The modern
chemotherapy era started with Fleming's discovery of
benzylpenicillin. He demonstrated that
benzylpenicillin did not kill Mycobacterium tuberculosis In this study, we found that >64 mg/liter of static
benzylpenicillin concentrations killed 1.16 to 1.43 log10 CFU/ml below starting inoculum of extracellular and intracellular M.
tuberculosis over 7 days. When we added the β-lactamase inhibitor
avibactam,
benzylpenicillin maximal kill (Emax) of extracellular log-phase-growth M.
tuberculosis was 6.80 ± 0.45 log10 CFU/ml at a 50% effective concentration (EC50) of 15.11 ± 2.31 mg/liter, while for intracellular M.
tuberculosis it was 2.42 ± 0.14 log10 CFU/ml at an EC50 of 6.70 ± 0.56 mg/liter. The median
penicillin (plus
avibactam) MIC against South African clinical M.
tuberculosis 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 M.
tuberculosis was 1.44 log10 CFU/ml/day, while 3.28 log10 CFU/ml of intracellular M.
tuberculosis was killed over 3 weeks. In an 8-week HFS-TB study of nonreplicating persistent M.
tuberculosis,
penicillin-
avibactam alone and the
drug combination of
isoniazid,
rifampin, and
pyrazinamide both killed >7.0 log10 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.