Treatment outcomes of patients with multidrug-resistant and extensively drug-resistant tuberculosis according to drug susceptibility testing to first- and second-line drugs: an individual patient data meta-analysis.

BACKGROUND: Individualized treatment for multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis depends upon reliable and valid drug susceptibility testing (DST) for pyrazinamide, ethambutol, and second-line tuberculosis drugs. However, the reliability of these tests is uncertain, due to unresolved methodological issues. We estimated the association of DST results for pyrazinamide, ethambutol, and second-line drugs with treatment outcomes in patients with MDR tuberculosis and XDR tuberculosis. METHODS: We conducted an analysis of individual patient data assembled from 31 previously published cohort studies of patients with MDR and XDR tuberculosis. We used data on patients' clinical characteristics including DST results, treatment received, outcomes, and laboratory methods in each center. RESULTS: DST methods and treatment regimens used in different centers varied considerably. Among 8955 analyzed patients, in vitro susceptibility to individual drugs was consistently and significantly associated with higher odds of treatment success (compared with resistance to the drug), if that drug was used in the treatment regimen. Various adjusted and sensitivity analyses suggest that this was not explained by confounding. The adjusted odds of treatment success for ethambutol, pyrazinamide, and the group 4 drugs ranged from 1.7 to 2.3, whereas for second-line injectables and fluoroquinolones, odds ranged from 2.4 to 4.6. CONCLUSIONS: DST for ethambutol, pyrazinamide, and second-line tuberculosis drugs appears to provide clinically useful information to guide selection of treatment regimens for MDR and XDR tuberculosis.

Pyrazinamide may improve fluoroquinolone-based treatment of multidrug-resistant tuberculosis.

The role of pyrazinamide in the current treatment of multidrug-resistant (MDR) tuberculosis (TB) is uncertain. From a territory-wide registry of MDR-TB cases diagnosed between 1995 and 2009, we assembled a cohort of 194 patients with MDR pulmonary TB given fluoroquinolone-containing regimens. Stratified by pyrazinamide use and susceptibility, there were 83 users with pyrazinamide-susceptible MDR-TB (subgroup A), 24 users with pyrazinamide-resistant MDR-TB (subgroup B), 40 nonusers with pyrazinamide-susceptible MDR-TB (subgroup C), and 47 nonusers with pyrazinamide-resistant MDR-TB (subgroup D). We estimated the adjusted risk ratio (ARR) of early sputum culture conversion (ARR-culture) that occurred within 90 days posttreatment and that of cure or treatment completion (ARR-success) that occurred by 2 years posttreatment due to pyrazinamide use with susceptibility. In comparison with subgroup B, ARR-culture and ARR-success were 1.38 (95% confidence interval [CI], 0.89 to 2.12) and 1.38 (95% confidence interval [CI], 0.88 to 2.17), respectively. Corresponding findings were 0.99 (95% CI, 0.81 to 1.22) and 0.99 (95% CI, 0.78 to 1.26) in comparison with subgroup C and 1.09 (95% CI, 0.84 to 1.42) and 0.94 (95% CI, 0.74 to 1.20) in comparison with subgroup D. Early culture conversion significantly increased the incidence proportion of cure or treatment completion by 71% (95% CI, 26% to 133%). Selection bias among pyrazinamide nonusers might have underestimated the role of pyrazinamide. Comparison of pyrazinamide users showed that pyrazinamide increased the incidence proportion of early culture conversion and that of cure or treatment completion by a best estimate of 38% for both. This magnitude of change exceeded the 15 to 20% increase in the 2-month culture conversion rate of drug-susceptible TB that results from adding pyrazinamide to isoniazid and rifampin. Pyrazinamide is likely important in fluoroquinolone-based treatment of MDR-TB.