Tawanda Gumbo M.D.

Deshpande, D., S. Srivastava, P. Bendet, K. R. Martin, K. N. Cirrincione, P. S. Lee, J. G. Pasipanodya, K. Dheda and T. Gumbo (2018). “Antibacterial and Sterilizing Effect of Benzylpenicillin in Tuberculosis.” Antimicrob Agents Chemother 62(2).

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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 beta-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.

Deshpande, D., S. Srivastava, P. Bendet, K. R. Martin, K. N. Cirrincione, P. S. Lee, J. G. Pasipanodya, K. Dheda and T. Gumbo (2017). “On the antibacterial and sterilizing effect of benzylpenicillin in tuberculosis.” Antimicrob Agents Chemother: 2017 Nov [Epub ahead of print].

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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 beta-lactamase-inhibitor avibactam, benzylpenicillin maximal kill (Emax) 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.

Emmett, M. (2016). “Stewart versus traditional approach to acid-base disorders.” Anesth Analg 123(4): 1063-1064.

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Undoubtedly, the Stewart methodology (and the “base excess” approach) can be used to diagnose metabolic acidbase disorders, but it has no advantage over the classic physiologic methodology advanced by Schwartz and Relman2 and Narins and Emmett.3 The “Stewart Approach” is a more complicated and less-intuitive framework for diagnosing and understanding acid-base physiology/pathophysiology. Dr Story describes an intubated cirrhotic patient (who had received generous intravenous saline expansion) with the following laboratory results: Na: 133; Cl: 110; lactate: 5 (all mmol/L); albumin: 22 g/L; arterial blood gas—pH 7.20; Pco2 40; HCO3 15. Potassium and venous HCO3 (or total CO2) were not reported.