title: Activity of LBM415 compared to those of 11 other agents against Haemophilus species.
abstract: When tested against 254 Haemophilus influenzae strains, LBM415, a peptide deformylase inhibitor, gave MIC50 and MIC90 values of 2.0 microg/ml and 8.0 microg/ml, respectively. The MICs were independent of beta-lactam or quinolone susceptibility and the presence or absence of macrolide efflux or ribosomal protein mutations. The MICs of LBM415 against 23 H. parainfluenzae strains were similar to those against H. influenzae. In contrast, erythromycin, azithromycin, and clarithromycin gave unimodal MIC distributions, and apart from beta-lactamase-negative, ampicillin-resistant strains, all strains were susceptible to the beta-lactams tested. Apart from selected quinolone-resistant strains, all strains were susceptible to ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin. Resistance to trimethoprim-sulfamethoxazole was common. The potencies of all drugs against 23 H. parainfluenzae strains were similar to those against H. influenzae. Time-kill studies with 10 Haemophilus strains showed LBM415 to be bactericidal at 2 x the MIC against 8 of 10 strains after 24 h. For comparison, the macrolides and beta-lactams were bactericidal against 8 to 10 strains each at 2 x the MIC after 24 h. Quinolones were bactericidal against all 10 strains tested at 2 x the MIC after 24 h. Against six H. influenzae strains, postantibiotic effects for LBM415 lasted between 0.8 and 2.2 h. In multistep resistance selection studies, LBM415 produced resistant clones in 7 of the 10 strains tested, with MICs ranging from 4 to 64 microg/ml. No mutations in deformylase (def) and formyltransferase (fmt) genes were detected in any of the LBM415-resistant mutants.
authors.affiliation: Hershey Medical Center, Hershey, PA 17033, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Bogdanovich
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Smith
authors.forename: Catherine
authors.initials: C
authors.lastname: Clark
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Pankuch
authors.forename: Gengrong
authors.initials: G
authors.lastname: Lin
authors.forename: Pamela
authors.initials: P
authors.lastname: McGhee
authors.forename: Bonifacio
authors.initials: B
authors.lastname: Dewasse
authors.forename: Peter C
authors.initials: PC
authors.lastname: Appelbaum
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015169:Colony Count, Microbial; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006190:Haemophilus / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006193:Haemophilus influenzae / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D006801:Humans; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000494:pharmacology*; D012641:Selection, Genetic
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; C487638:NVP PDF 713; D010455:Peptides; D000581:Amidohydrolases; C084507:peptide deformylase