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829 results for “Drug resistance”
Second-line drug resistance markers as proxy indicators of sputum culture conversion for samples tested in Uganda
<p>Increased TB disease burden arises as a result of low treatment success rates stemming from the emergence of second-line drug (SLD) resistance. We aimed at determining the usefulness of SLD resistance markers as proxy indicators of time to sputum culture conversion; a renowned predictor of Tuberculosis (TB) treatment outcome, among SLD-resistant TB patients tested at the Uganda National TB Reference Laboratory (NTRL). A cross-sectional study was conducted on 72 bacteriologically confirmed SLDR TB patients with datasets including culture conversion time and second-line probe assay mutation profiles between 01/06/2017 and 31/12/2019. The data were then imported into STATA v15 for descriptive statistical analysis, Univariate cox proportional hazard model analysis and Kaplan-Meier survival curves at a 5% level of significance; p-value ≤ 0.05. Results indicate the median time was achieved at 3 (0–12) months across the studied patients. The <em>rrs</em> G1484T mutation associated with conferring drug resistance to aminoglycosides was observed to have the shortest median conversion time of 1.5 months and the longest by the <em>gryB</em> E540D at 5 months. A single mutation in the <em>gryA</em> gene locus showed higher converted proportions 70.8% (58.9–81.0) than those that had two 8.3% (3.1–17.3) or three 2.7% (0.3–10.0) mutations. We conclude that the studied second-line drug resistance markers had no statistically significant association with the time to sputum culture conversion, although increased drug resistance levels reduced the converted proportions and stressed the need to utilize molecular diagnostics data to better comprehend proxy indicators of SLD-resistant tuberculosis management.</p>
PfCRT mutations conferring piperaquine resistance in falciparum malaria shape the kinetics of quinoline drug binding and transport
<p>These data were generated to investigate the effect of point mutations in PfCRT on the kinetics of chloroquine and piperaquine binding and transport. The protein confers resistance to a range of quinoline and quinoline-like antimalarials after the acquisition of certain amino acid substitutions, which occurs as a result of improper antimalarial use. The change in prescription from chloroquine (CQ) to piperaquine (PPQ) in Southeast Asian countries led to the emergence of a ninth mutation over the PfCRT Dd2 isoform, which renders the parasites resistant to piperaquine but re-sensitizes them to chloroquine. Despite structural information, how these individual mutations influence such opposing changes in the parasite's susceptibility to the aforementioned drugs remains unknown. Here, we show by biochemical studies that any of the piperaquine resistance-conferring mutations H97Y, F145I, M343L or G353V, either reduce the affinity of PfCRT Dd2 for CQ (Km) or reduce the efficiency of the transport cycle (Vmax). In parallel, they increase the Vmax, reduce the Km, or do both, in the case of PPQ transport. We also probed the binding cavity of PfCRT Dd2 and that of PfCRT Dd2_F145I, and found that it can readily bind both CQ and PPQ simultaneously, in a partial noncompetitive mechanism. We confirmed the latter finding through molecular docking and molecular dynamics simulations, describing for the first time the binding sites for both drugs in the cavity of PfCRT Dd2. With this, we found that the pocket where CQ binds seems to require an aromatic side chain, which is normally provided by F145, or by Y97 in the PPQ resistance-conferring H97Y mutant. Lastly, we generated an unnatural double mutant carrying both the H97Y and the F145I mutations. The engineered transporter displayed non-Michaelis-Menten kinetics both for CQ and PPQ transport and instead revealed sigmoidal kinetics, typical of proteins that bind substrate cooperatively. We thus provide new insights into the organization of the substrate-binding cavity of PfCRT and into the evolution of PfCRT.</p>
Data from: Fast drug rotation reduces bacterial resistance evolution in a microcosm experiment
<p><span>Drug rotation (cycling), in which multiple drugs are administrated alternatively, has the potential for limiting resistance evolution in pathogens. The frequency of drug alternation could be a major factor to determine the effectiveness of drug rotation. Drug rotation practices often have low frequency of drug alternation, with an expectation of resistance reversion. Here we, based on evolutionary rescue and compensatory evolution theories, suggest that fast drug rotation can limit resistance evolution in the first place. This is because fast drug rotation would give little time for the evolutionarily rescued populations to recover in population size and genetic diversity, and thus decrease the chance of future evolutionary rescue under alternate environmental stresses. We experimentally tested this hypothesis using the bacterium <em>Pseudomonas</em> <em>fluorescens</em> and two antibiotics (chloramphenicol and rifampin). Increasing drug rotation frequency reduced the chance of evolutionary rescue, and most of the final surviving bacterial populations are resistant to both drugs. Drug resistance incurred significant fitness costs, which did not differ among the drug treatment histories. A link between population sizes during the early stages of drug treatment and the end-point fates of populations (extinction versus survival) suggested that population size recovery and compensatory evolution before drug shift increase the chance of population survival. Our results therefore advocate fast drug rotation as a promising approach to reduce bacterial resistance evolution, which in particular could be a substitute for drug mixing when the latter has safety risks.</span></p>
Bacterial mediated green synthesis of silver nanoparticles and their antibacterial and antifungal activities against drug-resistant pathogens
<p>In the healthcare sector, the production of bioactive silver nanoparticles (AgNPs) with antimicrobial properties is of great importance. In this study, a novel bacterial strain, <em>Paenibacillus</em> sp. MAHUQ-63, was identified as a potential candidate for facile and rapid biosynthesis of AgNPs. The synthesized AgNPs were used to control the growth of human pathogens, <em>Salmonella</em> Enteritidis and <em>Candida</em> <em>albicans</em>. The bacterial culture supernatant was utilized to synthesize the nanoparticles. FE-TEM examination showed spherical-shaped nanoparticles with 15 to 55 nm in size. FTIR analysis identified various functional groups. The synthesized AgNPs demonstrated remarkable activity against <em>S</em>. Enteritidis and <em>C. albicans</em>. The zone of inhibition (ZOI) for 100 µL (0.5 mg/mL) of AgNPs against <em>S</em>. Enteritidis and <em>Candida</em> <em>albicans</em> were 18.0 ± 1.0 and 19.5 ± 1.3 mm, respectively. The minimum inhibitory concentrations (MICs) were 25.0 and 12.5 μg/mL against <em>S</em>. Enteritidis and <em>Candida albicans</em>, respectively. Additionally, the minimum bactericidal concentrations (MBC) were 25.0 μg/mL against both pathogenic microbes. The FE-SEM analysis showed that the treatment of AgNPs caused morphological and structural damage to both <em>S</em>. Enteritidis and <em>Candida albicans</em>. Therefore, these AgNPs can be used as a new and effective antimicrobial agent.</p>
Study to Test the Efficacy and Safety of Padsevonil as Adjunctive Treatment of Focal-onset Seizures in Adults With Drug-resistant Epilepsy
ClinicalTrials.gov study NCT03373383. IPD Sharing: YES. Countries: 19. Publications: 2.
