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

Antimicrob Agents Chemother. 2013 Jun;57(6):2506-10. doi: 10.1128/AAC.00023-13. Epub 2013 Mar 18.

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.

MeSH terms

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

Substances

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