A5025165126- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Antibiotics Pharmacokinetics and Efficacy
- Pneumonia and Respiratory Infections
- Antibiotic Resistance in Bacteria
- Pneumocystis jirovecii pneumonia detection and treatment
- Antifungal resistance and susceptibility
- Cancer therapeutics and mechanisms
- Quinazolinone synthesis and applications
- Infectious Diseases and Tuberculosis
- Infectious Diseases and Mycology
- Fungal Infections and Studies
- Biosimilars and Bioanalytical Methods
- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Diagnosis and treatment of tuberculosis
- Phenothiazines and Benzothiazines Synthesis and Activities
- Antimicrobial Resistance in Staphylococcus
- Drug-Induced Hepatotoxicity and Protection
- HIV/AIDS drug development and treatment
- Infective Endocarditis Diagnosis and Management
- Parasitic Infections and Diagnostics
- Parasites and Host Interactions
- Pericarditis and Cardiac Tamponade
- Helminth infection and control
Baylor University Medical Center
2015-2023
University of Cape Town
2014-2022
The University of Texas Health Science Center at Tyler
2021
Texas Tech University Health Sciences Center
2019-2020
Texas Tech University
2019-2020
University of Virginia
2020
Lung Institute
2018
National Center for Infectious Diseases
2018
South African Tuberculosis Vaccine Initiative
2018
Baylor University
2015-2017
Since the advent of modern era antimicrobial chemotherapy in 1930s, animal infection models have allowed for vivo evaluation agents treatment experimentally induced infection. Today, pharmacokinetic-pharmacodynamic (PK-PD) serve as a cornerstone preclinical assessment process antibacterial and dose dosing interval selection, decision support setting vitro susceptibility breakpoints, and, finally, meaning resistance. Over past 15 years, considerable PK-PD data been derived from infected...
Based on a hollow-fiber system model of tuberculosis, we hypothesize that microbiologic failure and acquired drug resistance are primarily driven by low concentrations result from pharmacokinetic variability.Clinical data were prospectively collected 142 tuberculosis patients in Western Cape, South Africa. Compartmental parameters isoniazid, rifampin, pyrazinamide identified for each patient. Patients then followed up to 2 years. Classification regression tree analysis was used identify rank...
ABSTRACT Rifampin is a cornerstone of modern antituberculosis therapy. However, rifampin's half-life 3 h believed to limit its utility for intermittent therapy, so new congeners with long half-lives are being developed. Using an in vitro pharmacokinetic-pharmacodynamic model tuberculosis, we examined the relationships between rifampin exposure, microbial killing log-phase-growth Mycobacterium tuberculosis , and suppression resistance. Rifampin's was linked area under concentration-time...
(See the editorial commentary by Dartois, on pages 1827–9.) Background. It is believed that nonadherence proximate cause of multidrug-resistant tuberculosis (MDR-tuberculosis) emergence. The level associated with emergence MDR-tuberculosis unknown. Performance a randomized controlled trial in which some patients are to would be unethical; therefore, other study designs should utilized. Methods. We performed hollow fiber studies for both bactericidal and sterilizing effect, inoculum spiked...
Moxifloxacin is a quinolone antimicrobial that has potent activity against Mycobacterium tuberculosis. To optimize moxifloxacin dose and regimen, pharmacodynamic antibiotic-exposure targets associated with maximal microbial kill complete suppression of drug resistance in M. tuberculosis must be identified.We used novel vitro infection model which we exposed to pharmacokinetic half-life decline similar encountered humans. Data obtained from this were mathematically modeled, the drug-exposure...
There are currently renewed efforts to develop drugs that could shorten the duration of antituberculosis therapy. This is best achieved by optimizing sterilizing effect. However, current pathway for development new molecules with potential have a effect inefficient. We designed an in vitro pharmacokinetic-pharmacodynamic model which Mycobacterium tuberculosis replicating slowly at pH 5.8 was exposed pyrazinamide use concentration-time profiles encountered patients. The rates and time...
