Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study

In a multicountry, prospective cohort treated with standardized regimens for rifampin-resistant/multidrug-resistant tuberculosis, serum pharmacokinetics and Mycobacterium tuberculosis minimum inhibitory concentrations were variable, yet parameters to certain drugs-fluoroquinolones, pyrazinamide, clofazimine-were predictive of clinical outcome. 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 (AUC(0-24)). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC(0-24)/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 AUC(0-24)/MIC exposures. Results Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC(0-24)/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21-11.56; P = .022); levofloxacin AUC(0-24)/MIC of 118.3, clofazimine AUC(0-24)/MIC of 50.5, and pyrazinamide AUC(0-24) of 379 mg x h/L were associated with faster culture conversion (HR >1.0, P < .05). Other individual drug exposures were not predictive. Clustering by AUC(0-24)/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.

Automated summary

In a multicountry, prospective cohort, serum pharmacokinetics and Mycobacterium tuberculosis minimum inhibitory concentrations were variable, yet certain drugs' parameters were predictive of clinical outcome for rifampin-resistant/multidrug-resistant tuberculosis.