ArticleClinical infectious diseases : an official publication of the Infectious Diseases Society of America2018
Ethionamide Pharmacokinetics/Pharmacodynamics-derived Dose, the Role of MICs in Clinical Outcome, and the Resistance Arrow of Time in Multidrug-resistant Tuberculosis.
Article in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it.
- d-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2018Pooled it
- Interaction of a porphyrinic cage with ethionamide: a spectroscopic and computational study.Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology · 2026Article
- Preclinical pharmacokinetics/pharmacodynamics studies defining the role of ethambutol inAntimicrobial agents and chemotherapy · 2026Article
- Preclinical evaluation of epetraborole in the hollow fibre system model of Mycobacterium abscessus lung disease.The Journal of antimicrobial chemotherapy · 2026Article
- Epetraborole pharmacokinetics/pharmacodynamics in the hollow fiber system model ofAntimicrobial agents and chemotherapy · 2025Article
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- Pharmacokinetic-Pharmacodynamic (PK-PD) Analysis of Second-Line Anti-Tubercular Drugs in Indian Children with Multi-Drug Resistance.Indian journal of pediatrics · 2025Article
- Imipenem Pharmacokinetics/Pharmacodynamics in Preclinical Hollow Fiber Model, Dose Finding in Virtual Patients, and Clinical Evidence of Efficacy for Mycobacterium abscessus Lung Disease.The Journal of infectious diseases · 2025Article
- Exploring the Potential of Pyridine Carboxylic Acid Isomers to Discover New Enzyme Inhibitors.Drug design, development and therapy · 2025Review
- Therapeutic drug monitoring in tuberculosis.European journal of clinical pharmacology · 2024Review
- Article
- Determining the Delamanid Pharmacokinetics/Pharmacodynamics Susceptibility Breakpoint Using Monte Carlo Experiments.Antimicrobial agents and chemotherapy · 2023Article
- Hollow-fibre system model of tuberculosis reproducibility and performance specifications for best practice in drug and combination therapy development.The Journal of antimicrobial chemotherapy · 2023Article
- Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2023Article
- Pharmacokinetics of Antimicrobials in Children with Emphasis on Challenges Faced by Low and Middle Income Countries, a Clinical Review.Antibiotics (Basel, Switzerland) · 2022Review
- Prothionamide Dose Optimization Using Population Pharmacokinetics for Multidrug-Resistant Tuberculosis Patients.Antimicrobial agents and chemotherapy · 2022Article
- Drug exposure and susceptibility of second-line drugs correlate with treatment response in patients with multidrug-resistant tuberculosis: a multicentre prospective cohort study in China.The European respiratory journal · 2022Article
- Molecular Determinants of Ethionamide Resistance in Clinical Isolates ofAntibiotics (Basel, Switzerland) · 2022Article
- Minocycline intra-bacterial pharmacokinetic hysteresis as a basis for pharmacologic memory and a backbone for once-a-week pan-tuberculosis therapy.Frontiers in pharmacology · 2022Article
- Pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs: An evaluation ofFrontiers in pharmacology · 2022Review
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9 authors.
Funding
Abstract
Background: Ethionamide is used to treat multidrug-resistant tuberculosis (MDR-TB). The antimicrobial pharmacokinetics/pharmacodynamics, the contribution of ethionamide to the multidrug regimen, and events that lead to acquired drug resistance (ADR) are unclear. Methods: We performed a multidose hollow fiber system model of tuberculosis (HFS-TB) study to identify the 0-24 hour area under the concentration-time curve (AUC0-24) to minimum inhibitory concentration (MIC) ratios that achieved maximal kill and ADR suppression, defined as target exposures. Ethionamide-resistant isolates underwent whole-genome and targeted Sanger sequencing. We utilized Monte Carlo experiments (MCEs) to identify ethionamide doses that would achieve the target exposures in 10000 patients with pulmonary tuberculosis. We also identified predictors of time-to-sputum conversion in Tanzanian patients on ethionamide- and levofloxacin-based regimens using multivariate adaptive regression splines (MARS). Results: An AUC0-24/MIC >56.2 was identified as the target exposure in the HFS-TB. Early efflux pump induction to ethionamide monotherapy led to simultaneous ethambutol and isoniazid ADR, which abrogated microbial kill of an isoniazid-ethambutol-ethionamide regimen. Genome sequencing of isolates that arose during ethionamide monotherapy revealed mutations in both ethA and embA. In MCEs, 20 mg/kg/day achieved the AUC0-24/MIC >56.2 in >95% of patients, provided the Sensititre assay MIC was <2.5 mg/L. In the clinic, MARS revealed that ethionamide Sensititre MIC had linear negative relationships with time-to-sputum conversion until an MIC of 2.5 mg/L, above which patients with MDR-TB failed combination therapy. Conclusions: Ethionamide is an important contributor to MDR-TB treatment regimens, at Sensititre MIC <2.5 mg/L. Suboptimal ethionamide exposures led to efflux pump-mediated ADR.
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