期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 62, 期 2, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.02232-17
关键词
avibactam; benzylpenicillin; childhood tuberculosis; pharmacodynamics; pregnancy; tuberculosis
资金
- Baylor Research Institute
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 log(10) CFU/ml below starting inoculum of extracellular and intracellular M. tuberculosis over 7 days. When we added the beta-lactamase inhibitor avibactam, benzylpenicillin maximal kill (E-max) of extracellular log-phase-growth M. tuberculosis was 6.80 +/- 0.45 log(10) 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 log(10) 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 logphase- growth M. tuberculosis was 1.44 log(10) CFU/ml/day, while 3.28 log(10) 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 log(10) 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.
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