Determination of MIC Breakpoints for Second-Line Drugs Associated with Clinical Outcomes in Multidrug-Resistant Tuberculosis Treatment in China

Abstract

Our study aims to identify the clinical breakpoints (CBPs) of second-line drugs (SLDs) above which standard therapy fails in order to improve multidrug-resistant tuberculosis (MDR-TB) treatment. MICs of SLDs were determined for M. tuberculosis isolates cultured from 207 MDR-TB patients in a prospective cohort study in China between January 2010 and December 2012. Classification and regression tree (CART) analysis was used to identify the CBPs predictive of treatment outcome. Of the 207 MDR-TB isolates included in the present study, the proportion of isolates above the critical concentration recommended by WHO ranged from 5.3% in pyrazinamide to 62.8% in amikacin. By selecting pyrazinamide as the primary node (CBP, 18.75 mg/liter), 72.1% of sputum culture conversions at month four could be predicted. As for treatment outcome, pyrazinamide (CBP, 37.5 mg/liter) was selected as the primary node to predict 89% of the treatment success, followed by ofloxacin (CBP, 3 mg/liter), improving the predictive capacity of the primary node by 10.6%. Adjusted by identified confounders, the CART-derived pyrazinamide CBP remained the strongest predictor in the model of treatment outcome. Our findings indicate that the critical breakpoints of some second-line drugs and PZA need to be reconsidered in order to better indicate MDR-TB treatment outcome.

FIG 1

MIC distribution of second-line drugs for M. tuberculosis isolates from 207 MDR-TB patients. The Gaussian distribution is skewed toward the right and is different from the MIC distribution summarized by EUCAST. Footnotes: a, the critical concentration of DST recommended by WHO except kanamycin, which was derived from existing literature (11); b, the suggested clinical breakpoints derived by CART analysis.

FIG 2

Variables predictive of sputum culture conversion after 4 months of treatment (A) and long-term treatment outcome (B) in 207 and 185 MDR-TB patients, respectively. MICs of second-line anti-TB drugs and confounders were examined in the classification and regression trees. In tree A, the MIC of pyrazinamide (18.75 mg/liter) was the best predictor of sputum culture conversion after 4 months of treatment. Furthermore, 75.6% of patients with a pyrazinamide MIC below the threshold were sputum negative after 4 months of treatment. In tree B, the decision nodes demonstrate that the primary node was the MIC of pyrazinamide (37.5 mg/liter), followed by the ofloxacin MIC. The MIC cutoff values that identified as important predictive factors are shown. In those who had a pyrazinamide MIC below the threshold (37.5 mg/liter), only 4.6% failed the treatment.