Mycobacterium tuberculosis sterilizing activity of faropenem, pyrazinamide and linezolid combination and failure to shorten the therapy duration

Abstract

BackgroundFaropenem (F), an orally bioavailable β-lactam, kills Mycobacterium tuberculosis (Mtb) without the help of a β-lactamase inhibitor. This study explored the sterilizing effect of adding F once or twice daily to a linezolid (L) plus pyrazinamide (Z) backbone regimen. MethodsIn vitro studies were performed using the hollow fiber model of tuberculosis (HFS-TB) to compare the kill rates of: 1) ZL two-drug combination; 2) F administered once daily plus ZL (F1ZL); 3) F administered twice-daily plus once daily ZL (F2ZL); 4) F2ZL with high-dose Z (F2ZhiL); 5) standard therapy of isoniazid, rifampin and Z; and 6) non-treated controls. The study was performed over 56 days with three HFS-TB replicates for each regimen. ResultsMtb in the non-treated HFS-TB grew at a rate of 0.018 ± 0.007 log10 CFU/mL/day. The exponential kill rates for standard therapy were 6.6–13.2-fold higher than ZL dual therapy. The F1ZL and F2ZL regimens ranked third. The pre-existing isoniazid-resistant sub-population in the inoculum (1.34 ± 0.57 log10 CFU/mL) grew to 4.21 ± 0.58 log10 CFU/mL in 56 days in non-treated HFS-TB. However, no isoniazid-resistant sub-population was recorded in any of the FZL combination regimens. ConclusionDue to the slow kill rate compared to standard therapy, FZL regimens are unlikely to shorten therapy duration. Efficacy of these regimens against drug-resistant tuberculosis needs to be determined.