ArticleClinical infectious diseases : an official publication of the Infectious Diseases Society of America2017
Concentration-Dependent Antagonism and Culture Conversion in Pulmonary Tuberculosis.
Article in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 34 papers, 1 of them a synthesis that pooled it.
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Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Intensified Antituberculosis Therapy Regimen Containing Higher Dose Rifampin for Tuberculous Meningitis: A Systematic Review and Meta-Analysis.Frontiers in medicine · 2022Pooled it
- Assessing whether isoniazid is essential during the first 14 days of tuberculosis therapy: a phase 2a, open-label, randomised controlled trial.The Lancet. Microbe · 2020Trial
- Artificial intelligence-derived 3-Way Concentration-dependent Antagonism of Gatifloxacin, Pyrazinamide, and Rifampicin During Treatment of Pulmonary Tuberculosis.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2018Trial
- Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial.American journal of respiratory and critical care medicine · 2018Trial
- Drug Resistance and Comorbidities in the Treatment of Pulmonary Tuberculosis: A Multicenter Retrospective Cohort Study.Antibiotics (Basel, Switzerland) · 2025Article
- High-dose isoniazid for TB with low-to-moderate isoniazid resistance after 1 week of treatment.JAC-antimicrobial resistance · 2025Article
- Exploratory analysis of non-linear clozapine dose-concentration relationship in real-life hospital database.Frontiers in pharmacology · 2025Article
- Examining effective monotherapy hypothesis for TB therapy failure and resistance emergence.The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease · 2024Article
- A Nanopore Sequencing-based Pharmacogenomic Panel to Personalize Tuberculosis Drug Dosing.American journal of respiratory and critical care medicine · 2024Article
- Pharmacokinetics and pharmacodynamics of high-dose isoniazid for the treatment of rifampicin- or multidrug-resistant tuberculosis in Indonesia.The Journal of antimicrobial chemotherapy · 2024Observational
- Is the Pharmacokinetics of First-Line Anti-TB Drugs a Cause of High Mortality Rates in TB Patients Admitted to the ICU? A Non-Compartmental Pharmacokinetic Analysis.Tropical medicine and infectious disease · 2023Article
- Determining the Delamanid Pharmacokinetics/Pharmacodynamics Susceptibility Breakpoint Using Monte Carlo Experiments.Antimicrobial agents and chemotherapy · 2023Article
- Omadacycline efficacy in the hollow fibre system model of pulmonary Mycobacterium avium complex and potency at clinically attainable doses.The Journal of antimicrobial chemotherapy · 2022Article
- Article
- Intrapulmonary Pharmacokinetics of First-line Anti-tuberculosis Drugs in Malawian Patients With Tuberculosis.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2021Article
- A Model-Informed Method for the Purpose of Precision Dosing of Isoniazid in Pulmonary Tuberculosis.Clinical pharmacokinetics · 2021Article
- Repurposing Cefazolin-Avibactam for the Treatment of Drug ResistantFrontiers in pharmacology · 2021Article
- The Impact of First-Line Anti-Tubercular Drugs' Pharmacokinetics on Treatment Outcome: A Systematic Review.Clinical pharmacology : advances and applications · 2021Article
- Integrating Pharmacokinetics and Pharmacodynamics in Operational Research to End Tuberculosis.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2020Article
- Quantitative assessment of the activity of antituberculosis drugs and regimens.Expert review of anti-infective therapy · 2019Review
Corrections and comments
- Erratum issuedErratum.2017
Authors and funding
9 authors.
Funding
Abstract
backgroundThere is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion.
methodsOne hundred patients with pulmonary tuberculosis (65% human immunodeficiency virus coinfected) were intensively sampled to determine rifampicin, isoniazid, and pyrazinamide plasma concentrations after 7-8 weeks of therapy, and PK parameters determined using nonlinear mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 months, and 5-6 months. Minimum inhibitory concentrations (MICs) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 0- to 24-hour area under the curve (AUC0-24), maximum concentration (Cmax), AUC0-24/MIC, Cmax/MIC, and percentage of time that concentrations persisted above the MIC (%TMIC).
resultsTwenty-six percent of patients had Cmax of rifampicin <8 mg/L, pyrazinamide <35 mg/L, and isoniazid <3 mg/L. No relationship was found between PK exposures and 2-month culture conversion using multivariate logistic regression after adjusting for MIC. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was <4.6 mg/L and rifampicin Cmax/MIC <28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax >4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion.
conclusionsPK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.
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