title: Antibacterial activities of a fosfomycin/tobramycin combination: a novel inhaled antibiotic for bronchiectasis.
abstract: OBJECTIVE
  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.
authors.affiliation: Gilead Sciences, Inc., Seattle, WA 98121, USA. Dave.MacLeod@gilead.com
authors.forename: David L
authors.initials: DL
authors.lastname: MacLeod
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Barker
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sutherland
authors.forename: Suzanne C
authors.initials: SC
authors.lastname: Moss
authors.forename: Jesse L
authors.initials: JL
authors.lastname: Gurgel
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Kenney
authors.forename: Jane L
authors.initials: JL
authors.lastname: Burns
authors.forename: William R
authors.initials: WR
authors.lastname: Baker
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001419:Bacteria / Q000187:drug effects* / Q000302:isolation & purification; D001424:Bacterial Infections / Q000382:microbiology; D001987:Bronchiectasis / Q000150:complications; D015169:Colony Count, Microbial; D004338:Drug Combinations; D004347:Drug Interactions; D005578:Fosfomycin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008168:Lung / Q000382:microbiology; D008297:Male; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D018410:Pneumonia, Bacterial / Q000188:drug therapy*; D051381:Rats; D014031:Tobramycin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D005578:Fosfomycin; D014031:Tobramycin
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