TMC207-TiDP13-C208: Anti-bacterial Activity, Safety, and Tolerability of TMC207 in Participants With Multi-drug Resistant Mycobacterium Tuberculosis (MDR-TB).
ClinicalTrials.gov study NCT00449644. IPD Sharing: Not stated. Countries: 8. Publications: 5.
Phase I Safety Study of the Drug MM-121 in Patients With Advanced Solid Tumors Resisting Ordinary Treatment
ClinicalTrials.gov study NCT00734305. IPD Sharing: NO. Countries: 1. Publications: 1.
Evaluation of 8 Weeks of Treatment With the Combination of Moxifloxacin, PA-824 and Pyrazinamide in Patients With Drug Sensitive and Multi Drug-Resistant Pulmonary Tuberculosis (TB) (NC-002)
ClinicalTrials.gov study NCT01498419. IPD Sharing: Not stated. Countries: 2. Publications: 1.
A Phase 2 to Evaluate the Efficacy, Safety and Tolerability of Combinations of Bedaquiline, Moxifloxacin, PA-824 and Pyrazinamide in Adult Subjects With Drug-Sensitive or Multi Drug-Resistant Pulmonar
ClinicalTrials.gov study NCT02193776. IPD Sharing: Not stated. Countries: 3. Publications: 1.
Trial to Evaluate the Efficacy, Safety and Tolerability of BPaMZ in Drug-Sensitive (DS-TB) Adult Patients and Drug-Resistant (DR-TB) Adult Patients
ClinicalTrials.gov study NCT03338621. IPD Sharing: YES. Countries: 8. Publications: 1.
Various Doses and Durations of Linezolid Plus Bedaquiline & Pretomanid in Participants With Drug Resistant Tuberculosis
ClinicalTrials.gov study NCT03086486. IPD Sharing: NO. Countries: 4. Publications: 1.
Evaluating the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and Delamanid, Alone and in Combination, For Drug-Resistant Pulmonary Tuberculosis
ClinicalTrials.gov study NCT02583048. IPD Sharing: Not stated. Countries: 2. Publications: 2.
Linezolid to Treat Extensively-Drug Resistant Tuberculosis
ClinicalTrials.gov study NCT00727844. IPD Sharing: Not stated. Countries: 1. Publications: 4.
Testing the Combination of Cediranib and Olaparib in Comparison to Each Drug Alone or Other Chemotherapy in Recurrent Platinum-Resistant Ovarian Cancer
ClinicalTrials.gov study NCT02502266. IPD Sharing: Not stated. Countries: 5. Publications: 1.
Reducing the Incidence of Nevirapine Resistance Mutations in Pregnant HIV Infected Women Who Receive Anti-HIV Drugs Prior to and After Giving Birth
ClinicalTrials.gov study NCT00109590. IPD Sharing: Not stated. Countries: 1. Publications: 6.
Tuberculosis Research of INA-RESPOND On Drug Resistance
ClinicalTrials.gov study NCT02758236. IPD Sharing: NO. Countries: 1. Publications: 1.
A Study to Test the Efficacy and Safety of Padsevonil as Treatment of Focal-onset Seizures in Adult Subjects With Drug-resistant Epilepsy
ClinicalTrials.gov study NCT03739840. IPD Sharing: YES. Countries: 28. Publications: 1.
Ibalizumab Plus Optimized Background Regimen in Patient With Multi-Drug Resistant HIV
ClinicalTrials.gov study NCT02475629. IPD Sharing: Not stated. Countries: 3. Publications: 1.
Enhanced Room Cleaning in Intensive Care Units to Reduce Gown and Glove Contamination With Multi-drug-resistant Bacteria
ClinicalTrials.gov study NCT01481935. IPD Sharing: Not stated. Countries: 1. Publications: 8.
Efficacy and Safety of Radiofrequency Renal Denervation in Drug Resistant Hypertension
ClinicalTrials.gov study NCT01499810. IPD Sharing: UNDECIDED. Countries: 1. Publications: 1.
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OpenNeuro
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