Antibacterial and Sterilizing Effect of Benzylpenicillin in Tuberculosis

Devyani Deshpande; Shashikant Srivastava; Paula Bendet; Katherine R Martin; Kayle N Cirrincione; Pooi S Lee; Jotam G Pasipanodya; Keertan Dheda; Tawanda Gumbo

doi:10.1128/AAC.02232-17

Antibacterial and Sterilizing Effect of Benzylpenicillin in Tuberculosis

Antimicrob Agents Chemother. 2018 Jan 25;62(2):e02232-17. doi: 10.1128/AAC.02232-17. Print 2018 Feb.

Authors

Devyani Deshpande¹, Shashikant Srivastava¹, Paula Bendet¹, Katherine R Martin¹, Kayle N Cirrincione¹, Pooi S Lee¹, Jotam G Pasipanodya¹, Keertan Dheda², Tawanda Gumbo^{3

2}

Affiliations

¹ Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA.
² Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa.
³ Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA tawanda.gumbo@BSWHealth.org.

Abstract

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 (E_max) 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.

Keywords: avibactam; benzylpenicillin; childhood tuberculosis; pharmacodynamics; pregnancy; tuberculosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antitubercular Agents / therapeutic use*
Azabicyclo Compounds / therapeutic use
Cell Line
Drug Combinations
Female
Humans
Isoniazid / therapeutic use
Microbial Sensitivity Tests / methods
Monte Carlo Method
Mycobacterium tuberculosis / drug effects*
Penicillin G / therapeutic use*
Pregnancy
Pyrazinamide / therapeutic use
Rifampin / therapeutic use
Tuberculosis, Multidrug-Resistant / drug therapy*

Substances

Antitubercular Agents
Azabicyclo Compounds
Drug Combinations
Pyrazinamide
avibactam
Penicillin G
Isoniazid
Rifampin