Intermediate Susceptibility Dose-Dependent Breakpoints For High-Dose Rifampin, Isoniazid, and Pyrazinamide Treatment in Multidrug-Resistant Tuberculosis Programs. (24th April 2018)

• Record Type: Journal Article
• Authors: Zuur, Marlanka A; Pasipanodya, Jotam G; van Soolingen, Dick; van der Werf, Tjip S; Gumbo, Tawanda; Alffenaar, Jan-Willem C
• Is Part Of: Clinical infectious diseases. Volume 67:Number 11(2018)
• Page Start: 1743
• Page End: 1749
• Publication Date: 2018-04-24
• Subjects: tuberculosis -- intermediate susceptibility -- high-dose first-line antituberculosis drugs; Communicable diseases -- Periodicals; 616.905
• DOI: 10.1093/cid/ciy346
• Languages: English
• ISSNs: 1058-4838

Abstract

Abstract : Clinical susceptibility breakpoints for first-line antituberculosis drugs might be lower than previously thought, which means that more patients should receive second-line treatment. We propose an intermediate susceptibility dose-dependent category, which allows continued use of first-line drugs in higher doses. Abstract: 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.