Antibacterial activities of a fosfomycin/tobramycin combination: a novel inhaled antibiotic for bronchiectasis

J Antimicrob Chemother. 2009 Oct;64(4):829-36. doi: 10.1093/jac/dkp282. Epub 2009 Aug 13.

Abstract

Objectives: To compare the in vitro and in vivo activities of a 4:1 (w/w) fosfomycin/tobramycin combination (FTI) with those of fosfomycin and tobramycin alone against cystic fibrosis (CF) and non-CF bronchiectasis pathogens.

Methods: Clinical isolates of CF Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Stenotrophomonas maltophilia, Burkholderia cepacia complex, Escherichia coli and Klebsiellia spp. were evaluated by MIC, MBC, post-antibiotic effect (PAE), synergy, time-kill, a rat pneumonia model and spontaneous mutation frequency (SMF).

Results: FTI showed high activity against E. coli, H. influenzae, S. aureus and Klebsiella spp. For the S. aureus strains, 75% of which were methicillin resistant (MRSA), FTI had a lower MIC(90) than tobramycin. For P. aeruginosa, FTI had a lower MIC(90) than fosfomycin, but tobramycin was more active than either. Synergy studies showed no antagonism between fosfomycin and tobramycin, and 93% of the isolates demonstrated no interaction. FTI was rapidly bactericidal and exhibited concentration-dependent killing in time-kill studies. In the rat pneumonia model, FTI and tobramycin demonstrated bactericidal killing of P. aeruginosa; both were more active than fosfomycin alone. The SMF for S. aureus resistance to FTI was 2-4 log(10) lower than that for tobramycin and 2-7 log(10) lower than that for fosfomycin. For P. aeruginosa, the FTI SMF was 2-3 log(10) lower than that for fosfomycin and 1-2 log(10) lower than that for tobramycin.

Conclusions: FTI is a broad-spectrum antibiotic combination with high activity in vitro and in vivo. These data suggest FTI could be a potential treatment for respiratory infections caused by gram-positive and gram-negative aerobic bacteria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Bacteria / drug effects*
  • Bacteria / isolation & purification
  • Bacterial Infections / microbiology
  • Bronchiectasis / complications
  • Colony Count, Microbial
  • Drug Combinations
  • Drug Interactions
  • Fosfomycin / administration & dosage
  • Fosfomycin / pharmacology
  • Fosfomycin / therapeutic use*
  • Humans
  • Lung / microbiology
  • Male
  • Microbial Sensitivity Tests
  • Microbial Viability
  • Pneumonia, Bacterial / drug therapy*
  • Rats
  • Tobramycin / administration & dosage
  • Tobramycin / pharmacology
  • Tobramycin / therapeutic use*
  • Treatment Outcome

Substances

  • Anti-Bacterial Agents
  • Drug Combinations
  • Fosfomycin
  • Tobramycin