ABSTRACTBeta-lactams, in combination with beta-lactamase inhibitors, are reported to have activity againstMycobacterium tuberculosisbacteria growing in broth, as well as inside the human macrophage. We tested representative beta-lactams belonging to 3 different classes for activity against replicatingM. tuberculosisin broth and nonreplicatingM. tuberculosisunder hypoxia, as well as against streptomycin-starvedM. tuberculosisstrain 18b (ss18b) in the presence or absence of clavulanate. Most of the combinations showed bactericidal activity against replicatingM. 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, killedM. tuberculosisunder 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.
The Bactericidal Activities of Combinations of Streptomycin, Isoniazid, p-Aminosalicylic Acid (PAS), Oxytetracycline (Terramycin) and Viomycin against Mycobacterium tuberculosis
