Concentration-Dependent Antagonism and Culture Conversion in Pulmonary Tuberculosis

Background. There 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. Methods. One 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 (AUC(0-24)), maximum concentration (C-max), AUC(0-24)/MIC, C-max/MIC, and percentage of time that concentrations persisted above the MIC (%T-MIC). Results. Twenty-six percent of patients had C-max 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 C-max and rifampicin C-max/MIC ratio on 2-month culture conversion. If isoniazid C-max was <4.6 mg/L and rifampicin C-max/MIC <28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid C-max >4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion. Conclusions. PK/PD analyses using MARS identified isoniazid C-max and rifampicin C-max/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.