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JAC Advance Access originally published online on August 13, 2009
Journal of Antimicrobial Chemotherapy 2009 64(4):829-836; doi:10.1093/jac/dkp282
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses?by-nc/2.0/uk/) which permits unrestricted non-commercial use distribution, and reproduction in any medium, provided the original work is properly cited.

Original research

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

David L. MacLeod1,*, Lynn M. Barker1, Jennifer L. Sutherland1, Suzanne C. Moss1, Jesse L. Gurgel1, Thomas F. Kenney1, Jane L. Burns2 and William R. Baker1

1 Gilead Sciences, Inc., Seattle, WA 98121, USA 2 University of Washington School of Medicine, Division of Infectious Diseases, Department of Pediatrics, Seattle, WA 98195, USA

Received 29 May 2009; returned 24 June 2009; revised 10 July 2009; accepted 10 July 2009

* Corresponding author. Tel: +1-206-728-5090, ext. 3024; Fax: +1-206-728-5095; E-mail: Dave.MacLeod{at}gilead.com

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 MIC90 than tobramycin. For P. aeruginosa, FTI had a lower MIC90 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 log10 lower than that for tobramycin and 2–7 log10 lower than that for fosfomycin. For P. aeruginosa, the FTI SMF was 2–3 log10 lower than that for fosfomycin and 1–2 log10 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.

Keywords: P. aeruginosa , S. aureus , respiratory infections


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