title: 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.affiliation: AstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India. suresh.solapure@astrazeneca.com
authors.forename: Suresh
authors.initials: S
authors.lastname: Solapure
authors.forename: Neela
authors.initials: N
authors.lastname: Dinesh
authors.forename: Radha
authors.initials: R
authors.lastname: Shandil
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Ramachandran
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.forename: Deepa
authors.initials: D
authors.lastname: Bhattacharjee
authors.forename: Samit
authors.initials: S
authors.lastname: Ganguly
authors.forename: Jitendar
authors.initials: J
authors.lastname: Reddy
authors.forename: Vijaykamal
authors.initials: V
authors.lastname: Ahuja
authors.forename: Vijender
authors.initials: V
authors.lastname: Panduga
authors.forename: Manish
authors.initials: M
authors.lastname: Parab
authors.forename: K G
authors.initials: KG
authors.lastname: Vishwas
authors.forename: Naveen
authors.initials: N
authors.lastname: Kumar
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Balganesh
authors.forename: V
authors.initials: V
authors.lastname: Balasubramanian
mesh_terms: D019980:Amoxicillin-Potassium Clavulanate Combination / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019818:Clavulanic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000077731:Meropenem; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests / Q000592:standards; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D013307:Streptomycin / Q000494:pharmacology; D013845:Thienamycins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology; D047090:beta-Lactams / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D047090:beta-Lactams; D019818:Clavulanic Acid; D019980:Amoxicillin-Potassium Clavulanate Combination; D000077731:Meropenem; D013307:Streptomycin