Antibacterial activities of a fosfomycin/tobramycin combination: a novel inhaled antibiotic for bronchiectasis.
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.
MacLeod
David L
DL
Gilead Sciences, Inc., Seattle, WA 98121, USA. Dave.MacLeod@gilead.com
Barker
Lynn M
LM
Sutherland
Jennifer L
JL
Moss
Suzanne C
SC
Gurgel
Jesse L
JL
Kenney
Thomas F
TF
Burns
Jane L
JL
Baker
William R
WR
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
D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D005578:Fosfomycin; D014031:Tobramycin
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