Redefining Multidrug-Resistant Tuberculosis Based on Clinical Response to Combination Therapy

In tuberculosis treatment, susceptibility is defined by a critical concentration of 1.0 mg/liter for rifampin and 0.2 or 1.0 mg/liter for low-and high-level isoniazid resistance on the basis of an epidemiologic cutoff method that uses the distribution of the MICs for isolates. However, pharmacokinetics-pharmacodynamics-based clinical trial simulations suggested that the breakpoints should be 0.0625 mg/liter for rifampin and 0.0312 or 0.125 mg/liter for isoniazid. We examined the outcomes of 36 patients with drug-susceptible tuberculosis whose rifampin and isoniazid MICs were determined, whose plasma drug concentrations were also measured, and who were part of a prospective cohort study in Western Cape, South Africa. We performed classification and regression tree analysis to identify clinical and laboratory factors that predicted 2-month sputum conversion rates and long-term clinical outcomes. Poor long-term clinical outcomes were defined as microbiological failure, relapse, or death within a 2-year follow-up period. Peak drug concentrations and areas under the concentration-time curve were most predictive of outcomes and constituted the primary node, similar to our findings on the larger cohort. However, rifampin and isoniazid MICs improved the predictive capacity of the primary decision node by 20 and 17%, respectively, for these 36 patients. The rifampin MIC cutoff above which there was therapy failure was 0.125 mg/liter, while that of isoniazid was 0.0312 mg/liter; these are similar to those derived in clinical trial simulations. The critical concentrations used to define multidrug resistance for clinical decision making should take clinical outcomes into account.