. All rights reserved.

  6. Drug-resistant post-neurosurgical nosocomial Acinetobacter ...

    African Journals Online (AJOL)

    Drug-resistant post-neurosurgical nosocomial Acinetobacter baumannii meningitis in two Iranian hospitals. ... Vol 11, No 17 (2012) >. Log in or Register to get access to full text downloads. ... Acinetobacter baumannii may cause meningitis and ventriculitis, particularly after head trauma and/or neurosurgery. The rate of ...

  7. Laboratory methods for diagnosis and detection of drug resistant ...

    African Journals Online (AJOL)

    Data source: Published series of peer reviewed journals and manuals written on laboratory methods that are currently used for diagnosis and detection of drug resistance of Mycobacterium tuberculosis complex were reviewed using the index medicus, pubmed and medline search. Conventional bacteriological microscopy ...

  8. Elucidating the Interdependence of Drug Resistance from Combinations of Mutations.

    Science.gov (United States)

    Ragland, Debra A; Whitfield, Troy W; Lee, Sook-Kyung; Swanstrom, Ronald; Zeldovich, Konstantin B; Kurt-Yilmaz, Nese; Schiffer, Celia A

    2017-11-14

    HIV-1 protease is responsible for the cleavage of 12 nonhomologous sites within the Gag and Gag-Pro-Pol polyproteins in the viral genome. Under the selective pressure of protease inhibition, the virus evolves mutations within (primary) and outside of (secondary) the active site, allowing the protease to process substrates while simultaneously countering inhibition. The primary protease mutations impede inhibitor binding directly, while the secondary mutations are considered accessory mutations that compensate for a loss in fitness. However, the role of secondary mutations in conferring drug resistance remains a largely unresolved topic. We have shown previously that mutations distal to the active site are able to perturb binding of darunavir (DRV) via the protein's internal hydrogen-bonding network. In this study, we show that mutations distal to the active site, regardless of context, can play an interdependent role in drug resistance. Applying eigenvalue decomposition to collections of hydrogen bonding and van der Waals interactions from a series of molecular dynamics simulations of 15 diverse HIV-1 protease variants, we identify sites in the protease where amino acid substitutions lead to perturbations in nonbonded interactions with DRV and/or the hydrogen-bonding network of the protease itself. While primary mutations are known to drive resistance in HIV-1 protease, these findings delineate the significant contributions of accessory mutations to resistance. Identifying the variable positions in the protease that have the greatest impact on drug resistance may aid in future structure-based design of inhibitors.

  9. Multiple Antimicrobial Resistance of Escherichia coli Isolated from Chickens in Iran

    Directory of Open Access Journals (Sweden)

    Reza Talebiyan

    2014-01-01

    Full Text Available Antimicrobial agents are used extremely in order to reduce the great losses caused by Escherichia coli infections in poultry industry. In this study, 318 pathogenic Escherichia coli (APEC strains isolated from commercial broiler flocks with coli-septicemia were examined for antimicrobials of both veterinary and human significance by disc diffusion method. Multiple resistances to antimicrobial agents were observed in all the isolates. Resistance to the antibiotics was as follows: Tylosin (88.68%, Erythromycin (71.70%, Oxytetracycline (43.40%, Sulfadimethoxine-Trimethoprim (39.62%, Enrofloxacin (37.74%, Florfenicol (35.85%, Chlortetracycline (33.96%, Doxycycline (16.98%, Difloxacin (32.08%, Danofloxacin (28.30%, Chloramphenicol (20.75%, Ciprofloxacin (7.55%, and Gentamicin (5.66%. This study showed resistance against the antimicrobial agents that are commonly applied in poultry, although resistance against the antibiotics that are only applied in humans or less frequently used in poultry was significantly low. This study emphasizes on the occurrence of multiple drug resistant E. coli among diseased broiler chickens in Iran. The data revealed the relative risks of using antimicrobials in poultry industry. It also concluded that use of antibiotics must be limited in poultry farms in order to reduce the antibiotic resistances.

  10. Multiple Antimicrobial Resistance of Escherichia coli Isolated from Chickens in Iran.

    Science.gov (United States)

    Talebiyan, Reza; Kheradmand, Mehdi; Khamesipour, Faham; Rabiee-Faradonbeh, Mohammad

    2014-01-01

    Antimicrobial agents are used extremely in order to reduce the great losses caused by Escherichia coli infections in poultry industry. In this study, 318 pathogenic Escherichia coli (APEC) strains isolated from commercial broiler flocks with coli-septicemia were examined for antimicrobials of both veterinary and human significance by disc diffusion method. Multiple resistances to antimicrobial agents were observed in all the isolates. Resistance to the antibiotics was as follows: Tylosin (88.68%), Erythromycin (71.70%), Oxytetracycline (43.40%), Sulfadimethoxine-Trimethoprim (39.62%), Enrofloxacin (37.74%), Florfenicol (35.85%), Chlortetracycline (33.96%), Doxycycline (16.98%), Difloxacin (32.08%), Danofloxacin (28.30%), Chloramphenicol (20.75%), Ciprofloxacin (7.55%), and Gentamicin (5.66%). This study showed resistance against the antimicrobial agents that are commonly applied in poultry, although resistance against the antibiotics that are only applied in humans or less frequently used in poultry was significantly low. This study emphasizes on the occurrence of multiple drug resistant E. coli among diseased broiler chickens in Iran. The data revealed the relative risks of using antimicrobials in poultry industry. It also concluded that use of antibiotics must be limited in poultry farms in order to reduce the antibiotic resistances.

  11. Mechanisms of antifungal drug resistance in Candida dubliniensis.

    LENUS (Irish Health Repository)

    Coleman, David C

    2010-06-01

    Candida dubliniensis was first described in 1995 and is the most closely related species to the predominant human fungal pathogen Candida albicans. C. dubliniensis is significantly less prevalent and less pathogenic than C. albicans and is primarily associated with infections in HIV-infected individuals and other immunocompromised cohorts. The population structure of C. dubliniensis consists of three well-defined major clades and is significantly less diverse than C. albicans. The majority of C. dubliniensis isolates are susceptible to antifungal drugs commonly used to treat Candida infections. To date only two major patterns of antifungal drug resistance have been identified and the molecular mechanisms of these are very similar to the resistance mechanisms that have been described previously in C. albicans. However, significant differences are evident in the predominant antifungal drug mechanisms employed by C. dubliniensis, differences that reflect its more clonal nature, its lower prevalence and characteristics of its genome, the complete sequence of which has only recently been determined.

  12. Effectiveness of multiple sclerosis treatment with current immunomodulatory drugs.

    Science.gov (United States)

    Milo, Ron

    2015-04-01

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS of a putative autoimmune origin characterized by neurologic dysfunction disseminated in space and time due to demyelination and axonal loss that results in progressive disability. Recent advances in understanding the immune pathogenesis of the disease resulted in the introduction of numerous effective immunomodulatoty drugs having diverse mechanisms of action, modes of administration and risk-benefit profiles. This results in more complex albeit more promising treatment selection and choices. The epidemiology, clinical features, pathogenesis and diagnosis of the disease are discussed. The mode of action and main characteristics of current immunomodulatory drugs for MS and their place in the therapeutic algorithm of the disease based on evidence from clinical trials are described. Speculation on new paradigms, treatment goals and outcome measures aimed at improving the landscape of MS treatment is presented. Multiple disease, drug and patient-related factors should be taken into consideration when selecting the appropriate drug and treatment strategy to the appropriate patient, thus paving the road for personalized medicine in MS.

  13. Parallel screening of wild-type and drug-resistant targets for anti-resistance neuraminidase inhibitors.

    Directory of Open Access Journals (Sweden)

    Kai-Cheng Hsu

    Full Text Available Infection with influenza virus is a major public health problem, causing serious illness and death each year. Emergence of drug-resistant influenza virus strains limits the effectiveness of drug treatment. Importantly, a dual H275Y/I223R mutation detected in the pandemic influenza A 2009 virus strain results in multidrug resistance to current neuraminidase (NA drugs. Therefore, discovery of new agents for treating multiple drug-resistant (MDR influenza virus infections is important. Here, we propose a parallel screening strategy that simultaneously screens wild-type (WT and MDR NAs, and identifies inhibitors matching the subsite characteristics of both NA-binding sites. These may maintain their potency when drug-resistant mutations arise. Initially, we analyzed the subsite of the dual H275Y/I223R NA mutant. Analysis of the site-moiety maps of NA protein structures show that the mutant subsite has a relatively small volume and is highly polar compared with the WT subsite. Moreover, the mutant subsite has a high preference for forming hydrogen-bonding interactions with polar moieties. These changes may drive multidrug resistance. Using this strategy, we identified a new inhibitor, Remazol Brilliant Blue R (RB19, an anthraquinone dye, which inhibited WT NA and MDR NA with IC(50 values of 3.4 and 4.5 µM, respectively. RB19 comprises a rigid core scaffold and a flexible chain with a large polar moiety. The former interacts with highly conserved residues, decreasing the probability of resistance. The latter forms van der Waals contacts with the WT subsite and yields hydrogen bonds with the mutant subsite by switching the orientation of its flexible side chain. Both scaffolds of RB19 are good starting points for lead optimization. The results reveal a parallel screening strategy for identifying resistance mechanisms and discovering anti-resistance neuraminidase inhibitors. We believe that this strategy may be applied to other diseases with high

  14. Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions.

    Science.gov (United States)

    Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

    2012-09-04

    In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane's biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug 5-aza-2'-deoxycytidine (decitabine) significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance.

  15. Thermoresponsive Supramolecular Chemotherapy by "V"-Shaped Armed β-Cyclodextrin Star Polymer to Overcome Drug Resistance.

    Science.gov (United States)

    Fan, Xiaoshan; Cheng, Hongwei; Wang, Xiaoyuan; Ye, Enyi; Loh, Xian Jun; Wu, Yun-Long; Li, Zibiao

    2018-04-01

    Pump mediated drug efflux is the key reason to result in the failure of chemotherapy. Herein, a novel star polymer β-CD-v-(PEG-β-PNIPAAm) 7 consisting of a β-CD core, grafted with thermo-responsive poly(N-isopropylacrylamide) (PNIPAAm) and biocompatible poly(ethylene glycol) (PEG) in the multiple "V"-shaped arms is designed and further fabricated into supramolecular nanocarriers for drug resistant cancer therapy. The star polymer could encapsulate chemotherapeutics between β-cyclodextrin and anti-cancer drug via inclusion complex (IC). Furthermore, the temperature induced chain association of PNIPAAm segments facilitated the IC to form supramolecular nanoparticles at 37 °C, whereas the presence of PEG impart great stability to the self-assemblies. When incubated with MDR-1 membrane pump regulated drug resistant tumor cells, much higher and faster cellular uptake of the supramolecular nanoparticles were detected, and the enhanced intracellular retention of drugs could lead to significant inhibition of cell growth. Further in vivo evaluation showed high therapeutic efficacy in suppressing drug resistant tumor growth without a significant impact on the normal functions of main organs. This work signifies thermo-responsive supramolecular chemotherapy is promising in combating pump mediated drug resistance in both in vitro and in vivo models, which may be encouraging for the advanced drug delivery platform design to overcome drug resistant cancer. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Resistance patterns and trends of extensively drug-resistant tuberculosis: 5-year experience

    Directory of Open Access Journals (Sweden)

    Amresh Kumar Singh

    2013-12-01

    Full Text Available Objective:Extensively drug-resistant tuberculosis (XDR-TB strains were emerged when multidrug-resistant TB (MDR- TB was inadequately treated. Inadequate treatment of MDR-TB cases may result in additional resistance especially non-XDR-TB and then XDR-TB. The aim of this study was to know the prevalence, resistance patterns and trends of the XDR-TB strains among the MDR-TB at a tertiary care hospital in Lucknow, India Methods: A total of 430 Mycobacterium isolates were underwent NAP test and TB MPT64 Ag test for the identification of Mycobacterium tuberculosis complex (MTBC. Drug-susceptibility test (DST was performed over MTBC for the first line drugs by 1% proportion method (Bactec and for the second-line drugs by 1% proportion method (Lowenstein- Jensen media. The XDR-TB status was further confirmed by line probe assay (GenoType® MTBDRsl assay. Results: Among the 430 isolates of mycobacterium, 365 (84.9% were MTBC and 139 (38.1% were MDR-TB respectively. Further 97 MDR-TB from “highly suspected drug resistant-TB (DR-TB” cases among MDR-TB were tested with second line drugs in which 15 (15.5% XDR-TB and 82 (84.5% were non-XDR-TB. Regarding XDR-TB status, using the 1% proportion method a 100% agreement was seen with the GenoType® MTBDRsl assay. Resistance patterns of XDR-TB were as; 10/15 (66.7% as isoniazid + rifampicin + ciprofloxacin + amikacin resistance and 5/15 (33.3% as isoniazid + rifampicin + ciprofloxacin + amikacin + kanamycin resistance. Conclusion:The prevalence of XDR-TB was 15.5% among MDR-TB. Hence laboratory testing of “highly suspected drug resistant-TB” isolates should be done for both first and second line drugs simultaneously especially in developing countries.J Microbiol Infect Dis 2013;3(4: 169-175

  17. Modeling HIV-1 drug resistance as episodic directional selection.

    Science.gov (United States)

    Murrell, Ben; de Oliveira, Tulio; Seebregts, Chris; Kosakovsky Pond, Sergei L; Scheffler, Konrad

    2012-01-01

    The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS) which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.

  18. Modeling HIV-1 drug resistance as episodic directional selection.

    Directory of Open Access Journals (Sweden)

    Ben Murrell

    Full Text Available The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.

  19. Molecular Basis for Drug Resistance in HIV-1 Protease

    Directory of Open Access Journals (Sweden)

    Celia A. Schiffer

    2010-11-01

    Full Text Available HIV-1 protease is one of the major antiviral targets in the treatment of patients infected with HIV-1. The nine FDA approved HIV-1 protease inhibitors were developed with extensive use of structure-based drug design, thus the atomic details of how the inhibitors bind are well characterized. From this structural understanding the molecular basis for drug resistance in HIV-1 protease can be elucidated. Selected mutations in response to therapy and diversity between clades in HIV-1 protease have altered the shape of the active site, potentially altered the dynamics and even altered the sequence of the cleavage sites in the Gag polyprotein. All of these interdependent changes act in synergy to confer drug resistance while simultaneously maintaining the fitness of the virus. New strategies, such as incorporation of the substrate envelope constraint to design robust inhibitors that incorporate details of HIV-1 protease’s function and decrease the probability of drug resistance, are necessary to continue to effectively target this key protein in HIV-1 life cycle.

  20. Use and Misuse of Antimicrobial Drugs in Poultry and Livestock: Mechanisms of Antimicrobial Resistance

    Directory of Open Access Journals (Sweden)

    Toni Poole* and Cynthia Sheffield

    2013-07-01

    Full Text Available Food safety begins on the farm with management practices that contribute to an abundant, safe, and affordable food supply. To attain this goal antimicrobials have been used in all stages of food animal production in the United States and elsewhere around the world at one time or another. Among food–production animals antimicrobials are used for growth promotion, disease prophylaxis or disease treatment, and are generally administered to the entire flock or herd. Over many decades bacteria have become resistant to multiple antimicrobial classes in a cumulative manner. Bacteria exhibit a number of well characterized mechanisms of resistance to antimicrobials that include: 1 modification of the antimicrobial; 2 alteration of the drug target; 3 decreased access of drug to target; and 4 implementation of an alternative metabolic pathway not affected by the drug. The mechanisms of resistance are complex and depend on the type of bacterium involved (e.g. Gram–positive or Gram–negative and the class of drug. Some bacterial species have accumulated resistance to nearly all antimicrobial classes due to a combination of intrinsic and acquired processes. This has and will continue to lead to clinical failures of antimicrobial treatment in both human and animal medicine.

  1. GENETIC DIVERSITY OF DRUG RESISTANT STRAINS OF MYCOBACTERIUM TUBERCULOSIS IN OMSK REGION

    Directory of Open Access Journals (Sweden)

    O. A. Pаsechnik

    2017-01-01

    Full Text Available The article presents the investigation results of the specific epidemic situation on tuberculous infection in Omsk Region in 2006-2015 and molecular genetic features of M. tuberculosis strains with multiple drug resistance circulating in this region. Bacteriological, molecular genetic methods, VNTR-typing were used as well as descriptive techniques of the epidemiological process. Tuberculosis prevalence made 269.2 per 100,000 population. There is an increase in those with bacillary excretion among new cases of respiratory tuberculosis from 39.8% to 53.4%. Drug resistance was detected in 48.0% of new cases. Among drug resistance patterns, MDR made 57%, and extensive drug resistance (XDR increased from 2.5 to 7.0%. In 2015 prevalence of XDR tuberculosis made 8.9 per 100,000 population in Omsk Region. When performing VNTR-typing of 77 samples of M. tuberculosis DNA with MDR, 27 genetic types were identified. The population of MDR strain of M. tuberculosis is heterogeneous and presented by strains of various genetic families -Beijing, LAM, S,Haarlem,Uganda. The investigation showed that isolates ofBeijing family prevailed (76.6%.

  2. Drug resistance following irradiation of RIF-1 tumors: Influence of the interval between irradiation and drug treatment

    International Nuclear Information System (INIS)

    Hopwood, L.E.; Davies, B.M.; Moulder, J.E.

    1990-01-01

    RIF-1 tumors contain a small number of cells (1 to 100 per 10(6) cells) that are resistant to 5-fluorouracil, methotrexate, or adriamycin. The frequency of drug-resistant cells among individual untreated tumors is highly variable. Radiation, delivered in vivo at doses of 3 to 12 Gy, increases the frequency of methotrexate- and 5-fluorouracil-resistant cells, but not the frequency of adriamycin-resistant cells. The magnitude of induction of 5-fluorouracil and methotrexate resistance shows a complex dependence on the radiation dose and on the interval between irradiation and assessment of drug resistance. For a dose of 3 Gy, induced 5-fluorouracil and methotrexate resistance is seen only after an interval of 5 to 7 days, whereas for a dose of 12 Gy, high levels of induced resistance are observed 1 to 3 days after irradiation. The maximum absolute risk for induction of resistance is 4 per 10(4) cells per Gy for methotrexate, and 3 per 10(6) cells per Gy for 5-fluorouracil. These results indicate that tumor hypoxia may play a role in the increased levels of drug resistance seen after irradiation, and that both genetic and environmental factors may influence radiation-induction of drug resistance. These studies provide essential data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be caused by radiation-induced drug resistance

  3. Drug resistance patterns of acinetobacter baumannii in makkah, saudi arabia

    International Nuclear Information System (INIS)

    Khan, M.A.; Ashshi, A.M.; Mahomed, M.F.

    2012-01-01

    Background: Acinetobacter baumannii causes infections of respiratory, urinary tract, blood stream and surgical sites. Its clinical significance has increased due to its rapidly developing resistance to major groups of antibiotics used for its treatment. There is limited data available on antimicrobial susceptibility of A. baumannii from Saudi Arabia. Objectives: To determine the patterns of drug resistance of Acinetobacter baumannii and predisposing factors for its acquisition.Subjects and Methods: In this descriptive study, 72 hospitalized patients infected with A baumannii were studied. The clinical and demographic data of the patients were collected using a predesigned questionnaire. Isolation and identification of A.baumannii from all clinical specimens were done using standard microbiological methods. Antibiotic susce ptibility testing was performed by disk diffusion method recommended by Clinical Laboratory Standards Institute. Results: Majority of the isolates (61.1%) were from respiratory tract infections. A.baumannii isolates showed high drug resistance to piperacil lin (93.1%), aztreonam (80.5%), ticarcillin, ampicillin, and tetracycline (76.4%, each) and cefotaxime (75%). Only amikacin showed low rate of resistance compared to other antibiotics (40.3%). About 36% patients had some underlying diseases with diabetes mellitus (11%) being the predominant underlying disease. Conclusions: High antimicrobial resistance to commonly used antibiotics was seen against A.baumannii isolates. Only amikacin was most effective against it. (author)

  4. Multi drug resistant tuberculosis presenting as anterior mediastinal mass

    Directory of Open Access Journals (Sweden)

    Parmarth Chandane

    2016-01-01

    Full Text Available Enlargement of the mediastinal lymphatic glands is a common presentation of intrathoracic tuberculosis (TB in children. However, usually, the mediastinal TB nodes enlarge to 2.8 ± 1.0 cm. In this report, we describe a case of anterior mediastinal lymphnode TB seen as huge mass (7 cm on computed tomography (CT thorax without respiratory or food pipe compromise despite anterior mediastinum being an enclosed space. CT guided biopsy of the mass cultured Mycobacterium TB complex which was resistant to isoniazide, rifampicin, streptomycin ofloxacin, moxifloxacin, and pyrazinamide. Hence, we report primary multi drug resistant TB presenting as anterior mediastinal mass as a rare case report.

  5. Personalized Cancer Medicine: Molecular Diagnostics, Predictive biomarkers, and Drug Resistance

    Science.gov (United States)

    Gonzalez de Castro, D; Clarke, P A; Al-Lazikani, B; Workman, P

    2013-01-01

    The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine. We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer. We envisage a future requiring the use of longitudinal genome sequencing and other omics technologies alongside combinatorial treatment to overcome cellular and molecular heterogeneity and prevent resistance caused by clonal evolution. PMID:23361103

  6. Drug membrane interaction and the importance for drug transport, distribution, accumulation, efficacy and resistance.

    Science.gov (United States)

    Seydel, J K; Coats, E A; Cordes, H P; Wiese, M

    1994-10-01

    Some aspects of drug membrane interaction and its influence on drug transport, accumulation, efficacy and resistance have been discussed. The interactions manifest themselves macroscopically in changes in the physical and thermodynamic properties of "pure membranes" or bilayers. As various amounts of foreign molecules enter the membrane, in particular the main gel to liquid crystalline phase transition can be dramatically changed. This may change permeability, cell-fusion, cell resistance and may also lead to changes in conformation of the embedded receptor proteins. Furthermore, specific interactions with lipids may lead to drug accumulation in membranes and thus to much larger concentrations at the active site than present in the surrounding water phase. The lipid environment may also lead to changes in the preferred conformation of drug molecules. These events are directly related to drug efficacy. The determination of essential molecular criteria for the interaction could be used to design new and more selective therapeutics. This excursion in some aspects of drug membrane interaction underlines the importance of lipids and their interaction with drug molecules for our understanding of drug action, but this is not really a new thought but has been formulated in 1884 by THUDICUM: "Phospholipids are the centre, life and chemical soul of all bioplasm whatsoever, that of plants as well as of animals".

  7. Drug accumulation in the presence of the multidrug resistance pump

    DEFF Research Database (Denmark)

    Ayesh, S; Litman, Thomas; Stein, W D

    1997-01-01

    We studied the interaction between the multidrug transporter, P-glycoprotein, and two compounds that interact with it: vinblastine, a classical substrate of the pump, and verapamil, a classical reverser. Steady-state levels of accumulation of these two drugs were determined in a multidrug resistant...... P388 leukemia cell line, P388/ADR. The time course of accumulation of these drugs, and the effect of energy starvation and the presence of chloroquine on the level of their steady-state accumulation were quite disparate. Vinblastine inhibited the accumulation of verapamil whereas it enhanced...

  8. A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance

    KAUST Repository

    Sheen, Patricia

    2017-10-11

    Tuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear.We genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes. We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion.These results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.

  9. A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance

    KAUST Repository

    Sheen, Patricia; Requena, David; Gushiken, Eduardo; Gilman, Robert H.; Antiparra, Ricardo; Lucero, Bryan; Lizá rraga, Pilar; Cieza, Basilio; Roncal, Elisa; Grandjean, Louis; Pain, Arnab; McNerney, Ruth; Clark, Taane G.; Moore, David; Zimic, Mirko

    2017-01-01

    Tuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear.We genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes. We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion.These results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.

  10. IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer.

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M; Zhou, Zhiyang; Wang, Liya; Wang, Andrew; Mao, Hui; Yang, Lily

    2016-04-17

    Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer.

  11. IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M.; Zhou, Zhiyang; Wang, Liya; Wang, Andrew; Mao, Hui; Yang, Lily

    2016-05-01

    Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer.

  12. Androgen receptor variation affects prostate cancer progression and drug resistance.

    Science.gov (United States)

    McCrea, Edel; Sissung, Tristan M; Price, Douglas K; Chau, Cindy H; Figg, William D

    2016-12-01

    Significant therapeutic progress has been made in treating prostate cancer in recent years. Drugs such as enzalutamide, abiraterone, and cabazitaxel have expanded the treatment armamentarium, although it is not completely clear which of these drugs are the most-effective option for individual patients. Moreover, such advances have been tempered by the development of therapeutic resistance. The purpose of this review is to summarize the current literature pertaining to the biochemical effects of AR variants and their consequences on prostate cancer therapies at both the molecular level and in clinical treatment. We address how these AR splice variants and mutations affect tumor progression and therapeutic resistance and discuss potential novel therapeutic strategies under development. It is hoped that these therapies can be administered with increasing precision as tumor genotyping methods become more sophisticated, thereby lending clinicians a better understanding of the underlying biology of prostate tumors in individual patients. Published by Elsevier Ltd.

  13. Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids.

    Science.gov (United States)

    He, Susu; Chandler, Michael; Varani, Alessandro M; Hickman, Alison B; Dekker, John P; Dyda, Fred

    2016-12-06

    The dissemination of resistance among bacteria has been facilitated by the fact that resistance genes are usually located on a diverse and evolving set of transmissible plasmids. However, the mechanisms generating diversity and enabling adaptation within highly successful resistance plasmids have remained obscure, despite their profound clinical significance. To understand these mechanisms, we have performed a detailed analysis of the mobilome (the entire mobile genetic element content) of a set of previously sequenced carbapenemase-producing Enterobacteriaceae (CPE) from the National Institutes of Health Clinical Center. This analysis revealed that plasmid reorganizations occurring in the natural context of colonization of human hosts were overwhelmingly driven by genetic rearrangements carried out by replicative transposons working in concert with the process of homologous recombination. A more complete understanding of the molecular mechanisms and evolutionary forces driving rearrangements in resistance plasmids may lead to fundamentally new strategies to address the problem of antibiotic resistance. The spread of antibiotic resistance among Gram-negative bacteria is a serious public health threat, as it can critically limit the types of drugs that can be used to treat infected patients. In particular, carbapenem-resistant members of the Enterobacteriaceae family are responsible for a significant and growing burden of morbidity and mortality. Here, we report on the mechanisms underlying the evolution of several plasmids carried by previously sequenced clinical Enterobacteriaceae isolates from the National Institutes of Health Clinical Center (NIH CC). Our ability to track genetic rearrangements that occurred within resistance plasmids was dependent on accurate annotation of the mobile genetic elements within the plasmids, which was greatly aided by access to long-read DNA sequencing data and knowledge of their mechanisms. Mobile genetic elements such as

  14. Implementation of a national anti-tuberculosis drug resistance survey in Tanzania

    NARCIS (Netherlands)

    Chonde, Timothy M.; Doulla, Basra; van Leth, Frank; Mfinanga, Sayoki G. M.; Range, Nyagosya; Lwilla, Fred; Mfaume, Saidi M.; van Deun, Armand; Zignol, Matteo; Cobelens, Frank G.; Egwaga, Saidi M.

    2008-01-01

    BACKGROUND: A drug resistance survey is an essential public health management tool for evaluating and improving the performance of National Tuberculosis control programmes. The current manuscript describes the implementation of the first national drug resistance survey in Tanzania. METHODS:

  15. Central neurotoxicity of immunomodulatory drugs in multiple myeloma

    Directory of Open Access Journals (Sweden)

    Urmeel H. Patel

    2015-03-01

    Full Text Available Immunomodulatory drugs (IMiDs currently used in the treatment of multiple myeloma, are thalidomide, lenalidomide and pomalidomide. One of the most common side effects of thalidomide is neurotoxicity, predominantly in the form of peripheral neuropathy. We report 6 cases of significant central neurotoxicity associated with IMiD therapy. Treatment with thalidomide (1 patient, lenalidomide (4 patients, and pomalidomide (1 patient was associated with various clinical manifestations of central neurotoxicity, including reversible coma, amnesia, expressive aphasia, and dysarthria. Central neurotoxicity should be recognized as an important side effect of IMiD therapy.

  16. Central neurotoxicity of immunomodulatory drugs in multiple myeloma.

    Science.gov (United States)

    Patel, Urmeel H; Mir, Muhammad A; Sivik, Jeffrey K; Raheja, Divisha; Pandey, Manoj K; Talamo, Giampaolo

    2015-02-24

    Immunomodulatory drugs (IMiDs) currently used in the treatment of multiple myeloma, are thalidomide, lenalidomide and pomalidomide. One of the most common side effects of thalidomide is neurotoxicity, predominantly in the form of peripheral neuropathy. We report 6 cases of significant central neurotoxicity associated with IMiD therapy. Treatment with thalidomide (1 patient), lenalidomide (4 patients), and pomalidomide (1 patient) was associated with various clinical manifestations of central neurotoxicity, including reversible coma, amnesia, expressive aphasia, and dysarthria. Central neurotoxicity should be recognized as an important side effect of IMiD therapy.

  17. Rationale and uses of a public HIV drug-resistance database.

    Science.gov (United States)

    Shafer, Robert W

    2006-09-15

    Knowledge regarding the drug resistance of human immunodeficiency virus (HIV) is critical for surveillance of drug resistance, development of antiretroviral drugs, and management of infections with drug-resistant viruses. Such knowledge is derived from studies that correlate genetic variation in the targets of therapy with the antiretroviral treatments received by persons from whom the variant was obtained (genotype-treatment), with drug-susceptibility data on genetic variants (genotype-phenotype), and with virological and clinical response to a new treatment regimen (genotype-outcome). An HIV drug-resistance database is required to represent, store, and analyze the diverse forms of data underlying our knowledge of drug resistance and to make these data available to the broad community of researchers studying drug resistance in HIV and clinicians using HIV drug-resistance tests. Such genotype-treatment, genotype-phenotype, and genotype-outcome correlations are contained in the Stanford HIV RT and Protease Sequence Database and have specific usefulness.

  18. Drug resistance-related mutations in multidrug-resistant Mycobacterium tuberculosis isolates from diverse geographical regions

    Directory of Open Access Journals (Sweden)

    Senia Rosales-Klintz

    2012-01-01

    Conclusion: This study confirms that there are significant geographical differences in the distribution of resistance-related mutations and suggests that an increased understanding of such differences in the specific distribution of resistance conferring mutations is crucial for development of new, generally applicable, molecular tools for rapid diagnosis of drug-resistant TB. The fact that a narrower distribution of mutations in high MDR-TB prevalence settings was seen suggests that much of the problems in these settings can be a result of an ongoing transmission of certain MDR-TB strains.

  19. Changing prevalence and resistance patterns in children with drug-resistant tuberculosis in Mumbai.

    Science.gov (United States)

    Shah, Ira; Shah, Forum

    2017-05-01

    The prevalence of drug-resistant (DR) tuberculosis (TB) in children is increasing. Although, in India, multi-drug-resistant (MDR) TB rates have been relatively stable, the number of children with pre-extensively drug-resistant and extensively drug-resistant (XDR) TB is increasing. To determine whether the prevalence of DR TB in children in Mumbai is changing and to study the evolving patterns of resistance. A retrospective study was undertaken in 1311 paediatric patients referred between April 2007 and March 2013 to the Paediatric TB clinic at B. J. Wadia Hospital for Children, Mumbai. Children were defined as having DR TB on the basis of drug susceptibility testing (DST) of Mycobacterium tuberculosis grown on culture of body fluids (in the case of extra pulmonary TB) or from gastric lavage/bronchi-alveolar lavage/sputum in patients with pulmonary TB or from DST of the contacts. The prevalence of DR TB was calculated and the type of DR was evaluated yearly and in the pre-2010 and post-2010 eras. The overall prevalence of DR TB was 86 (6.6%) with an increase from 23 (5.6%) patients pre-2010 to 63 (7%) post-2010 (P = 0.40). Nine (10.4%) patients were diagnosed on the basis of contact with a parent with DR TB. Overall fluoroquinolone resistance increased from 9 (39.1%) pre-2010 to 59 (93.7%) post-2010 (P = 0.0001): moxifloxacin resistance increased from 2 (8.7%) to 29 (46%) (P = 0.0018) and ofloxacin resistance increased from 7 (30.4%) to 30 (47.6%) (P = 0.14). Ethionamide resistance also increased from 6 (26.1%) to 31 (49.2%) (P = 0.04), aminoglycoside resistance was one (4.3%) pre-2010 and 12 (19%) post-2010 (P = 0.17) and resistance remained virtually the same for both amikacin [0 pre-2010 and 6 (9.5%) after 2010] and kanamycin [one (4.3%) pre- and 6 (9.5%) post-2010]. Of the first-line drugs, resistance remained the same for isoniazid [23 (100%) to 61 (96.8%)], rifampicin [22 (95.7%) to 51 (80.9%),P = 0.17], pyrazinamide [15 (65.2%) to

  20. Impact of drug resistance on the tuberculosis treatment outcome

    Directory of Open Access Journals (Sweden)

    E. Lesnic

    2017-03-01

    Full Text Available Background. The standard treatment of a new case of multidrug-resistant tuberculosis (MDR-TB according to WHO recommendations in the Republic of Moldova is performed since 2005 showing a low treatment succes. Actually the treatment success rate increased due to excluding of MDR-TB patients from the general cohort. The major rate of patients with low outcome is represented by the failed and lost to follow-up cases. The purpose of the study was to assess the impact of multidrug-resiatnce and MDR-TB on the tuberculosis treatment outcome. Materials and methods. A retrospective selective, descriptive study targeting social, demographic, economic and epidemiological peculiarities, case-management, diagnostic radiological aspects and microbiological characteristics of 187 patients with pulmonary tuberculosis registered during 2013–2015 distributed in two groups: 1st group (61 patients with established multidrug-resistant strains using conventional cultural methods and the 2nd group (126 patients with MDR-TB. Results. Multidrug-resistance was established more frequently in new cases and MDR-TB in two thirds of retreated patients. No difference was identified in gender and age distribution, social, economical, educational characteristics; case-management assessment identified a similar proportion of patients revealed by general practitioners and specialists, with low rate of screened high risk groups. All patients from the multidrug-resistant group began the standard treatment for drug-responsiveness tuberculosis before drug susceptibility testing and one third of MDR-TB group was treated from the onset with the DOTS-Plus regimen. Highest success rate was identified in the new-case subgroups of both groups and higher rate of died patients was determined in the retreated subgroups. Such a low rate of patients aggrevates the resistance. Conclusions. Early diagnosis, drug responsiveness testing and raising awareness among about treatment compliance will

  1. Drug Resistance Mechanisms of Mycoplasma pneumoniae to Macrolide Antibiotics

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    Xijie Liu

    2014-01-01

    Full Text Available Throat swabs from children with suspected Mycoplasma pneumoniae (M. pneumoniae infection were cultured for the presence of M. pneumoniae and its species specificity using the 16S rRNA gene. Seventy-six M. pneumoniae strains isolated from 580 swabs showed that 70 were erythromycin resistant with minimum inhibitory concentrations (MIC around 32–512 mg/L. Fifty M. pneumoniae strains (46 resistant, 4 sensitive were tested for sensitivity to tetracycline, ciprofloxacin, and gentamicin. Tetracycline and ciprofloxacin had some effect, and gentamicin had an effect on the majority of M. pneumoniae strains. Domains II and V of the 23S rRNA gene and the ribosomal protein L4 and L22 genes, both of which are considered to be associated with macrolide resistance, were sequenced and the sequences were compared with the corresponding sequences in M129 registered with NCBI and the FH strain. The 70 resistant strains all showed a 2063 or 2064 site mutation in domain V of the 23S rRNA but no mutations in domain II. Site mutations of L4 or L22 can be observed in either resistant or sensitive strains, although it is not known whether this is associated with drug resistance.

