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.