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JAC Advance Access published online on March 20, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl093
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© The Author 2006. 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
Received November 9, 2005
Revised February 24, 2006
Accepted February 27, 2006

Original article

Antimicrobial activity of a novel peptide deformylase inhibitor, LBM415, tested against respiratory tract and cutaneous infection pathogens: a global surveillance report (2003-2004)

Amy A. Watters 1 *, Ronald N. Jones 2, Jennifer A. Leeds 3, Gerald Denys 4, Helio S. Sader 1, and Thomas R. Fritsche 1

1 JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, USA
2 JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, USA; Tufts University School of Medicine, Boston, MA, USA
3 Novartis Institute for Biomedical Research, Cambridge, MA, USA
4 Clarian Health Partners, Inc., Methodist Hospital, Indianapolis, IN, USA

* To whom correspondence should be addressed.
Amy A. Watters, E-mail: amy-watters{at}jmilabs.com


  Abstract

Objectives: To evaluate the spectrum of activity and potency of LBM415, the first of the peptide deformylase inhibitor (PDFI) class to be developed for treatment of community-acquired respiratory tract infections and uncomplicated skin and soft tissue infections (uSSTI), against a large, contemporary international collection of targeted pathogens collected during 2003-2004.

Methods: A total of 21 636 isolates were tested by reference broth microdilution methods as part of a longitudinal international antimicrobial resistance surveillance study. Characteristics of the organism collection included resistance to oxacillin among 35.0% of Staphylococcus aureus and 76.0% of coagulase-negative staphylococci (CoNS); resistance to penicillin (MIC ≥ 2 mg/L) among 18.0% of Streptococcus pneumoniae; vancomycin resistance among 20.0% of Enterococcus spp. and ampicillin resistance among 22.0% of Haemophilus influenzae.

Results: LBM415 displayed potent activity against staphylococci, streptococci, Enterococcus faecium and Moraxella catarrhalis, with ≥99.0% of strains being inhibited at ≤4 mg/L; 97.0% of Enterococcus faecalis isolates and 92.0% of H. influenzae isolates were also inhibited at this concentration. Seventy-seven percent of Burkholderia cepacia and 82.0% of Stenotrophomonas maltophilia were inhibited at ≤8 mg/L. No differences in LBM415 activity against S. aureus, CoNS, S. pneumoniae, Enterococcus spp. and H. influenzae were detected for subsets susceptible or resistant to antimicrobials such as oxacillin, penicillin, ampicillin, macrolides, vancomycin and fluoroquinolones. While regional differences were apparent with some comparator agents, sensitivity to LBM415 did not vary significantly among strains from the various geographic areas sampled. One isolate of S. aureus displayed high-level resistance to LBM415 owing to multiple sequence changes in resistance phenotype genes (defB and fmt), despite the absence of the compound in clinical practice. This isolate remained susceptible to all other antimicrobials tested except for penicillin.

Conclusions: With few differences detected among strains from various geographic regions, the first PDFI class agent to enter clinical development has consistently demonstrated a broad spectrum of activity against commonly isolated pathogens associated with uncomplicated respiratory and cutaneous infections. These compounds represent a significant therapeutic advance owing to their novel mechanism of action and antibacterial spectrum, including activity against resistant organisms, should pharmacokinetic and pharmacodynamic parameters support their continued development. Given the detection of a pre-existing PDFI-resistant isolate of S. aureus as demonstrated here, surveillance for resistance among the PDFI-targeted pathogens following introduction of this class of agent into clinical usage will be an important component of future studies.

Keywords: PDFI; resistance; respiratory tract infections; uSSTI.
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