  2. Surgery for Drug-Resistant Epilepsy in Children.

    Science.gov (United States)

    Dwivedi, Rekha; Ramanujam, Bhargavi; Chandra, P Sarat; Sapra, Savita; Gulati, Sheffali; Kalaivani, Mani; Garg, Ajay; Bal, Chandra S; Tripathi, Madhavi; Dwivedi, Sada N; Sagar, Rajesh; Sarkar, Chitra; Tripathi, Manjari

    2017-10-26

    Neurosurgical treatment may improve seizures in children and adolescents with drug-resistant epilepsy, but additional data are needed from randomized trials. In this single-center trial, we randomly assigned 116 patients who were 18 years of age or younger with drug-resistant epilepsy to undergo brain surgery appropriate to the underlying cause of epilepsy along with appropriate medical therapy (surgery group, 57 patients) or to receive medical therapy alone (medical-therapy group, 59 patients). The patients in the medical-therapy group were assigned to a waiting list for surgery. The primary outcome was freedom from seizures at 12 months. Secondary outcomes were the score on the Hague Seizure Severity scale, the Binet-Kamat intelligence quotient, the social quotient on the Vineland Social Maturity Scale, and scores on the Child Behavior Checklist and the Pediatric Quality of Life Inventory. At 12 months, freedom from seizures occurred in 44 patients (77%) in the surgery group and in 4 (7%) in the medical-therapy group (Pchildren and adolescents with drug-resistant epilepsy who had undergone epilepsy surgery had a significantly higher rate of freedom from seizures and better scores with respect to behavior and quality of life than did those who continued medical therapy alone at 12 months. Surgery resulted in anticipated neurologic deficits related to the region of brain resection. (Funded by the Indian Council of Medical Research and others; Clinical Trial Registry-India number, CTRI/2010/091/000525 .).

  3. Sleep instability and cognitive status in drug-resistant epilepsies.

    Science.gov (United States)

    Pereira, Alessandra Marques; Bruni, Oliviero; Ferri, Raffaele; Nunes, Magda Lahorgue

    2012-05-01

    The aims of this study were to evaluate the sleep habits of children with drug resistant epilepsy and to correlate sleep abnormalities with epilepsy and level of intelligence. Twenty five subjects with drug resistant epilepsy (14 males, age range 2-16.4 years) were recruited for this study. A control group was formed by 23 normal children. Two instruments to assess sleep habits were administered to the patients with epilepsy: a questionnaire on sleep habits (to preschool children) and a questionnaire on sleep behavior (for children aged more than seven years old); a cognitive test (Wechsler Intelligence Scale for Children-WISC) was also performed. Patients underwent a complete polysomnographic study and sleep parameters, including CAP, were analyzed and correlated according to cognitive-behavioral measures in children with epilepsy. Children with drug-resistant epilepsy and severe mental retardation showed sleep abnormalities such as low sleep efficiency, high percentage of wakefulness after sleep onset, reduced slow wave sleep, and reduced REM sleep. Sleep microstructure evaluated by means of CAP analysis showed a decrease in A1 index during N3 in patients with more severe cognitive impairment. Children with epilepsy and cognitive impairment (n=10) had higher Sleep Behavior Questionnaire for Children (SBQC) total scores (65.60 ± 18.56) compared to children with epilepsy and normal IQ (50.00 ± 10.40), pintellectual disability. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Investigational drugs to treat methicillin-resistant Staphylococcus aureus

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    Vuong, Cuong; Yeh, Anthony J; Cheung, Gordon YC; Otto, Michael

    2016-01-01

    Introduction Staphylococcus aureus remains one of the leading causes of morbidity and mortality worldwide. This is to a large extent due to antibiotic-resistant strains, in particular methicillin-resistant S. aureus (MRSA). While the toll of invasive MRSA infections appears to decrease in U.S. hospitals, the rate of community-associated MRSA infections remains constant and there is a surge of MRSA in many other countries. This situation calls for continuing if not increased efforts to find novel strategies to combat MRSA infections. Areas covered This review will provide an overview of current investigational antibiotics in clinical development (up to phase II), and of therapeutic antibodies and alternative drugs against S. aureus in preclinical and clinical development, including a short description of the mechanism of action and a presentation of microbiological and clinical data. Expert opinion Increased recent antibiotic development efforts and results from pathogenesis research have led to several new antibiotics and alternative drugs, as well as a more informed selection of targets for vaccination efforts against MRSA. This developing portfolio of novel anti-staphylococcal drugs will hopefully provide us with additional and more efficient ways to combat MRSA infections in the near future and prevent us from running out of treatment options, even if new resistances arise. PMID:26536498

  5. Comparison of drug treatment histories of single and multiple drug abusers in detox.

    Science.gov (United States)

    Greberman, S B; Jasinski, D

    2001-01-01

    This study was undertaken to determine differences in previous treatment patterns in individuals currently using different numbers of substances. Medical records of 1198 inpatient detoxification (detox) admissions were analyzed. Numbers of past admissions to completed detox, methadone, or other types of drug abuse treatment were totaled and ranked to determine most frequent type. Within gender, treatment histories of single and multiple drug abusers usually do not differ. The one exception is male multiple drug abusers ages 26-30, who show increased admissions. Possible explanations are that men do not seek treatment before developing medical complications of addiction or until external factors influence admission. There were differences in treatment histories between genders in multiple drug abusers only. Before age 30, women reported increased treatment of certain types. Possible explanations are that treatment priority is given to women who are, or may be, pregnant. Also, younger men may not enter or complete treatment. Previous treatment history may influence many behaviors. The results of this study delineate several valuable indicators for assessing past history.

  6. Molecular Genetics of Drug-resistance in Epilepsies

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    Kurupath Radhakrishnan

    2015-06-01

    Full Text Available Nearly one-third of newly diagnosed patients with epilepsy remain unresponsive to antiepileptic drugs (AEDs, etiopathogenesis of which is poorly understood. The genes encoding the proteins that regulate the pharmacokinetics such as P-glycoprotein [ABCBI], major vault protein [MVP gene] and drug metabolizing enzymes [ABCB1, ABCG2, MVP, CYP2C9, CYP2C19, CYP3A4, CYP3A5, EPHX1, UGT1A1, UGT2B7], and pharmacodynamics such as sodium channels [SCN1A, SCN2A] and GABA receptors [GABRA1, GABRA6, GABRB2, GABRG2] of AEDs are under intense investigation to unravel the mysteries of AED-resistance. However, till today, a consistent and reliable result that could help the clinician either to predict drug resistance or to overcome it has not been forthcoming. The discrepant results may be related to variations in the definition of drug-resistance, heterogeneous patient populations, ethnic variations in the frequency distribution of single nucleotide polymorphisms (SNPs and the selection of SNPs. Understanding of these limitations of existing studies, hopefully, will help in designing better studies. Nearly one-third of newly diagnosed patients with epilepsy remain unresponsive toantiepileptic drugs (AEDs, etiopathogenesis of which is poorly understood. The genesencoding the proteins that regulate the pharmacokinetics such as P-glycoprotein[ABCBI], major vault protein [MVP gene] and drug metabolizing enzymes [ABCB1,ABCG2, MVP, CYP2C9, CYP2C19, CYP3A4, CYP3A5, EPHX1, UGT1A1, UGT2B7],and pharmacodynamics such as sodium channels [SCN1A, SCN2A] and GABAreceptors [GABRA1, GABRA6, GABRB2, GABRG2] of AEDs are under intenseinvestigation to unravel the mysteries of AED-resistance. However, till today, aconsistent and reliable result that could help the clinician either to predict drugresistanceor to overcome it has not been forthcoming. The discrepant results may berelated to variations in the definition of drug-resistance, heterogeneous patientpopulations, ethnic

  7. CHEMOTHERAPY, WITHIN-HOST ECOLOGY AND THE FITNESS OF DRUG-RESISTANT MALARIA PARASITES

    OpenAIRE

    Huijben, Silvie; Nelson, William A.; Wargo, Andrew R.; Sim, Derek G.; Drew, Damien R.; Read, Andrew F.

    2010-01-01

    A major determinant of the rate at which drug-resistant malaria parasites spread through a population is the ecology of resistant and sensitive parasites sharing the same host. Drug treatment can significantly alter this ecology by removing the drug-sensitive parasites, leading to competitive release of resistant parasites. Here, we test the hypothesis that the spread of resistance can be slowed by reducing drug treatment and hence restricting competitive release. Using the rodent malaria mod...

  8. Molecular biological studies on the human radioresistance and drug resistance

    International Nuclear Information System (INIS)

    Kim, Chang Min; Hong, Weon Seon

    1992-04-01

    We irradiated the MKN45 and PC14 cell lines with 500 rads and also established the adriamycin-resistant and cis-platinum resistant cell line. The genomic DNA and total RNA were extracted and subjected to the Southern and Northern analysis using various probes including heat shock protein 70, MDR1, fos, TGFb etc. The mRNA transcript was increased 1 hour after the irradiation and sustained during the 48 hours and returned to the level of pre-irradiation. No significant change was observed with the drug resistant cell lines at the level of gene dosage. We suggest that the marked increase of the hsp70 transcript is very important finding and is believed to be a good candidate for the modulation of the cellular response to irradiation and the radioresistance. (Author)

  9. SURGERY FOR DRUG-RESISTANT DESTRUCTIVE PULMONARY TUBERCULOSIS

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    S. N. Skornyakov

    2015-01-01

    Full Text Available The paper presents the experience in surgically treating 145 patients with destructive, mainly fibrocavernous pulmonary tuberculosis. All the patients completed treatment. In the preoperative preparation, particular emphasis is laid on the promptest determination of a spectrum of pathogen susceptibility/resistance, individualized chemotherapy, and collapse therapy options. Postoperative complications occurred in 27 (18.6% patients, fatal outcomes in 4 (2.7%. The former were recorded most frequently after pneumonectomy in 13 (37.1% cases, the later were seen in 3 (8.6%. Sputum culture conversion was generally achieved in 111 (78% patients, particularly in 97 (78.2% patients with multidrug-resistant tuberculosis and in 14 (66.7% with a broad drug resistance in the pathogen. Out of the 64 patients followed up for more than 3 years, 48 (75.0% were in clinical and bacteriological remission.

  10. Mechanisms of first-line antimicrobial resistance in multi-drug and extensively drug resistant strains of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa

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    Navisha Dookie

    2016-10-01

    Full Text Available Abstract Background In South Africa, drug resistant tuberculosis is a major public health crisis in the face of the colossal HIV pandemic. Methods In an attempt to understand the distribution of drug resistance in our setting, we analysed the rpoB, katG, inhA, pncA and embB genes associated with resistance to key drugs used in the treatment of tuberculosis in clinical isolates of Mycobacterium tuberculosis in the KwaZulu-Natal province. Results Classical mutations were detected in the katG, inhA and embB genes associated with resistance to isoniazid and ethambutol. Diverse mutations were recorded in the multidrug resistant (MDR and extensively drug resistant (XDR isolates for the rpoB and pncA gene associated with resistance to rifampicin and pyrazinamide. Conclusions M.tuberculosis strains circulating in our setting display a combination of previously observed mutations, each mediating resistance to a different drug. The MDR and XDR TB isolates analysed in this study displayed classical mutations linked to INH and EMB resistance, whilst diverse mutations were linked to RIF and PZA resistance. The similarity of the XDR strains confirms reports of the clonality of the XDR epidemic. The successful dissemination of the drug resistant strains in the province underscores the need for rapid diagnostics to effectively diagnose drug resistance and guide treatment.

  11. Dinitroaniline herbicide resistance in a multiple-resistant Lolium rigidum population.

    Science.gov (United States)

    Chen, Jinyi; Yu, Qin; Owen, Mechelle; Han, Heping; Powles, Stephen

    2018-04-01

    The pre-emergence dinitroaniline herbicides (such as trifluralin and pendimethalin) are vital to Australian no-till farming systems. A Lolium rigidum population collected from the Western Australian grain belt with a 12-year trifluralin use history was characterised for resistance to dinitroaniline, acetyl CoA carboxylase (ACCase)- and acetolactate synthase (ALS)-inhibiting herbicides. Target-site resistance mechanisms were investigated. This L. rigidum population exhibited 32-fold resistance to trifluralin, as compared with the susceptible population. It also displayed 12- to 30-fold cross-resistance to other dinitroaniline herbicides (pendimethalin, ethalfluralin and oryzalin). In addition, this population showed multiple resistance to commonly used post-emergence ACCase- and ALS-inhibiting herbicides. Two target-site α-tubulin gene mutations (Val-202-Phe and Thr-239-Ile) previously documented in other dinitroaniline-resistant weed species were identified, and some known target-site mutations in ACCase (Ile-1781-Leu, Asp-2078-Gly and Cys-2088-Arg) and ALS (Pro-197-Gln/Ser) were found in the same population. An agar-based Petri dish screening method was established for the rapid diagnosis of resistance to dinitroaniline herbicides. Evolution of target-site resistance to both pre- and post-emergence herbicides was confirmed in a single L. rigidum population. The α-tubulin mutations Val-202-Phe and Thr-239-Ile, documented here for the first time in L. rigidum, are likely to be responsible for dinitroaniline resistance in this population. Early detection of dinitroaniline herbicide resistance and integrated weed management strategies are needed to maintain the effectiveness of dinitroaniline herbicides. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  12. Characterization of extensively drug-resistant Mycobacterium tuberculosis in Nepal.

    Science.gov (United States)

    Poudel, Ajay; Maharjan, Bhagwan; Nakajima, Chie; Fukushima, Yukari; Pandey, Basu D; Beneke, Antje; Suzuki, Yasuhiko

    2013-01-01

    The emergence of extensively drug-resistant tuberculosis (XDR-TB) has raised public health concern for global control of TB. Although molecular characterization of drug resistance-associated mutations in multidrug-resistant isolates in Nepal has been made, mutations in XDR isolates and their genotypes have not been reported previously. In this study, we identified and characterized 13 XDR Mycobacterium tuberculosis isolates from clinical isolates in Nepal. The most prevalent mutations involved in rifampicin, isoniazid, ofloxacin, and kanamycin/capreomycin resistance were Ser531Leu in rpoB gene (92.3%), Ser315Thr in katG gene (92.3%), Asp94Gly in gyrA gene (53.9%) and A1400G in rrs gene (61.5%), respectively. Spoligotyping and multilocus sequence typing revealed that 69% belonged to Beijing family, especially modern types. Further typing with 26-loci variable number of tandem repeats suggested the current spread of XDR M. tuberculosis. Our result highlights the need to reinforce the TB policy in Nepal with regard to control and detection strategies. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. First report of multiple anthelmintic resistance in nematodes of sheep in Colombia

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    Carlos M.B. Gárcia

    2016-03-01

    Full Text Available This study aimed to report the presence of parasites resistant to the most used anthelmintic drugs in sheep in Colombia. Four farms (denominated farm 1, 2, 3 and 4 were selected where the animals were not treated with anthelmintics for two months before the trial. Animals with faecal egg count (FEC above 150 and of different ages were allocated into six groups, each consisting of at least 5 animals. The drugs and dosages used were: ivermectin 1% (0.2 mg/kg, albendazole 25% (5 mg/kg, fenbendazole 10% (5 mg/kg, levamisole 10% (5 mg/kg, and moxidectin 1% (0.2 mg/kg. Anthelmintic efficacy was determined by the FEC reduction test (FECRT with a second sampling 14 days post-treatment. The efficacy of albendazole and fenbendazole at farm 1 was above 95%, which was different from the others farms. The FECRT indicated the presence of multidrug resistance in the other farms where no tested drugs showed activity higher than 79% (albendazole: 0 to 55%, fenbendazole: 51.4 to 76.6%, ivermectin: 67.3 to 93.1%, levamisole: 0 to 78.1%, and moxidectin: 49.2 to 64.1%.Haemonchus contortus was the predominant (96% species, followed by a small presence of Trichostrongylus sp. (3% andCooperia sp. (1%. Therefore, we report for the first time the existence of multiple anthelmintic resistance in gastrointestinal nematodes of sheep in Colombia.

  14. Genetic diversity of drug and multidrug-resistant Mycobacterium tuberculosis circulating in Veracruz, Mexico

    Science.gov (United States)

    Munro-Rojas, Daniela; Fernandez-Morales, Esdras; Zarrabal-Meza, José; Martínez-Cazares, Ma. Teresa; Parissi-Crivelli, Aurora; Fuentes-Domínguez, Javier; Séraphin, Marie Nancy; Lauzardo, Michael; González-y-Merchand, Jorge Alberto; Rivera-Gutierrez, Sandra

    2018-01-01

    Background Mexico is one of the most important contributors of drug and multidrug-resistant tuberculosis in Latin America; however, knowledge of the genetic diversity of drug-resistant tuberculosis isolates is limited. Methods In this study, the genetic structure of 112 Mycobacterium tuberculosis strains from the southeastern Mexico was determined by spoligotyping and 24-loci MIRU-VNTRs. Findings The results show eight major lineages, the most of which was T1 (24%), followed by LAM (16%) and H (15%). A total of 29 (25%) isolates were identified as orphan. The most abundant SITs were SIT53/T1 and SIT42/LAM9 with 10 isolates each and SIT50/H3 with eight isolates. Fifty-two spoligotype patterns, twenty-seven clusters and ten clonal complexes were observed, demonstrating an important genetic diversity of drug and multidrug-resistant tuberculosis isolates in circulation and transmission level of these aggravated forms of tuberculosis. Being defined as orphan or as part of an orphan cluster, was a risk factor for multidrug resistant-tuberculosis (OR 2.5, IC 1.05–5.86 and OR 3.3, IC 1–11.03, respectively). Multiple correspondence analyses showed association of some clusters and SITs with specific geographical locations. Conclusions Our study provides one of the most detailed description of the genetic structure of drug and multidrug-resistant tuberculosis strains in southeast Mexico, establishing for the first time a baseline of the genotypes observed in resistant isolates circulating, however further studies are required to better elucidate the genetic structure of tuberculosis in region and the factors that could be participating in their dispersion. PMID:29543819

  15. Drug Resistance and the Kinetics of Metastatic Cancer

    Science.gov (United States)

    Blagoev, Krastan B.

    2012-02-01

    Most metastatic cancers after initial response to current drug therapies develop resistance to the treatment. We present cancer data and a theory that explains the observed kinetics of tumor growth in cancer patients and using a stochastic model based on this theory we relate the kinetics of tumor growth to Kaplan-Meyer survival curves. The theory points to the tumor growth rate as the most important parameter determining the outcome of a drug treatment. The overall tumor growth or decay rate is a reflection of the balance between cell division, senescence and apoptosis and we propose that the deviation of the decay rate from exponential is a measure of the emergence of drug resistance. In clinical trials the progression free survival, the overall survival, and the shape of the Kaplan-Meyer plots are determined by the tumor growth rate probability distribution among the patients in the trial. How drug treatments modify this distribution will also be described. At the end of the talk we will discuss the connection between the theory described here and the age related cancer mortality rates in the United States.

  16. Exosomes in development, metastasis and drug resistance of breast cancer.

    Science.gov (United States)

    Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua

    2015-08-01

    Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  17. Novel diagnostics and therapeutics for drug-resistant tuberculosis.

    Science.gov (United States)

    Toosky, Melody; Javid, Babak

    2014-06-01

    Drug-resistant tuberculosis (DR-TB) is associated with increased mortality and morbidity. This is at least partly due to late diagnosis and ineffective treatment of drug-resistant status. Selective search of the literature on DR-TB supplemented by recent guidelines from the World Health Organization. Better and more rapid diagnosis of DR-TB by new techniques such as Xpert Mtb/RIF are likely to make a substantial impact on the disease. New therapeutics for DR-TB are entering, or about to enter the market for the first time in decades. It is not clear whether new treatments should be restricted for DR-TB or also used for drug-susceptible tuberculosis. With several new agents on the horizon, there is the real possibility of an entirely new regimen for tuberculosis. An inexpensive 'near-patient' diagnostic test is still needed. Optimizing new drug combination regimens in a timely manner is urgently required. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  18. Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations.

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    Michal Yalon

    Full Text Available Inhibitors of poly[ADP-ribose] polymerase 1 (PARPis show promise for treatment of cancers which lack capacity for homologous recombination repair (HRR. However, new therapeutic strategies are required in order to overcome innate and acquired resistance to these drugs and thus expand the array of cancers that could benefit from them. We show that human cancer cell lines which respond poorly to ABT-888 (a PARPi, become sensitive to it when co-treated with vorinostat (a histone deacetylase inhibitor (HDACi. Vorinostat also sensitized PARPis insensitive cancer cell lines to 6-thioguanine (6-TG-a drug that targets PARPis sensitive cells. The sensitizing effect of vorinostat was associated with increased phosphorylation of eukaryotic initiation factor (eIF 2α which in and of itself increases the sensitivity of cancer cells to ABT-888. Importantly, these drug combinations did not affect survival of normal fibroblasts and breast cells, and significantly increased the inhibition of xenograft tumor growth relative to each drug alone, without affecting the mice weight or their liver and kidney function. Our results show that combination of vorinostat and ABT-888 could potentially prove useful for treatment of cancer with innate resistance to PARPis due to active HRR machinery, while the combination of vorinostat and 6-TG could potentially overcome innate or acquired resistance to PARPis due to secondary or reversal BRCA mutations, to decreased PARP-1 level or to increased expression of multiple drug resistant proteins. Importantly, drugs which increase phosphorylation of eIF2α may mimic the sensitizing effect of vorinostat on cellular response to PARPis or to 6-TG, without activating all of its downstream effectors.

  19. Definition of drug resistance of Mycobacterium tuberculosis to antituberculosis drugs in patients with multidrugresistant tuberculosis and TB with extremely drug resistant depending on the case of the disease

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    Kryzhanovsky D.G.

    2014-11-01

    Full Text Available There was studied the profile of drug resistance to the main (I line and reserve (II line antituberculosis drugs in patients with MDR and XDR tuberculosis, depending of the case of the disease. According to the randomized retrospective research 200 patients with MDR and XDR tuberculosis, who received treatment in the clinic of hospital Municipal institution «Dnipropetrovsk rigional clinical association «Phthisiology» Dnipropetrovsk regional Council» during the period 2010 – 2012 were involved. Data about patients contained the data on a case of the disease and the results of the test of drug sensitivity to MBT. XDR – TB was revealed in 7.5% of patients with MDR tuberculosis. In patients with MDR tuberculosis as compared with patients with XDR tuberculosis «new cases» were diagnosed in 19.5% against 18.5% (p <0.05. In patients with MDR tuberculosis and with XDR tuberculosis resistance to the antituberculosis drug more commonly developed to S - 88.5%, E - 55% and Z - 24%. The presence of MDR-TB and XDR-TB prevails in patients, who underwent previous courses of treatment with anti-TB drugs in case history as compared with patients with «new cases» of treatment. The development of resistance to anti-TB drugs depends on the availability of these drugs in the previous treatment regimens.

  20. Activity of siderophores against drug-resistant Gram-positive and Gram-negative bacteria

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    Gokarn K

    2018-01-01

    Full Text Available Karuna Gokarn,1,2 Ramprasad B Pal1 1Department of Microbiology, Sir Hurkisondas Nurrotumdas Medical Research Society, 2Caius Research Laboratory, St Xavier’s College, Mumbai, India Abstract: Infections by drug-resistant bacteria are life-threatening. As iron is a vital element for the growth of bacteria, iron-chelating agents (siderophores can be used to arrest their multiplication. Exogenous siderophores – exochelin-MS and deferoxamine-B – were evaluated for their inhibitory activity against methicillin-resistant Staphylococcus aureus and metallo-β-lactamase producers – Pseudomonas aeruginosa and Acinetobacter baumannii – by disc diffusion, micro-broth dilution, and turbidimetric growth assays. The drug-resistant isolates were inhibited by the synergistic activity of siderophores and antibiotics. Minimum inhibitory concentration of exochelin-MS+ampicillin for different isolates was between 0.05 and 0.5 mg/mL. Minimum inhibitory concentration of deferoxamine-B+ampicillin was 1.0 mg/mL and greater. Iron-chelation therapy could provide a complementary approach to overcome drug resistance in pathogenic bacteria. Keywords: iron-chelation, xenosiderophores, exochelin MS, deferoxamine B

  1. Doxorubicin loaded Polymeric Nanoparticulate Delivery System to overcome drug resistance in osteosarcoma

    International Nuclear Information System (INIS)

    Susa, Michiro; Iyer, Arun K; Ryu, Keinosuke; Hornicek, Francis J; Mankin, Henry; Amiji, Mansoor M; Duan, Zhenfeng

    2009-01-01

    Drug resistance is a primary hindrance for the efficiency of chemotherapy against osteosarcoma. Although chemotherapy has improved the prognosis of osteosarcoma patients dramatically after introduction of neo-adjuvant therapy in the early 1980's, the outcome has since reached plateau at approximately 70% for 5 year survival. The remaining 30% of the patients eventually develop resistance to multiple types of chemotherapy. In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) tumor cells, we explored the possibility of loading doxorubicin onto biocompatible, lipid-modified dextran-based polymeric nanoparticles and evaluated the efficacy. Doxorubicin was loaded onto a lipid-modified dextran based polymeric nano-system. The effect of various concentrations of doxorubicin alone or nanoparticle loaded doxorubicin on KHOS, KHOS R2 , U-2OS, and U-2OS R2 cells was analyzed. Effects on drug retention, immunofluorescence, Pgp expression, and induction of apoptosis were also analyzed. Dextran nanoparticles loaded with doxorubicin had a curative effect on multidrug resistant osteosarcoma cell lines by increasing the amount of drug accumulation in the nucleus via Pgp independent pathway. Nanoparticles loaded with doxorubicin also showed increased apoptosis in osteosarcoma cells as compared with doxorubicin alone. Lipid-modified dextran nanoparticles loaded with doxorubicin showed pronounced anti-proliferative effects against osteosarcoma cell lines. These findings may lead to new treatment options for MDR osteosarcoma

  2. CRISPR-Cas9-mediated saturated mutagenesis screen predicts clinical drug resistance with improved accuracy.

    Science.gov (United States)

    Ma, Leyuan; Boucher, Jeffrey I; Paulsen, Janet; Matuszewski, Sebastian; Eide, Christopher A; Ou, Jianhong; Eickelberg, Garrett; Press, Richard D; Zhu, Lihua Julie; Druker, Brian J; Branford, Susan; Wolfe, Scot A; Jensen, Jeffrey D; Schiffer, Celia A; Green, Michael R; Bolon, Daniel N

    2017-10-31

    Developing tools to accurately predict the clinical prevalence of drug-resistant mutations is a key step toward generating more effective therapeutics. Here we describe a high-throughput CRISPR-Cas9-based saturated mutagenesis approach to generate comprehensive libraries of point mutations at a defined genomic location and systematically study their effect on cell growth. As proof of concept, we mutagenized a selected region within the leukemic oncogene BCR-ABL1 Using bulk competitions with a deep-sequencing readout, we analyzed hundreds of mutations under multiple drug conditions and found that the effects of mutations on growth in the presence or absence of drug were critical for predicting clinically relevant resistant mutations, many of which were cancer adaptive in the absence of drug pressure. Using this approach, we identified all clinically isolated BCR-ABL1 mutations and achieved a prediction score that correlated highly with their clinical prevalence. The strategy described here can be broadly applied to a variety of oncogenes to predict patient mutations and evaluate resistance susceptibility in the development of new therapeutics. Published under the PNAS license.

  3. Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes.

    Science.gov (United States)

    Shen, Ding-Wu; Pouliot, Lynn M; Hall, Matthew D; Gottesman, Michael M

    2012-07-01

    Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis.

  4. Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens.

    Directory of Open Access Journals (Sweden)

    Shankar Thangamani

    Full Text Available Without a doubt, our current antimicrobials are losing the battle in the fight against newly-emerged multidrug-resistant pathogens. There is a pressing, unmet need for novel antimicrobials and novel approaches to develop them; however, it is becoming increasingly difficult and costly to develop new antimicrobials. One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug. Ebselen, an organoselenium clinical molecule, possesses potent antimicrobial activity against clinical multidrug-resistant Gram-positive pathogens, including Staphylococcus, Streptococcus, and Enterococcus, but not against Gram-negative pathogens. Moreover, the activity of ebselen against Gram-positive pathogens exceeded those activities determined for vancomycin and linezolid, drugs of choice for treatment of Enterococcus and Staphylococcus infections. The minimum inhibitory concentrations of ebselen at which 90% of clinical isolates of Enterococcus and Staphylococcus were inhibited (MIC90 were found to be 0.5 and 0.25 mg/L, respectively. Ebselen showed significant clearance of intracellular methicillin-resistant S. aureus (MRSA in comparison to vancomycin and linezolid. We demonstrated that ebselen inhibits the bacterial translation process without affecting mitochondrial biogenesis. Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model. Finally, ebselen showed synergistic activities with conventional antimicrobials against MRSA. Taken together, our results demonstrate that ebselen, with its potent antimicrobial activity and safety profiles, can be potentially used to treat multidrug resistant Gram-positive bacterial infections alone or in combination with other antibiotics and should be further clinically evaluated.

  5. Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens.

    Science.gov (United States)

    Thangamani, Shankar; Younis, Waleed; Seleem, Mohamed N

    2015-01-01

    Without a doubt, our current antimicrobials are losing the battle in the fight against newly-emerged multidrug-resistant pathogens. There is a pressing, unmet need for novel antimicrobials and novel approaches to develop them; however, it is becoming increasingly difficult and costly to develop new antimicrobials. One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug. Ebselen, an organoselenium clinical molecule, possesses potent antimicrobial activity against clinical multidrug-resistant Gram-positive pathogens, including Staphylococcus, Streptococcus, and Enterococcus, but not against Gram-negative pathogens. Moreover, the activity of ebselen against Gram-positive pathogens exceeded those activities determined for vancomycin and linezolid, drugs of choice for treatment of Enterococcus and Staphylococcus infections. The minimum inhibitory concentrations of ebselen at which 90% of clinical isolates of Enterococcus and Staphylococcus were inhibited (MIC90) were found to be 0.5 and 0.25 mg/L, respectively. Ebselen showed significant clearance of intracellular methicillin-resistant S. aureus (MRSA) in comparison to vancomycin and linezolid. We demonstrated that ebselen inhibits the bacterial translation process without affecting mitochondrial biogenesis. Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model. Finally, ebselen showed synergistic activities with conventional antimicrobials against MRSA. Taken together, our results demonstrate that ebselen, with its potent antimicrobial activity and safety profiles, can be potentially used to treat multidrug resistant Gram-positive bacterial infections alone or in combination with other antibiotics and should be further clinically evaluated.

  6. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    International Nuclear Information System (INIS)

    Florea, Ana-Maria; Büsselberg, Dietrich

    2011-01-01

    Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects

  7. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    Energy Technology Data Exchange (ETDEWEB)

    Florea, Ana-Maria [Department of Neuropathology, Heinrich-Heine University, Düsseldorf (Germany); Büsselberg, Dietrich, E-mail: dib2015@qatar-med.cornell.edu [Weil Cornell Medical College in Qatar, Qatar Foundation-Education City, P.O. Box 24144, Doha (Qatar)

    2011-03-15

    Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.

  8. Analysis of metal and biocides resistance genes in drug resistance and susceptible Salmonella enterica from food animals

    Science.gov (United States)

    Background Generally drug resistant bacteria carry antibiotic resistance genes and heavy metal and biocide resistance genes on large conjugative plasmids. The presence of these metal and biocide resistance genes in susceptible bacteria are not assessed comprehensively. Hence, WGS data of susceptib...

  9. "DRUG RESISTANCE PATTERN IN ISOLATED BACTERIA FROM BLOOD CULTURES"

    Directory of Open Access Journals (Sweden)

    A. Sobhani

    2004-05-01

    Full Text Available Bacteremia is an important infectious disease which may lead to death. Common bacteria and pattern of antibiotic resistance in different communities are different and understanding these differences is important. In the present study, relative frequency and pattern of drug resistance have been examined in bacteria isolated from blood cultures in Razi Hospital laboratory. The method of the study was descriptive. Data collection was carried out retrospectively. Total sample consisted of 311 positive blood cultures from 1999 to 2001. Variables under study were bacterial strains, antibiotics examined in antibiogram, microbial resistance, and patients' age and sex. The most common isolated bacteria were Salmonella typhi (22.2% and the least common ones were Citrobacter (1.6%. The highest antibiotic resistance was seen against amoxicillin (88.4%. The proportion of males to females was1: 1/1 and the most common age group was 15-44 (47.3%. Common bacteria and pattern of antibiotic resistance were different in some areas and this subject requires further studies in the future.

