• Suresh Solapure, Neela Dinesh, Radha Shandil, Vasanthi Ramachandran, Sreevalli Sharma, Deepa Bhattacharjee, Samit Ganguly, Jitendar Reddy, Vijaykamal Ahuja, Vijender Panduga, Manish Parab, K G Vishwas, Naveen Kumar, Meenakshi Balganesh, and V Balasubramanian.
• AstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India. suresh.solapure@astrazeneca.com
• Antimicrob. Agents Chemother. 2013 Jun 1; 57 (6): 2506-10.

AbstractBeta-lactams, in combination with beta-lactamase inhibitors, are reported to have activity against Mycobacterium tuberculosis bacteria growing in broth, as well as inside the human macrophage. We tested representative beta-lactams belonging to 3 different classes for activity against replicating M. tuberculosis in broth and nonreplicating M. tuberculosis under hypoxia, as well as against streptomycin-starved M. tuberculosis strain 18b (ss18b) in the presence or absence of clavulanate. Most of the combinations showed bactericidal activity against replicating M. tuberculosis, with up to 200-fold improvement in potency in the presence of clavulanate. None of the combinations, including those containing meropenem, imipenem, and faropenem, killed M. tuberculosis under hypoxia. However, faropenem- and meropenem-containing combinations killed strain ss18b moderately. We tested the bactericidal activities of meropenem-clavulanate and amoxicillin-clavulanate combinations in the acute and chronic aerosol infection models of tuberculosis in BALB/c mice. Based on pharmacokinetic/pharmacodynamic indexes reported for beta-lactams against other bacterial pathogens, a cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%TMIC) of 20 to 40% was achieved in mice using a suitable dosing regimen. Both combinations showed marginal reduction in lung CFU compared to the late controls in the acute model, whereas both were inactive in the chronic model.

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