Intermediate Susceptibility Dose-Dependent Breakpoints For High-Dose Rifampin, Isoniazid, and Pyrazinamide Treatment in Multidrug-Resistant Tuberculosis Programs.

Background: Bacterial susceptibility is categorized as susceptible, intermediate-susceptible dose-dependent (ISDD), and resistant. The strategy is to use higher doses of first-line agents in the ISDD category, thereby preserving the use of these drugs. This system has not been applied to antituberculosis drugs. Pharmacokinetic/pharmacodynamic (PK/PD) target exposures, in tandem with Monte Carlo experiments, recently identified susceptibility breakpoints of 0.0312 mg/L for isoniazid, 0.0625 mg/L for rifampin, and 50 mg/L for pyrazinamide. These have been confirmed in clinical studies.
Methods: Target attainment studies were carried out using Monte Carlo experiments to investigate whether rifampin, isoniazid, and pyrazinamide dose increases would achieve the PK/PD target in >90% of 10000 patients with tuberculosis caused by bacteria, revealing minimum inhibitory concentrations (MICs) between the proposed and the traditional breakpoints.
Results: We found that an isoniazid dose of 900 mg/day identified a new ISDD MIC range of 0.0312-0.25 mg/L and resistance at MIC ≥0.5 mg/L. Rifampin 1800 mg/day would result in an ISDD of 0.0625-0.25 mg/L and resistance at MIC ≥0.5 mg/L. At a dose of pyrazinamide 4 g/day, the ISDD MIC range was 37.5-50 mg/L and resistance at MIC ≥100 mg/L. Based on MIC distributions, 93% (isoniazid), 78% (rifampin), and 27% (pyrazinamide) of isolates would be within the ISDD range. Conclusions: Drug susceptibility testing at 2 concentrations delineating the ISDD range, and subsequently using higher doses, could prevent switching to a more toxic second-line treatment. Confirmatory clinical studies would provide evidence to change treatment guidelines.