  10. 'CM 88' - A multiple disease resistant chickpea mutant variety

    International Nuclear Information System (INIS)

    Haq, M.A.; Hassan, Mahmudul; Sadiq, M.

    2001-01-01

    Full text: Chickpea is the most important grain legume crop of Pakistan. Ascochyta blight (Ascochyta rabiei) and Fusarium wilt (Fusarium oxysporum F. sp cicer) are most serious diseases, having the potential to devastate a crop. A multiple disease resistant and high yielding mutant CM 88 has been developed through 100 Gy gamma irradiation treatment of variety 'C 727'. This was once a widely grown and popular variety, which lost its resistance to Ascochyta and was replaced. The selection of mutants was performed in the M2 generation grown in the Ascochyta blight nursery and sixteen mutants were selected. In the subsequent generations CM 88 proved resistant to both Ascochyta blight and Fusarium wilt, and exhibited superiority in agronomic characteristics. CM 88 was also tested for many years in the various yield trials on research stations and farmers fields throughout the country. In these trials it out yielded both the parent and standard varieties. The mutant CM 88 has been approved by the Punjab Seed Council on 27 October 1994 for general cultivation in the Punjab Province, especially the Thal area which accounts for more than 70% of the area under chickpea cultivation. (author)

  11. Clostridium difficile Infections: A Global Overview of Drug Sensitivity and Resistance Mechanisms

    Directory of Open Access Journals (Sweden)

    Saeed S. Banawas

    2018-01-01

    Full Text Available Clostridium difficile (C. difficile is the most prevalent causative pathogen of healthcare-associated diarrhea. Notably, over the past 10 years, the number of Clostridium difficile outbreaks has increased with the rate of morbidity and mortality. The occurrence and spread of C. difficile strains that are resistant to multiple antimicrobial drugs complicate prevention as well as potential treatment options. Most C. difficile isolates are still susceptible to metronidazole and vancomycin. Incidences of C. difficile resistance to other antimicrobial drugs have also been reported. Most of the antibiotics correlated with C. difficile infection (CDI, such as ampicillin, amoxicillin, cephalosporins, clindamycin, and fluoroquinolones, continue to be associated with the highest risk for CDI. Still, the detailed mechanism of resistance to metronidazole or vancomycin is not clear. Alternation in the target sites of the antibiotics is the main mechanism of erythromycin, fluoroquinolone, and rifamycin resistance in C. difficile. In this review, different antimicrobial agents are discussed and C. difficile resistance patterns and their mechanism of survival are summarized.

  12. Accelerating resistance, inadequate antibacterial drug pipelines and international responses.

    Science.gov (United States)

    Theuretzbacher, Ursula

    2012-04-01

    The pandemic of multidrug-resistant (MDR) pathogens and their continuing spread is beyond dispute. In contrast to the past, today's antibacterial research and development (R&D) pipelines are nearly dry, failing to provide the flow of novel antibiotics required to match the clinical challenges of the multidrug resistance (MDR) crisis. Concerned over the rapidly worsening potential global healthcare crisis caused by MDR bacteria and the lack of robust drug pipelines, several multinational campaigns have issued policy recommendations and have initiated broad discussion with a goal of stimulating the development of novel antibacterial drugs and technologies. These activities have resulted in intensified co-operation between the USA and the EU. The recently announced extensive 'Action plan against the rising threats from antimicrobial resistance' substantially ramps up action within the EU. In recognising the potential crisis caused by MDR and the limited treatment options, the European Commission decided on an unprecedented approach to drive the search for novel antibiotics by integrating the pharmaceutical industry, the research capacities of universities and small companies supported by public funding along with pricing/reimbursement and regulatory bodies. The European Commission has shown leadership and put action plans in place. Only the future will tell whether these initiatives will help curb the impact of the MDR pandemic. Copyright © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  13. Candidate genes for cross-resistance against DNA-damaging drugs

    DEFF Research Database (Denmark)

    Wittig, Rainer; Nessling, Michelle; Will, Rainer D

    2002-01-01

    Drug resistance of tumor cells leads to major drawbacks in the treatment of cancer. To identify candidate genes for drug resistance, we compared the expression patterns of the drug-sensitive human malignant melanoma cell line MeWo and three derived sublines with acquired resistance to the DNA...... as several apoptosis-related genes, in particular STK17A and CRYAB. As MPP1 and CRYAB are also among the 14 genes differentially expressed in all three of the drug-resistant sublines, they represent the strongest candidates for resistance against DNA-damaging drugs....

  14. Definition of drug-resistant epilepsy: is it evidence based?

    Science.gov (United States)

    Wiebe, Samuel

    2013-05-01

    Clinical case definitions are the cornerstone of clinical communication and of clinical and epidemiologic research. The ramifications of establishing a case definition are extensive, including potentially large changes in epidemiologic estimates of frequency, and decisions for clinical management. Yet, defining a condition entails numerous challenges such as defining the scope and purpose, incorporating the strongest evidence base with clinical expertise, accounting for patients' values, and considering impact on care. The clinical case definition of drug-resistant epilepsy, in addition, must address what constitutes an adequate intervention for an individual drug, what are the outcomes of relevance, what period of observation is sufficient to determine success or failure, how many medications should be tried, whether seizure frequency should play a role, and what is the role of side effects and tolerability. On the other hand, the principles of evidence-based medicine (EBM) aim at providing a systematic approach to incorporating the best available evidence into the process of clinical decision for individual patients. The case definition of drug-resistant epilepsy proposed by the the International League Against Epilepsy (ILAE) in 2009 is evaluated in terms of the principles of EBM as well as the stated goals of the authors of the definition. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

  15. Risk Factors for Acquisition of Drug Resistance during Multidrug-Resistant Tuberculosis Treatment, Arkhangelsk Oblast, Russia, 2005–2010

    Science.gov (United States)

    Ershova, Julia; Vlasova, Natalia; Nikishova, Elena; Tarasova, Irina; Eliseev, Platon; Maryandyshev, Andrey O.; Shemyakin, Igor G.; Kurbatova, Ekaterina; Cegielski, J. Peter

    2015-01-01

    Acquired resistance to antituberculosis drugs decreases effective treatment options and the likelihood of treatment success. We identified risk factors for acquisition of drug resistance during treatment for multidrug-resistant tuberculosis (MDR TB) and evaluated the effect on treatment outcomes. Data were collected prospectively from adults from Arkhangelsk Oblast, Russia, who had pulmonary MDR TB during 2005–2008. Acquisition of resistance to capreomycin and of extensively drug-resistant TB were more likely among patients who received 3 effective drugs (9.4% vs. 0% and 8.6% vs. 0.8%, respectively). Poor outcomes were more likely among patients with acquired capreomycin resistance (100% vs. 25.9%), acquired ofloxacin resistance (83.6% vs. 22.7%), or acquired extensive drug resistance (100% vs. 24.4%). To prevent acquired drug resistance and poor outcomes, baseline susceptibility to first- and second-line drugs should be determined quickly, and treatment should be adjusted to contain >3 effective drugs. PMID:25988954

  16. Collateral Resistance and Sensitivity Modulate Evolution of High-Level Resistance to Drug Combination Treatment in Staphylococcus aureus

    DEFF Research Database (Denmark)

    de Evgrafov, Mari Cristina Rodriguez; Gumpert, Heidi; Munck, Christian

    2015-01-01

    As drug-resistant pathogens continue to emerge, combination therapy will increasingly be relied upon to treat infections and to help combat further development of multidrug resistance. At present a dichotomy exists between clinical practice, which favors therapeutically synergistic combinations......, to reflect drug concentrations more likely to be encountered during treatment. We performed a series of adaptive evolution experiments using Staphylococcus aureus. Interestingly, no relationship between drug interaction type and resistance evolution was found as resistance increased significantly beyond wild......-type levels. All drug combinations, irrespective of interaction types, effectively limited resistance evolution compared with monotreatment. Cross-resistance and collateral sensitivity were found to be important factors in the extent of resistance evolution toward a combination. Comparative genomic analyses...

  17. Low-level quinolone-resistance in multi-drug resistant typhoid

    Energy Technology Data Exchange (ETDEWEB)

    Mirza, S H; Khan, M A [Armed Forces Inst. of Pathology, Rawalpindi (Pakistan). Dept. of Microbiolgy

    2008-01-15

    To find out the frequency of low-level quinolone-resistance in Multi-Drug Resistant (MDR) typhoid using nalidixic acid screening disc. Blood was obtained from suspected cases of typhoid fever and cultured in to BacT/ALERT. The positive blood cultures bottles were subcultured. The isolates were identified by colony morphology and biochemical tests using API-20E galleries. Susceptibility testing of isolates was done by modified Kirby-Bauer disc diffusion method on Muellar Hinton Agar. For the isolates, which were resistant to nalidixic acid by disc diffusion method, Minimal Inhibitory Concentrations (MICs) of ciprofloxacin and nalidixic acid were determined by using the E-test strips. Disc diffusion susceptibility tests and MICs were interpreted according to the guidelines provided by National Committee for Control Laboratory Standard (NCCLS). A total of 21(65.5%) out of 32 isolates of Salmonellae were nalidixic acid-resistant by disk diffusion method. All the nalidixic acid-resistant isolates by disc diffusion method were confirmed by MICs for both ciprofloxacin and nalidixic acid. All the nalidixic acid-resistant isolates had a ciprofloxacin MIC of 0.25-1 microg/ml (reduced susceptibility) and nalidixic acid MICs > 32 microg (resistant). Out of all Salmonella isolates, 24 (75%) were found to be MDR, and all were S. typbi. Low-level quinolone-resistance in typhoid was high in this small series. Screening for nalidixic acid resistance with a 30 microg nalidixic acid disk is a reliable and cost-effective method to detect low-level fluoroquinolone resistance, especially in the developing countries. (author)

  18. Low-level quinolone-resistance in multi-drug resistant typhoid

    International Nuclear Information System (INIS)

    Mirza, S.H.; Khan, M.A.

    2008-01-01

    To find out the frequency of low-level quinolone-resistance in Multi-Drug Resistant (MDR) typhoid using nalidixic acid screening disc. Blood was obtained from suspected cases of typhoid fever and cultured in to BacT/ALERT. The positive blood cultures bottles were subcultured. The isolates were identified by colony morphology and biochemical tests using API-20E galleries. Susceptibility testing of isolates was done by modified Kirby-Bauer disc diffusion method on Muellar Hinton Agar. For the isolates, which were resistant to nalidixic acid by disc diffusion method, Minimal Inhibitory Concentrations (MICs) of ciprofloxacin and nalidixic acid were determined by using the E-test strips. Disc diffusion susceptibility tests and MICs were interpreted according to the guidelines provided by National Committee for Control Laboratory Standard (NCCLS). A total of 21(65.5%) out of 32 isolates of Salmonellae were nalidixic acid-resistant by disk diffusion method. All the nalidixic acid-resistant isolates by disc diffusion method were confirmed by MICs for both ciprofloxacin and nalidixic acid. All the nalidixic acid-resistant isolates had a ciprofloxacin MIC of 0.25-1 microg/ml (reduced susceptibility) and nalidixic acid MICs > 32 microg (resistant). Out of all Salmonella isolates, 24 (75%) were found to be MDR, and all were S. typbi. Low-level quinolone-resistance in typhoid was high in this small series. Screening for nalidixic acid resistance with a 30 microg nalidixic acid disk is a reliable and cost-effective method to detect low-level fluoroquinolone resistance, especially in the developing countries. (author)

  19. Treatment Options for Carbapenem-Resistant and Extensively Drug-Resistant Acinetobacter baumannii Infections

    Science.gov (United States)

    Viehman, J. Alexander; Nguyen, Minh-Hong; Doi, Yohei

    2014-01-01

    Acinetobacter baumannii is a leading cause of healthcare-associated infections worldwide. Due to various intrinsic and acquired mechanisms of resistance, most β-lactam agents are not effective against many strains, and carbapenems have played an important role in therapy. Recent trends show many infections are caused by carbapenem-resistant, or even extensively drug-resistant (XDR) strains, for which effective therapy is not well established. Evidence to date suggests that colistin constitutes the backbone of therapy, but the unique pharmacokinetic properties of colistin have led many to suggest the use of combination antimicrobial therapy. However, the combination of agents and dosing regimens that delivers the best clinical efficacy while minimizing toxicity is yet to be defined. Carbapenems, sulbactam, rifampin and tigecycline have been the most studied in the context of combination therapy. Most data regarding therapy for invasive, resistant A. baumannii infections come from uncontrolled case series and retrospective analyses, though some clinical trials have been completed and others are underway. Early institution of appropriate antimicrobial therapy is shown to consistently improve survival of patients with carbapenem-resistant and XDR A. baumannii infection, but the choice of empiric therapy in these infections remains an open question. This review summarizes the most current knowledge regarding the epidemiology, mechanisms of resistance, and treatment considerations of carbapenem-resistant and XDR A. baumannii. PMID:25091170

  20. Cattle breeding, trypanosomosis prevalence and drug resistance in Northern Togo.

    Science.gov (United States)

    Tchamdja, E; Kulo, A E; Vitouley, H S; Batawui, K; Bankolé, A A; Adomefa, K; Cecchi, G; Hoppenheit, A; Clausen, P H; De Deken, R; Van Den Abbeele, J; Marcotty, T; Delespaux, V

    2017-03-15

    African Animal Trypanosomosis (AAT) is a major disease of cattle in Togo and its control is essentially based on chemotherapy. However, because of excessive use of trypanocides during the past decades, chemo-resistance in the parasites has developed. In order to assess the current situation of AAT and resistance to trypanocidal drugs in Northern Togo, a study was conducted on cattle from December 2012 to August 2013 in the regions of Kara and Savanes. An initial cross-sectional survey was carried out in 40 villages using the Haematocrit Centrifugation Technique (HCT). Out of these, 5 villages with a trypanosome prevalence of >10% were selected for a block treatment study (BT) with diminazene diaceturate (DA: 3.5mg/kg for a 14-day follow-up) and isometamidium chloride (ISM: 0.5mg/kg for a 28-day follow-up). Positive blood samples collected during the parasitological surveys and an equivalent number of negatives were further analyzed by PCR-RFLP for trypanosome species confirmation and molecular diagnosis of resistance to DA in Trypanosoma congolense. The results from 1883 bovine blood samples confirmed a high overall trypanosome prevalence of 10.8% in Northern Togo. PCR-RFLP revealed that T. congolense is the dominant pathogenic trypanosome species (50.5%) followed by T. vivax (27.3%), and T. brucei (16.2%). The BT showed varying levels of treatment failures ranging from 0 to 30% and from 0 to 50% for DA and for ISM respectively, suggesting the existence of resistant trypanosome populations in the study area. Our results show that AAT still represents a major obstacle to the development of cattle husbandry in Northern Togo. In areas of high AAT risk, a community-based integrated strategy combining vector control, rational use of trypanocidal drugs and improving the general condition of the animals is recommended to decision makers. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Oxidative Stress in Patients with Drug Resistant Partial Complex Seizure

    Directory of Open Access Journals (Sweden)

    Lourdes Lorigados Pedre

    2018-06-01

    Full Text Available Oxidative stress (OS has been implicated as a pathophysiological mechanism of drug-resistant epilepsy, but little is known about the relationship between OS markers and clinical parameters, such as the number of drugs, age onset of seizure and frequency of seizures per month. The current study’s aim was to evaluate several oxidative stress markers and antioxidants in 18 drug-resistant partial complex seizure (DRPCS patients compared to a control group (age and sex matched, and the results were related to clinical variables. We examined malondialdehyde (MDA, advanced oxidation protein products (AOPP, advanced glycation end products (AGEs, nitric oxide (NO, uric acid, superoxide dismutase (SOD, glutathione, vitamin C, 4-hydroxy-2-nonenal (4-HNE and nitrotyrosine (3-NT. All markers except 4-HNE and 3-NT were studied by spectrophotometry. The expressions of 4-HNE and 3-NT were evaluated by Western blot analysis. MDA levels in patients were significantly increased (p ≤ 0.0001 while AOPP levels were similar to the control group. AGEs, NO and uric acid concentrations were significantly decreased (p ≤ 0.004, p ≤ 0.005, p ≤ 0.0001, respectively. Expressions of 3-NT and 4-HNE were increased (p ≤ 0.005 similarly to SOD activity (p = 0.0001, whereas vitamin C was considerably diminished (p = 0.0001. Glutathione levels were similar to the control group. There was a positive correlation between NO and MDA with the number of drugs. The expression of 3-NT was positively related with the frequency of seizures per month. There was a negative relationship between MDA and age at onset of seizures, as well as vitamin C with seizure frequency/month. We detected an imbalance in the redox state in patients with DRCPS, supporting oxidative stress as a relevant mechanism in this pathology. Thus, it is apparent that some oxidant and antioxidant parameters are closely linked with clinical variables.

  2. Plasmonic Nanobubbles Rapidly Detect and Destroy Drug-Resistant Tumors

    Science.gov (United States)

    Lukianova-Hleb, Ekaterina Y.; Ren, Xiaoyang; Townley, Debra; Wu, Xiangwei; Kupferman, Michael E.; Lapotko, Dmitri O.

    2012-01-01

    The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC). The patients' survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil) in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB). HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres) converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment. PMID:23139725

  3. HIV-1 diversity and drug-resistant mutations in infected individuals in Changchun, China.

    Directory of Open Access Journals (Sweden)

    Ming Yan

    Full Text Available OBJECTIVES: Human immunodeficiency virus type 1 (HIV-1 infection has been detected in all provinces of China. Although epidemiological and phylogenetic studies have been conducted in many regions, such analyses are lacking from Jilin province in northeastern China. METHOD: Epidemiological and phylogenetic analyses, as well as detection of drug-resistant mutations, were conducted on 57 HIV-1 infected patients from Changchun city identified and confirmed through annual surveillance by local Centers for Disease Control in Jilin province of northeastern China in 2012. RESULTS: Sexual contact was determined to be the major pathway for HIV-1 transmission in Jilin, where hetero- and homosexual activities contributed almost equally. Phylogenetic analyses detected multiple subtypes of HIV-1 including subtype G circulating in Jilin, with multiple origins for each of them. Both subtype B and CRF01_AE were dominant, and evidence of subtype B transmitting between different high-risk groups was observed. Mutations in the viral protease at position 71 indicated the presence of a selective pressure. Several drug-resistant mutations were detected, although they were predicted with low-level resistance to antiviral treatments. CONCLUSIONS: Information from this study fills the gap in knowledge of HIV-1 transmission in Changchun city, Jilin province, China. By revealing the origin and evolutionary status of local HIV-1 strains, this work contributes to ongoing efforts in the control and prevention of AIDS.

  4. Horizontal antimicrobial resistance transfer drives epidemics of multiple Shigella species.

    Science.gov (United States)

    Baker, Kate S; Dallman, Timothy J; Field, Nigel; Childs, Tristan; Mitchell, Holly; Day, Martin; Weill, François-Xavier; Lefèvre, Sophie; Tourdjman, Mathieu; Hughes, Gwenda; Jenkins, Claire; Thomson, Nicholas

    2018-04-13

    Horizontal gene transfer has played a role in developing the global public health crisis of antimicrobial resistance (AMR). However, the dynamics of AMR transfer through bacterial populations and its direct impact on human disease is poorly elucidated. Here, we study parallel epidemic emergences of multiple Shigella species, a priority AMR organism, in men who have sex with men to gain insight into AMR emergence and spread. Using genomic epidemiology, we show that repeated horizontal transfer of a single AMR plasmid among Shigella enhanced existing and facilitated new epidemics. These epidemic patterns contrasted with slighter, slower increases in disease caused by organisms with vertically inherited (chromosomally encoded) AMR. This demonstrates that horizontal transfer of AMR directly affects epidemiological outcomes of globally important AMR pathogens and highlights the need for integration of genomic analyses into all areas of AMR research, surveillance and management.

  5. Radiation induction of drug resistance in RIF-1: Correlation of tumor and cell culture results

    International Nuclear Information System (INIS)

    Moulder, J.E.; Hopwood, L.E.; Volk, D.M.; Davies, B.M.

    1991-01-01

    The RIF-1 tumor line contains cells that are resistant to various anti-neoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), adriamycin (ADR), and etoposide (VP16). The frequency of these drug-resistant cells is increased after irradiation. The frequency of drug-resistant cells and the magnitude of radiation-induced drug resistance are different in cell culture than in tumors. The dose-response and expression time relationships for radiation induction of drug resistance observed in RIF-1 tumors are unusual.We hypothesize that at high radiation doses in vivo, we are selecting for cells that are both drug resistant and radiation resistant due to microenvironmental factors, whereas at low radiation doses in vivo and all radiation doses in vitro, we are observing true mutants. These studies indicate that there can be significant differences in drug-resistance frequencies between tumors and their cell lines of origin, and that radiation induction of drug resistance depends significantly on whether the induction is done in tumors or in cell culture. These results imply that theories about the induction of drug resistance that are based on cell culture studies may be inapplicable to the induction of drug resistance in tumors

  6. Ectoparasites of medical and veterinary importance: drug resistance and the need for alternative control methods.

    Science.gov (United States)

    McNair, Carol M

    2015-03-01

    Despite multiple attempts at eradication, many ectoparasites of humans and domestic livestock remain a persistent problem in the modern world. For many years, a range of pesticide drugs including organophosphates, organochlorides and synthetic pyrethroids provided effective control of these parasites; but intensive use of these drugs has led to the evolution of resistance in many target species. This paper aims to review the effectiveness of current control methods and discuss potential alternatives for the long term sustainable control of ectoparasites. Important medical ectoparasites such as scabies mites, head lice and bed bugs present a significant public health problem, and so adequate control methods are essential. Ectoparasites of domestic livestock and farmed fish (for example sheep scab mites, poultry mites and sea lice) are also of concern given the increasing strain on the world's food supply. These parasites have become resistant to several classes of pesticide, making control very difficult. Recently, an increasing amount of research has focussed on alternative control methods such as insect growth regulators, biological control using essential oils or fungi, as well as vaccine development against some ectoparasites of medical and veterinary importance. Drug resistance is prevalent in all of the ectoparasites discussed in this review. A wide variety of alternative control methods have been identified, however further research is necessary in order for these to be used to successfully control ectoparasitic diseases in the future. © 2015 Royal Pharmaceutical Society.

  7. Radiation induction of drug resistance in RIF-1 tumors and tumor cells

    International Nuclear Information System (INIS)

    Hopwood, L.E.; Moulder, J.E.

    1989-01-01

    The RIF-1 tumor cell line contains a small number of cells (1-20 per 10(6) cells) that are resistant to various single antineoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), and adriamycin (ADR). For 5FU the frequency of drug resistance is lower for tumor-derived cells than for cells from cell culture; for MTX the reverse is true, and for ADR there is no difference. In vitro irradiation at 5 Gy significantly increased the frequency of drug-resistant cells for 5FU, MTX, and ADR. In vivo irradiation at 3 Gy significantly increased the frequency of drug-resistant cells for 5FU and MTX, but not for ADR. The absolute risk for in vitro induction of MTX, 5FU, and ADR resistance, and for in vivo induction of 5FU resistance, was 1-3 per 10(6) cells per Gy; but the absolute risk for in vivo induction of MTX resistance was 54 per 10(6) cells per Gy. The frequency of drug-resistant cells among individual untreated tumors was highly variable; among individual irradiated tumors the frequency of drug-resistant cells was significantly less variable. These studies provide supporting data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be due to radiation-induced drug resistance

  8. Extensively and Pre-Extensively Drug Resistant Tuberculosis in Clinical Isolates of Multi-Drug Resistant Tuberculosis Using Classical Second Line Drugs (Levofloxacin and Amikacin)

    International Nuclear Information System (INIS)

    Mirza, I. A.; Khan, F. A.; Khan, K. A.; Satti, L.; Ghafoor, T.; Fayyaz, M.

    2015-01-01

    Objective:To find out the frequency of Extensively Drug Resistant (XDR) and pre-XDR tuberculosis in clinical isolates of Multi-Drug Resistant (MDR) Tuberculosis (TB) by determining the susceptibilities against Levofloxacin and Amikacin (classical second line antituberculosis drugs). Study Design: A descriptive cross-sectional study. Place and Duration of Study: Microbiology Department, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from September 2011 to August 2013. Methodology: Amikacin (AK) and Levofloxacin (LEVO) were obtained in chemically pure form from Sigma (Taufkirchen, Germany). The breakpoint concentration used for AK was 1.0 micro g/ml and for LEVO 2.0 micro g/ml. Mycobacterial Growth Indicator Tube (MGIT) 960 system was used to carry out drug susceptibility testing as per recommended protocol. Results: A total of 3 MDR-TB isolates (3 percentage) turned out to be XDR-TB based upon simultaneous resistance to injectable second line antituberculosis drug AK and one of the fluoro-quinolones (LEVO). A total of 24 MDR-TB isolates (24 percentage) were found to be pre-XDR based upon resistance to LEVO alone. Treatment status record of patients with XDR and pre-XDRTB isolates revealed that majority of patients had received fluoroquinolones (FQs) during the course of treatment. Conclusion: XDR-TB has started to emerge in MDR-TB isolates in our set up. The worrying sign is the high frequency of pre-XDR tuberculosis. Urgent steps need to be taken to stem the tide of pre-XDR-TB in our population. It is thus recommended to develop facilities to carry out drug susceptibility testing to monitor the status of pre-XDR and XDR-TB in our population. (author)

  9. In silico repositioning-chemogenomics strategy identifies new drugs with potential activity against multiple life stages of Schistosoma mansoni.

    Directory of Open Access Journals (Sweden)

    Bruno J Neves

    2015-01-01

    Full Text Available Morbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD, DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes.

  10. Detection of First-Line Drug Resistance Mutations and Drug-Protein Interaction Dynamics from Tuberculosis Patients in South India.

    Science.gov (United States)

    Nachappa, Somanna Ajjamada; Neelambike, Sumana M; Amruthavalli, Chokkanna; Ramachandra, Nallur B

    2018-05-01

    Diagnosis of drug-resistant tuberculosis predominantly relies on culture-based drug susceptibility testing, which take weeks to produce a result and a more time-efficient alternative method is multiplex allele-specific PCR (MAS-PCR). Also, understanding the role of mutations in causing resistance helps better drug designing. To evaluate the ability of MAS-PCR in the detection of drug resistance and to understand the mechanism of interaction of drugs with mutant proteins in Mycobacterium tuberculosis. Detection of drug-resistant mutations using MAS-PCR and validation through DNA sequencing. MAS-PCR targeted five loci on three genes, katG 315 and inhA -15 for the drug isoniazid (INH), and rpoB 516, 526, and 531 for rifampicin (RIF). Furthermore, the sequence data were analyzed to study the effect on interaction of the anti-TB drug molecule with the target protein using in silico docking. We identified drug-resistant mutations in 8 out of 114 isolates with 2 of them as multidrug-resistant TB using MAS-PCR. DNA sequencing confirmed only six of these, recording a sensitivity of 85.7% and specificity of 99.3% for MAS-PCR. Molecular docking showed estimated free energy of binding (ΔG) being higher for RIF binding with RpoB S531L mutant. Codon 315 in KatG does not directly interact with INH but blocks the drug access to active site. We propose DNA sequencing-based drug resistance detection for TB, which is more accurate than MAS-PCR. Understanding the action of resistant mutations in disrupting the normal drug-protein interaction aids in designing effective drug alternatives.

  11. Ion channels and transporters in the development of drug resistance in cancer cells

    DEFF Research Database (Denmark)

    Hoffmann, Else Kay; Lambert, Ian Henry

    2014-01-01

    Multi-drug resistance (MDR) to chemotherapy is the major challenge in the treatment of cancer. MDR can develop by numerous mechanisms including decreased drug uptake, increased drug efflux and the failure to undergo drug-induced apoptosis. Evasion of drug-induced apoptosis through modulation of i...

  12. Incidence of multidrug-resistant, extensively drug-resistant and pan-drug-resistant bacteria in children hospitalized at Dr. Hasan Sadikin general hospital Bandung Indonesia

    Science.gov (United States)

    Adrizain, R.; Suryaningrat, F.; Alam, A.; Setiabudi, D.

    2018-03-01

    Antibiotic resistance has become a global issue, with 700,000 deaths attributable to multidrug-resistance (MDR) occurring each year. Centers for Disease Control and Prevention (CDC) show rapidly increasing rates of infection due to antibiotic-resistant bacteria. The aim of the study isto describe the incidence of MDR, extensively drug-resistant (XDR) and pan drug-resistant (PDR) in Enterococcus spp., Staphylococcus aureus, K. pneumonia, Acinetobacter baumanii, P. aeruginosin, and Enterobacter spp. (ESKAPE) pathogens in children admitted to Dr. Hasan Sadikin Hospital. All pediatric patients having blood culture drawn from January 2015 to December 2016 were retrospectively studied. Data include the number of drawn blood culture, number of positive results, type of bacteria, sensitivity pattern. International standard definitions for acquired resistance by ECDC and CDC was used as definitions for MDR, XDR and PDR bacteria. From January 2015 to December 2016, 299 from 2.542 (11.7%) blood culture was positive, with Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp., respectively 5, 6, 24, 5, 20 with total 60 (20%). The MDR and XDR pathogen found were 47 and 13 patients, respectively.

  13. Antihypertensive drug use in resistant and nonresistant hypertension and in controlled and uncontrolled resistant hypertension.

    Science.gov (United States)

    de la Sierra, Alejandro; Armario, Pedro; Oliveras, Anna; Banegas, José R; Gorostidi, Manuel; Vinyoles, Ernest; de la Cruz, Juan J; Segura, Julián; Ruilope, Luis M

    2018-07-01

    Treatment-resistant hypertension (TRH) is associated with particular clinical features, nonadherence, and suboptimal treatment. We assessed possible associations of antihypertensive drug classes, specific agents inside each class, and types of combinations, with the presence of non-TRH vs. TRH, and with controlled vs. uncontrolled TRH. Comparisons were done in 14 264 patients treated with three drugs (non-TRH: 2988; TRH: 11 276) and in 6974 treated with at least four drugs (controlled TRH: 1383; uncontrolled TRH: 5591). Associations were adjusted for age, sex, and previous cardiovascular event. In both groups of patients treated with three or with at least four drugs, aldosterone antagonists among drug classes [adjusted odds ratio (OR): 1.82 and 1.41, respectively], and ramipril (OR: 1.28 and 1.30), olmesartan (OR: 1.31 and 1.37), and amlodipine (OR: 1.11 and 1.41) inside each class were significantly associated with blood pressure control (non-TRH or controlled TRH). In patients treated with three drugs, non-TRH was also associated with the use of chlorthalidone (OR: 1.50) and bisoprolol (OR: 1.19), whereas in patients treated with at least four drugs, controlled TRH was significantly associated with the triple combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic (OR: 1.17). The use of aldosterone antagonists is associated with blood pressure control in patients treated with three or more drugs. Similar results are observed with specific agents inside each class, being ramipril, olmesartan, chlorthalidone, amlodipine, and bisoprolol those exhibiting significant results. An increased use of these drugs might probably reduce the burden of TRH.

  14. Emergence of fluoroquinolone resistance among drug resistant tuberculosis patients at a tertiary care facility in Karachi, Pakistan.

    Science.gov (United States)

    Zaidi, Syed Mohammad Asad; Haseeb, Abdul; Habib, Shifa Salman; Malik, Amyn; Khowaja, Saira; SaifUllah, Nausheen; Rizvi, Nadeem

    2017-07-25

    Pakistan is classified as one of the high multi-drug resistant tuberculosis (MDR-TB) burden countries. A poorly regulated private sector, over-prescription of antibiotics and self-medication has led to augmented rates of drug-resistance in the country. Pakistan's first national anti-tuberculosis drug resistance survey identified high prevalence of fluoroquinolone resistance among MDR-TB patients. Further institutional evidence of fluoroquinolone drug-resistance can support re-evaluation of treatment regimens as well as invigorate efforts to control antibiotic resistance in the country. In this study, data for drug-susceptibility testing (DST) was retrospectively analyzed for a total of 133 patients receiving MDR-TB treatment at the Chest Department of Jinnah Postgraduate Medical Center, Karachi, Pakistan. Frequency analyses for resistance patterns was carried out and association of fluoroquinolone (ofloxacin) resistance with demographics and past TB treatment category were assessed. Within first-line drugs, resistance to isoniazid was detected in 97.7% of cases, followed by rifampicin (96.9%), pyrazinamide (86.4%), ethambutol (69.2%) and streptomycin (64.6%). Within second-line drugs, ofloxacin resistance was detected in 34.6% of cases. Resistance to ethionamide and amikacin was 2.3% and 1.6%, respectively. Combined resistance of oflaxacin and isoniazid was detected in 33.9% of cases. Age, gender and past TB treatment category were not significantly associated with resistance to ofloxacin. Fluoroquinolone resistance was observed in an alarmingly high proportion of MDR-TB cases. Our results suggest caution in their use for empirical management of MDR-TB cases and recommended treatment regimens for MDR-TB may require re-evaluation. Greater engagement of private providers and stringent pharmacy regulations are urgently required.

  15. Surgical management of cavernous malformations coursing with drug resistant epilepsy

    Directory of Open Access Journals (Sweden)

    Mario Arturo Alonso-Vanegas

    2012-01-01

    Full Text Available Cerebral cavernous malformations (CM are dynamic lesions characterized by continuous size changes and repeated bleeding. When involving cortical tissue, CM pose a significant risk for the development of drug-resistant epilepsy, which is thought to be result of an altered neuronal network caused by the lesion itself and its blood degradation products. Preoperative evaluation should comprise a complete seizure history, neurological examination, epilepsy-oriented MRI, EEG, video-EEG, completed with SPECT, PET, functional MRI and/or invasive monitoring as needed. Radiosurgery shows variable rates of seizure freedom and a high incidence of complications, thus microsurgical resection remains the optimal treatment for CM coursing with drug-resistant epilepsy.Two thirds of patients reach Engel I class at three-year follow-up, regardless of lobar location. Those with secondarily generalized seizures, a higher seizure frequency, and generalized abnormalities on preoperative or postoperative EEG, show poorer outcomes, while factors such as gender, duration of epilepsy, lesion size, age, bleeding at the time of surgery, do not correlate consistently with seizure outcome. Electrocorticography and a meticulous removal of all cortical hemosiderin –beyond pure lesionectomy– reduce the risk of symptomatic recurrences.

