ArticleAntimicrobial agents and chemotherapy2009
Pharmacokinetics-pharmacodynamics of pyrazinamide in a novel in vitro model of tuberculosis for sterilizing effect: a paradigm for faster assessment of new antituberculosis drugs.
Article in Antimicrobial agents and chemotherapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 128 papers, 2 of them syntheses that pooled it.
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Who cites it
128 citing papers in PubMed, 2 syntheses or guidelines pooled it, 192 citations in OpenAlex.
- Systematic and quantitative analyses of hollow fiber model ofMicrobiology spectrum · 2026Pooled it
- Clinical and toxicodynamic evidence that high-dose pyrazinamide is not more hepatotoxic than the low doses currently used.Antimicrobial agents and chemotherapy · 2010Pooled it
- Pharmacokinetics of Second-Line Antituberculosis Drugs in Children with Multidrug-Resistant Tuberculosis in India.Antimicrobial agents and chemotherapy · 2018Trial
- Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model.Antimicrobial agents and chemotherapy · 2017Trial
- Impact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis.Antimicrobial agents and chemotherapy · 2015Trial
- The pyrazinamide susceptibility breakpoint above which combination therapy fails.The Journal of antimicrobial chemotherapy · 2014Trial
- Sulbactam-durlobactam plus ceftriaxone dosing and novel treatment regimens forAntimicrobial agents and chemotherapy · 2026Article
- Preclinical pharmacokinetics/pharmacodynamics studies defining the role of ethambutol inAntimicrobial agents and chemotherapy · 2026Article
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- Epetraborole pharmacokinetics/pharmacodynamics in the hollow fiber system model ofAntimicrobial agents and chemotherapy · 2025Article
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- Sulbactam-Durlobactam Plus Ceftriaxone Dosing and Novel Treatment Regimens forbioRxiv : the preprint server for biology · 2025Article
- Fluoroquinolones and rifampin combination in the backdrop of heteroresistant tuberculosis.Antimicrobial agents and chemotherapy · 2025Article
- Within-host population dynamics of extensively drug-resistantEvolution, medicine, and public health · 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
- Therapeutic drug monitoring in tuberculosis.European journal of clinical pharmacology · 2024Review
- Role of therapeutic drug monitoring in the treatment of multi-drug resistant tuberculosis.Journal of clinical tuberculosis and other mycobacterial diseases · 2024Article
- Omadacycline pharmacokinetics/pharmacodynamics and efficacy against multidrug-resistantAntimicrobial agents and chemotherapy · 2024Article
- A Microtiter Plate Assay at Acidic pH to Identify Potentiators that Enhance Pyrazinamide Activity Against Mycobacterium tuberculosis.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Pharmacokinetic Considerations for Optimizing Inhaled Spray-Dried Pyrazinoic Acid Formulations.Molecular pharmaceutics · 2023Article
68 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
There are currently renewed efforts to develop drugs that could shorten the duration of antituberculosis therapy. This is best achieved by optimizing the sterilizing effect. However, the current pathway for the development of new molecules with the potential to have a sterilizing effect is inefficient. We designed an in vitro pharmacokinetic-pharmacodynamic model in which Mycobacterium tuberculosis replicating slowly at pH 5.8 was exposed to pyrazinamide by use of the concentration-time profiles encountered in patients. The sterilizing effect rates and the time to the emergence of drug resistance were examined. Daily pyrazinamide dosing for 28 days accurately achieved (i) the pyrazinamide pharmacokinetic parameters, (ii) the lack of early bactericidal activity, (iii) a sterilizing effect rate of 0.10 log(10) CFU/ml per day starting on day 6 of therapy, and (iv) a time to the emergence of resistance of the from 2 to 3 weeks of monotherapy encountered in patients with tuberculosis. Next, dose-scheduling studies were performed. The sterilizing effect was linked to the pyrazinamide ratio of the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the MIC (r(2) = 0.80 to 0.90), with 90% of the maximal effect being achieved by an AUC(0-24)/MIC of 209.08. Resistance suppression was associated with the percentage of time that the concentration persisted above the MIC (r(2) = 0.73 to 0.91). Monte Carlo simulations of 10,000 patients demonstrated that the currently recommended pyrazinamide doses (15 to 30 mg/kg of body weight/day) achieved the AUC(0-24)/MIC of 209.08 in the epithelial lining fluid of only 15.1 to 53.3% of patients. Doses of >60 mg/kg per day performed better. Our vitro model for the sterilizing effect, together with Monte Carlo simulations, can be used for the faster identification of the clinical doses that are needed to achieve a sterilizing effect and that can then be studied in clinical trials.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.