Antimicrobial activity of a novel peptide deformylase inhibitor, LBM415, tested against respiratory tract and cutaneous infection pathogens: a global surveillance report (2003-2004).
OBJECTIVE
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 > or = 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 > or = 99.0% of strains being inhibited at < or = 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 < or = 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.
JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, USA. amy-watters@jmilabs.com
Amy A
AA
Watters
Ronald N
RN
Jones
Jennifer A
JA
Leeds
Gerald
G
Denys
Helio S
HS
Sader
Thomas R
TR
Fritsche
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017714:Community-Acquired Infections / Q000382:microbiology*; D024901:Drug Resistance, Multiple, Bacterial; D005060:Europe; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000302:isolation & purification; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000302:isolation & purification; D006801:Humans; D008826:Microbial Sensitivity Tests; D009656:North America; D010455:Peptides / Q000494:pharmacology*; D011159:Population Surveillance; D012141:Respiratory Tract Infections / Q000382:microbiology*; D017192:Skin Diseases, Bacterial / Q000382:microbiology*; D013020:South America
D000900:Anti-Bacterial Agents; C487638:NVP PDF 713; D010455:Peptides; D000581:Amidohydrolases; C084507:peptide deformylase