  16. Drug Resistance versus Spiritual Resistance: A Comparative Analysis from the Perspective of Spiritual Health

    Directory of Open Access Journals (Sweden)

    Mohammad Baqer Mohammadi Laini

    2014-12-01

    Full Text Available Background and Objectives: Taking into account a few principles concerning human being, it becomes plausible that the human spirit would also have a similar reaction to spiritual “medicine” provided to it. In order to better understand how this is possible, we must consider the means by which the human spirit becomes resistant to spiritual remedies and compare them with the resistance developed by the body against physical drugs. As such, this research aimed at creating a comparative analysis between the elements that cause the human spirit to become resistant against spiritual remedies in comparison to the body’s resistance against physical treatments (e.g. drugs and other physical treatment. Methods: The research at hand highlights the conclusions of an overall study of the Holy Quran, books of Islamic narration, and extensive Internet research concerning this subject. With these resources, the various aspects of the spirit’s resistance against spiritual remedies were discussed in detail. Results: According to Holy Quran and Islamic narrations: Based on the expectations which God has of man, his heart (i.e. spirit has the potential to fall under one of two categories – positive or negative. An afflicted heart may at times, like an afflicted body, become resistant against a remedy designed to cure it. In both cases of physical or metaphysical resistance, the underlying element that causes this resistance as well as the symptoms which accompany it are similar to one another. Having considered the teachings found in religious texts, this research discovered the underlying causes of spiritual resistance, and outlined some solutions which can prevent this issue from arising in the first place. Conclusion: Based on the standards of health and spiritual wellbeing as outlined in Holy Quran, it is said that some hearts are unhealthy and require treatment and healing. In Holy Quran, there is also no doubt in it, guidance to the God wary

  17. Differences in quality of life of women and men with drug-resistant epilepsy in Poland.

    Science.gov (United States)

    Bala, Aleksandra; Szantroch, Marta; Gleinert, Alicja; Rysz, Andrzej; Marchel, Andrzej

    2016-07-01

    The aim of the study was to assess the differences in health-related quality of life in groups of men and women suffering with drug-resistant epilepsy and to determine which factors influence quality of life. The examined group consisted of 64 subjects with drug-resistant epilepsy - 31 men and 33 women. The mean duration of epilepsy was 17.56±8.92 and 19±9.56years, respectively. The following diagnostic tools were used: QOLIE-31-P, Wechsler Adult Intelligence Scale - Revised (WAIS-R (PL)), and Hamilton Rating Scale for Depression (HRSD). Scores in QOLIE-31-P did not differ significantly between groups of men and women with drug-resistant epilepsy; however, a more detailed analysis revealed certain disparities. Multiple regression analyses indicated that some distinct factors were associated with quality of life in each sex. In the group of women, there were no significant predictors of their quality of life. Among the group of men, depression intensity was the only statistically significant QoL predictor, explaining 16% of the variance (adjusted R(2)=0.16, F(6, 24)=19.7, pEmotional Well-Being and Energy/Fatigue subscales, regardless of the sex. The study revealed that, despite similar scores in QOLIE-31-P, specific factors may differentially affect the quality of life of men and women with drug-resistant epilepsy in Poland. Nevertheless, replication of these results with a larger number of participants is needed for a more definitive conclusion. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. 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.

  19. Structural Biology Meets Drug Resistance: An Overview on Multidrug Resistance Transporters

    DEFF Research Database (Denmark)

    Shaheen, Aqsa; Iqbal, Mazhar; Mirza, Osman

    2017-01-01

    . Research on the underlying causes of multidrug resistance in cancerous cells and later on in infectious bacteria revealed the involvement of integral membrane transporters, capable of recognizing a broad range of structurally different molecules as substrates and exporting them from the cell using cellular...... superfamilies, viz., ATP-binding cassette superfamily, major facilitator superfamily and resistance nodulation division superfamily are presented. Further, the future role of structural biology in improving our understanding of drug-transporter interactions and in designing novel inhibitors against MDR pump...... century, mankind has become aware and confronted with the emergence of antibiotic-resistant pathogens. In parallel to the failure of antibiotic therapy against infectious pathogens, there had been continuous reports of cancerous cells not responding to chemotherapy with increase in the duration of therapy...

  20. In vitro transfer of multiple resistance observed in vivo during a Salmonella london epidemic.

    Science.gov (United States)

    Lantos, J; Marjai, E

    1980-01-01

    Between 1976 and 1978, waves of Salmonella london infections conveyed by raw meat and meat products were observed. The strains isolated during the epidemic were first susceptible then developed multiple antibiotic resistance. The identical antibiotic resistance patterns of the strain and their more frequent occurrence in hospital environments indicated plasmid-mediated resistance. R-plasmid transfer, minimum inhibition concentration and resistance elimination were studied in representative strains. The resistant S. london strain and transconjugants of Escherichia coli rendered resistant were compared. The results proved that multiple resistance was plasmid-mediated.

  1. Childhood Idiopathic Steroid Resistant Nephrotic Syndrome, Different Drugs and Outcome

    International Nuclear Information System (INIS)

    Shah, S. S. H.; Hafeez, F.

    2016-01-01

    Background: The management of steroid resistant nephrotic syndrome (SRNS) is quite difficult in paediatric patients. Not only the remission is difficult but also these patients are at risk of progression to end stage renal disease (ESRD). The goal of treatment is either to achieve complete remission or even partial remission as it is the most important predictor of disease outcome. Methods: This study was conducted at The Children Hospital, Lahore from February 2014 to May 2015. The SRNS patients of either sex between ages of 1-12 years were included with histology showing mesangioproliferative glomerulonephritis (MesangioPGN), focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD). Patients were given different immunosuppressant drugs and steroid 30 mg/m/sup 2/ alternate day therapy on case to case basis and kept on regular follow up to check for response and adverse effects. Results: Total of 105 patients included, 63 (60 percent) male and 42 (40 percent) female patients. The age ranges from 1.08 to 12 years, mean age of 6.53 years and SD of ±3.17. Tacrolimus was the most common drug used 43 (41 percent) patients followed by cyclosporine in 38 (36.2 percent) patients, while Mycophenolate mofetil (MMF) was prescribed in 21 (20 percent) patients. Complete response was in 96 (91.4 percent) initially while partial response was seen in 8 (7.6 percent) patients. On follow up, 92 (87.6 percent) patients showed complete response and partial response was in 5 (4.7 percent) patients. Cushingoid features and hypertrichosis were the most common adverse effect seen. Conclusion: Steroid resistant nephrotic syndrome can be managed well with various immunosuppressant drugs and steroids but treatment should be individualized according to clinical presentation, disease histology and cost/social factors. (author)

  2. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump

    NARCIS (Netherlands)

    Zaman, G. J.; Flens, M. J.; van Leusden, M. R.; de Haas, M.; Mülder, H. S.; Lankelma, J.; Pinedo, H. M.; Scheper, R. J.; Baas, F.; Broxterman, H. J.

    1994-01-01

    The multidrug-resistance associated protein MRP is a 180- to 195-kDa membrane protein associated with resistance of human tumor cells to cytotoxic drugs. We have investigated how MRP confers drug resistance in SW-1573 human lung carcinoma cells by generating a subline stably transfected with an

  3. Drug resistance and genetic diversity of Plasmodium falciparum parasites from Suriname

    NARCIS (Netherlands)

    Peek, Ron; van Gool, Tom; Panchoe, Daynand; Greve, Sophie; Bus, Ellen; Resida, Lesley

    2005-01-01

    Plasmodium falciparum in Suriname was studied for the presence of drug resistance and genetic variation in blood samples of 86 patients with symptomatic malaria. Drug resistance was predicted by determining point mutations in the chloroquine resistance marker of the P. falciparum chloroquine

  4. Multiple drug resistance Staphylococcus aureus isolated in foods of ...

    African Journals Online (AJOL)

    Background: StaphylococcuS. aureus is the most important agent, which is known to cause a wide range of diseases in both human and animals. Extended use and misuse of antibiotics in agriculture, stock farming and in the treatment of human diseases, has contributed to the rapid increase of the number of bacteria that ...

  5. Isolation, Characterization and Anti-Multiple Drug Resistant (MDR ...

    African Journals Online (AJOL)

    (MDR) Bacterial Activity of Endophytic Fungi Isolated from ... Institute of Protection & Development of Beibu Wan Ocean Resources, Qinzhou University, Qinzhou, Guangxi Province, ..... isolated from secondary metabolites of the mangrove.

  6. Alterations in glutathione levels and apoptotic regulators are associated with acquisition of arsenic trioxide resistance in multiple myeloma.

    Directory of Open Access Journals (Sweden)

    Shannon M Matulis

    Full Text Available Arsenic trioxide (ATO has been tested in relapsed/refractory multiple myeloma with limited success. In order to better understand drug mechanism and resistance pathways in myeloma we generated an ATO-resistant cell line, 8226/S-ATOR05, with an IC50 that is 2-3-fold higher than control cell lines and significantly higher than clinically achievable concentrations. Interestingly we found two parallel pathways governing resistance to ATO in 8226/S-ATOR05, and the relevance of these pathways appears to be linked to the concentration of ATO used. We found changes in the expression of Bcl-2 family proteins Bfl-1 and Noxa as well as an increase in cellular glutathione (GSH levels. At low, clinically achievable concentrations, resistance was primarily associated with an increase in expression of the anti-apoptotic protein Bfl-1 and a decrease in expression of the pro-apoptotic protein Noxa. However, as the concentration of ATO increased, elevated levels of intracellular GSH in 8226/S-ATOR05 became the primary mechanism of ATO resistance. Removal of arsenic selection resulted in a loss of the resistance phenotype, with cells becoming sensitive to high concentrations of ATO within 7 days following drug removal, indicating changes associated with high level resistance (elevated GSH are dependent upon the presence of arsenic. Conversely, not until 50 days without arsenic did cells once again become sensitive to clinically relevant doses of ATO, coinciding with a decrease in the expression of Bfl-1. In addition we found cross-resistance to melphalan and doxorubicin in 8226/S-ATOR05, suggesting ATO-resistance pathways may also be involved in resistance to other chemotherapeutic agents used in the treatment of multiple myeloma.

  7. A meta-analysis of Drug resistant Tuberculosis in Sub-Saharan Africa

    African Journals Online (AJOL)

    Background: In Sub-Saharan Africa, the fight against tuberculosis (TB) has encountered a great challenge because of the emergence of drug resistant TB strains and the high prevalence of HIV infection. The aim of this meta-analysis was to determine the association of drug-resistant TB with anti-TB drug treatment history ...

  8. New-Onset Psychosis in a Multi-Drug Resistant Tuberculosis Patient ...

    African Journals Online (AJOL)

    Drug-resistant tuberculosis poses a serious challenge to global control of TB. These forms of TB do not respond to the standard six-month treatment; it can take two years or more to treat with category IV drugs that are less potent, more toxic and much more expensive. Treatment of multi-drug resistant tuberculosis is still ...

  9. Simple PCR assays improve the sensitivity of HIV-1 subtype B drug resistance testing and allow linking of resistance mutations.

    Directory of Open Access Journals (Sweden)

    Jeffrey A Johnson

    Full Text Available BACKGROUND: The success of antiretroviral therapy is known to be compromised by drug-resistant HIV-1 at frequencies detectable by conventional bulk sequencing. Currently, there is a need to assess the clinical consequences of low-frequency drug resistant variants occurring below the detection limit of conventional genotyping. Sensitive detection of drug-resistant subpopulations, however, requires simple and practical methods for routine testing. METHODOLOGY: We developed highly-sensitive and simple real-time PCR assays for nine key drug resistance mutations and show that these tests overcome substantial sequence heterogeneity in HIV-1 clinical specimens. We specifically used early wildtype virus samples from the pre-antiretroviral drug era to measure background reactivity and were able to define highly-specific screening cut-offs that are up to 67-fold more sensitive than conventional genotyping. We also demonstrate that sequencing the mutation-specific PCR products provided a direct and novel strategy to further detect and link associated resistance mutations, allowing easy identification of multi-drug-resistant variants. Resistance mutation associations revealed in mutation-specific amplicon sequences were verified by clonal sequencing. SIGNIFICANCE: Combined, sensitive real-time PCR testing and mutation-specific amplicon sequencing provides a powerful and simple approach that allows for improved detection and evaluation of HIV-1 drug resistance mutations.

  10. RNA disruption is associated with response to multiple classes of chemotherapy drugs in tumor cell lines

    International Nuclear Information System (INIS)

    Narendrula, Rashmi; Mispel-Beyer, Kyle; Guo, Baoqing; Parissenti, Amadeo M.; Pritzker, Laura B.; Pritzker, Ken; Masilamani, Twinkle; Wang, Xiaohui; Lannér, Carita

    2016-01-01

    Cellular stressors and apoptosis-inducing agents have been shown to induce ribosomal RNA (rRNA) degradation in eukaryotic cells. Recently, RNA degradation in vivo was observed in patients with locally advanced breast cancer, where mid-treatment tumor RNA degradation was associated with complete tumor destruction and enhanced patient survival. However, it is not clear how widespread chemotherapy induced “RNA disruption” is, the extent to which it is associated with drug response or what the underlying mechanisms are. Ovarian (A2780, CaOV3) and breast (MDA-MB-231, MCF-7, BT474, SKBR3) cancer cell lines were treated with several cytotoxic chemotherapy drugs and total RNA was isolated. RNA was also prepared from docetaxel resistant A2780DXL and carboplatin resistant A2780CBN cells following drug exposure. Disruption of RNA was analyzed by capillary electrophoresis. Northern blotting was performed using probes complementary to the 28S and 18S rRNA to determine the origins of degradation bands. Apoptosis activation was assessed by flow cytometric monitoring of annexin-V and propidium iodide (PI) binding to cells and by measuring caspase-3 activation. The link between apoptosis and RNA degradation (disruption) was investigated using a caspase-3 inhibitor. All chemotherapy drugs tested were capable of inducing similar RNA disruption patterns. Docetaxel treatment of the resistant A2780DXL cells and carboplatin treatment of the A2780CBN cells did not result in RNA disruption. Northern blotting indicated that two RNA disruption bands were derived from the 3’-end of the 28S rRNA. Annexin-V and PI staining of docetaxel treated cells, along with assessment of caspase-3 activation, showed concurrent initiation of apoptosis and RNA disruption, while inhibition of caspase-3 activity significantly reduced RNA disruption. Supporting the in vivo evidence, our results demonstrate that RNA disruption is induced by multiple chemotherapy agents in cell lines from different tissues

  11. RNA disruption is associated with response to multiple classes of chemotherapy drugs in tumor cell lines.

    Science.gov (United States)

    Narendrula, Rashmi; Mispel-Beyer, Kyle; Guo, Baoqing; Parissenti, Amadeo M; Pritzker, Laura B; Pritzker, Ken; Masilamani, Twinkle; Wang, Xiaohui; Lannér, Carita

    2016-02-24

    Cellular stressors and apoptosis-inducing agents have been shown to induce ribosomal RNA (rRNA) degradation in eukaryotic cells. Recently, RNA degradation in vivo was observed in patients with locally advanced breast cancer, where mid-treatment tumor RNA degradation was associated with complete tumor destruction and enhanced patient survival. However, it is not clear how widespread chemotherapy induced "RNA disruption" is, the extent to which it is associated with drug response or what the underlying mechanisms are. Ovarian (A2780, CaOV3) and breast (MDA-MB-231, MCF-7, BT474, SKBR3) cancer cell lines were treated with several cytotoxic chemotherapy drugs and total RNA was isolated. RNA was also prepared from docetaxel resistant A2780DXL and carboplatin resistant A2780CBN cells following drug exposure. Disruption of RNA was analyzed by capillary electrophoresis. Northern blotting was performed using probes complementary to the 28S and 18S rRNA to determine the origins of degradation bands. Apoptosis activation was assessed by flow cytometric monitoring of annexin-V and propidium iodide (PI) binding to cells and by measuring caspase-3 activation. The link between apoptosis and RNA degradation (disruption) was investigated using a caspase-3 inhibitor. All chemotherapy drugs tested were capable of inducing similar RNA disruption patterns. Docetaxel treatment of the resistant A2780DXL cells and carboplatin treatment of the A2780CBN cells did not result in RNA disruption. Northern blotting indicated that two RNA disruption bands were derived from the 3'-end of the 28S rRNA. Annexin-V and PI staining of docetaxel treated cells, along with assessment of caspase-3 activation, showed concurrent initiation of apoptosis and RNA disruption, while inhibition of caspase-3 activity significantly reduced RNA disruption. Supporting the in vivo evidence, our results demonstrate that RNA disruption is induced by multiple chemotherapy agents in cell lines from different tissues and is

  12. Multiple polysaccharide-drug complex-loaded liposomes: A unique strategy in drug loading and cancer targeting.

    Science.gov (United States)

    Ruttala, Hima Bindu; Ramasamy, Thiruganesh; Gupta, Biki; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

    2017-10-01

    In the present study, a unique strategy was developed to develop nanocarriers containing multiple therapeutics with controlled release characteristics. In this study, we demonstrated the synthesis of dextran sulfate-doxorubicin (DS-DOX) and alginate-cisplatin (AL-CIS) polymer-drug complexes to produce a transferrin ligand-conjugated liposome. The targeted nanoparticles (TL-DDAC) were nano-sized and spherical. The targeted liposome exhibited a specific receptor-mediated endocytic uptake in cancer cells. The enhanced cellular uptake of TL-DDAC resulted in a significantly better anticancer effect in resistant and sensitive breast cancer cells compared to that of the free drugs. Specifically, DOX and CIS at a molar ratio of 1:1 exhibited better therapeutic performance compared to that of other combinations. The combination of an anthracycline-based topoisomerase II inhibitor (DOX) and a platinum compound (CIS) resulted in significantly higher cell apoptosis (early and late) in both types of cancer cells. In conclusion, treatment with DS-DOX and AL-CIS based combination liposomes modified with transferrin (TL-DDAC) was an effective cancer treatment strategy. Further investigation in clinically relevant animal models is warranted to prove the therapeutic efficacy of this unique strategy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Comparative genomics and drug resistance of a geographic variant of ST239 methicillin-resistant Staphylococcus aureus emerged in Russia.

    Directory of Open Access Journals (Sweden)

    Tatsuo Yamamoto

    Full Text Available Two distinct classes of methicillin-resistant Staphylococcus aureus (MRSA are spreading in hospitals (as hospital-acquired MRSA, HA-MRSA and in the community (as community-acquired MRSA, CA-MRSA. Multilocus sequence type (ST 239 MRSA, one of the most worldwide-disseminated lineages, has been noted as a representative HA-MRSA. Here, we isolated ST239 MRSA (spa type 3 [t037] and staphylococcal cassette chromosome mec [SCCmec] type III.1.1.1 and its novel variant with ST239/spa351 (t030/SCCmecIII.1.1.4 (SCCmecIII(R not only from hospitals but also from patients with urethritis in the community in Russia. The Russian variant (strain 16K possessed a hybrid genome consisting of CC8 and CC30, similar to the ST239/spa3/SCCmecIII.1.1.1 HA-MRSA (TW20 genome, but with marked diversity. The 16K' CC30 section had SCCmecIII(R carrying the dcs-carrying unit (which corresponded to the SCCmecIVc J3 joining region of ST30 CA-MRSA, lacked SCCmercury, and possessed a novel mobile element structure (MES16K carrying the ccrC-carrying unit (with the recombinase gene ccrC1 allele 3 and drug resistance tranposons. The Russian variant included strains with a high ability to transfer its multiple drug resistance by conjugation; e.g., for strain 16K, the transfer frequency of a chloramphenicol resistance plasmid (p16K-1 with 2.9 kb in size reached 1.4×10(-2, followed by Tn554 conjugative transfer at 3.6×l0(-4. The Russian variant, which has been increasing recently, included divergent strains with different plasmid patterns and pulsed field gel electrophoresis profiles. The data demonstrate the alternative nature of ST239 MRSA as CA-MRSA and also as a drug resistance disseminator, and its micro but dynamic evolution in Russia.

  14. High Levels of Transmitted HIV Drug Resistance in a Study in Papua New Guinea.

    Science.gov (United States)

    Lavu, Evelyn; Kave, Ellan; Mosoro, Euodia; Markby, Jessica; Aleksic, Eman; Gare, Janet; Elsum, Imogen A; Nano, Gideon; Kaima, Petronia; Dala, Nick; Gurung, Anup; Bertagnolio, Silvia; Crowe, Suzanne M; Myatt, Mark; Hearps, Anna C; Jordan, Michael R

    2017-01-01

    Papua New Guinea is a Pacific Island nation of 7.3 million people with an estimated HIV prevalence of 0.8%. ART initiation and monitoring are guided by clinical staging and CD4 cell counts, when available. Little is known about levels of transmitted HIV drug resistance in recently infected individuals in Papua New Guinea. Surveillance of transmitted HIV drug resistance in a total of 123 individuals recently infected with HIV and aged less than 30 years was implemented in Port Moresby (n = 62) and Mount Hagen (n = 61) during the period May 2013-April 2014. HIV drug resistance testing was performed using dried blood spots. Transmitted HIV drug resistance was defined by the presence of one or more drug resistance mutations as defined by the World Health Organization surveillance drug resistance mutations list. The prevalence of non-nucleoside reverse transcriptase inhibitor transmitted HIV drug resistance was 16.1% (95% CI 8.8%-27.4%) and 8.2% (95% CI 3.2%-18.2%) in Port Moresby and Mount Hagen, respectively. The prevalence of nucleoside reverse transcriptase inhibitor transmitted HIV drug resistance was 3.2% (95% CI 0.2%-11.7%) and 3.3% (95% CI 0.2%-11.8%) in Port Moresby and Mount Hagen, respectively. No protease inhibitor transmitted HIV drug resistance was observed. The level of non-nucleoside reverse transcriptase inhibitor drug resistance in antiretroviral drug naïve individuals recently infected with HIV in Port Moresby is amongst the highest reported globally. This alarming level of transmitted HIV drug resistance in a young sexually active population threatens to limit the on-going effective use of NNRTIs as a component of first-line ART in Papua New Guinea. To support the choice of nationally recommended first-line antiretroviral therapy, representative surveillance of HIV drug resistance among antiretroviral therapy initiators in Papua New Guinea should be urgently implemented.

  15. Drug resistance detection and mutation patterns of multidrug resistant tuberculosis strains from children in Delhi

    Directory of Open Access Journals (Sweden)

    Jyoti Arora

    2017-06-01

    Full Text Available A total of 312 sputum samples from pediatric patients presumptive of multidrug resistant tuberculosis were tested for the detection of drug resistance using the GenoTypeMTBDRplus assay. A total of 193 (61.8% patients were smear positive and 119 (38.1% were smear negative by Ziehl–Neelsen staining. Line probe assay (LPA was performed for 208 samples/cultures (193 smear positive samples and 15 cultures from smear negative samples. Valid results were obtained from 198 tests. Of these, 125/198 (63.1% were sensitive to both rifampicin (RIF and isoniazid (INH. 73/198 (36.9% were resistant to at least INH/RIF, out of which 49 (24.7% were resistant to both INH and RIF (multidrug resistant. Children with tuberculosis are often infected by someone close to them, so strengthening of contact tracing in the program may help in early diagnosis to identify additional cases within the household. There is a need to evaluate newer diagnostic assays which have a high sensitivity in the case of smear negative samples, additional samples other than sputum among young children not able to expectorate, and also to fill the gap between estimated and reported cases under the program.

  16. Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

    Science.gov (United States)

    Fernández, Lucía

    2012-01-01

    Summary: The substantial use of antibiotics in the clinic, combined with a dearth of new antibiotic classes, has led to a gradual increase in the resistance of bacterial pathogens to these compounds. Among the various mechanisms by which bacteria endure the action of antibiotics, those affecting influx and efflux are of particular importance, as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. This review evaluates the impact of porins and efflux pumps on two major types of resistance, namely, mutational and adaptive types of resistance, both of which are regarded as key phenomena in the global rise of antibiotic resistance among pathogenic microorganisms. In particular, we explain how adaptive and mutational events can dramatically influence the outcome of antibiotic therapy by altering the mechanisms of influx and efflux of antibiotics. The identification of porins and pumps as major resistance markers has opened new possibilities for the development of novel therapeutic strategies directed specifically against these mechanisms. PMID:23034325

  17. HIV-1 evolution, drug resistance, and host genetics: The Indian scenario

    OpenAIRE

    Shankarkumar, U.; Pawar,Aruna; Ghosh,Kanjaksha

    2009-01-01

    U Shankarkumar, A Pawar, K GhoshNational Institute of Immunohaematology (ICMR), KEM Hospital, Parel, Mumbai, Maharashtra, IndiaAbstract: A regimen with varied side effects and compliance is of paramount importance to prevent viral drug resistance. Most of the drug-resistance studies, as well as interpretation algorithms, are based on sequence data from HIV-1 subtype B viruses. Increased resistance to antiretroviral drugs leads to poor prognosis by restricting treatment optio...

  18. Experimental studies on the ecology and evolution of drug-resistant malaria parasites

    OpenAIRE

    Huijben, Silvie

    2010-01-01

    Drug resistance is a serious problem in health care in general, and in malaria treatment in particular, rendering many of our previously considered ‘wonder drugs’ useless. Recently, large sums of money have been allocated for the continuous development of new drugs to replace the failing ones. We seem to be one step behind the evolution of antimalarial resistance; is it possible to get one step ahead? Are interventions which slow down the evolution and spread of drug-resistant ...

  19. Drug Resistance to EGFR Inhibitors in Lung Cancer | Office of Cancer Genomics

    Science.gov (United States)

    The discovery of mutations in epidermal growth factor receptor (EGFR) has dramatically changed the treatment of patients with non-small-cell lung cancer (NSCLC), the leading cause of cancer deaths worldwide. EGFR-targeted therapies show considerable promise, but drug resistance has become a substantial issue. We reviewed the literature to provide an overview of the drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. The mechanisms causing primary, acquired and persistent drug resistance to TKIs vary.

  20. Nanoantibiotics: strategic assets in the fight against drug- resistant superbugs

    Directory of Open Access Journals (Sweden)

    Khurana C

    2018-03-01

    Full Text Available Chandni Khurana, Bhupendra Chudasama Laboratory of Nanomedicine, School of Physics and Materials Science, Thapar University, Patiala, Punjab, India Abstract: Antimicrobial characteristics of metals reveal that Ag despite its economic constraints remains the most popular antibiotic agent. Antimicrobial characteristics of copper nanoparticles (CNPs are not well understood. To our knowledge, no systematic comparative study on microbial properties of silver nanoparticles (SNPs and CNPs exists. In this article, a comparative study on microbial properties of engineered metal nanoantibiotics against clinically important strains has been attempted. Our results indicate that biocidal activities of CNPs are better than SNPs. Minimum inhibitory concentration (MIC values of CNPs are 10 times lower than the corresponding MICs of SNPs. These improved biocidal activities of CNPs would make it affordable and potent nontraditional antibiotics against which microbes are least susceptible to develop any drug resistance. Keywords: antibiotics, silver, copper, nanoparticles

  1. The problem of resistant Trichomonas vaginalis to antiprotozoal drugs

    Directory of Open Access Journals (Sweden)

    A. L. Poznyak

    2011-01-01

    Full Text Available This review presents recent data on the energy metabolism of Trichomonas vaginalis and ways the activation of metronidazole. The sensitivity of microorganisms to the 5-nitroimidazole by the presence of their enzyme systems, generating and transporting electrons, which can then transfer them to the nitro group of the drug. In T.vaginalis these are pyruvate ferredoxin-oxydoreductase, thioredoxin reductase and flavin reductase. The development of resistance T.vaginalis to metronidazole preparations of this multistep process, based on the gradual reduction (up to a loss activity hydrogenosomal enzymes and / or violation of the flavindependent metabolic pathways.

  2. Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia

    NARCIS (Netherlands)

    A. Holleman (Amy); M.L. den Boer (Monique); K.M. Kazemier (Karin); G.E. Janka-Schaub (Gritta); R. Pieters (Rob)

    2003-01-01

    textabstractResistance of leukemic cells to chemotherapeutic agents is associated with an unfavorable outcome in pediatric acute lymphoblastic leukemia (ALL). To investigate the underlying mechanisms of cellular drug resistance, the activation of various apoptotic parameters in

  3. Tuberculosis drug resistance isolates from pulmonary tuberculosis patients, Kassala State, Sudan

    Directory of Open Access Journals (Sweden)

    Fatima A Khalid

    2015-01-01

    This study revealed that high resistance to rifampicin was associated with various point mutations in and out of the RRDR of the rpoB gene. Molecular methods are needed for early detection of TB disease and drug resistance.

  4. Drug resistant Salmonella in broiler chicken sold at local market in ...

    African Journals Online (AJOL)

    user

    2015-10-28

    Oct 28, 2015 ... Key words: Antibiogram, Salmonellosis, PCR, broiler chicken, drug resistance. ... of zoonotic origin and have gained their resistance in an animal host ..... dynamics of Salmonella enterica serotypes in commercial egg and.

  5. Molecular Evidence of Drug Resistance in Asymptomatic Malaria Infections, Myanmar, 2015.

    Science.gov (United States)

    Nyunt, Myat Htut; Shein, Thinzar; Zaw, Ni Ni; Han, Soe Soe; Muh, Fauzi; Lee, Seong-Kyun; Han, Jin-Hee; Thant, Kyaw Zin; Han, Eun-Taek; Kyaw, Myat Phone

    2017-03-01

    Artemisinin resistance containment in Myanmar was initiated in 2011 after artemisinin-resistant Plasmodium falciparum malaria was reported. Molecular evidence suggests that asymptomatic malaria infections harboring drug resistance genes are present among residents of the Myanmar artemisinin resistance containment zone. This evidence supports efforts to eliminate these hidden infections.

  6. Transcriptomic responses to emamectin benzoate in Pacific and Atlantic Canada salmon lice Lepeophtheirus salmonis with differing levels of drug resistance.

    Science.gov (United States)

    Sutherland, Ben J G; Poley, Jordan D; Igboeli, Okechukwu O; Jantzen, Johanna R; Fast, Mark D; Koop, Ben F; Jones, Simon R M

    2015-02-01

    Salmon lice Lepeophtheirus salmonis are an ecologically and economically important parasite of wild and farmed salmon. In Scotland, Norway, and Eastern Canada, L. salmonis have developed resistance to emamectin benzoate (EMB), one of the few parasiticides available for salmon lice. Drug resistance mechanisms can be complex, potentially differing among populations and involving multiple genes with additive effects (i.e., polygenic resistance). Indicators of resistance development may enable early detection and countermeasures to avoid the spread of resistance. Here, we collect sensitive Pacific L. salmonis and sensitive and resistant Atlantic L. salmonis from salmon farms, propagate in laboratory (F1), expose to EMB in bioassays, and evaluate either baseline (Atlantic only) or induced transcriptomic differences between populations. In all populations, induced responses were minor and a cellular stress response was not identified. Pacific lice did not upregulate any genes in response to EMB, but downregulated degradative enzymes and transport proteins at 50 ppb EMB. Baseline differences between sensitive and now resistant Atlantic lice were much greater than responses to exposures. All resistant lice overexpressed degradative enzymes, and resistant males, the most resistant group, overexpressed collagenases to the greatest extent. These results indicate an accumulation of baseline expression differences related to resistance.

  7. Disinfectant-susceptibility of multi-drug-resistant Mycobacterium tuberculosis isolated in Japan

    Directory of Open Access Journals (Sweden)

    Noriko Shinoda

    2016-02-01

    Full Text Available Abstract Background Multi-drug-resistant Mycobacterium tuberculosis has been an important problem in public health around the world. However, limited information about disinfectant-susceptibility of multi-drug-resistant strain of M. tuberculosis was available. Findings We studied susceptibility of several Japanese isolates of multi-drug-resistant M. tuberculosis against disinfectants, which are commonly used in clinical and research laboratories. We selected a laboratory reference strain (H37Rv and eight Japanese isolates, containing five drug-susceptible strains and three multi-drug-resistant strains, and determined profiles of susceptibility against eight disinfectants. The M. tuberculosis strains were distinguished into two groups by the susceptibility profile. There was no relationship between multi-drug-resistance and disinfectant-susceptibility in the M. tuberculosis strains. Cresol soap and oxydol were effective against all strains we tested, regardless of drug resistance. Conclusions Disinfectant-resistance is independent from multi-drug-resistance in M. tuberculosis. Cresol soap and oxydol were effective against all strains we tested, regardless of drug resistance.

  8. Primary drug resistance in a region with high burden of tuberculosis. A critical problem.

    Science.gov (United States)

    Villa-Rosas, Cecilia; Laniado-Laborín, Rafael; Oceguera-Palao, Lorena

    2015-01-01

    To determine rates of drug resistance in new cases of pulmonary tuberculosis in a region with a high burden of the disease. New case suspects were referred for drug susceptibility testing. 28.9% of new cases were resistant to at least one first line drug; 3.9% had a multidrug-resistant strain, 15.6% a monoresistant strain and 9.4% a polyresistant strain. Our rate of drug resistant tuberculosis in new cases is very high; this has important clinical implications, since even monoresistance can have a negative impact on the outcome of new cases treated empirically with a six month regimen.

  9. Molecular detection methods of resistance to antituberculosis drugs in Mycobacterium tuberculosis.

    Science.gov (United States)

    Brossier, F; Sougakoff, W

    2017-09-01

    Molecular methods predict drug resistance several weeks before phenotypic methods and enable rapid implementation of appropriate therapeutic treatment. We aimed to detail the most representative molecular tools used in routine practice for the rapid detection of resistance to antituberculosis drugs among Mycobacterium tuberculosis strains. The molecular diagnosis of resistance to antituberculosis drugs in clinical samples or from in vitro cultures is based on the detection of the most common mutations in the genes involved in the development of resistance in M. tuberculosis strains (encoding either protein targets of antibiotics, or antibiotic activating enzymes) by commercial molecular kits or by sequencing. Three hypotheses could explain the discrepancies between the genotypic results and the phenotypic drug susceptibility testing results: a low percentage of resistant mutants precluding the detection by genotypic methods on the primary culture; a low level of resistance not detected by phenotypic testing; and other resistance mechanisms not yet characterized. Molecular methods have varying sensitivity with regards to detecting antituberculosis drug resistance; that is why phenotypic susceptibility testing methods are mandatory for detecting antituberculosis drug-resistant isolates that have not been detected by molecular methods. The questionable ability of existing phenotypic and genotypic drug susceptibility testing to properly classify strains as susceptible or resistant, and at what level of resistance, was raised for several antituberculosis agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. The role of compensatory mutations in the emergence of drug resistance.

