Antibacterial and Sterilizing Effect of Benzylpenicillin in Tuberculosis.

The modern chemotherapy era started with Fleming's discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill In this study, we found that >64 mg/liter of static benzylpenicillin concentrations killed 1.16 to 1.43 log CFU/ml below starting inoculum of extracellular and intracellular over 7 days. When we added the β-lactamase inhibitor avibactam, benzylpenicillin maximal kill () of extracellular log-phase-growth was 6.80 ± 0.45 log CFU/ml at a 50% effective concentration (EC) of 15.11 ± 2.31 mg/liter, while for intracellular it was 2.42 ± 0.14 log CFU/ml at an EC of 6.70 ± 0.56 mg/liter. The median penicillin (plus avibactam) MIC against South African clinical strains (80% either multidrug or extensively drug resistant) was 2 mg/liter. We mimicked human-like benzylpenicillin and avibactam concentration-time profiles in the hollow-fiber model of tuberculosis (HFS-TB). The percent time above the 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 was 1.44 log CFU/ml/day, while 3.28 log CFU/ml of intracellular was killed over 3 weeks. In an 8-week HFS-TB study of nonreplicating persistent , penicillin-avibactam alone and the drug combination of isoniazid, rifampin, and pyrazinamide both killed >7.0 log CFU/ml. Monte Carlo simulations of 10,000 preterm infants with disseminated disease identified an optimal dose of 10,000 U/kg (of body weight)/h, while for pregnant women or nonpregnant adults with pulmonary tuberculosis the optimal dose was 25,000 U/kg/h, 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.