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- Title
Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study.
- Authors
Heysell, Scott K; Mpagama, Stellah G; Ogarkov, Oleg B; Conaway, Mark; Ahmed, Shahriar; Zhdanova, Svetlana; Pholwat, Suporn; Alshaer, Mohammad H; Chongolo, Anna M; Mujaga, Buliga; Sariko, Margaretha; Saba, Sabrina; Rahman, S M Mazidur; Uddin, Mohammad Khaja Mafij; Suzdalnitsky, Alexey; Moiseeva, Elena; Zorkaltseva, Elena; Koshcheyev, Mikhail; Vitko, Serhiy; Mmbaga, Blandina T
- Abstract
Background Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome. Methods Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug's area under the concentration-time curve over 24 hours (AUC0–24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0–24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0–24/MIC exposures. Results Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0–24/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21–11.56; P =.022); levofloxacin AUC0–24/MIC of 118.3, clofazimine AUC0–24/MIC of 50.5, and pyrazinamide AUC0–24 of 379 mg × h/L were associated with faster culture conversion (HR >1.0, P <.05). Other individual drug exposures were not predictive. Clustering by AUC0–24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion. Conclusions Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs—fluoroquinolones, pyrazinamide, clofazimine—were predictive and should be optimized to improve clinical outcome. Clinical Trials Registration NCT03559582.
- Subjects
BANGLADESH; RUSSIA; TANZANIA; CONFIDENCE intervals; HETEROCYCLIC compounds; PYRAZINAMIDE; TREATMENT effectiveness; TREATMENT failure; ANTITUBERCULAR agents; DESCRIPTIVE statistics; DOSE-effect relationship in pharmacology; RESEARCH funding; RIFAMPIN; ODDS ratio; RECEIVER operating characteristic curves; QUINOLONE antibacterial agents; PHARMACODYNAMICS
- Publication
Clinical Infectious Diseases, 2023, Vol 76, Issue 3, p497
- ISSN
1058-4838
- Publication type
Article
- DOI
10.1093/cid/ciac511