    Directory of Open Access Journals (Sweden)

    Andreas Handel

    2006-10-01

    Full Text Available Pathogens that evolve resistance to drugs usually have reduced fitness. However, mutations that largely compensate for this reduction in fitness often arise. We investigate how these compensatory mutations affect population-wide resistance emergence as a function of drug treatment. Using a model of gonorrhea transmission dynamics, we obtain generally applicable, qualitative results that show how compensatory mutations lead to more likely and faster resistance emergence. We further show that resistance emergence depends on the level of drug use in a strongly nonlinear fashion. We also discuss what data need to be obtained to allow future quantitative predictions of resistance emergence.

  11. The Imipridone ONC201 Induces Apoptosis and Overcomes Chemotherapy Resistance by Up-Regulation of Bim in Multiple Myeloma.

    Science.gov (United States)

    Tu, Yong-Sheng; He, Jin; Liu, Huan; Lee, Hans C; Wang, Hua; Ishizawa, Jo; Allen, Joshua E; Andreeff, Michael; Orlowski, Robert Z; Davis, Richard E; Yang, Jing

    2017-10-01

    In multiple myeloma, despite recent improvements offered by new therapies, disease relapse and drug resistance still occur in the majority of patients. Therefore, there is an urgent need for new drugs that can overcome drug resistance and prolong patient survival after failure of standard therapies. The imipridone ONC201 causes downstream inactivation of ERK1/2 signaling and has tumoricidal activity against a variety of tumor types, while its efficacy in preclinical models of myeloma remains unclear. In this study, we treated human myeloma cell lines and patient-derived tumor cells with ONC201. Treatment decreased cellular viability and induced apoptosis in myeloma cell lines, with IC50 values of 1 to 1.5 μM, even in those with high risk features or TP53 loss. ONC201 increased levels of the pro-apoptotic protein Bim in myeloma cells, resulting from decreased phosphorylation of degradation-promoting Bim Ser69 by ERK1/2. In addition, myeloma cell lines made resistant to several standard-of-care agents (by chronic exposure) were equally sensitive to ONC201 as their drug-naïve counterparts, and combinations of ONC201 with proteasome inhibitors had synergistic anti-myeloma activity. Overall, these findings demonstrate that ONC201 kills myeloma cells regardless of resistance to standard-of-care therapies, making it promising for clinical testing in relapsed/refractory myeloma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  12. The Imipridone ONC201 Induces Apoptosis and Overcomes Chemotherapy Resistance by Up-Regulation of Bim in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Yong-sheng Tu

    2017-10-01

    Full Text Available In multiple myeloma, despite recent improvements offered by new therapies, disease relapse and drug resistance still occur in the majority of patients. Therefore, there is an urgent need for new drugs that can overcome drug resistance and prolong patient survival after failure of standard therapies. The imipridone ONC201 causes downstream inactivation of ERK1/2 signaling and has tumoricidal activity against a variety of tumor types, while its efficacy in preclinical models of myeloma remains unclear. In this study, we treated human myeloma cell lines and patient-derived tumor cells with ONC201. Treatment decreased cellular viability and induced apoptosis in myeloma cell lines, with IC50 values of 1 to 1.5 μM, even in those with high risk features or TP53 loss. ONC201 increased levels of the pro-apoptotic protein Bim in myeloma cells, resulting from decreased phosphorylation of degradation-promoting Bim Ser69 by ERK1/2. In addition, myeloma cell lines made resistant to several standard-of-care agents (by chronic exposure were equally sensitive to ONC201 as their drug-naïve counterparts, and combinations of ONC201 with proteasome inhibitors had synergistic anti-myeloma activity. Overall, these findings demonstrate that ONC201 kills myeloma cells regardless of resistance to standard-of-care therapies, making it promising for clinical testing in relapsed/refractory myeloma.

  13. Multiple origins of resistance-conferring mutations in Plasmodium vivax dihydrofolate reductase

    Directory of Open Access Journals (Sweden)

    O'Neil Michael T

    2008-04-01

    sharply with the selective sweep of rare antifolate resistant alleles observed in the P. falciparum populations in Asia and Africa. The finding of multiple origins of resistance-conferring mutations has important implications for drug policy.

  14. Status of drug-resistant tuberculosis in China: A systematic review and meta-analysis.

    Science.gov (United States)

    Zhang, Jingya; Gou, Haimei; Hu, Xuejiao; Hu, Xin; Shang, Mengqiao; Zhou, Juan; Zhou, Yi; Ye, Yuanxin; Song, Xingbo; Lu, Xiaojun; Chen, Xuerong; Ying, Binwu; Wang, Lanlan

    2016-06-01

    We conducted a systematic review and meta-analysis on drug-resistant tuberculosis in China to provide useful data for tuberculosis (TB) surveillance and treatment. Several databases, including PubMed, Embase, and the Chinese Biological Medical Database, were systematically searched between January 1, 1999, and August 31, 2015, using strict inclusion and exclusion criteria. The corresponding drug-resistant TB prevalence between the new and previously treated cases was significantly different in almost all of the economic regions. The Eastern coastal region is the most developed economic region with the lowest total drug-resistant TB prevalence (any drug resistance: 28%; 95% confidence interval [CI], 25%-32%; multidrug resistance: 9%; 95% CI, 8%-12%) and the lowest number of new cases (any drug resistance: 21%; 95% CI, 19%-23%; multidrug resistance: 4%; 95% CI, 3%-5%). The Northwest is the least developed area with the lowest drug-resistant TB prevalence for previously treated cases (any drug resistance: 45%; 95% CI, 36%-55%; multidrug resistance: 17%; 95% CI, 11%-26%). The prevalence (multidrug and first-line drug resistance) exhibited a downward trend from 1996-2014. The extensively drug-resistant prevalence in China was 3% (95% CI, 2%-5%) in this review. Overall, the status of drug-resistant tuberculosis in China is notably grim and exhibits regional epidemiologic characteristics. We are in urgent need of several comprehensive and effective control efforts to reverse this situation. Copyright © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

  15. Genome-wide mutagenesis and multi-drug resistance in American trypanosomes induced by the front-line drug benznidazole

    KAUST Repository

    Campos, Mônica C.

    2017-10-25

    Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects 5–8 million people in Latin America. Although the nitroheterocyclic compound benznidazole has been the front-line drug for several decades, treatment failures are common. Benznidazole is a pro-drug and is bio-activated within the parasite by the mitochondrial nitroreductase TcNTR-1, leading to the generation of reactive metabolites that have trypanocidal activity. To better assess drug action and resistance, we sequenced the genomes of T. cruzi Y strain (35.5 Mb) and three benznidazole-resistant clones derived from a single drug-selected population. This revealed the genome-wide accumulation of mutations in the resistant parasites, in addition to variations in DNA copy-number. We observed mutations in DNA repair genes, linked with increased susceptibility to DNA alkylating and inter-strand cross-linking agents. Stop-codon-generating mutations in TcNTR-1 were associated with cross-resistance to other nitroheterocyclic drugs. Unexpectedly, the clones were also highly resistant to the ergosterol biosynthesis inhibitor posaconazole, a drug proposed for use against T. cruzi infections, in combination with benznidazole. Our findings therefore identify the highly mutagenic activity of benznidazole metabolites in T. cruzi, demonstrate that this can result in multi-drug resistance, and indicate that vigilance will be required if benznidazole is used in combination therapy.

  16. Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease

    Directory of Open Access Journals (Sweden)

    Ladislau C. Kovari

    2012-05-01

    Full Text Available Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1’F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates.

  17. Prevalence of transmitted drug resistance and impact of transmitted resistance on treatment success in the German HIV-1 Seroconverter Cohort.

    Directory of Open Access Journals (Sweden)

    Barbara Bartmeyer

    Full Text Available BACKGROUND: The aim of this study is to analyse the prevalence of transmitted drug resistance, TDR, and the impact of TDR on treatment success in the German HIV-1 Seroconverter Cohort. METHODS: Genotypic resistance analysis was performed in treatment-naïve study patients whose sample was available 1,312/1,564 (83.9% October 2008. A genotypic resistance result was obtained for 1,276/1,312 (97.3%. The resistance associated mutations were identified according to the surveillance drug resistance mutations list recommended for drug-naïve patients. Treatment success was determined as viral suppression below 500 copies/ml. RESULTS: Prevalence of TDR was stable at a high level between 1996 and 2007 in the German HIV-1 Seroconverter Cohort (N = 158/1,276; 12.4%; CI(wilson 10.7-14.3; p(for trend = 0.25. NRTI resistance was predominant (7.5% but decreased significantly over time (CI(Wilson: 6.2-9.1, p(for trend = 0.02. NNRTI resistance tended to increase over time (NNRTI: 3.5%; CI(Wilson: 2.6-4.6; p(for trend= 0.07, whereas PI resistance remained stable (PI: 3.0%; CI(Wilson: 2.1-4.0; p(for trend = 0.24. Resistance to all drug classes was frequently caused by singleton resistance mutations (NRTI 55.6%, PI 68.4%, NNRTI 99.1%. The majority of NRTI-resistant strains (79.8% carried resistance-associated mutations selected by the thymidine analogues zidovudine and stavudine. Preferably 2NRTI/1PIr combinations were prescribed as first line regimen in patients with resistant HIV as well as in patients with susceptible strains (susceptible 45.3%; 173/382 vs. resistant 65.5%; 40/61. The majority of patients in both groups were treated successfully within the first year after ART-initiation (susceptible: 89.9%; 62/69; resistant: 7/9; 77.8%. CONCLUSION: Overall prevalence of TDR remained stable at a high level but trends of resistance against drug classes differed over time. The significant decrease of NRTI-resistance in patients newly infected

  18. Pan Drug-Resistant Environmental Isolate of Acinetobacter baumannii from Croatia.

    Science.gov (United States)

    Goic-Barisic, Ivana; Seruga Music, Martina; Kovacic, Ana; Tonkic, Marija; Hrenovic, Jasna

    2017-06-01

    Acinetobacter baumannii is an emerging nosocomial pathogen with also emerging resistance to different antibiotics. Multidrug and pan drug-resistant clinical isolates were reported worldwide. Here we report the first evidence of pan drug-resistant environmental isolate of A. baumannii. The isolate was recovered from the effluent of secondary treated municipal wastewater of the City of Zagreb, Croatia. The isolate was resistant to penicillins/β-lactamase inhibitors, carbapenems, fluoroquinolones, aminoglycosides, folate pathway inhibitors, and polymyxins, except intermediately susceptible to minocycline and tigecycline. Intrinsic chromosomally located bla OXA-51-like gene and acquired plasmid-located bla OXA-23-like gene were related to clinical isolates. Pan drug-resistant A. baumannii can occur in natural environments outside of the hospital. Secondary treated municipal wastewater represents a potential epidemiological reservoir of pan drug-resistant A. baumannii and carbapenem resistance gene.

  19. Regulatory issues with multiplicity in drug approval: Principles and controversies in a changing landscape.

    Science.gov (United States)

    Benda, Norbert; Brandt, Andreas

    2018-01-01

    Recently, new draft guidelines on multiplicity issues in clinical trials have been issued by European Medicine Agency (EMA) and Food and Drug Administration (FDA), respectively. Multiplicity is an issue in clinical trials, if the probability of a false-positive decision is increased by insufficiently accounting for testing multiple hypotheses. We outline the regulatory principles related to multiplicity issues in confirmatory clinical trials intended to support a marketing authorization application in the EU, describe the reasons for an increasing complexity regarding multiple hypotheses testing and discuss the specific multiplicity issues emerging within the regulatory context and being relevant for drug approval.

  20. Mechanisms of Acquired Drug Resistance to the HDAC6 Selective Inhibitor Ricolinostat Reveals Rational Drug-Drug Combination with Ibrutinib.

    Science.gov (United States)

    Amengual, Jennifer E; Prabhu, Sathyen A; Lombardo, Maximilian; Zullo, Kelly; Johannet, Paul M; Gonzalez, Yulissa; Scotto, Luigi; Serrano, Xavier Jirau; Wei, Ying; Duong, Jimmy; Nandakumar, Renu; Cremers, Serge; Verma, Akanksha; Elemento, Olivier; O'Connor, Owen A

    2017-06-15

    Purpose: Pan-class I/II histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. ACY-1215 (ricolinostat) is a first-in-class selective HDAC6 inhibitor. To better understand the discrete function of HDAC6 and its role in lymphoma, we developed a lymphoma cell line resistant to ACY-1215. Experimental Design: The diffuse large B-cell lymphoma cell line OCI-Ly10 was exposed to increasing concentrations of ACY-1215 over an extended period of time, leading to the development of a resistant cell line. Gene expression profiling (GEP) was performed to investigate differentially expressed genes. Combination studies of ACY-1215 and ibrutinib were performed in cell lines, primary human lymphoma tissue, and a xenograft mouse model. Results: Systematic incremental increases in drug exposure led to the development of distinct resistant cell lines with IC 50 values 10- to 20-fold greater than that for parental lines. GEP revealed upregulation of MAPK10, HELIOS, HDAC9, and FYN, as well as downregulation of SH3BP5 and LCK. Gene-set enrichment analysis (GSEA) revealed modulation of the BTK pathway. Ibrutinib was found to be synergistic with ACY-1215 in cell lines as well as in 3 primary patient samples of lymphoma. In vivo confirmation of antitumor synergy was demonstrated with a xenograft of DLBCL. Conclusions: The development of this ACY-1215-resistant cell line has provided valuable insights into the mechanistic role of HDAC6 in lymphoma and offered a novel method to identify rational synergistic drug combinations. Translation of these findings to the clinic is underway. Clin Cancer Res; 23(12); 3084-96. ©2016 AACR . ©2016 American Association for Cancer Research.

  1. Investigational drugs for the treatment of infections caused by multidrug-resistant Gram-negative bacteria.

    Science.gov (United States)

    Avery, Lindsay M; Nicolau, David P

    2018-04-01

    Infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) are associated with significant mortality and costs. New drugs in development to combat these difficult-to-treat infections primarily target carbapenem-resistant Enterobacteriaceae, MDR Pseudomonas aeruginosa, and MDR Acinetobacter baumannii. Areas covered: The authors summarize in vitro and in vivo efficacy studies, as well as available clinical trial findings, for new agents in development for treatment of infection caused by MDR-GNB. Information regarding dosage regimens utilized in clinical trials and key pharmacokinetic and pharmacodynamic considerations are provided if available. A summary of recently approved agents, delafloxacin and meropenem/vaborbactam, is also included. Expert opinion: The development of multiple novel agents to fight MDR-GNB is promising to help save the lives of patients who acquire infection, and judicious use of these agents is imperative once they come to market to prevent the development of resistance. The other component paramount to this field of research is implementation of effective infection control policies and carbapenem-resistant Enterobacteriaceae (CRE) carrier screening protocols to mitigate the worldwide spread of MDR-GNB. Further investigation of anti-infective synergistic combinations will also be important, as well as support for economic research to reveal the true cost-benefit of utilization of the new agents discussed herein.

  2. Prevalence of drug resistance and importance of viral load measurements in Honduran HIV-infected patients failing antiretroviral treatment.

    Science.gov (United States)

    Murillo, Wendy; de Rivera, I L; Parham, L; Jovel, E; Palou, E; Karlsson, A C; Albert, J

    2010-02-01

    The Honduran HIV/AIDS Program began to scale up access to HIV therapy in 2002. Up to May 2008, more than 6000 patients received combination antiretroviral therapy (cART). As HIV drug resistance is the major obstacle for effective treatment, the purpose of this study was to assess the prevalence of antiretroviral drug resistance in Honduran HIV-1-infected individuals. We collected samples from 138 individuals (97 adults and 41 children) on cART with virological, immunological or clinical signs of treatment failure. HIV-1 pol sequences were obtained using an in-house method. Resistance mutations were identified according to the 2007 International AIDS Society (IAS)-USA list and predicted susceptibility to cART was scored using the ANRS algorithm. Resistance mutations were detected in 112 patients (81%), 74% in adults and 98% in children. Triple-, dual- and single-class drug resistance was documented in 27%, 43% and 11% of the study subjects, respectively. Multiple logistic regression showed that resistance was independently associated with type of treatment failure [virological failure (odds ratio (OR) = 1) vs. immunological failure (OR = 0.11; 95% confidence interval (CI) 0.030-0.43) vs. clinical failure (OR = 0.037; 95% CI 0.0063-0.22)], route of transmission (OR = 42.8; 95% CI 3.73-491), and years on therapy (OR = 1.81; 95% CI 1.11-2.93). The prevalence of antiretroviral resistance was high in Honduran HIV-infected patients with signs of treatment failure. A majority of study subjects showed dual- or triple-class resistance to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors and protease inhibitors. Virologically defined treatment failure was a strong predictor of resistance, indicating that viral load testing is needed to correctly identify patients with treatment failure attributable to resistance.

  3. Time-programmable drug dosing allows the manipulation, suppression and reversal of antibiotic drug resistance in vitro

    OpenAIRE

    Yoshida, Mari; Galiñanes Reyes, Sabrina Galiñanes; Tsuda, Soichiro; Horinouchi, Takaaki; Furusawa, Chikara; Cronin, Leroy

    2017-01-01

    Multi-drug strategies have been attempted to prolong the efficacy of existing antibiotics, but with limited success. Here we show that the evolution of multi-drug-resistant Escherichia coli can be manipulated in vitro by administering pairs of antibiotics and switching between them in ON/OFF manner. Using a multiplexed cell culture system, we find that switching between certain combinations of antibiotics completely suppresses the development of resistance to one of the antibiotics. Using thi...

  4. Programmable release of multiple protein drugs from aptamer-functionalized hydrogels via nucleic acid hybridization.

    Science.gov (United States)

    Battig, Mark R; Soontornworajit, Boonchoy; Wang, Yong

    2012-08-01

    Polymeric delivery systems have been extensively studied to achieve localized and controlled release of protein drugs. However, it is still challenging to control the release of multiple protein drugs in distinct stages according to the progress of disease or treatment. This study successfully demonstrates that multiple protein drugs can be released from aptamer-functionalized hydrogels with adjustable release rates at predetermined time points using complementary sequences (CSs) as biomolecular triggers. Because both aptamer-protein interactions and aptamer-CS hybridization are sequence-specific, aptamer-functionalized hydrogels constitute a promising polymeric delivery system for the programmable release of multiple protein drugs to treat complex human diseases.

  5. Quantitative genome re-sequencing defines multiple mutations conferring chloroquine resistance in rodent malaria

    Science.gov (United States)

    2012-01-01

    Background Drug resistance in the malaria parasite Plasmodium falciparum severely compromises the treatment and control of malaria. A knowledge of the critical mutations conferring resistance to particular drugs is important in understanding modes of drug action and mechanisms of resistances. They are required to design better therapies and limit drug resistance. A mutation in the gene (pfcrt) encoding a membrane transporter has been identified as a principal determinant of chloroquine resistance in P. falciparum, but we lack a full account of higher level chloroquine resistance. Furthermore, the determinants of resistance in the other major human malaria parasite, P. vivax, are not known. To address these questions, we investigated the genetic basis of chloroquine resistance in an isogenic lineage of rodent malaria parasite P. chabaudi in which high level resistance to chloroquine has been progressively selected under laboratory conditions. Results Loci containing the critical genes were mapped by Linkage Group Selection, using a genetic cross between the high-level chloroquine-resistant mutant and a genetically distinct sensitive strain. A novel high-resolution quantitative whole-genome re-sequencing approach was used to reveal three regions of selection on chr11, chr03 and chr02 that appear progressively at increasing drug doses on three chromosomes. Whole-genome sequencing of the chloroquine-resistant parent identified just four point mutations in different genes on these chromosomes. Three mutations are located at the foci of the selection valleys and are therefore predicted to confer different levels of chloroquine resistance. The critical mutation conferring the first level of chloroquine resistance is found in aat1, a putative aminoacid transporter. Conclusions Quantitative trait loci conferring selectable phenotypes, such as drug resistance, can be mapped directly using progressive genome-wide linkage group selection. Quantitative genome-wide short

  6. Multiple disease resistance to fungal and oomycete pathogens using a recombinant inbred line population in pepper

    Science.gov (United States)

    Incorporating disease resistance into cultivars is a primary focus of modern breeding programs. Resistance to pathogens is often introgressed from landrace or wild individuals with poor fruit quality into commercial-quality cultivars. Sites of multiple disease resistance (MDR) are regions or “hotspo...

  7. Exosomes from adriamycin-resistant breast cancer cells transmit drug resistance partly by delivering miR-222.

    Science.gov (United States)

    Yu, Dan-Dan; Wu, Ying; Zhang, Xiao-Hui; Lv, Meng-Meng; Chen, Wei-Xian; Chen, Xiu; Yang, Su-Jin; Shen, Hongyu; Zhong, Shan-Liang; Tang, Jin-Hai; Zhao, Jian-Hua

    2016-03-01

    Breast cancer (BCa) is one of the major deadly cancers in women. However, treatment of BCa is still hindered by the acquired-drug resistance. It is increasingly reported that exosomes take part in the development, metastasis, and drug resistance of BCa. However, the specific role of exosomes in drug resistance of BCa is poorly understood. In this study, we investigate whether exosomes transmit drug resistance through delivering miR-222. We established an adriamycin-resistant variant of Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line (MCF-7/Adr) from a drug-sensitive variant (MCF-7/S). Exosomes were isolated from cell supernatant by ultracentrifugation. Cell viability was assessed by MTT assay and apoptosis assay. Individual miR-222 molecules in BCa cells were detected by fluorescence in situ hybridization (FISH). Then, FISH was combined with locked nucleic acid probes and enzyme-labeled fluorescence (LNA-ELF-FISH). Individual miR-222 could be detected as bright photostable fluorescent spots and then the quantity of miR-222 per cell could be counted. Stained exosomes were taken in by the receipt cells. MCF-7/S acquired drug resistance after co-culture with exosomes from MCF-7/Adr (A/exo) but did not after co-culture with exosomes from MCF-7/S (S/exo). The quantity of miR-222 in A/exo-treated MCF-7/S was significantly greater than in S/exo-treated MCF-7/S. MCF-7/S transfected with miR-222 mimics acquired adriamycin resistance while MCF-7/S transfected with miR-222 inhibitors lost resistance. In conclusion, exosomes are effective in transmitting drug resistance and the delivery of miR-222 via exosomes may be a mechanism.

  8. Drug ratio-dependent antagonism: a new category of multidrug resistance and strategies for its circumvention.

    Science.gov (United States)

    Harasym, Troy O; Liboiron, Barry D; Mayer, Lawrence D

    2010-01-01

    A newly identified form of multidrug resistance (MDR) in tumor cells is presented, pertaining to the commonly encountered resistance of cancer cells to anticancer drug combinations at discrete drug:drug ratios. In vitro studies have revealed that whether anticancer drug combinations interact synergistically or antagonistically can depend on the ratio of the combined agents. Failure to control drug ratios in vivo due to uncoordinated pharmacokinetics could therefore lead to drug resistance if tumor cells are exposed to antagonistic drug ratios. Consequently, the most efficacious drug combination may not occur at the typically employed maximum tolerated doses of the combined drugs if this leads to antagonistic ratios in vivo after administration and resistance to therapeutic effects of the drug combination. Our approach to systematically screen a wide range of drug ratios and concentrations and encapsulate the drug combination in a liposomal delivery vehicle at identified synergistic ratios represents a means to mitigate this drug ratio-dependent MDR mechanism. The in vivo efficacy of the improved agents (CombiPlex formulations) is demonstrated and contrasted with the decreased efficacy when drug combinations are exposed to tumor cells in vivo at antagonistic ratios.

  9. Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition

    Directory of Open Access Journals (Sweden)

    Morales Eva

    2012-05-01

    Full Text Available Abstract Background We aimed to assess the hospital economic costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. Methods A retrospective study of all hospital admissions between January 1, 2005, and December 31, 2006 was carried out in a 420-bed, urban, tertiary-care teaching hospital in Barcelona (Spain. All patients with a first positive clinical culture for P. aeruginosa more than 48 h after admission were included. Patient and hospitalization characteristics were collected from hospital and microbiology laboratory computerized records. According to antibiotic susceptibility, isolates were classified as non-resistant, resistant and multi-drug resistant. Cost estimation was based on a full-costing cost accounting system and on the criteria of clinical Activity-Based Costing methods. Multivariate analyses were performed using generalized linear models of log-transformed costs. Results Cost estimations were available for 402 nosocomial incident P. aeruginosa positive cultures. Their distribution by antibiotic susceptibility pattern was 37.1% non-resistant, 29.6% resistant and 33.3% multi-drug resistant. The total mean economic cost per admission of patients with multi-drug resistant P. aeruginosa strains was higher than that for non-resistant strains (15,265 vs. 4,933 Euros. In multivariate analysis, resistant and multi-drug resistant strains were independently predictive of an increased hospital total cost in compared with non-resistant strains (the incremental increase in total hospital cost was more than 1.37-fold and 1.77-fold that for non-resistant strains, respectively. Conclusions P. aeruginosa multi-drug resistance independently predicted higher hospital costs with a more than 70% increase per admission compared with non-resistant strains. Prevention of the nosocomial emergence and spread of antimicrobial resistant microorganisms is essential to limit the strong economic impact.

  10. Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition.

    Science.gov (United States)

    Morales, Eva; Cots, Francesc; Sala, Maria; Comas, Mercè; Belvis, Francesc; Riu, Marta; Salvadó, Margarita; Grau, Santiago; Horcajada, Juan P; Montero, Maria Milagro; Castells, Xavier

    2012-05-23

    We aimed to assess the hospital economic costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. A retrospective study of all hospital admissions between January 1, 2005, and December 31, 2006 was carried out in a 420-bed, urban, tertiary-care teaching hospital in Barcelona (Spain). All patients with a first positive clinical culture for P. aeruginosa more than 48 h after admission were included. Patient and hospitalization characteristics were collected from hospital and microbiology laboratory computerized records. According to antibiotic susceptibility, isolates were classified as non-resistant, resistant and multi-drug resistant. Cost estimation was based on a full-costing cost accounting system and on the criteria of clinical Activity-Based Costing methods. Multivariate analyses were performed using generalized linear models of log-transformed costs. Cost estimations were available for 402 nosocomial incident P. aeruginosa positive cultures. Their distribution by antibiotic susceptibility pattern was 37.1% non-resistant, 29.6% resistant and 33.3% multi-drug resistant. The total mean economic cost per admission of patients with multi-drug resistant P. aeruginosa strains was higher than that for non-resistant strains (15,265 vs. 4,933 Euros). In multivariate analysis, resistant and multi-drug resistant strains were independently predictive of an increased hospital total cost in compared with non-resistant strains (the incremental increase in total hospital cost was more than 1.37-fold and 1.77-fold that for non-resistant strains, respectively). P. aeruginosa multi-drug resistance independently predicted higher hospital costs with a more than 70% increase per admission compared with non-resistant strains. Prevention of the nosocomial emergence and spread of antimicrobial resistant microorganisms is essential to limit the strong economic impact.

  11. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

    Directory of Open Access Journals (Sweden)

    Yoon-Dong Park

    2016-08-01

    Full Text Available Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development.

  12. Immune resistance of Multiple Myeloma : the role of the microenvironment

    NARCIS (Netherlands)

    de Haart, SJ

    2017-01-01

    Immunotherapeutic strategies in Multiple Myeloma are under development. In this thesis we present a new perspective in optimizing immunotherapy in Multiple Myeloma patient. We propose that currently, immunotherapy is limited in efficacy through interactions of Multiple Myeloma cells with the bone

  13. Transferable and non-transferable drug resistance in enteric bacteria from hospital and from general practice

    DEFF Research Database (Denmark)

    Møller, JK; Bak, AL; Bülow, P

    1976-01-01

    Drug resistance to 8 different antibiotics in Enterobacteriaceae isolated from different hospitals and two groups of general practitioners was studied. Escherichia coli dominated among the 632 strains investigated. Drug resistance was found in 62% of the 512 hospital strains and in 38% of the 120...

  14. Surveillance of extensively drug-resistant tuberculosis in Europe, 2003-2007.

    NARCIS (Netherlands)

    Devaux, I.; Manissero, D.; Fernandez de la Hoz, K.; Kremer, K.; Soolingen, D. van

    2010-01-01

    This paper describes the results of second-line drug (SLD) susceptibility tests among multidrug-resistant tuberculosis (MDR TB) cases reported in 20 European countries aiming to identify extensively drug-resistant tuberculosis (XDR TB) cases. A project on molecular surveillance of MDR TB cases was

  15. A study on demographic characteristics of drug resistant Mycobacterium tuberculosis isolates in Belarus

    Directory of Open Access Journals (Sweden)

    L Surkova

    2012-01-01

    Conclusion: As Belarus is a high-burden MDR-TB country and treatment of drug-resistant TB is long and complicated, the findings of this study provided useful information to deliver effective community-based disease control measures and a proposed plane for the effective management of drug-resistant TB at the national level.

  16. Exploring Culturally Specific Drug Resistance Strategies of Hawaiian Youth in Rural Communities

    Science.gov (United States)

    Okamoto, Scott K.; Po'a-Kekuawela, Ka'ohinani; Chin, Coralee I. H.; Nebre, La Risa H.; Helm, Susana

    2010-01-01

    This qualitative study examined the drug resistance strategies of Hawaiian youth residing in rural communities in Hawai'i. Forty seven youth participated in 14 focus groups which focused on the social and environmental context of drug use for these youth. The findings indicated that there were 47 references to resistance strategies used in drug…

  17. Antituberculosis drug resistance in the south of Vietnam: prevalence and trends

    NARCIS (Netherlands)

    Huong, Nguyen T.; Lan, Nguyen T. N.; Cobelens, Frank G. J.; Duong, Bui D.; Co, Nguyen V.; Bosman, Maarten C.; Kim, Sang-Jae; van Soolingen, Dick; Borgdorff, Martien W.

    2006-01-01

    BACKGROUND: There is limited evidence that the DOTS (directly observed therapy, short course) strategy for tuberculosis (TB) control can contain the emergence and spread of drug resistance in the absence of second-line treatment. We compared drug-resistance levels between 1996 and 2001 in the south

  18. Efficacy of verapamil as an adjunctive treatment in children with drug-resistant epilepsy

    DEFF Research Database (Denmark)

    Nicita, Francesco; Spalice, Alberto; Papetti, Laura

    2014-01-01

    Verapamil, a voltage-gated calcium channel blocker, has been occasionally reported to have some effect on reducing seizure frequency in drug-resistant epilepsy or status epilepticus. We aimed to investigate the efficacy of verapamil as add-on treatment in children with drug-resistant epilepsy....

  19. Comparative analysis of drug resistance mutations in the human immunodeficiency virus reverse transcriptase gene in patients who are non-responsive, responsive and naive to antiretroviral therapy.

    Science.gov (United States)

    Misbah, Mohammad; Roy, Gaurav; Shahid, Mudassar; Nag, Nalin; Kumar, Suresh; Husain, Mohammad

    2016-05-01

    Drug resistance mutations in the Pol gene of human immunodeficiency virus 1 (HIV-1) are one of the critical factors associated with antiretroviral therapy (ART) failure in HIV-1 patients. The issue of resistance to reverse transcriptase inhibitors (RTIs) in HIV infection has not been adequately addressed in the Indian subcontinent. We compared HIV-1 reverse transcriptase (RT) gene sequences to identify mutations present in HIV-1 patients who were ART non-responders, ART responders and drug naive. Genotypic drug resistance testing was performed by sequencing a 655-bp region of the RT gene from 102 HIV-1 patients, consisting of 30 ART-non-responding, 35 ART-responding and 37 drug-naive patients. The Stanford HIV Resistance Database (HIVDBv 6.2), IAS-USA mutation list, ANRS_09/2012 algorithm, and Rega v8.02 algorithm were used to interpret the pattern of drug resistance. The majority of the sequences (96 %) belonged to subtype C, and a few of them (3.9 %) to subtype A1. The frequency of drug resistance mutations observed in ART-non-responding, ART-responding and drug-naive patients was 40.1 %, 10.7 % and 20.58 %, respectively. It was observed that in non-responders, multiple mutations were present in the same patient, while in responders, a single mutation was found. Some of the drug-naive patients had more than one mutation. Thymidine analogue mutations (TAMs), however, were found in non-responders and naive patients but not in responders. Although drug resistance mutations were widely distributed among ART non-responders, the presence of resistance mutations in the viruses of drug-naive patients poses a big concern in the absence of a genotyping resistance test.

  20. The Association between Mycobacterium Tuberculosis Genotype and Drug Resistance in Peru.

    Directory of Open Access Journals (Sweden)

    Louis Grandjean

    Full Text Available The comparison of Mycobacterium tuberculosis bacterial genotypes with phenotypic, demographic, geospatial and clinical data improves our understanding of how strain lineage influences the development of drug-resistance and the spread of tuberculosis.To investigate the association of Mycobacterium tuberculosis bacterial genotype with drug-resistance. Drug susceptibility testing together with genotyping using both 15-loci MIRU-typing and spoligotyping, was performed on 2,139 culture positive isolates, each from a different patient in Lima, Peru. Demographic, geospatial and socio-economic data were collected using questionnaires, global positioning equipment and the latest national census.The Latin American Mediterranean (LAM clade (OR 2.4, p<0.001 was significantly associated with drug-resistance and alone accounted for more than half of all drug resistance in the region. Previously treated patients, prisoners and genetically clustered cases were also significantly associated with drug-resistance (OR's 2.5, 2.4 and 1.8, p<0.001, p<0.05, p<0.001 respectively.Tuberculosis disease caused by the LAM clade was more likely to be drug resistant independent of important clinical, genetic and socio-economic confounding factors. Explanations for this include; the preferential co-evolution of LAM strains in a Latin American population, a LAM strain bacterial genetic background that favors drug-resistance or the "founder effect" from pre-existing LAM strains disproportionately exposed to drugs.

