In vitro and in vivo efficacy of β-lactams against replicating and slowly growing/nonreplicating Mycobacterium tuberculosis.

Abstract

Beta-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.

• Authors: 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, V Balasubramanian
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 57 Issue 6 Pg. 2506-10 (Jun 2013) ISSN: 1098-6596 [Electronic] United States
• PMID: 23507276 (Publication Type: Journal Article)

Chemical References

• Anti-Bacterial Agents
• Thienamycins
• beta-Lactams
• Clavulanic Acid
• Amoxicillin-Potassium Clavulanate Combination
• Meropenem
• Streptomycin

Topics

• Amoxicillin-Potassium Clavulanate Combination (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Animals
• Anti-Bacterial Agents (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Clavulanic Acid (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Disease Models, Animal
• Drug Therapy, Combination
• Female
• Humans
• Meropenem
• Mice
• Mice, Inbred BALB C
• Microbial Sensitivity Tests (standards)
• Mycobacterium tuberculosis (drug effects, growth & development)
• Streptomycin (pharmacology)
• Thienamycins (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Treatment Outcome
• Tuberculosis, Pulmonary (drug therapy, microbiology)
• beta-Lactams (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)