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

Background Faropenem (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. Methods In 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 (F 1 ZL); 3) F administered twice-daily plus once daily ZL (F 2 ZL); 4) F 2 ZL with high-dose Z (F 2 Z hi L); 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. Results Mtb in the non-treated HFS-TB grew at a rate of 0.018 ± 0.007 log 10 CFU/mL/day. The exponential kill rates for standard therapy were 6.6-13.2-fold higher than ZL dual therapy. The F 1 ZL and F 2 ZL regimens ranked third. The pre-existing isoniazid-resistant sub-population in the inoculum (1.34 ± 0.57 log 10 CFU/mL) grew to 4.21 ± 0.58 log 10 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. Conclusion Due 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.