  1. A typology and analysis of drug resistance strategies of rural Native Hawaiian youth.

    Science.gov (United States)

    Okamoto, Scott K; Helm, Susana; Giroux, Danielle; Kaliades, Alexis; Kawano, Kaycee Nahe; Kulis, Stephen

    2010-12-01

    This study examines the drug resistance strategies described by Native Hawaiian youth residing in rural communities. Sixty-four youth from 7 middle and intermediate schools on the Island of Hawai'i participated in a series of gender-specific focus groups. Youth responded to 15 drug-related problem situations developed and validated from prior research. A total of 509 responses reflecting primary or secondary drug resistance strategies were identified by the youth, which were qualitatively collapsed into 16 different categories. Primary drug resistance strategies were those that participants listed as a single response, or the first part of a two-part response, while secondary drug resistance strategies were those that were used in tandem with primary drug resistance strategies. Over half of the responses reflecting primary drug resistance strategies fell into three different categories ("refuse," "explain," or "angry refusal"), whereas over half of the responses reflecting secondary drug resistance strategies represented one category ("explain"). Significant gender differences were found in the frequency of using different strategies as well as variations in the frequency of using different strategies based on the type of drug offerer (family versus friends/peers). Implications for prevention practice are discussed.

  2. Reducing the Risk of Drug Involvement among Early Adolescents: An Evaluation of Drug Abuse Resistance Education (DARE).

    Science.gov (United States)

    Harmon, Michele Alicia

    1993-01-01

    DARE's effectiveness in Charleston County (South Carolina) was studied by comparing 341 DARE to 367 non-DARE fifth-grade students. DARE teaches students to recognize and resist social pressures to use drugs. DARE has positive impacts on anti-substance abuse attitudes, assertiveness, positive peer association, association with drug-using peers, and…

  3. Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins

    NARCIS (Netherlands)

    Cummings, Jeffrey; Zelcer, Noam; Allen, John D.; Yao, Denggao; Boyd, Gary; Maliepaard, Mark; Friedberg, Thomas H.; Smyth, John F.; Jodrell, Duncan I.

    2004-01-01

    We have recently shown that drug conjugation catalysed by UDP-glucuronosyltransferases (UGTs) functions as an intrinsic mechanism of resistance to the topoisomerase I inhibitors 7-ethyl-10-hydroxycamptothecin and NU/ICRF 505 in human colon cancer cells and now report on the role of drug transport in

  4. Within-host selection of drug resistance in a mouse model reveals dose-dependent selection of atovaquone resistance mutations

    NARCIS (Netherlands)

    Nuralitha, Suci; Murdiyarso, Lydia S.; Siregar, Josephine E.; Syafruddin, Din; Roelands, Jessica; Verhoef, Jan; Hoepelman, Andy I.M.; Marzuki, Sangkot

    2017-01-01

    The evolutionary selection of malaria parasites within an individual host plays a critical role in the emergence of drug resistance. We have compared the selection of atovaquone resistance mutants in mouse models reflecting two different causes of failure of malaria treatment, an inadequate

  5. Pretreatment HIV drug resistance results in virological failure and accumulation of additional resistance mutations in Ugandan children

    NARCIS (Netherlands)

    Kityo, Cissy; Boerma, Ragna S.; Sigaloff, Kim C. E.; Kaudha, Elizabeth; Calis, Job C. J.; Musiime, Victor; Balinda, Sheila; Nakanjako, Rita; Boender, T. Sonia; Mugyenyi, Peter N.; Rinke de Wit, Tobias F.

    2017-01-01

    Background: Pretreatment HIV drug resistance (PDR) can impair virological response to ART, jeopardizing effective treatment for children. Methods: Children aged <12 years initiated first-line ART in Uganda during 2010-11. Baseline and 6 monthly viral load (VL) and genotypic resistance testing if VL.

  6. Providing context: antimicrobial resistance from multiple environmental sources

    Science.gov (United States)

    Background: Animal agriculture has been identified as encouraging the spread of resistance due to the use of large quantities of antimicrobials for animal production purposes. When antimicrobial resistance (AMR) is reported in agricultural settings without comparison to other environments there is a...

  7. Transmission of Drug-Resistant Leprosy in Guinea-Conakry Detected Using Molecular Epidemiological Approaches.

    Science.gov (United States)

    Avanzi, Charlotte; Busso, Philippe; Benjak, Andrej; Loiseau, Chloé; Fomba, Abdoulaye; Doumbia, Glodia; Camara, Idrissa; Lamou, André; Sock, Gouressy; Drame, Tiguidanké; Kodio, Mamadou; Sakho, Fatoumata; Sow, Samba O; Cole, Stewart T; Johnson, Roch Christian

    2016-12-01

    Molecular drug susceptibility testing was performed on skin biopsies from 24 leprosy patients from Guinea-Conakry for the first time. We identified primary drug resistance in 4 cases and a dapsone-resistant cluster caused by the same strain. Primary transmission of drug-resistant Mycobacterium leprae, including a rifampicin-resistant strain, is reported. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  8. Drug Resistance and Population Structure of Mycobacterium tuberculosis Beijing Strains Isolated in Poland.

    Science.gov (United States)

    Kozińska, Monika; Augustynowicz-Kopeć, Ewa

    2015-01-01

    In total, 1095 Mycobacterium tuberculosis clinical isolates from 282 patients with drug-resistant and 813 with drug-sensitive tuberculosis (TB) in Poland during 2007-2011 were analysed. Seventy-one (6.5%) patients were found to have strains of Beijing genotype as defined by spoligotyping. The majority of patients were Polish-born; among foreign-born a large proportion came from Chechnya and Vietnam. Analysis showed strong associations between Beijing genotype infection and MDR, pre-XDR and XDR resistance, with a considerable relative risk among new patients, suggesting that this is due to increased spread of drug-resistant strains rather than acquisition of resistance during treatment.

  9. High prevalence of drug-resistant tuberculosis, Republic of Lithuania, 2002

    DEFF Research Database (Denmark)

    Dewan, P; Sosnovskaja, A; Thomsen, V

    2005-01-01

    BACKGROUND: Nations of the former Soviet Union have the world's highest reported levels of resistance to anti-tuberculosis drugs. We conducted the first national survey of anti-tuberculosis drug resistance in the Republic of Lithuania. METHODS: We tested Mycobacterium tuberculosis isolates from all...... isolates, 475 (41%) were resistant to at least one first-line drug, and 263 (23%) were resistant to at least INH and RMP (MDR); this included 76/818 (9.3%) from new patients and 187/345 (54%) from previously treated patients. Of 52 MDR isolates randomly selected for extended testing at an international...

  10. The impact of a multiple intelligences teaching approach drug education programme on drug refusal skills of Nigerian pupils.

    Science.gov (United States)

    Nwagu, Evelyn N; Ezedum, Chuks E; Nwagu, Eric K N

    2015-09-01

    The rising incidence of drug abuse among youths in Nigeria is a source of concern for health educators. This study was carried out on primary six pupils to determine the effect of a Multiple Intelligences Teaching Approach Drug Education Programme (MITA-DEP) on pupils' acquisition of drug refusal skills. A programme of drug education based on the Multiple Intelligences Teaching Approach (MITA) was developed. An experimental group was taught using this programme while a control group was taught using the same programme but developed based on the Traditional Teaching Approach. Pupils taught with the MITA acquired more drug refusal skills than those taught with the Traditional Teaching Approach. Urban pupils taught with the MITA acquired more skills than rural pupils. There was no statistically significant difference in the mean refusal skills of male and female pupils taught with the MITA. © The Author(s) 2014.

  11. Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Marna S Costanzo

    Full Text Available Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness.We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine.Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possible public health implications of these findings are discussed.

  12. Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a TBNET/RESIST-TB consensus statement

    NARCIS (Netherlands)

    Domínguez, J.; Boettger, E. C.; Cirillo, D.; Cobelens, F.; Eisenach, K. D.; Gagneux, S.; Hillemann, D.; Horsburgh, R.; Molina-Moya, B.; Niemann, S.; Tortoli, E.; Whitelaw, A.; Lange, C.

    2016-01-01

    The emergence of drug-resistant strains of Mycobacterium tuberculosis is a challenge to global tuberculosis (TB) control. Although culture-based methods have been regarded as the gold standard for drug susceptibility testing (DST), molecular methods provide rapid information on mutations in the M.

  13. HIV drug resistance in infants increases with changing prevention of mother-to-child transmission regimens.

    Science.gov (United States)

    Poppe, Lisa K; Chunda-Liyoka, Catherine; Kwon, Eun H; Gondwe, Clement; West, John T; Kankasa, Chipepo; Ndongmo, Clement B; Wood, Charles

    2017-08-24

    The objectives of this study were to determine HIV drug resistance (HIVDR) prevalence in Zambian infants upon diagnosis, and to determine how changing prevention of mother-to-child transmission (PMTCT) drug regimens affect drug resistance. Dried blood spot (DBS) samples from infants in the Lusaka District of Zambia, obtained during routine diagnostic screening, were collected during four different years representing three different PMTCT drug treatment regimens. DNA extracted from dried blood spot samples was used to sequence a 1493 bp region of the reverse transcriptase gene. Sequences were analyzed via the Stanford HIVDRdatabase (http://hivdb.standford.edu) to screen for resistance mutations. HIVDR in infants increased from 21.5 in 2007/2009 to 40.2% in 2014. Nonnucleoside reverse transcriptase inhibitor resistance increased steadily over the sampling period, whereas nucleoside reverse transcriptase inhibitor resistance and dual class resistance both increased more than threefold in 2014. Analysis of drug resistance scores in each group revealed increasing strength of resistance over time. In 2014, children with reported PMTCT exposure, defined as infant prophylaxis and/or maternal treatment, showed a higher prevalence and strength of resistance compared to those with no reported exposure. HIVDR is on the rise in Zambia and presents a serious problem for the successful lifelong treatment of HIV-infected children. PMTCT affects both the prevalence and strength of resistance and further research is needed to determine how to mitigate its role leading to resistance.

  14. Prevalence and patterns of HIV transmitted drug resistance in Guatemala.

    Science.gov (United States)

    Avila-Ríos, Santiago; Mejía-Villatoro, Carlos R; García-Morales, Claudia; Soto-Nava, Maribel; Escobar, Ingrid; Mendizabal, Ricardo; Girón, Amalia; García, Leticia; Reyes-Terán, Gustavo

    2011-12-01

    To assess human immunodeficiency virus (HIV) diversity and the prevalence of transmitted drug resistance (TDR) in Guatemala. One hundred forty-five antiretroviral treatment-naïve patients referred to the Roosevelt Hospital in Guatemala City were enrolled from October 2010 to March 2011. Plasma HIV pol sequences were obtained and TDR was assessed with the Stanford algorithm and the World Health Organization (WHO) TDR surveillance mutation list. HIV subtype B was highly prevalent in Guatemala (96.6%, 140/145), and a 2.8% (4/145) prevalence of BF1 recombinants and 0.7% (1/145) prevalence of subtype C viruses were found. TDR prevalence for the study period was 8.3% (12/145) with the Stanford database algorithm (score > 15) and the WHO TDR surveillance mutation list. Most TDR cases were associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (83.3%, 10/12); a low prevalence of nucleoside reverse transcriptase inhibitors and protease inhibitors was observed in the cohort (Guatemala. TDR prevalence in Guatemala was at the intermediate level. Most TDR cases were associated with NNRTIs. Further and continuous TDR surveillance is necessary to gain more indepth knowledge about TDR spread and trends in Guatemala and to optimize treatment outcomes in the country.

  15. Renal denervation for treatment of drug-resistant hypertension.

    Science.gov (United States)

    Esler, Murray

    2015-02-01

    At the seven-year anniversary of the first catheter-based renal denervation procedure for resistant hypertension, it is timely to reflect on the past, present, and future of the development and clinical application of this treatment. Unresolved procedural and technical questions are central: How much renal denervation is optimal? How can this level of denervation be achieved? What test for denervation can be applied in renal denervation trials? Will renal denervation show a "class effect," with the different energy forms now used for renal nerve ablation producing equivalent blood pressure lowering? When I have assessed renal denervation efficacy, using measurements of the spillover of norepinephrine from the renal sympathetic nerves to plasma, the only test validated to this point, denervation was found to be incomplete and non-uniform between patients. It is probable that the degree of denervation has commonly been suboptimal in renal denervation trials; this criticism applying with special force to the Symplicity HTN-3 trial, where the proceduralists, although expert interventional cardiologists, had no prior experience with the renal denervation technique. Recently presented results from the Symplicity HTN-3 trial confirm that renal denervation was not achieved effectively or consistently. Given this, and other difficulties in the execution of the trial relating to drug adherence, an idea mooted is that the US pivotal trial of the future may be in younger, untreated patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background.

    Directory of Open Access Journals (Sweden)

    Saskia Decuypere

    Full Text Available The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether drug-resistance mechanisms vary with the pathogen's genotype. Nevertheless this is of critical importance in gaining an understanding of the complexity of this global threat and in underpinning epidemiological surveillance of pathogen drug resistance in the field. This study aimed to assess the molecular and phenotypic heterogeneity that emerges in natural parasite populations under drug treatment pressure. We studied lines of the protozoan parasite Leishmania (L. donovani with differential susceptibility to antimonial drugs; the lines being derived from clinical isolates belonging to two distinct genetic populations that circulate in the leishmaniasis endemic region of Nepal. Parasite pathways known to be affected by antimonial drugs were characterised on five experimental levels in the lines of the two populations. Characterisation of DNA sequence, gene expression, protein expression and thiol levels revealed a number of molecular features that mark antimonial-resistant parasites in only one of the two populations studied. A final series of in vitro stress phenotyping experiments confirmed this heterogeneity amongst drug-resistant parasites from the two populations. These data provide evidence that the molecular changes associated with antimonial-resistance in natural Leishmania populations depend on the genetic background of the Leishmania population, which has resulted in a divergent set of resistance markers in the Leishmania populations. This heterogeneity of parasite adaptations provides severe challenges for the control of drug resistance in the field and the design of molecular surveillance tools for widespread

  17. Laboratory-Based Surveillance of Extensively Drug-Resistant Tuberculosis in Eastern China.

    Science.gov (United States)

    Huang, Yu; Wu, Qingqing; Xu, Shuiyang; Zhong, Jieming; Chen, Songhua; Xu, Jinghang; Zhu, Liping; He, Haibo; Wang, Xiaomeng

    2017-03-01

    With 25% of the global burden, China has the highest incidence of drug-resistant tuberculosis (TB) in the world. However, surveillance data on extensively drug-resistant TB (XDR-TB) from China are scant. To estimate the prevalence of XDR-TB in Zhejiang, Eastern China, 30 of 90 TB treatment centers in Zhejiang were recruited. Patients with suspected TB who reported to the clinics for diagnosis were requested to undergo a smear sputum test. Positive sputum samples were tested for drug susceptibility. Data on anti-TB drug resistance from 1999 to 2008 were also collected to assess drug resistance trends. A total of 931 cases were recruited for drug susceptibility testing (DST). Among these, 23.6% (95% confidence interval [CI], 18.8-24.4) were resistant to any of the following drugs: isoniazid, rifampin, streptomycin, and ethambutol. Multidrug resistant (MDR) strains were identified in 5.1% of all cases (95% CI, 3.61-6.49). Among MDR-TB cases, 6.4% were XDR (95% CI, 1.7-18.6) and 8.9% (95% CI, 7.0-10.8) of all cases were resistant to either isoniazid or rifampin (but not both). Among MDR-TB cases, 23.4% (95% CI, 12.8-38.4) were resistant to either fluoroquinolones or a second-line anti-TB injectable drug, but not both. From 1999 to 2014, the percentage of MDR cases decreased significantly, from 8.6% to 5.1% (p = 0.00). The Global Fund to Fight TB program showed signs of success in Eastern China. However, drug-resistant TB, MDR-TB, and XDR-TB still pose a challenge for TB control in Eastern China. High-quality directly observed treatment, short-course, and universal DST for TB cases to determine appropriate treatment regimens are urgently needed to prevent acquired drug resistance.

  18. Using National Drug Codes and drug knowledge bases to organize prescription records from multiple sources.

    Science.gov (United States)

    Simonaitis, Linas; McDonald, Clement J

    2009-10-01

    The utility of National Drug Codes (NDCs) and drug knowledge bases (DKBs) in the organization of prescription records from multiple sources was studied. The master files of most pharmacy systems include NDCs and local codes to identify the products they dispense. We obtained a large sample of prescription records from seven different sources. These records carried a national product code or a local code that could be translated into a national product code via their formulary master. We obtained mapping tables from five DKBs. We measured the degree to which the DKB mapping tables covered the national product codes carried in or associated with the sample of prescription records. Considering the total prescription volume, DKBs covered 93.0-99.8% of the product codes from three outpatient sources and 77.4-97.0% of the product codes from four inpatient sources. Among the in-patient sources, invented codes explained 36-94% of the noncoverage. Outpatient pharmacy sources rarely invented codes, which comprised only 0.11-0.21% of their total prescription volume, compared with inpatient pharmacy sources for which invented codes comprised 1.7-7.4% of their prescription volume. The distribution of prescribed products was highly skewed, with 1.4-4.4% of codes accounting for 50% of the message volume and 10.7-34.5% accounting for 90% of the message volume. DKBs cover the product codes used by outpatient sources sufficiently well to permit automatic mapping. Changes in policies and standards could increase coverage of product codes used by inpatient sources.

  19. Breeding of Yangfumai No.5 with multiple disease resistance

    International Nuclear Information System (INIS)

    He Zhentian; Chen Xiulan; Zhang Rong; Wang Jianhua; Wang Jinrong

    2013-01-01

    To control the damage of wheat yellow mosaic disease and powdery mildew, new wheat cultivar with high-yield, disease-resistant was bred. Yangfumai 9311 with yellow mosaic disease resistant was used as donor parent to backcross with recurrent parent Yangmai 11, and combined with conventional breeding techniques and irradiation methods, a new wheat variety Yangfumai No.5 was developed and registered in 2011. Yangfumai No.5 with resistance of yellow mosaic disease and powdery mildew is suitable to grow in the Yangtze River region. (authors)

  20. The meek cry or the importance of resisting multiple forms

    Directory of Open Access Journals (Sweden)

    Diego Alejandro Muñoz Gaviria

    2011-07-01

    Full Text Available First step, seeks to broadly down some of the known theories of resistance. The idea in this item will be the statement configured stress field around the idea of resistance as a political option. In a second step, seeks to identify the key ideas of Paulo Freire around the resistor, as a Latin American perspective able to shed light on the "other" ways to act politically in our territories, from a critical or resistance. Finally, some conclusions are proposed that will synthesize the above and leave open questions for further reflection exercises and thematic depth.

  1. Fracture resistance enhancement of layered structures by multiple cracks

    DEFF Research Database (Denmark)

    Goutianos, Stergios; Sørensen, Bent F.

    2016-01-01

    A theoretical model is developed to test if the fracture resistance of a layered structure can be increased by introducing weak layers changing the cracking mechanism. An analytical model, based on the J integral, predicts a linear dependency between the number of cracks and the steady state...... fracture resistance. A finite element cohesive zone model, containing two cracking planes for simplicity, is used to check the theoretical model and its predictions. It is shown that for a wide range of cohesive law parameters, the numerical predictions agree well quantitatively with the theoretical model....... Thus, it is possible to enhance considerably the fracture resistance of a structure by adding weak layers....

  2. Alpinetin inhibits lung cancer progression and elevates sensitization drug-resistant lung cancer cells to cis-diammined dichloridoplatium

    Directory of Open Access Journals (Sweden)

    Wu L

    2015-11-01

    Full Text Available Lin Wu, Wei Yang, Su-ning Zhang, Ji-bin Lu Department of Thoracic Surgery, Sheng Jing Hospital of China Medical University, Shenyang, People’s Republic of China Objective: Alpinetin is a novel flavonoid that has demonstrated potent antitumor activity in previous studies. However, the efficacy and mechanism of alpinetin in treating lung cancer have not been determined. Methods: We evaluated the impact of different doses and durations of alpinetin treatment on the cell proliferation, the apoptosis of lung cancer cells, as well as the drug-resistant lung cancer cells. Results: This study showed that the alpinetin inhibited the cell proliferation, enhanced the apoptosis, and inhibited the PI3K/Akt signaling in lung cancer cells. Moreover, alpinetin significantly increased the sensitivity of drug-resistant lung cancer cells to the chemotherapeutic effect of cis-diammined dichloridoplatium. Taken together, this study demonstrated that alpinetin significantly suppressed the development of human lung cancer possibly by influencing mitochondria and the PI3K/Akt signaling pathway and sensitized drug-resistant lung cancer cells. Conclusion: Alpinetin may be used as a potential compound for combinatorial therapy or as a complement to other chemotherapeutic agents when multiple lines of treatments have failed to reduce lung cancer. Keywords: alpinetin, cell proliferation and apoptosis, drug resistance reversal, PI3K/Akt, lung cancer

  3. Consensus Statement on Research Definitions for Drug-Resistant Tuberculosis in Children

    OpenAIRE

    Seddon, James A.; Perez-Velez, Carlos M.; Schaaf, H. Simon; Furin, Jennifer J.; Marais, Ben J.; Tebruegge, Marc; Detjen, Anne; Hesseling, Anneke C.; Shah, Sarita; Adams, Lisa V.; Starke, Jeffrey R.; Swaminathan, Soumya; Becerra, Mercedes C.

    2013-01-01

    Few children with drug-resistant (DR) tuberculosis (TB) are identified, diagnosed, and given an appropriate treatment. The few studies that have described this vulnerable population have used inconsistent definitions. TheWorld Health Organization (WHO) definitions used for adults with DR-TB and for children with drug-susceptible TB are not always appropriate for children with DR-TB. The Sentinel Project on Pediatric Drug-Resistant Tuberculosis was formed in 2011 as a network of experts and st...

  4. Antimicrobial Drug-Resistant Shiga Toxin-Producing Escherichia coli Infections, Michigan, USA.

    Science.gov (United States)

    Mukherjee, Sanjana; Mosci, Rebekah E; Anderson, Chase M; Snyder, Brian A; Collins, James; Rudrik, James T; Manning, Shannon D

    2017-09-01

    High frequencies of antimicrobial drug resistance were observed in O157 and non-O157 Shiga toxin-producing E. coli strains recovered from patients in Michigan during 2010-2014. Resistance was more common in non-O157 strains and independently associated with hospitalization, indicating that resistance could contribute to more severe disease outcomes.

  5. High proportion of modern genotypes of M. tuberculosis and their affinity with drug resistance in northern region of India.

    Science.gov (United States)

    Dhatwalia, Sunil Kumar; Yadav, Rakesh; Behera, Digambar; Kaur, Harsimran; Kumar, Manoj; Sethi, Sunil

    2017-09-01

    Comparative genomics on the basis of TbD1 deletion has differentiated the members of Mycobacterium tuberculosis complex (MTC) in two major genogroups. They exhibit differential distribution and virulence potential. The present study was carried out to see the proportion of these genogroups and their association with drug resistance. The drug resistance pattern of 205 culture positive cases of M. tuberculosis and their relation with TbD1 deletion was analysed from the tertiary care centre. Overall proportion of genotypes (TbD1- and Tbd1+) and their association with drug resistance was also observed from the various studies from India. Our study reports that 85.4% of the isolates of M. tuberculosis were modern genotypes (TbD1-) and rest of 14.6% were ancient genotypes (TbD1+). 37 cases were of multiple drug resistant-TB (MDR-TB), 35 of them belongs to modern genogrop and rest of (2) were in ancient genogroup (p=0.12). Overall pooled estimate of proportion of modern genotype is 75.5% (CI 95%, 73.03-77.87) and 24.55% (CI 95%, 22.13-26.97) for ancient genotypes from the studies carried out in India. Modern genotypes were more rarely drug sensitive phenotypes with a relative risk (RR) of 0.89 (CI 95%, 0.74-1.07) while MDR cases were more in this group with an odds ratio (OR) of 2.27 (CI 95%, 0-1.07). This study demonstrates a higher proportion of modern genotypes in our region/India; which are more likely to be associated with drug resistance. Future, epidemiological/in vitro studies are required to ascertain the relationship between genotypes and their virulence potential. Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

  6. Association of metal tolerance with multiple antibiotic resistance of bacteria isolated from drinking water.

    Science.gov (United States)

    Calomiris, J J; Armstrong, J L; Seidler, R J

    1984-06-01

    Bacterial isolates from the drinking water system of an Oregon coastal community were examined to assess the association of metal tolerance with multiple antibiotic resistance. Positive correlations between tolerance to high levels of Cu2+, Pb2+, and Zn2+ and multiple antibiotic resistance were noted among bacteria from distribution waters but not among bacteria from raw waters. Tolerances to higher levels of Al3+ and Sn2+ were demonstrated more often by raw water isolates which were not typically multiple antibiotic resistant. A similar incidence of tolerance to Cd2+ was demonstrated by isolates of both water types and was not associated with multiple antibiotic resistance. These results suggest that simultaneous selection phenomena occurred in distribution water for bacteria which exhibited unique patterns of tolerance to Cu2+, Pb2+, and Zn2+ and antibiotic resistance.

  7. [Tuberculosis and drug-resistance tuberculosis in prisoners. Colombia, 2010-2012].

    Science.gov (United States)

    Gómez, Ingrid T; Llerena, Claudia R; Zabaleta, Angie P

    2015-01-01

    To characterize tuberculosis drug-resistance using anti-tuberculosis drug-sensitivity tests in Colombian prisoners. Descriptive-retrospective analyses were performed on cases of tuberculosis in prisoners. Samples were evaluated by the National Reference Laboratory. Conditions like gender, TB/VIH co-infection and drug-resistance were evaluated. Anti-tuberculosis drug-sensitivity tests were carried out on 72 prisoners. Results showed a distribution of 90.7 % of cases in males and 9.3 % of cases in females. 12 % of cases were TB/VIH co-infections, 94 % of the cases had not received any anti-tuberculosis treatment before, six isolates were drug-resistant corresponding to 8.8 % of total cases, and two cases were multi drug-resistant representing 1.3 % of the cases. Of the drug-resistant cases, 83.3 % were TB/VIH co-infected. Previously treated cases corresponded to 5.6 % of the total cases analyzed. One case with TB/VIH co-infection and rifampicin resistance was observed, representing 1.3 % of the total cases. The government must create a clear policy for prisoners in Colombia, because a high rate of disease in prisoners was observed. In addition, the results showed an association between drug-resistance and TB/VIH co-infection. Overcrowding and low quality of life in penitentiaries could become an important public health problem.

  8. Clinical and Drug Resistance Characteristics of New Pediatric Tuberculosis Cases in Northern China.

    Science.gov (United States)

    Wang, Ting; Dong, Fang; Li, Qin-Jing; Yin, Qing-Qin; Song, Wen-Qi; Mokrousov, Igor; Jiao, Wei-Wei; Shen, A-Dong

    2018-05-09

    The aim of this study was to evaluate the clinical features and characteristics of drug resistance in newly diagnosed pediatric tuberculosis (TB) patients in northern China. Mycobacterium tuberculosis isolates were collected from September 2010 to October 2016 at the Beijing Children's Hospital. Patients were divided into two groups (resistant to at least one drug and pan-susceptible) according to drug susceptibility testing (DST) results. A total of 132 new cases, mainly from northern China (87.9%), were included in the study. The median age was 1.9 years (1 month-15 years). Resistance to at least one drug was detected in Mycobacterium tuberculosis isolates from 33 (25%) cases. Eight cases of multidrug-resistant TB (MDR-TB) (6.1%) were detected. The two groups did not differ in clinical presentations (disease site, fever >2 weeks, and cough >2 weeks) or in chest imaging (lesion location, lymphadenitis [mediastinal], and pleural effusion). The rate of Mycobacterium tuberculosis drug resistance in new pediatric TB cases was as high as in the new adult patients surveyed in the national drug resistance survey conducted in 2007. No significant difference was observed in clinical features between patients infected with drug-resistant and drug-susceptible strains. Routine DST is important for prescribing effective antituberculosis treatment regimens.

  9. Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia

    Science.gov (United States)

    Miotto, Olivo; Almagro-Garcia, Jacob; Manske, Magnus; MacInnis, Bronwyn; Campino, Susana; Rockett, Kirk A; Amaratunga, Chanaki; Lim, Pharath; Suon, Seila; Sreng, Sokunthea; Anderson, Jennifer M; Duong, Socheat; Nguon, Chea; Chuor, Char Meng; Saunders, David; Se, Youry; Lon, Chantap; Fukuda, Mark M; Amenga-Etego, Lucas; Hodgson, Abraham VO; Asoala, Victor; Imwong, Mallika; Takala-Harrison, Shannon; Nosten, Francois; Su, Xin-zhuan; Ringwald, Pascal; Ariey, Frédéric; Dolecek, Christiane; Hien, Tran Tinh; Boni, Maciej F; Thai, Cao Quang; Amambua-Ngwa, Alfred; Conway, David J; Djimdé, Abdoulaye A; Doumbo, Ogobara K; Zongo, Issaka; Ouedraogo, Jean-Bosco; Alcock, Daniel; Drury, Eleanor; Auburn, Sarah; Koch, Oliver; Sanders, Mandy; Hubbart, Christina; Maslen, Gareth; Ruano-Rubio, Valentin; Jyothi, Dushyanth; Miles, Alistair; O’Brien, John; Gamble, Chris; Oyola, Samuel O; Rayner, Julian C; Newbold, Chris I; Berriman, Matthew; Spencer, Chris CA; McVean, Gilean; Day, Nicholas P; White, Nicholas J; Bethell, Delia; Dondorp, Arjen M; Plowe, Christopher V; Fairhurst, Rick M; Kwiatkowski, Dominic P

    2013-01-01

    We describe an analysis of genome variation in 825 Plasmodium falciparum samples from Asia and Africa that reveals an unusual pattern of parasite population structure at the epicentre of artemisinin resistance in western Cambodia. Within this relatively small geographical area we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to artemisinin, which have skewed allele frequency spectra and remarkably high levels of haplotype homozygosity, indicative of founder effects and recent population expansion. We provide a catalogue of SNPs that show high levels of differentiation in the artemisinin-resistant subpopulations, including codon variants in various transporter proteins and DNA mismatch repair proteins. These data provide a population genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular markers to assist its elimination. PMID:23624527

  10. Use of Lot Quality Assurance Sampling to Ascertain Levels of Drug Resistant Tuberculosis in Western Kenya.

    Directory of Open Access Journals (Sweden)

    Julia Jezmir

    Full Text Available To classify the prevalence of multi-drug resistant tuberculosis (MDR-TB in two different geographic settings in western Kenya using the Lot Quality Assurance Sampling (LQAS methodology.The prevalence of drug resistance was classified among treatment-naïve smear positive TB patients in two settings, one rural and one urban. These regions were classified as having high or low prevalence of MDR-TB according to a static, two-way LQAS sampling plan selected to classify high resistance regions at greater than 5% resistance and low resistance regions at less than 1% resistance.This study classified both the urban and rural settings as having low levels of TB drug resistance. Out of the 105 patients screened in each setting, two patients were diagnosed with MDR-TB in the urban setting and one patient was diagnosed with MDR-TB in the rural setting. An additional 27 patients were diagnosed with a variety of mono- and poly- resistant strains.Further drug resistance surveillance using LQAS may help identify the levels and geographical distribution of drug resistance in Kenya and may have applications in other countries in the African Region facing similar resource constraints.

  11. A review of mechanisms of circumvention and modulation of chemotherapeutic drug resistance.

    Science.gov (United States)

    O'Connor, R

    2009-05-01

    Drug resistance is a serious limitation to the effective treatment of a number of common malignancies. Thirty years of laboratory and clinical research have greatly defined the molecular alterations underlying many drug resistance processes in cancer. Based on this knowledge, strategies to overcome the impact of resistance and increase the efficacy of cancer treatment have been translated from laboratory models to clinical trials. This article reviews laboratory and, in particular, clinical attempts at drug resistance circumvention from early forays in the inhibition of cellular efflux pump-mediated drug resistance through to more selective circumvention agent strategies and into inhibition of the other important mechanisms which can allow cancer cells to survive therapy, such as apoptosis resistance. Despite some promising results to date, resistance inhibition strategies have largely failed due to poor understanding of the pharmacology, dynamics and complexity of the resistance phenotype. With the realisation that new molecularly-targeted agents can also be rendered ineffectual by the actions of resistance mechanisms, a major focus is once again emerging on identifying new strategies/pharmaceuticals which can augment the activity of the arsenal of more conventional cytotoxics and newer targeted anti-cancer drugs. Future tactical directions where old and new resistance strategies may merge to overcome this challenge are discussed.

  12. Use of Lot Quality Assurance Sampling to Ascertain Levels of Drug Resistant Tuberculosis in Western Kenya.

    Science.gov (United States)

    Jezmir, Julia; Cohen, Ted; Zignol, Matteo; Nyakan, Edwin; Hedt-Gauthier, Bethany L; Gardner, Adrian; Kamle, Lydia; Injera, Wilfred; Carter, E Jane

    2016-01-01

    To classify the prevalence of multi-drug resistant tuberculosis (MDR-TB) in two different geographic settings in western Kenya using the Lot Quality Assurance Sampling (LQAS) methodology. The prevalence of drug resistance was classified among treatment-naïve smear positive TB patients in two settings, one rural and one urban. These regions were classified as having high or low prevalence of MDR-TB according to a static, two-way LQAS sampling plan selected to classify high resistance regions at greater than 5% resistance and low resistance regions at less than 1% resistance. This study classified both the urban and rural settings as having low levels of TB drug resistance. Out of the 105 patients screened in each setting, two patients were diagnosed with MDR-TB in the urban setting and one patient was diagnosed with MDR-TB in the rural setting. An additional 27 patients were diagnosed with a variety of mono- and poly- resistant strains. Further drug resistance surveillance using LQAS may help identify the levels and geographical distribution of drug resistance in Kenya and may have applications in other countries in the African Region facing similar resource constraints.

  13. From Leflunomide to Teriflunomide: Drug Development and Immunosuppressive Oral Drugs in the Treatment of Multiple Sclerosis.

