Concentration-Dependent Antagonism and Culture Conversion in Pulmonary Tuberculosis

Abstract

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 (AUC0-24), maximum concentration (Cmax), AUC0-24/MIC, Cmax/MIC, and percentage of time that concentrations persisted above the MIC (%TMIC).

Results: Twenty-six percent of patients had Cmax 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 Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was <4.6 mg/L and rifampicin Cmax/MIC <28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax >4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion.

Conclusions: PK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.

Keywords: Mycobacterium tuberculosis; drug–drug antagonism.; minimum inhibitory concentrations; pharmacokinetic-pharmacodynamic variability; tuberculosis treatment outcomes.

Figure 1.

Histograms showing distributions of minimum inhibitory concentrations (MICs) in baseline Mycobacterium tuberculosis isolates.

Figure 2.

The pharmacokinetic (PK) measures maximum concentration (C_max), 0- to 24-hour area under the curve (AUC_0-24; with and without adjustment for minimum inhibitory concentration [MIC]) and percentage of time above the MIC (%T_MIC), stratified by culture converter status. The box-and-whisker plots show model-derived PK measures. C_max and AUC_0-24 (with and without adjustment for MIC) are plotted on the left and right y-axes. The boxes show median PK and PK/pharmacodynamic measures (and interquartile range) and the whiskers show 5th–95th percentile and illustrate considerable variability within converter (C) and nonconverter (NC) groups. The proportion of 2-month culture conversion is also shown stratified by AUC_0-24/ MIC quartile for isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA). The dotted black line indicates current recommended thresholds for C_max of 3 mg/L, 8 mg/L, and 30 mg/L for INH, RIF, and PZA, respectively. There were 2 patients in whom pyrazinamide values were missing and in whom the median AUC_0-24 and C_max values for pyrazinamide were imputed in the PK analysis. %T_MIC is the proportion of time between dosing intervals that drug concentration is above the MIC; %T_MIC(free) is the proportion of time between dosing intervals that unbound drug concentration is above MIC.

Figure 3.

V-shaped relationship between 2-month sputum conversion and isoniazid maximum concentration (C_max). The figure depicts the “mirror” basis function identified by multivariate adaptive regression splines with hinge at isoniazid C_max of 4.6 mg/L such that for patients with concentration above the threshold have an increase in probability of sputum conversion. On the other hand, for patients below the same threshold, the probability for sputum conversion increased as isoniazid C_max concentration decreased and has interactions with other factors (such as human immunodeficiency virus and rifampicin concentration).