On the antibacterial and sterilizing effect of benzylpenicillin in tuberculosis [PublishAheadOfPrint]

The modern chemotherapy era started with Fleming's discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill Mycobacterium tuberculosis (Mtb). Here, we found that >64 mg/L of static benzylpenicillin concentrations killed 1.16-1.43 log₁₀ CFU/mL below starting inoculum of extracellular and intracellular Mtb over 7 days. When we added the β-lactamase-inhibitor avibactam, benzylpenicillin maximal kill (E_max) of either extracellular log-phase growth Mtb was 6.80±0.45 log₁₀ CFU/mL at an EC₅₀ of 15.11±5.2.32 mg/L, while for intracellular Mtb was 2.42±0.14 log₁₀ CFU/mL at an EC₅₀ of 6.70±0.56 mg/L. The median penicillin (plus avibactam) MIC against South African clinical Mtb strains (80% either multi- or extensively drug-resistant) was 2 mg/L. We mimicked human-like benzylpenicillin and avibactam concentration-time profiles in the hollow fiber model of tuberculosis (HFS-TB). The percentage time above MIC was linked to effect, with an optimal exposure of ≥65%. At optimal exposure in the HFS-TB, the bactericidal activity in log-phase growth Mtb was 1.44 log₁₀ CFU/mL/day, while 3.28 log₁₀ CFU/mL of intracellular Mtb was killed over 3 weeks. In an 8 week HFS-TB study of non-replicating persistent Mtb, penicillin-avibactam alone versus the drug combination of isoniazid, rifampin, and pyrazinamide, both killed >7.0 log₁₀ CFU/mL. Monte Carlo simulations of 10,000 pre-term infants with disseminated disease identified an optimal dose of 10,000 U/kg/hr, while for pregnant women or non-pregnant adults with pulmonary tuberculosis optima dose was 25,000 U/kg/hr, by continuous intravenous infusion. Penicillin-avibactam should be examined for effect in pregnant women and infants with drug-resistant tuberculosis, to replace injectable ototoxic and teratogenic second-line drugs.

http://ift.tt/2Bh9f5O