    Science.gov (United States)

    Aly, Lilian; Hemmer, Bernhard; Korn, Thomas

    2017-01-01

    Immunosuppressive drugs have been used in the treatment of multiple sclerosis (MS) for a long time. Today, orally available second generation immunosuppressive agents have been approved or are filed for licensing as MS therapeutics. Due to semi-selective targeting of cellular processes, these second-generation immunosuppressive compounds might rather be immunomodulatory. For example, Teriflunomide inhibits the de novo pyrimidine synthesis and thus only targets rapidly proliferating cells, including lymphocytes. It is used as first line disease modifying therapy (DMT) in relapsing-remitting MS (RRMS). Review of online content related to oral immunosuppressants in MS with an emphasis on Teriflunomide. Teriflunomide and Cladribine are second-generation immunosuppressants that are efficient in the treatment of MS patients. For Teriflunomide, a daily dose of 14 mg reduces the annualized relapse rate (ARR) by more than 30% and disability progression by 30% compared to placebo. Cladribine reduces the ARR by about 50% compared to placebo but has not yet been licensed due to unresolved safety concerns. We also discuss the significance of older immunosuppressive compounds including Azathioprine, Mycophenolate mofetile, and Cyclophosphamide in current MS therapy. Teriflunomide has shown a favorable safety and efficacy profile in RRMS and is a therapeutic option for a distinct group of adult patients with RRMS. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Optimising strategies for Plasmodium falciparum malaria elimination in Cambodia: primaquine, mass drug administration and artemisinin resistance.

    Directory of Open Access Journals (Sweden)

    Richard J Maude

    Full Text Available Malaria elimination requires a variety of approaches individually optimized for different transmission settings. A recent field study in an area of low seasonal transmission in South West Cambodia demonstrated dramatic reductions in malaria parasite prevalence following both mass drug administration (MDA and high treatment coverage of symptomatic patients with artemisinin-piperaquine plus primaquine. This study employed multiple combined strategies and it was unclear what contribution each made to the reductions in malaria.A mathematical model fitted to the trial results was used to assess the effects of the various components of these interventions, design optimal elimination strategies, and explore their interactions with artemisinin resistance, which has recently been discovered in Western Cambodia. The modelling indicated that most of the initial reduction of P. falciparum malaria resulted from MDA with artemisinin-piperaquine. The subsequent continued decline and near elimination resulted mainly from high coverage with artemisinin-piperaquine treatment. Both these strategies were more effective with the addition of primaquine. MDA with artemisinin combination therapy (ACT increased the proportion of artemisinin resistant infections, although much less than treatment of symptomatic cases with ACT, and this increase was slowed by adding primaquine. Artemisinin resistance reduced the effectiveness of interventions using ACT when the prevalence of resistance was very high. The main results were robust to assumptions about primaquine action, and immunity.The key messages of these modelling results for policy makers were: high coverage with ACT treatment can produce a long-term reduction in malaria whereas the impact of MDA is generally only short-term; primaquine enhances the effect of ACT in eliminating malaria and reduces the increase in proportion of artemisinin resistant infections; parasite prevalence is a better surveillance measure for

  15. Different frequencies of drug resistance mutations among HIV-1 subtypes circulating in China: a comprehensive study.

    Directory of Open Access Journals (Sweden)

    Hongshuai Sui

    Full Text Available The rapid spreading of HIV drug resistance is threatening the overall success of free HAART in China. Much work has been done on drug-resistant mutations, however, most of which were based on subtype B. Due to different genetic background, subtypes difference would have an effect on the development of drug-resistant mutations, which has already been proved by more and more studies. In China, the main epidemic subtypes are CRF07_BC, CRF08_BC, Thai B and CRF01_AE. The depiction of drug resistance mutations in those subtypes will be helpful for the selection of regimens for Chinese. In this study, the distributions difference of amino acids at sites related to HIV drug resistance were compared among subtype B, CRF01_AE, CRF07_BC and CRF08_BC strains prevalent in China. The amino acid composition of sequences belonging to different subtypes, which were obtained from untreated and treated individuals separately, were also compared. The amino acids proportions of 19 sites in RT among subtype B, CRF01_AE and CRF08_BC have significant difference in drug resistance groups (chi-square test, p<0.05. Genetic barriers analysis revealed that sites 69, 138, 181, 215 and 238 were significantly different among subtypes (Kruskal Wallis test, p<0.05. All subtypes shared three highest prevalent drug resistance sites 103, 181 and 184 in common. Many drug resistant sites in protease show surprising high proportions in almost all subtypes in drug-naïve patients. This is the first comprehensive study in China on different development of drug resistance among different subtypes. The detailed data will lay a foundation for HIV treatment regimens design and improve HIV therapy in China.

  16. Interplay between Mutations and Efflux in Drug Resistant Clinical Isolates of Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Miguel Viveiros

    2017-04-01

    Full Text Available Numerous studies show efflux as a universal bacterial mechanism contributing to antibiotic resistance and also that the activity of the antibiotics subject to efflux can be enhanced by the combined use of efflux inhibitors. Nevertheless, the contribution of efflux to the overall drug resistance levels of clinical isolates of Mycobacterium tuberculosis is poorly understood and still is ignored by many. Here, we evaluated the contribution of drug efflux plus target-gene mutations to the drug resistance levels in clinical isolates of M. tuberculosis. A panel of 17 M. tuberculosis clinical strains were characterized for drug resistance associated mutations and antibiotic profiles in the presence and absence of efflux inhibitors. The correlation between the effect of the efflux inhibitors and the resistance levels was assessed by quantitative drug susceptibility testing. The bacterial growth/survival vs. growth inhibition was analyzed through the comparison between the time of growth in the presence and absence of an inhibitor. For the same mutation conferring antibiotic resistance, different MICs were observed and the different resistance levels found could be reduced by efflux inhibitors. Although susceptibility was not restored, the results demonstrate the existence of a broad-spectrum synergistic interaction between antibiotics and efflux inhibitors. The existence of efflux activity was confirmed by real-time fluorometry. Moreover, the efflux pump genes mmr, mmpL7, Rv1258c, p55, and efpA were shown to be overexpressed in the presence of antibiotics, demonstrating the contribution of these efflux pumps to the overall resistance phenotype of the M. tuberculosis clinical isolates studied, independently of the genotype of the strains. These results showed that the drug resistance levels of multi- and extensively-drug resistant M. tuberculosis clinical strains are a combination between drug efflux and the presence of target-gene mutations, a reality

  17. Molecular approaches for detection of the multi-drug resistant tuberculosis (MDR-TB in Bangladesh.

    Directory of Open Access Journals (Sweden)

    Tafsina Haque Aurin

    Full Text Available The principal obstacles in the treatment of tuberculosis (TB are delayed and inaccurate diagnosis which often leads to the onset of the drug resistant TB cases. To avail the appropriate treatment of the patients and to hinder the transmission of drug-resistant TB, accurate and rapid detection of resistant isolates is critical. Present study was designed to demonstrate the efficacy of molecular techniques inclusive of line probe assay (LPA and GeneXpert MTB/RIF methods for the detection of multi-drug resistant (MDR TB. Sputum samples from 300 different categories of treated and new TB cases were tested for the detection of possible mutation in the resistance specific genes (rpoB, inhA and katG through Genotype MTBDRplus assay or LPA and GeneXpert MTB/RIF tests. Culture based conventional drug susceptibility test (DST was also carried out to measure the efficacy of the molecular methods employed. Among 300 samples, 191 (63.7% and 193 (64.3% cases were found to be resistant against rifampicin in LPA and GeneXpert methods, respectively; while 189 (63% cases of rifampicin resistance were detected by conventional DST methods. On the other hand, 196 (65.3% and 191 (63.7% isolates showed isoniazid resistance as detected by LPA and conventional drug susceptibility test (DST, respectively. Among the drug resistant isolates (collectively 198 in LPA and 193 in conventional DST, 189 (95.6% and 187 (96.9% were considered to be MDR as examined by LPA and conventional DST, respectively. Category-II and -IV patients encountered higher frequency of drug resistance compared to those from category-I and new cases. Considering the higher sensitivity, specificity and accuracy along with the required time to results significantly shorter, our study supports the adoption of LPA and GeneXpert assay as efficient tools in detecting drug resistant TB in Bangladesh.

  18. Radiation response of drug-resistant variants of a human breast cancer cell line

    International Nuclear Information System (INIS)

    Lehnert, S.; Greene, D.; Batist, G.

    1989-01-01

    The radiation response of drug-resistant variants of the human tumor breast cancer cell line MCF-7 has been investigated. Two sublines, one resistant to adriamycin (ADRR) and the other to melphalan (MLNR), have been selected by exposure to stepwise increasing concentrations of the respective drugs. ADRR cells are 200-fold resistant to adriamycin and cross-resistant to a number of other drugs and are characterized by the presence of elevated levels of selenium-dependent glutathione peroxidase and glutathione-S-transferase. MLNR cells are fourfold resistant to melphalan and cross-resistant to some other drugs. The only mechanism of drug resistance established for MLNR cells to date is an enhancement of DNA excision repair processes. While the spectrum of drug resistance and the underlying mechanisms differ for the two sublines, their response to radiation is qualitatively similar. Radiation survival curves for ADRR and MLNR cells differ from that for wild-type cells in a complex manner with, for the linear-quadratic model, a decrease in the size of alpha and an increase in the size of beta. There is a concomitant decrease in the size of the alpha/beta ratio which is greater for ADRR cells than for MLNR cells. Analysis of results using the multitarget model gave values of D0 of 1.48, 1.43, and 1.67 Gy for MCF-7 cells are not a consequence of cell kinetic differences between these sublines. Results of split-dose experiments indicated that for both drug-resistant sublines the extent of sublethal damage repair reflected the width of the shoulder on the single-dose survival curve. For MCF-7 cells in the stationary phase of growth, the drug-resistant sublines did not show cross-resistance to radiation; however, delayed subculture following irradiation of stationary-phase cultures increased survival to a greater extent for ADRR and MLNR cells than for wild-type cells

  19. Label-free recognition of drug resistance via impedimetric screening of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Bilge Eker

    Full Text Available We present a novel study on label-free recognition and distinction of drug resistant breast cancer cells (MCF-7 DOX from their parental cells (MCF-7 WT via impedimetric measurements. Drug resistant cells exhibited significant differences in their dielectric properties compared to wild-type cells, exerting much higher extracellular resistance (Rextra . Immunostaining revealed that MCF-7 DOX cells gained a much denser F-actin network upon acquiring drug resistance indicating that remodeling of actin cytoskeleton is probably the reason behind higher Rextra , providing stronger cell architecture. Moreover, having exposed both cell types to doxorubicin, we were able to distinguish these two phenotypes based on their substantially different drug response. Interestingly, impedimetric measurements identified a concentration-dependent and reversible increase in cell stiffness in the presence of low non-lethal drug doses. Combined with a profound frequency analysis, these findings enabled distinguishing distinct cellular responses during drug exposure within four concentration ranges without using any labeling. Overall, this study highlights the possibility to differentiate drug resistant phenotypes from their parental cells and to assess their drug response by using microelectrodes, offering direct, real-time and noninvasive measurements of cell dependent parameters under drug exposure, hence providing a promising step for personalized medicine applications such as evaluation of the disease progress and optimization of the drug treatment of a patient during chemotherapy.

  20. Successful Treatment of Nivolumab-Resistant Multiple In-Transit Melanomas with Ipilimumab and Topical Imiquimod

    Directory of Open Access Journals (Sweden)

    Taku Fujimura

    2018-01-01

    Full Text Available Simultaneous or sequential, planned administration of ipilimumab could significantly enhance the antitumor effects of nivolumab in advanced melanoma patients. On the other hand, the efficacy of ipilimumab for nivolumab-resistant advanced melanoma is extremely poor. Therefore, additional supportive therapy for anti-PD-1 antibody therapy-resistant advanced melanoma has been widely investigated. In this report, we describe a case of multiple in-transit melanomas developing in a nivolumab-resistant patient successfully treated with ipilimumab in combination with imiquimod. Our present case suggested a possible therapy for nivolumab-resistant multiple in-transit melanomas using ipilimumab in combination with topical imiquimod.

  1. Assessing the potential impact of artemisinin and partner drug resistance in sub-Saharan Africa.

    Science.gov (United States)

    Slater, Hannah C; Griffin, Jamie T; Ghani, Azra C; Okell, Lucy C

    2016-01-06

    Artemisinin and partner drug resistant malaria parasites have emerged in Southeast Asia. If resistance were to emerge in Africa it could have a devastating impact on malaria-related morbidity and mortality. This study estimates the potential impact of artemisinin and partner drug resistance on disease burden in Africa if it were to emerge. Using data from Asia and Africa, five possible artemisinin and partner drug resistance scenarios are characterized. An individual-based malaria transmission model is used to estimate the impact of each resistance scenario on clinical incidence and parasite prevalence across Africa. Artemisinin resistance is characterized by slow parasite clearance and partner drug resistance is associated with late clinical failure or late parasitological failure. Scenarios with high levels of recrudescent infections resulted in far greater increases in clinical incidence compared to scenarios with high levels of slow parasite clearance. Across Africa, it is estimated that artemisinin and partner drug resistance at levels similar to those observed in Oddar Meanchey province in Cambodia could result in an additional 78 million cases over a 5 year period, a 7% increase in cases compared to a scenario with no resistance. A scenario with high levels of slow clearance but no recrudescence resulted in an additional 10 million additional cases over the same period. Artemisinin resistance is potentially a more pressing concern than partner drug resistance due to the lack of viable alternatives. However, it is predicted that a failing partner drug will result in greater increases in malaria cases and morbidity than would be observed from artemisinin resistance only.

  2. Drug response prediction in high-risk multiple myeloma

    DEFF Research Database (Denmark)

    Vangsted, A J; Helm-Petersen, S; Cowland, J B

    2018-01-01

    from high-risk patients by GEP70 at diagnosis from Total Therapy 2 and 3A to predict the response by the DRP score of drugs used in the treatment of myeloma patients. The DRP score stratified patients further. High-risk myeloma with a predicted sensitivity to melphalan by the DRP score had a prolonged...

  3. Transmission of HIV drug resistance and the predicted effect on current first-line regimens in Europe

    NARCIS (Netherlands)

    Hofstra, L. Marije; Sauvageot, Nicolas; Albert, Jan; Alexiev, Ivailo; Garcia, Federico; Struck, Daniel; Van De Vijver, David A M C; Åsjö, Birgitta; Beshkov, Danail; Coughlan, Suzie; Descamps, Diane; Griskevicius, Algirdas; Hamouda, Osamah; Horban, Andrzej; Van Kasteren, Marjo; Kolupajeva, Tatjana; Kostrikis, Leontios G.; Liitsola, Kirsi; Linka, Marek; Mor, Orna; Nielsen, Claus; Otelea, Dan; Paraskevis, Dimitrios; Paredes, Roger; Poljak, Mario; Puchhammer-Stöckl, Elisabeth; Sönnerborg, Anders; Staneková, Danica; Stanojevic, Maja; Van Laethem, Kristel; Zazzi, Maurizio; Lepej, Snjezana Zidovec; Boucher, Charles A B; Schmit, Jean Claude; Wensing, Annemarie M J; Puchhammer-Stockl, E.; Sarcletti, M.; Schmied, B.; Geit, M.; Balluch, G.; Vandamme, A. M.; Vercauteren, J.; Derdelinckx, I.; Sasse, A.; Bogaert, M.; Ceunen, H.; De Roo, A.; De Wit, S.; Echahidi, F.; Fransen, K.; Goffard, J. C.; Goubau, P.; Goudeseune, E.; Yombi, J. C.; Lacor, P.; Liesnard, C.; Moutschen, M.; Pierard, D.; Rens, R.; Schrooten, Y.; Vaira, D.; Vandekerckhove, L. P R; Van Den Heuvel, A.; Van Der Gucht, B.; Van Ranst, M.; Van Wijngaerden, E.; Vandercam, B.; Vekemans, M.; Verhofstede, C.; Clumeck, N.; Van Laethem, K.; Beshkov, D.; Alexiev, I.; Lepej, S. Zidovec; Begovac, J.; Kostrikis, Leontios G.; Demetriades, I.; Kousiappa, I.; Demetriou, V.; Hezka, J.; Linka, M.; Maly, M.; Machala, L.; Nielsen, C.; Jørgensen, L. B.; Gerstoft, J.; Mathiesen, L.; Pedersen, C.; Nielsen, H.; Laursen, A.; Kvinesdal, B.; Liitsola, K.; Ristola, M.; Suni, J.; Sutinen, J.; Descamps, D.; Assoumou, L.; Castor, G.; Grude, M.; Flandre, P.; Storto, A.; Hamouda, O.; Kücherer, C.; Berg, T.; Braun, P.; Poggensee, G.; Däumer, M.; Eberle, J.; Heiken, H.; Kaiser, R.; Knechten, H.; Korn, K.; Müller, H.; Neifer, S.; Schmidt, B.; Walter, H.; Gunsenheimer-Bartmeyer, B.; Harrer, T.; Paraskevis, D.; Hatzakis, A.; Zavitsanou, A.; Vassilakis, A.; Lazanas, M.; Chini, M.; Lioni, A.; Sakka, V.; Kourkounti, S.; Paparizos, V.; Antoniadou, A.; Papadopoulos, A.; Poulakou, G.; Katsarolis, I.; Protopapas, K.; Chryssos, G.; Drimis, S.; Gargalianos, P.; Xylomenos, G.; Lourida, G.; Psichogiou, M.; Daikos, G. L.; Sipsas, N. V.; Kontos, A.; Gamaletsou, M. N.; Koratzanis, G.; Sambatakou, E.; Mariolis, H.; Skoutelis, A.; Papastamopoulos, V.; Georgiou, O.; Panagopoulos, P.; Maltezos, E.; Coughlan, S.; De Gascun, C.; Byrne, C.; Duffy, M.; Bergin, C.; Reidy, D.; Farrell, G.; Lambert, J.; O'Connor, E.; Rochford, A.; Low, J.; Coakely, P.; O'Dea, S.; Hall, W.; Mor, O.; Levi, I.; Chemtob, D.; Grossman, Z.; Zazzi, M.; De Luca, A.; Balotta, C.; Riva, C.; Mussini, C.; Caramma, I.; Capetti, A.; Colombo, M. C.; Rossi, C.; Prati, F.; Tramuto, F.; Vitale, F.; Ciccozzi, M.; Angarano, G.; Rezza, G.; Kolupajeva, T.; Kolupajeva, T.; Vasins, O.; Griskevicius, A.; Lipnickiene, V.; Schmit, J. C.; Struck, D.; Sauvageot, N.; Hemmer, R.; Arendt, V.; Michaux, C.; Staub, T.; Sequin-Devaux, C.; Wensing, A. M J; Boucher, C. A B; Van Kessel, A.; Van Bentum, P. H M; Brinkman, K.; Connell, B. J.; Van Der Ende, M. E.; Hoepelman, I. M.; Van Kasteren, M.; Kuipers, M.; Langebeek, N.; Richter, C.; Santegoets, R. M W J; Schrijnders-Gudde, L.; Schuurman, R.; Van De Ven, B. J M; Åsjö, B.; Kran, A. M Bakken; Ormaasen, V.; Aavitsland, P.; Horban, A.; Stanczak, J. J.; Stanczak, G. P.; Firlag-Burkacka, E.; Wiercinska-Drapalo, A.; Jablonowska, E.; Maolepsza, E.; Leszczyszyn-Pynka, M.; Szata, W.; Camacho, R.; Palma, C.; Borges, F.; Paixão, T.; Duque, V.; Araújo, F.; Otelea, D.; Paraschiv, S.; Tudor, A. M.; Cernat, R.; Chiriac, C.; Dumitrescu, F.; Prisecariu, L. J.; Stanojevic, M.; Jevtovic, Dj; Salemovic, D.; Stanekova, D.; Habekova, M.; Chabadová, Z.; Drobkova, T.; Bukovinova, P.; Shunnar, A.; Truska, P.; Poljak, M.; Lunar, M.; Babic, D.; Tomazic, J.; Vidmar, L.; Vovko, T.; Karner, P.; Garcia, F.; Paredes, R.; Monge, S.; Moreno, S.; Del Amo, J.; Asensi, V.; Sirvent, J. L.; De Mendoza, C.; Delgado, R.; Gutiérrez, F.; Berenguer, J.; Garcia-Bujalance, S.; Stella, N.; De Los Santos, I.; Blanco, J. R.; Dalmau, D.; Rivero, M.; Segura, F.; Elías, M. J Pérez; Alvarez, M.; Chueca, N.; Rodríguez-Martín, C.; Vidal, C.; Palomares, J. C.; Viciana, I.; Viciana, P.; Cordoba, J.; Aguilera, A.; Domingo, P.; Galindo, M. J.; Miralles, C.; Del Pozo, M. A.; Ribera, E.; Iribarren, J. A.; Ruiz, L.; De La Torre, J.; Vidal, F.; Clotet, B.; Albert, J.; Heidarian, A.; Aperia-Peipke, K.; Axelsson, M.; Mild, M.; Karlsson, A.; Sönnerborg, A.; Thalme, A.; Navér, L.; Bratt, G.; Karlsson, A.; Blaxhult, A.; Gisslén, M.; Svennerholm, B.; Bergbrant, I.; Björkman, P.; Säll, C.; Lindholm, A.; Kuylenstierna, N.; Montelius, R.; Azimi, F.; Johansson, B.; Carlsson, M.; Johansson, E.; Ljungberg, B.; Ekvall, H.; Strand, A.; Mäkitalo, S.; Öberg, S.; Holmblad, P.; Höfer, M.; Holmberg, H.; Josefson, P.; Ryding, U.

    2016-01-01

    Background. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline

  4. Supplementary Material for: Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance

    KAUST Repository

    Phelan, Jody; Coll, Francesc; McNerney, Ruth; Ascher, David; Pires, Douglas; Furnham, Nick; Coeck, Nele; Hill-Cawthorne, Grant; Nair, Mridul; Mallard, Kim; Ramsay, Andrew; Campino, Susana; Hibberd, Martin; Pain, Arnab; Rigouts, Leen; Clark, Taane

    2016-01-01

    Abstract Background Combating the spread of drug resistant tuberculosis is a global health priority. Whole genome association studies are being applied to identify genetic determinants of resistance to anti-tuberculosis drugs. Protein structure

  5. Molecular mechanisms and theranostic potential of miRNAs in drug resistance of gastric cancer.

    Science.gov (United States)

    Yang, Wanli; Ma, Jiaojiao; Zhou, Wei; Cao, Bo; Zhou, Xin; Yang, Zhiping; Zhang, Hongwei; Zhao, Qingchuan; Fan, Daiming; Hong, Liu

    2017-11-01

    Systemic chemotherapy is a curative approach to inhibit gastric cancer cells proliferation. Despite the great progress in anti-cancer treatment achieved during the last decades, drug resistance and treatment refractoriness still extensively persists. Recently, accumulating studies have highlighted the role of miRNAs in drug resistance of gastric cancers by modulating some drug resistance-related proteins and genes expression. Pre-clinical reports indicate that miRNAs might serve as ideal biomarkers and potential targets, thus holding great promise for developing targeted therapy and personalized treatment for the patients with gastric cancer. Areas covered: This review provide a comprehensive overview of the current advances of miRNAs and molecular mechanisms underlying miRNA-mediated drug resistance in gastric cancer. We particularly focus on the potential values of drug resistance-related miRNAs as biomarkers and novel targets in gastric cancer therapy and envisage the future research developments of these miRNAs and challenges in translating the new findings into clinical applications. Expert opinion: Although the concrete mechanisms of miRNAs in drug resistance of gastric cancer have not been fully clarified, miRNA may be a promising theranostic approach. Further studies are still needed to facilitate the clinical applications of miRNAs in drug resistant gastric cancer.

  6. European recommendations for the clinical use of HIV drug resistance testing: 2011 update

    DEFF Research Database (Denmark)

    Vandamme, Anne-Mieke; Camacho, Ricardo J; Ceccherini-Silberstein, Francesca

    2011-01-01

    , and other drug targets (integrase and envelope) if such drugs were part of the failing regimen; (iii) consider testing for CCR5 tropism at virologic failure or when a change of therapy has to be made in absence of detectable viral load, and in the latter case test DNA or last detectable plasma RNA; (iv...... the following recommendations concerning the indications for resistance testing: for HIV-1 (i) test earliest sample for protease and reverse transcriptase drug resistance in drug-naive patients with acute or chronic infection; (ii) test protease and reverse transcriptase drug resistance at virologic failure...... is needed after treatment failure. The Panel recommends genotyping in most situations, using updated and clinically evaluated interpretation systems. It is mandatory that laboratories performing HIV resistance tests take part regularly in external quality assurance programs, and that they consider storing...

  7. Genotypic diversity of multidrug-, quinolone- and extensively drug-resistant Mycobacterium tuberculosis isolates in Thailand.

    Science.gov (United States)

    Disratthakit, Areeya; Meada, Shinji; Prammananan, Therdsak; Thaipisuttikul, Iyarit; Doi, Norio; Chaiprasert, Angkana

    2015-06-01

    Drug-resistant tuberculosis (TB), which includes multidrug-resistant (MDR-TB), quinolone-resistant (QR-TB) and extensively drug-resistant tuberculosis (XDR-TB), is a serious threat to TB control. We aimed to characterize the genotypic diversity of drug-resistant TB clinical isolates collected in Thailand to establish whether the emergence of drug-resistant TB is attributable to transmitted resistance or acquired resistance. We constructed the first molecular phylogeny of MDR-TB (n=95), QR-TB (n=69) and XDR-TB (n=28) in Thailand based on spoligotyping and proposed 24-locus multilocus variable-number of tandem repeat analysis (MLVA). Clustering analysis was performed using the unweighted pair group method with arithmetic mean. Spoligotyping identified the Beijing strain (SIT1) as the most predominant genotype (n=139; 72.4%). The discriminatory power of 0.9235 Hunter-Gaston Discriminatory Index (HGDI) with the 15-locus variable-number tandem repeats of mycobacterial interspersed repetitive units typing was improved to a 0.9574 HGDI with proposed 24-locus MLVA, thereby resulting in the subdivision of a large cluster of Beijing strains (SIT1) into 17 subclusters. We identified the spread of drug-resistant TB clones caused by three different MLVA types in the Beijing strain (SIT1) and a specific clone of XDR-TB caused by a rare genotype, the Manu-ancestor strain (SIT523). Overall, 49.5% of all isolates were clustered. These findings suggest that a remarkable transmission of drug-resistant TB occurred in Thailand. The remaining 50% of drug-resistant TB isolates were unique genotypes, which may have arisen from the individual acquisition of drug resistance. Our results suggest that transmitted and acquired resistance have played an equal role in the emergence of drug-resistant TB. Further characterization of whole genome sequences of clonal strains could help to elucidate the mycobacterial genetic factors relevant for drug resistance, transmissibility and virulence

  8. Antimicrobial drug resistance of Salmonella isolates from meat and humans, Denmark

    DEFF Research Database (Denmark)

    Skov, Marianne Nielsine; Andersen, Jens Strodl; Aabo, Søren

    2007-01-01

    We compared 8,144 Salmonella isolates collected from meat imported to or produced in Denmark, as well as from Danish patients. Isolates from imported meat showed a higher rate of antimicrobial drug resistance, including multidrug resistance, than did isolates from domestic meat. Isolates from...... humans showed resistance rates lower than those found in imported meat but higher than in domestic meat. These findings indicate that programs for controlling resistant Salmonella spp. are a global issue...

  9. Antimicrobial drug resistance of Salmonella isolates from meat and humans, Denmark

    DEFF Research Database (Denmark)

    Skov, Marianne; Andersen, Jens Strodl; Aabo, Søren

    2007-01-01

    We compared 8,144 Salmonella isolates collected from meat imported to or produced in Denmark, as well as from Danish patients. Isolates from imported meat showed a higher rate of antimicrobial drug resistance, including multidrug resistance, than did isolates from domestic meat. Isolates from...... humans showed resistance rates lower than those found in imported meat but higher than in domestic meat. These findings indicate that programs for controlling resistant Salmonella spp. are a global issue....

  10. Effect of pretreatment HIV-1 drug resistance on immunological, virological, and drug-resistance outcomes of first-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study

    NARCIS (Netherlands)

    Hamers, Raph L.; Schuurman, Rob; Sigaloff, Kim C. E.; Wallis, Carole L.; Kityo, Cissy; Siwale, Margaret; Mandaliya, Kishor; Ive, Prudence; Botes, Mariette E.; Wellington, Maureen; Osibogun, Akin; Wit, Ferdinand W.; van Vugt, Michèle; Stevens, Wendy S.; de Wit, Tobias F. Rinke

    2012-01-01

    Background The effect of pretreatment HIV-1 drug resistance on the response to first-line combination antiretroviral therapy (ART) in sub-Saharan Africa has not been assessed. We studied pretreatment drug resistance and virological, immunological, and drug-resistance treatment outcomes in a large

  11. HIV-1 evolution, drug resistance, and host genetics: The Indian scenario

    Directory of Open Access Journals (Sweden)

    U Shankarkumar

    2009-03-01

    Full Text Available U Shankarkumar, A Pawar, K GhoshNational Institute of Immunohaematology (ICMR, KEM Hospital, Parel, Mumbai, Maharashtra, IndiaAbstract: A regimen with varied side effects and compliance is of paramount importance to prevent viral drug resistance. Most of the drug-resistance studies, as well as interpretation algorithms, are based on sequence data from HIV-1 subtype B viruses. Increased resistance to antiretroviral drugs leads to poor prognosis by restricting treatment options. Due to suboptimal adherence to antiretroviral therapy there is an emergence of drug-resistant HIV-1 strains. The other factors responsible for this viral evolution are antiretroviral drug types and host genetics, especially major histocompatibility complex (MHC. Both primary and secondary drug resistances occur due to mutations in specific epitopes of viral protein regions which may influence the T cell recognition by immune system through MHC Class I and class II alleles. Mutations in viral epitopes enable the virus to escape the immune system. New drugs under clinical trials are being added but their exorbitant costs limit their access in developing countries. Thus the environmental consequences and, the impact of both viral and host genetic variations on the therapy in persons infected with HIV-1 clade C from India need to be determined.Keywords: HIV-1 C drug resistance, virus adaptation, HARRT, India

  12. Clinical characteristics, drug resistance, and treatment outcomes among tuberculosis patients with diabetes in Peru.

    Science.gov (United States)

    Magee, M J; Bloss, E; Shin, S S; Contreras, C; Huaman, H Arbanil; Ticona, J Calderon; Bayona, J; Bonilla, C; Yagui, M; Jave, O; Cegielski, J P

    2013-06-01

    Diabetes is a risk factor for active tuberculosis (TB). Data are limited regarding the association between diabetes and TB drug resistance and treatment outcomes. We examined characteristics of TB patients with and without diabetes in a Peruvian cohort at high risk for drug-resistant TB. Among TB patients with diabetes (TB-DM), we studied the association between diabetes clinical/management characteristics and TB drug resistance and treatment outcomes. During 2005-2008, adults with suspected TB with respiratory symptoms in Lima, Peru, who received rapid drug susceptibility testing (DST), were prospectively enrolled and followed during treatment. Bivariate and Kaplan-Meier analyses were used to examine the relationships of diabetes characteristics with drug-resistant TB and TB outcomes. Of 1671 adult TB patients enrolled, 186 (11.1%) had diabetes. TB-DM patients were significantly more likely than TB patients without diabetes to be older, have had no previous TB treatment, and to have a body mass index (BMI) >18.5 kg/m(2) (pdiabetes, and 12% and 28%, respectively, among TB-DM patients. Among 149 TB-DM patients with DST results, 104 (69.8%) had drug-susceptible TB and 45 (30.2%) had drug-resistant TB, of whom 29 had multidrug-resistant TB. There was no association between diabetes characteristics and drug-resistant TB. Of 136 TB-DM patients with outcome information, 107 (78.7%) had a favorable TB outcome; active diabetes management was associated with a favorable outcome. Diabetes was common in a cohort of TB patients at high risk for drug-resistant TB. Despite prevalent multidrug-resistant TB among TB-DM patients, the majority had a favorable TB treatment outcome. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  13. Alteration of gene expression and DNA methylation in drug-resistant gastric cancer.

    Science.gov (United States)

    Maeda, Osamu; Ando, Takafumi; Ohmiya, Naoki; Ishiguro, Kazuhiro; Watanabe, Osamu; Miyahara, Ryoji; Hibi, Yoko; Nagai, Taku; Yamada, Kiyofumi; Goto, Hidemi

    2014-04-01

    The mechanisms of drug resistance in cancer are not fully elucidated. To study the drug resistance of gastric cancer, we analyzed gene expression and DNA methylation profiles of 5-fluorouracil (5-FU)- and cisplatin (CDDP)-resistant gastric cancer cells and biopsy specimens. Drug-resistant gastric cancer cells were established with culture for >10 months in a medium containing 5-FU or CDDP. Endoscopic biopsy specimens were obtained from gastric cancer patients who underwent chemotherapy with oral fluoropyrimidine S-1 and CDDP. Gene expression and DNA methylation analyses were performed using microarray, and validated using real-time PCR and pyrosequencing, respectively. Out of 17,933 genes, 541 genes commonly increased and 569 genes decreased in both 5-FU- and CDDP-resistant AGS cells. Genes with expression changed by drugs were related to GO term 'extracellular region' and 'p53 signaling pathway' in both 5-FU- and CDDP-treated cells. Expression of 15 genes including KLK13 increased and 12 genes including ETV7 decreased, in both drug-resistant cells and biopsy specimens of two patients after chemotherapy. Out of 10,365 genes evaluated with both expression microarray and methylation microarray, 74 genes were hypermethylated and downregulated, or hypomethylated and upregulated in either 5-FU-resistant or CDDP-resistant cells. Of these genes, expression of 21 genes including FSCN1, CPT1C and NOTCH3, increased from treatment with a demethylating agent. There are alterations of gene expression and DNA methylation in drug-resistant gastric cancer; they may be related to mechanisms of drug resistance and may be useful as biomarkers of gastric cancer drug sensitivity.