We hypothesize that low-level efflux pump expression is the first step in development of high-level drug resistance mycobacteria. performed 28-day azithromycin dose-effect and dose-scheduling studies our hollow-fiber model disseminated Mycobacterium avium-M. intracellulare complex. Both microbial kill emergence were most closely linked to within-macrophage area under concentration-time curve (AUC)/MIC ratio. Quantitative PCR revealed subtherapeutic exposures over 3 days led a 56-fold...
Isoniazid, administered as part of combination antituberculosis therapy, is responsible for most the early bactericidal activity (EBA) regimen. However, emergence Mycobacterium tuberculosis resistance to isoniazid a major problem. We examined relationship between exposure and M. microbial kill, well resistance, in our vitro pharmacodynamic model tuberculosis. Since single-nucleotide polymorphisms N-acetyltransferase-2 gene lead two different clearances from serum patients, we simulated...
Acquired resistance is an important driver of multidrug-resistant tuberculosis (TB), even with good treatment adherence. However, exactly what initiates the and how it arises remain poorly understood.To identify relationship between drug concentrations susceptibility readouts (minimum inhibitory [MICs]) in TB cavity.We recruited patients medically incurable who were undergoing therapeutic lung resection while on a cocktail second-line anti-TB drugs. On day surgery, antibiotic measured blood...
Arguably, one of the most common and consequential laboratory tests performed in world is Mycobacterium tuberculosis susceptibility testing. M. resistance defined by growth > or =1% a bacillary inoculum on critical concentration an antibiotic. The was chosen based inhibition =95% wild-type isolates. isoniazid either 0.2 1.0 mg/liter, that rifampin pyrazinamide 100 ethambutol 5.0 fluoroquinolones mg/liter. However, relevance these concentrations to microbiologic clinical outcomes unclear....
The relationships between antituberculosis drug exposure and treatment effects on humans receiving multidrug therapy are complex nonlinear. In patients treatment, an analysis of the rate decline in sputum bacillary burden reveals two slopes. first is α-slope, which thought to reflect bactericidal effect, followed by a β-slope, sterilizing activity. We sought characterize standard first-line Fifty-four combination for pulmonary tuberculosis clinical trial had concentrations measured...
Background. Ethambutol is used for the treatment of tuberculosis in cases where there isoniazid resistance. We examined emergence drug resistance to ethambutol monotherapy pharmacokinetic-pharmacodynamic studies a hollow-fiber system.
Background. The role of drug concentrations in clinical outcomes children with tuberculosis is unclear. Target for dose optimization are unknown. Methods. Plasma measured Indian were modeled using compartmental pharmacokinetic analyses. followed until end therapy to ascertain failure or death. An ensemble artificial intelligence algorithms, including random forests, was used identify predictors outcome from among 30 clinical, laboratory, and variables. Results. Among the 143 known outcomes,...
ABSTRACT Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect dose-scheduling studies the hollow fiber system model of (HFS-TB) for effect. HFS-TB units were treated with several doses to mimic human-like intrapulmonary pharmacokinetics repetitively sampled drug concentration, total bacterial burden, linezolid-resistant subpopulations, RNA...
Levofloxacin is used for the treatment of multidrug-resistant tuberculosis; however optimal dose unknown.We hollow fiber system model tuberculosis (HFS-TB) to identify 0-24 hour area under concentration-time curve (AUC0-24) minimum inhibitory concentration (MIC) ratios associated with maximal microbial kill and suppression acquired drug resistance (ADR) Mycobacterium (Mtb). Levofloxacin-resistant isolates underwent whole-genome sequencing. Ten thousands patient Monte Carlo experiments (MCEs)...
Tuberculosis (TB) elimination requires innovative approaches. The new Global Network (GTN) aims to conduct research on key unmet therapeutic and diagnostic needs in the field of TB using multidisciplinary, multisectorial Pharmacology section within GTN detect study current knowledge gaps, test potential solutions human pharmacokinetics informed through preclinical infection systems, return those findings bedside. Moreover, this approach would allow prospective identification validation...