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

Abstract

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 (F₁ZL); 3) F administered twice-daily plus once daily ZL (F₂ZL); 4) F₂ZL with high-dose Z (F₂Z_hiL); 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 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.

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.