  14. The role of miRNA regulation in cancer progression and drug resistance

    DEFF Research Database (Denmark)

    Joshi, Tejal

    RNAs in the context of cancer biology, drug resistance and disease progression. The first project described in Chapter 6 addresses the problem of tamoxifen resistance, an anti-estrogen drug that is generally highly effective in the treatment of ER-positive breast cancers. The underlying molecular mechanisms...... to the disease transformation. In summary, this thesis focuses on regulatory role of miRNAs in drug resistance and disease progression. The findings provide hints toward various biologically and perhaps therapeutically relevant gene regulatory events. This thesis demonstrates the right choice of data analysis...... for the acquired resistance to tamoxifen are not very well understood. Therefore, with the aid of miRNA and gene expression profiles for MCF7/S0.5 (tamoxifen sensitive) and three MCF7/S0.5 derived tamoxifen resistant cell lines, we obtained several miRNA-mediated regulatory events in the tamoxifen resistant cell...

  15. The cfr and cfr-like multiple resistance genes

    DEFF Research Database (Denmark)

    Vester, Birte

    2018-01-01

    . The cfr gene is found in various bacteria in many geographical locations and placed on plasmids or associated with transposons. Cfr-related genes providing similar resistance have been identified in Bacillales, and now also in the pathogens Clostridium difficile and Enterococcus faecium. In addition......, the presence of the cfr gene has been detected in harbours and food markets....

  16. The culturable soil antibiotic resistome: a community of multi-drug resistant bacteria.

    Science.gov (United States)

    Walsh, Fiona; Duffy, Brion

    2013-01-01

    Understanding the soil bacterial resistome is essential to understanding the evolution and development of antibiotic resistance, and its spread between species and biomes. We have identified and characterized multi-drug resistance (MDR) mechanisms in the culturable soil antibiotic resistome and linked the resistance profiles to bacterial species. We isolated 412 antibiotic resistant bacteria from agricultural, urban and pristine soils. All isolates were multi-drug resistant, of which greater than 80% were resistant to 16-23 antibiotics, comprising almost all classes of antibiotic. The mobile resistance genes investigated, (ESBL, bla NDM-1, and plasmid mediated quinolone resistance (PMQR) resistance genes) were not responsible for the respective resistance phenotypes nor were they present in the extracted soil DNA. Efflux was demonstrated to play an important role in MDR and many resistance phenotypes. Clinically relevant Burkholderia species are intrinsically resistant to ciprofloxacin but the soil Burkholderia species were not intrinsically resistant to ciprofloxacin. Using a phenotypic enzyme assay we identified the antibiotic specific inactivation of trimethoprim in 21 bacteria from different soils. The results of this study identified the importance of the efflux mechanism in the soil resistome and variations between the intrinsic resistance profiles of clinical and soil bacteria of the same family.

  17. The culturable soil antibiotic resistome: a community of multi-drug resistant bacteria.

    Directory of Open Access Journals (Sweden)

    Fiona Walsh

    Full Text Available Understanding the soil bacterial resistome is essential to understanding the evolution and development of antibiotic resistance, and its spread between species and biomes. We have identified and characterized multi-drug resistance (MDR mechanisms in the culturable soil antibiotic resistome and linked the resistance profiles to bacterial species. We isolated 412 antibiotic resistant bacteria from agricultural, urban and pristine soils. All isolates were multi-drug resistant, of which greater than 80% were resistant to 16-23 antibiotics, comprising almost all classes of antibiotic. The mobile resistance genes investigated, (ESBL, bla NDM-1, and plasmid mediated quinolone resistance (PMQR resistance genes were not responsible for the respective resistance phenotypes nor were they present in the extracted soil DNA. Efflux was demonstrated to play an important role in MDR and many resistance phenotypes. Clinically relevant Burkholderia species are intrinsically resistant to ciprofloxacin but the soil Burkholderia species were not intrinsically resistant to ciprofloxacin. Using a phenotypic enzyme assay we identified the antibiotic specific inactivation of trimethoprim in 21 bacteria from different soils. The results of this study identified the importance of the efflux mechanism in the soil resistome and variations between the intrinsic resistance profiles of clinical and soil bacteria of the same family.

  18. Complete genome analysis of three Acinetobacter baumannii clinical isolates in China for insight into the diversification of drug resistance elements.

    Science.gov (United States)

    Zhu, Lingxiang; Yan, Zhongqiang; Zhang, Zhaojun; Zhou, Qiming; Zhou, Jinchun; Wakeland, Edward K; Fang, Xiangdong; Xuan, Zhenyu; Shen, Dingxia; Li, Quan-Zhen

    2013-01-01

    The emergence and rapid spreading of multidrug-resistant Acinetobacter baumannii strains has become a major health threat worldwide. To better understand the genetic recombination related with the acquisition of drug-resistant elements during bacterial infection, we performed complete genome analysis on three newly isolated multidrug-resistant A. baumannii strains from Beijing using next-generation sequencing technology. Whole genome comparison revealed that all 3 strains share some common drug resistant elements including carbapenem-resistant bla OXA-23 and tetracycline (tet) resistance islands, but the genome structures are diversified among strains. Various genomic islands intersperse on the genome with transposons and insertions, reflecting the recombination flexibility during the acquisition of the resistant elements. The blood-isolated BJAB07104 and ascites-isolated BJAB0868 exhibit high similarity on their genome structure with most of the global clone II strains, suggesting these two strains belong to the dominant outbreak strains prevalent worldwide. A large resistance island (RI) of about 121-kb, carrying a cluster of resistance-related genes, was inserted into the ATPase gene on BJAB07104 and BJAB0868 genomes. A 78-kb insertion element carrying tra-locus and bla OXA-23 island, can be either inserted into one of the tniB gene in the 121-kb RI on the chromosome, or transformed to conjugative plasmid in the two BJAB strains. The third strains of this study, BJAB0715, which was isolated from spinal fluid, exhibit much more divergence compared with above two strains. It harbors multiple drug-resistance elements including a truncated AbaR-22-like RI on its genome. One of the unique features of this strain is that it carries both bla OXA-23 and bla OXA-58 genes on its genome. Besides, an Acinetobacter lwoffii adeABC efflux element was found inserted into the ATPase position in BJAB0715. Our comparative analysis on currently completed Acinetobacter baumannii

  19. Complete genome analysis of three Acinetobacter baumannii clinical isolates in China for insight into the diversification of drug resistance elements.

    Directory of Open Access Journals (Sweden)

    Lingxiang Zhu

    Full Text Available The emergence and rapid spreading of multidrug-resistant Acinetobacter baumannii strains has become a major health threat worldwide. To better understand the genetic recombination related with the acquisition of drug-resistant elements during bacterial infection, we performed complete genome analysis on three newly isolated multidrug-resistant A. baumannii strains from Beijing using next-generation sequencing technology.Whole genome comparison revealed that all 3 strains share some common drug resistant elements including carbapenem-resistant bla OXA-23 and tetracycline (tet resistance islands, but the genome structures are diversified among strains. Various genomic islands intersperse on the genome with transposons and insertions, reflecting the recombination flexibility during the acquisition of the resistant elements. The blood-isolated BJAB07104 and ascites-isolated BJAB0868 exhibit high similarity on their genome structure with most of the global clone II strains, suggesting these two strains belong to the dominant outbreak strains prevalent worldwide. A large resistance island (RI of about 121-kb, carrying a cluster of resistance-related genes, was inserted into the ATPase gene on BJAB07104 and BJAB0868 genomes. A 78-kb insertion element carrying tra-locus and bla OXA-23 island, can be either inserted into one of the tniB gene in the 121-kb RI on the chromosome, or transformed to conjugative plasmid in the two BJAB strains. The third strains of this study, BJAB0715, which was isolated from spinal fluid, exhibit much more divergence compared with above two strains. It harbors multiple drug-resistance elements including a truncated AbaR-22-like RI on its genome. One of the unique features of this strain is that it carries both bla OXA-23 and bla OXA-58 genes on its genome. Besides, an Acinetobacter lwoffii adeABC efflux element was found inserted into the ATPase position in BJAB0715.Our comparative analysis on currently completed

  20. Multiple comparisons in drug efficacy studies: scientific or marketing principles?

    Science.gov (United States)

    Leo, Jonathan

    2004-01-01

    When researchers design an experiment to compare a given medication to another medication, a behavioral therapy, or a placebo, the experiment often involves numerous comparisons. For instance, there may be several different evaluation methods, raters, and time points. Although scientifically justified, such comparisons can be abused in the interests of drug marketing. This article provides two recent examples of such questionable practices. The first involves the case of the arthritis drug celecoxib (Celebrex), where the study lasted 12 months but the authors only presented 6 months of data. The second case involves the NIMH Multimodal Treatment Study (MTA) study evaluating the efficacy of stimulant medication for attention-deficit hyperactivity disorder where ratings made by several groups are reported in contradictory fashion. The MTA authors have not clarified the confusion, at least in print, suggesting that the actual findings of the study may have played little role in the authors' reported conclusions.

  1. Combination Therapy Strategies Against Multiple-Resistant Streptococcus Suis

    Directory of Open Access Journals (Sweden)

    Yang Yu

    2018-05-01

    Full Text Available Streptococcus suis is a major swine pathogen, an emerging zoonotic agent responsible for meningitis, endocarditis and septicaemia followed by deafness in humans. The development of antimicrobial resistance in S. suis increases the risk for therapeutic failure in both animals and humans. In this study, we report the synergism of combination therapy against multi-resistant S. suis isolates from swine. Twelve antibiotic profiles were determined against 11 S. suis strains. To investigate their synergistic/antagonistic activity, checkerboard assay was performed for all the possible combinations. In-vitro killing curves and in-vivo treatment trials were used to confirm the synergistic activity of special combinations against S. suis dominant clones. In this study, 11 S. suis isolates were highly resistant to erythromycin, clindamycin, trimethoprim/sulfamethoxazole, and tetracycline with ratios of 80–100%, and the resistance percentages to enrofloxacin, florfenicol, and spectinomycin were ~50%. The checkerboard data identified two combination regimens, ampicillin plus apramycin and tiamulin plus spectinomycin which gave the greatest level of synergism against the S. suis strains. In-vitro kill-curves showed a bacterial reduction of over 3-logCFU with the use of combination treatments, whilst the application of mono-therapies achieve less than a 2-logCFU cell killing. In-vivo models confirm that administration of these two combinations significantly reduced the number of bacterial cells after 24 h of treatment. In conclusions, the combinations of ampicillin plus apramycin and tiamulin plus spectinomycin showed the greatest synergism and may be potential strategies for treatment of multi-resistant S. suis in animal.

  2. A meta-analysis of drug resistant tuberculosis in Sub-Saharan Africa: how strongly associated with previous treatment and HIV co-infection?

    Science.gov (United States)

    Berhan, Asres; Berhan, Yifru; Yizengaw, Desalegn

    2013-11-01

    In Sub-Saharan Africa, the fight against tuberculosis (TB) has encountered a great challenge because of the emergence of drug resistant TB strains and the high prevalence of HIV infection. The aim of this meta-analysis was to determine the association of drug-resistant TB with anti-TB drug treatment history and HIV co-infection. After electronic based literature search in the databases of Medline, HINARI, EMBASE and the Cochrane library, article selection and data extraction were carried out. HIV co-infection and previous history of TB treatment were used as predictors for the occurrence of any anti-TB drug resistant or multiple drug resistant TB (MDR-TB). The risk ratios for each included study and for the pooled sample were computed using the random-effects model. Heterogeneity test, sensitivity analyses and funnel plots were also done. The pooled analysis showed that the risk of developing drug-resistant TB to at least one anti-TB drug was about 3 times higher in individuals who had a previous history of anti-TB treatment than new TB cases. The risk of having MDR-TB in previously anti-TB treated TB cases was more than 5-fold higher than that of new TB cases. Resistance to Ethambutol and Rifampicin was more than fivefold higher among the previously treated with anti-TB drugs. However, HIV infection was not associated with drug-resistant TB. There was a strong association of previous anti-TB treatment with MDR-TB. Primary treatment warrants special emphasis, and screening for anti-TB drugs sensitivity has to be strengthened.

  3. Changing patterns of drug-resistant Shigella isolates in egypt.

    Science.gov (United States)

    Abd-Elmeged, Ghada M; Khairy, Rasha M; Abo-Eloyoon, Sahar M; Abdelwahab, Sayed F

    2015-06-01

    The emergence of multidrug resistance (MDR) is a serious problem in treating shigellosis. There are limited existing data examining the change in the antimicrobial resistance profile of Shigella in Egypt. We previously reported that 58% of the Shigella isolates in Egypt were resistant to at least one member of the three different antimicrobial groups. This study was performed to determine the antimicrobial resistance profile of Shigella, determine their possible mechanisms of resistance, and compare their resistance profile to those reported 20 years ago. Stool samples were collected from 500 subjects and processed for the isolation and identification of Shigella. The susceptibility of the isolates to 11 different antimicrobials was determined using the disc diffusion method. Of 500 stool cultures, 24 (4.8%) samples were positive for Shigella. There was a high percentage of resistance to ampicillin (88%), tetracycline (83%), and sulfamethoxazole-trimethoprim (75%). Also, there was a moderate percentage of resistance to chloramphenicol (46%), streptomycin (42%), ceftazidime (33%), and cefotaxime (25%). A lower percentage of resistance was recorded for amikacin, nalidixic acid (17% each), and ofloxacin (7%), while no resistance was found to ciprofloxacin (0%). Twenty-one of the isolates (88%) were resistant to at least three different antimicrobial groups (indicating MDR). The average number of antimicrobial agents to which the Shigella isolates were resistant was 4.3±1.4, while it was 3.4±1.5 in the same locality in 1994. These data demonstrate that there is a marked increase in MDR and change in the resistance patterns of Shigella over the past 20 years.

  4. Genotypic drug resistance and long-term mortality in patients with triple-class antiretroviral drug failure

    DEFF Research Database (Denmark)

    Lohse, Nicolai; Jørgensen, LB; Kronborg, G

    2007-01-01

    OBJECTIVE: To examine the prevalence of drug-resistance-associated mutations in HIV patients with triple-drug class virological failure (TCF) and their association with long-term mortality. DESIGN: Population-based study from the Danish HIV Cohort Study (DHCS). METHODS: We included all patients...... range 2-10), and 81 (61%) patients had mutations conferring resistance towards all three major drug classes. In a regression model adjusted for CD4+ T-cell count, HIV RNA, year of TCF, age, gender and previous inferior antiretroviral therapy, harbouring > or =9 versus ... in the DHCS who experienced TCF between January 1995 and November 2004, and we performed genotypic resistance tests for International AIDS Society (IAS)-USA primary mutations on virus from plasma samples taken around the date of TCF. We computed time to all-cause death from date of TCF. The relative risk...

  5. Shifts in Mycobacterial Populations and Emerging Drug-Resistance in West and Central Africa.

    Directory of Open Access Journals (Sweden)

    Florian Gehre

    Full Text Available In this study, we retrospectively analysed a total of 605 clinical isolates from six West or Central African countries (Benin, Cameroon, Central African Republic, Guinea-Conakry, Niger and Senegal. Besides spoligotyping to assign isolates to ancient and modern mycobacterial lineages, we conducted phenotypic drug-susceptibility-testing for each isolate for the four first-line drugs. We showed that phylogenetically modern Mycobacterium tuberculosis strains are more likely associated with drug resistance than ancient strains and predict that the currently ongoing replacement of the endemic ancient by a modern mycobacterial population in West/Central Africa might result in increased drug resistance in the sub-region.

  6. ZK DrugResist 2.0: A TextMiner to extract semantic relations of drug resistance from PubMed.

    Science.gov (United States)

    Khalid, Zoya; Sezerman, Osman Ugur

    2017-05-01

    Extracting useful knowledge from an unstructured textual data is a challenging task for biologists, since biomedical literature is growing exponentially on a daily basis. Building an automated method for such tasks is gaining much attention of researchers. ZK DrugResist is an online tool that automatically extracts mutations and expression changes associated with drug resistance from PubMed. In this study we have extended our tool to include semantic relations extracted from biomedical text covering drug resistance and established a server including both of these features. Our system was tested for three relations, Resistance (R), Intermediate (I) and Susceptible (S) by applying hybrid feature set. From the last few decades the focus has changed to hybrid approaches as it provides better results. In our case this approach combines rule-based methods with machine learning techniques. The results showed 97.67% accuracy with 96% precision, recall and F-measure. The results have outperformed the previously existing relation extraction systems thus can facilitate computational analysis of drug resistance against complex diseases and further can be implemented on other areas of biomedicine. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Update on HIV-1 acquired and transmitted drug resistance in Africa.

    Science.gov (United States)

    Ssemwanga, Deogratius; Lihana, Raphael W; Ugoji, Chinenye; Abimiku, Alash'le; Nkengasong, John; Dakum, Patrick; Ndembi, Nicaise

    2015-01-01

    The last ten years have witnessed a significant scale-up and access to antiretroviral therapy in Africa, which has improved patient quality of life and survival. One major challenge associated with increased access to antiretroviral therapy is the development of antiretroviral resistance due to inconsistent drug supply and/or poor patient adherence. We review the current state of both acquired and transmitted drug resistance in Africa over the past ten years (2001-2011) to identify drug resistance associated with the different drug regimens used on the continent and to help guide affordable strategies for drug resistance surveillance. A total of 161 references (153 articles, six reports and two conference abstracts) were reviewed. Antiretroviral resistance data was available for 40 of 53 African countries. A total of 5,541 adult patients from 99 studies in Africa were included in this analysis. The pooled prevalence of drug resistance mutations in Africa was 10.6%, and Central Africa had the highest prevalence of 54.9%. The highest prevalence of nucleoside reverse transcriptase inhibitor mutations was in the west (55.3%) and central (54.8%) areas; nonnucleoside reverse transcriptase inhibitor mutations were highest in East Africa (57.0%) and protease inhibitors mutations highest in Southern Africa (16.3%). The major nucleoside reverse transcriptase inhibitor mutation in all four African regions was M184V. Major nonnucleoside reverse transcriptase inhibitor as well as protease inhibitor mutations varied by region. The prevalence of drug resistance has remained low in several African countries although the emergence of drug resistance mutations varied across countries. Continued surveillance of antiretroviral therapy resistance remains crucial in gauging the effectiveness of country antiretroviral therapy programs and strategizing on effective and affordable strategies for successful treatment.

  8. Antimicrobial drug resistance in Staphylococcus aureus isolated from cattle in Brazil.

    Science.gov (United States)

    Pereira, M S; Siqueira-Júnior, J P

    1995-06-01

    Isolates of Staphylococcus aureus obtained from apparently healthy cattle in the State of Paraiba, Brazil were characterized in relation to resistance to 21 antimicrobial agents. Among the 46 isolates obtained, resistance to penicillin was most frequent, followed by resistance to cadmium, streptomycin, arsenate, tetracycline, mercury, erythromycin and kanamycin/neomycin. All isolates were susceptible to fusidic acid, ethidium bromide, cetrimide, chloramphenicol, benzalkonium chloride, doxycycline, gentamicin, methicillin, minocycline, novobiocin, rifamycin, tylosin and vancomycin. Only six isolates were susceptible to all the drugs tested. With respect to the antibiotics, multi-resistant isolates were uncommon. These results are probably a consequence of the peculiarities of local drug usage pressures. In relation to metal ions, resistance to mercury was rare while resistance to arsenate was relatively frequent, which contrasts with the situation for human Staph. aureus strains. After treatment with ethidium bromide, elimination of resistance to penicillin, tetracycline, streptomycin, erythromycin and cadmium was observed, which was consistent with the genetic determinants being plasmid-borne.

  9. Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases.

    Science.gov (United States)

    Sarafianos, Stefan G; Das, Kalyan; Hughes, Stephen H; Arnold, Eddy

    2004-12-01

    HIV undergoes rapid genetic variation; this variation is caused primarily by the enormous number of viruses produced daily in an infected individual. Because of this variation, HIV presents a moving target for drug and vaccine development. The variation within individuals has led to the generation of diverse HIV-1 subtypes, which further complicates the development of effective drugs and vaccines. In general, it is more difficult to hit a moving target than a stationary target. Two broad strategies for hitting a moving target (in this case, HIV replication) are to understand the movement and to aim at the portions that move the least. In the case of anti-HIV drug development, the first option can be addressed by understanding the mechanism(s) of drug resistance and developing drugs that effectively inhibit mutant viruses. The second can be addressed by designing drugs that interact with portions of the viral machinery that are evolutionarily conserved, such as enzyme active sites.

  10. Efflux drug transporters at the forefront of antimicrobial resistance

    OpenAIRE

    Rahman, Tahmina; Yarnall, Benjamin; Doyle, Declan A.

    2017-01-01

    Bacterial antibiotic resistance is rapidly becoming a major world health consideration. To combat antibiotics, microorganisms employ their pre-existing defence mechanisms that existed long before man’s discovery of antibiotics. Bacteria utilise levels of protection that range from gene upregulation, mutations, adaptive resistance, and production of resistant phenotypes (persisters) to communal behaviour, as in swarming and the ultimate defence of a biofilm. A major part of all of these respon...

  11. [Detection of CRISPR and its relationship to drug resistance in Shigella].

    Science.gov (United States)

    Wang, Linlin; Wang, Yingfang; Duan, Guangcai; Xue, Zerun; Guo, Xiangjiao; Wang, Pengfei; Xi, Yuanlin; Yang, Haiyan

    2015-04-04

    To detect clustered regularly interspaced short palindromic repeats (CRISPR) in Shigella, and to analyze its relationship to drug resistance. Four pairs of primers were used for the detection of convincing CRISPR structures CRISPR-S2 and CRISPR-S4, questionable CRISPR structures CRISPR-S1 and CRISPR-S3 in 60 Shigella strains. All primers were designed using sequences in CRISPR database. CRISPR Finder was used to analyze CRISPR and susceptibilities of Shigella strains were tested by agar diffusion method. Furthermore, we analyzed the relationship between drug resistance and CRISPR-S4. The positive rate of convincing CRISPR structures was 95%. The four CRISPR loci formed 12 spectral patterns (A-L), all of which contained convincing CRISPR structures except type K. We found one new repeat and 12 new spacers. The multi-drug resistance rate was 53. 33% . We found no significant difference between CRISPR-S4 and drug resistant. However, the repeat sequence of CRISPR-S4 in multi- or TE-resistance strains was mainly R4.1 with AC deletions in the 3' end, and the spacer sequences of CRISPR-S4 in multi-drug resistance strains were mainly Sp5.1, Sp6.1 and Sp7. CRISPR was common in Shigella. Variations df repeat sequences and diversities of spacer sequences might be related to drug resistance in Shigella.

  12. Drug resistance pattern of M. tuberculosis in category II treatment failure pulmonary tuberculosis patients

    Directory of Open Access Journals (Sweden)

    Fahmida Rahman

    2013-01-01

    Full Text Available This study was designed to determine the extent of drug resistance of M. tuberculosis (MTB isolated from category II treatment failure pulmonary tuberculosis (PTB patients. A total of 100 Ziehl-Neelsen (Z-N smear positive category II failure PTB patients were included in this study. Sputum culture was done in Lowenstein-Jensen (L-J media. Conventional proportion method on Lowenstein-Jensen (L-J media was used to determine the drug susceptibility of M. tuberculosis to isoniazid (INH, rifampicin (RMP, ofloxacin (OFX and kanamycin (KA. Out of 100 sputum samples, a total of 87 samples were positive by culture. Drug susceptibility test (DST revealed that 82 (94.25% isolates were resistant to one or more anti -TB drugs. Resistance to isoniazide (INH, rifampicin (RMP, ofloxacin (OFX and kanamycin (KA was 94.25%, 82.75%, 29.90% and 3.45% respectively. Among these isolates, 79.31% and 3.45% isolates were multi-drug resistant (MDR and extended drug resistant (XDR M. tuberculosis respectively. High rate of anti-tubercular drug resistance was observed among the category II treatment failure TB patients. Ibrahim Med. Coll. J. 2013; 7(1: 9-11

  13. Setting priorities for a research agenda to combat drug-resistant tuberculosis in children.

    Science.gov (United States)

    Velayutham, B; Nair, D; Ramalingam, S; Perez-Velez, C M; Becerra, M C; Swaminathan, S

    2015-12-21

    Numerous knowledge gaps hamper the prevention and treatment of childhood drug-resistant tuberculosis (TB). Identifying research priorities is vital to inform and develop strategies to address this neglected problem. To systematically identify and rank research priorities in childhood drug-resistant TB. Adapting the Child Health and Nutrition Research Initiative (CHNRI) methodology, we compiled 53 research questions in four research areas, then classified the questions into three research types. We invited experts in childhood drug-resistant TB to score these questions through an online survey. A total of 81 respondents participated in the survey. The top-ranked research question was to identify the best combination of existing diagnostic tools for early diagnosis. Highly ranked treatment-related questions centred on the reasons for and interventions to improve treatment outcomes, adverse effects of drugs and optimal treatment duration. The prevalence of drug-resistant TB was the highest-ranked question in the epidemiology area. The development type questions that ranked highest focused on interventions for optimal diagnosis, treatment and modalities for treatment delivery. This is the first effort to identify and rank research priorities for childhood drug-resistant TB. The result is a resource to guide research to improve prevention and treatment of drug-resistant TB in children.

  14. Multiple Measures of Outcome in Assessing a Prison-Based Drug Treatment Program

    Science.gov (United States)

    Prendergast, Michael L.; Hall, Elizabeth A.; Wexler, Harry K.

    2003-01-01

    Evaluations of prison-based drug treatment programs typically focus on one or two dichotomous outcome variables related to recidivism. In contrast, this paper uses multiple measures of outcomes related to crime and drug use to examine the impact of prison treatment. Crime variables included self-report data of time to first illegal activity,…

  15. Whole animal automated platform for drug discovery against multi-drug resistant Staphylococcus aureus.

    Directory of Open Access Journals (Sweden)

    Rajmohan Rajamuthiah

    Full Text Available Staphylococcus aureus, the leading cause of hospital-acquired infections in the United States, is also pathogenic to the model nematode Caenorhabditis elegans. The C. elegans-S. aureus infection model was previously carried out on solid agar plates where the bacteriovorous C. elegans feeds on a lawn of S. aureus. However, agar-based assays are not amenable to large scale screens for antibacterial compounds. We have developed a high throughput liquid screening assay that uses robotic instrumentation to dispense a precise amount of methicillin resistant S. aureus (MRSA and worms in 384-well assay plates, followed by automated microscopy and image analysis. In validation of the liquid assay, an MRSA cell wall defective mutant, MW2ΔtarO, which is attenuated for killing in the agar-based assay, was found to be less virulent in the liquid assay. This robust assay with a Z'-factor consistently greater than 0.5 was utilized to screen the Biomol 4 compound library consisting of 640 small molecules with well characterized bioactivities. As proof of principle, 27 of the 30 clinically used antibiotics present in the library conferred increased C. elegans survival and were identified as hits in the screen. Surprisingly, the antihelminthic drug closantel was also identified as a hit in the screen. In further studies, we confirmed the anti-staphylococcal activity of closantel against vancomycin-resistant S. aureus isolates and other Gram-positive bacteria. The liquid C. elegans-S. aureus assay described here allows screening for anti-staphylococcal compounds that are not toxic to the host.

  16. Whole animal automated platform for drug discovery against multi-drug resistant Staphylococcus aureus.

    Science.gov (United States)

    Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Jayamani, Elamparithi; Kim, Younghoon; Larkins-Ford, Jonah; Conery, Annie; Ausubel, Frederick M; Mylonakis, Eleftherios

    2014-01-01

    Staphylococcus aureus, the leading cause of hospital-acquired infections in the United States, is also pathogenic to the model nematode Caenorhabditis elegans. The C. elegans-S. aureus infection model was previously carried out on solid agar plates where the bacteriovorous C. elegans feeds on a lawn of S. aureus. However, agar-based assays are not amenable to large scale screens for antibacterial compounds. We have developed a high throughput liquid screening assay that uses robotic instrumentation to dispense a precise amount of methicillin resistant S. aureus (MRSA) and worms in 384-well assay plates, followed by automated microscopy and image analysis. In validation of the liquid assay, an MRSA cell wall defective mutant, MW2ΔtarO, which is attenuated for killing in the agar-based assay, was found to be less virulent in the liquid assay. This robust assay with a Z'-factor consistently greater than 0.5 was utilized to screen the Biomol 4 compound library consisting of 640 small molecules with well characterized bioactivities. As proof of principle, 27 of the 30 clinically used antibiotics present in the library conferred increased C. elegans survival and were identified as hits in the screen. Surprisingly, the antihelminthic drug closantel was also identified as a hit in the screen. In further studies, we confirmed the anti-staphylococcal activity of closantel against vancomycin-resistant S. aureus isolates and other Gram-positive bacteria. The liquid C. elegans-S. aureus assay described here allows screening for anti-staphylococcal compounds that are not toxic to the host.

  17. Hypoxia-induced cytotoxic drug resistance in osteosarcoma is independent of HIF-1Alpha.

    Directory of Open Access Journals (Sweden)

    Jennifer Adamski

    Full Text Available Survival rates from childhood cancer have improved dramatically in the last 40 years, such that over 80% of children are now cured. However in certain subgroups, including metastatic osteosarcoma, survival has remained stubbornly poor, despite dose intensive multi-agent chemotherapy regimens, and new therapeutic approaches are needed. Hypoxia is common in adult solid tumours and is associated with treatment resistance and poorer outcome. Hypoxia induces chemotherapy resistance in paediatric tumours including neuroblastoma, rhabdomyosarcoma and Ewing's sarcoma, in vitro, and this drug resistance is dependent on the oxygen-regulated transcription factor hypoxia inducible factor-1 (HIF-1. In this study the effects of hypoxia on the response of the osteosarcoma cell lines 791T, HOS and U2OS to the clinically relevant cytotoxics cisplatin, doxorubicin and etoposide were evaluated. Significant hypoxia-induced resistance to all three agents was seen in all three cell lines and hypoxia significantly reduced drug-induced apoptosis. Hypoxia also attenuated drug-induced activation of p53 in the p53 wild-type U2OS osteosarcoma cells. Drug resistance was not induced by HIF-1α stabilisation in normoxia by cobalt chloride nor reversed by the suppression of HIF-1α in hypoxia by shRNAi, siRNA, dominant negative HIF or inhibition with the small molecule NSC-134754, strongly suggesting that hypoxia-induced drug resistance in osteosarcoma cells is independent of HIF-1α. Inhibition of the phosphoinositide 3-kinase (PI3K pathway using the inhibitor PI-103 did not reverse hypoxia-induced drug resistance, suggesting the hypoxic activation of Akt in osteosarcoma cells does not play a significant role in hypoxia-induced drug resistance. Targeting hypoxia is an exciting prospect to improve current anti-cancer therapy and combat drug resistance. Significant hypoxia-induced drug resistance in osteosarcoma cells highlights the potential importance of hypoxia as a target

  18. Multiple Breed Validation of Five QTL Affecting Mastitis Resistance

    DEFF Research Database (Denmark)

    Vilkki, Johanna; Dolezal, Marlies A; Sahana, Goutam

    Ayrshire (SCC, clinical mastitis, udder conformation) and Valdostana (SCC, milk bacteriological results). Furthermore, association analysis across the regions was performed with a linear mixed model using imputed sequence for 845 Danish Red sires with nine mastitis phenotypes. Associations in five regions......Mastitis is a major animal welfare problem and the most costly disease in dairy cattle worldwide. Within the EU FP7 Quantomics project, we aimed at validating quantitative trait loci affecting mastitis resistance at the molecular level. Eight chromosome regions with major effects on resistance...... to mastitis were identified by GWAS using high-density SNP array in the Finnish Ayrshire and Brown Swiss breeds. These targeted regions were analyzed for polymorphisms from 20X whole-genome sequences of 38 ancestral bulls of the two populations. A set of 384 SNPs were selected based on their ranking from...

  19. Re-sensitizing drug-resistant bacteria to antibiotics by designing Antisense Therapeutics

    Science.gov (United States)

    Courtney, Colleen; Chatterjee, Anushree

    2014-03-01

    ``Super-bugs'' or ``multi-drug resistant organisms'' are a serious international health problem, with devastating consequences to patient health care. The Center for Disease Control has identified antibiotic resistance as one of the world's most pressing public health problems as a significant fraction of bacterial infections contracted are drug resistant. Typically, antibiotic resistance is encoded by ``resistance-genes'' which express proteins that carryout the resistance causing functions inside the bacterium. We present a RNA based therapeutic strategy for designing antimicrobials capable of re-sensitizing resistant bacteria to antibiotics by targeting labile regions of messenger RNAs encoding for resistance-causing proteins. We perform in silico RNA secondary structure modeling to identify labile target regions in an mRNA of interest. A synthetic biology approach is then used to administer antisense nucleic acids to our model system of ampicillin resistant Escherichia coli. Our results show a prolonged lag phase and decrease in viability of drug-resistant E. colitreated with antisense molecules. The antisense strategy can be applied to alter expression of other genes in antibiotic resistance pathways or other pathways of interest.

  20. Drug resistance in Mycobacterium leprae from patients with leprosy in China.

    Science.gov (United States)

    Liu, D; Zhang, Q; Sun, Y; Wang, C; Zhang, Y; Fu, X; Chen, M; Zhou, G; Yu, X; Wang, J; Liu, H; Zhang, F

    2015-12-01

    Previous studies of drug resistance have shown that mutations in the drug resistance-determining region (DRDR) in the Folp1, RpoB and GyrA genes of Mycobacterium leprae are responsible for resistance to dapsone, rifampin and ofloxacin, respectively. To investigate the prevalence of mutations in genes associated with drug resistance in M. leprae isolates from patients with leprosy in Shandong Province. The DRDR in the FolP1, RpoB and GyrA genes was analysed by direct sequencing of the PCR product from 85 isolates of M. leprae sampled from patients with leprosy in Shandong, China. Sequencing results were obtained for FolP1, RpoB and GyrA in 67, 57 and 81 of the 85 samples, with mutation rates of 1.5% (1/67), 8.8% 5/57 and 25.9% (21/81). Three multidrug-resistant samples were found among the new cases: one had a mutation in both Folp1 and RpoB, while the other two had a mutation in both RpoB and GyrA. Primary resistance appears to be to either single drugs or combinations of two drugs. The resistance rate to dapsone seems to be low. To our knowledge, this is the first case of multidrug-resistant M. leprae from China. © 2015 British Association of Dermatologists.

  1. Identifying co-targets to fight drug resistance based on a random walk model

    Directory of Open Access Journals (Sweden)

    Chen Liang-Chun

    2012-01-01

    Full Text Available Abstract Background Drug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs. Results We use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH-related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes. Conclusions With gene expression and