title: Molecular evolution of beta-lactam-resistant Haemophilus influenzae: 9-year surveillance of penicillin-binding protein 3 mutations in isolates from Japan.
abstract: A total of 621 clinical isolates of Haemophilus influenzae collected in Japan between 1995 and 2003 were studied for their susceptibilities to several antimicrobial agents, beta-lactamase production, and amino acid substitutions in penicillin-binding protein 3 (PBP 3). Over the four study periods (first period, 1995 to 1996; second period, 1997 to 1998; third period, 2000 to 2001; fourth period, 2002 to 2003), the susceptibilities to beta-lactam agents decreased and the incidence of isolates with substitutions at positions 377, 385, 389, 517, and/or 526 in PBP 3 increased from 28.8% to 52.0%. Five hundred seventy-one beta-lactamase-nonproducing isolates were grouped into 18 classes, based on the pattern of the five mutations in PBP 3. The Asp526Lys substitution led to 6.0-, 4.3-, 2.4-, and 5.4-fold increases in amoxicillin-clavulanic acid, cefdinir, cefditoren, and faropenem resistance, respectively. PBP 3 with multiple substitutions (Met377Ile, Ser385Thr, and/or Leu389Phe) together with Asp526Lys resulted in increased resistance compared to that for PBP 3 with the Asp526Lys substitution alone. These results indicate that mutations at these five positions increased resistance to most beta-lactams. Although a significant change in the prevalence of beta-lactamase-producing strains was not observed, the proportions of those possessing both PBP 3 alterations and beta-lactamase production have slightly increased (from 1.4% to 5.0%). The ROB-1 beta-lactamase was rare, but this is the first report of this beta-lactamase in Japan.
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Kaisha Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Sanbongi
authors.forename: Takahisa
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yumi
authors.initials: Y
authors.lastname: Osaki
authors.forename: Nami
authors.initials: N
authors.lastname: Senju
authors.forename: Takashi
authors.initials: T
authors.lastname: Ida
authors.forename: Kimiko
authors.initials: K
authors.lastname: Ubukata
mesh_terms: D019943:Amino Acid Substitution; D019143:Evolution, Molecular; D006192:Haemophilus Infections / Q000453:epidemiology / Q000382:microbiology; D006193:Haemophilus influenzae / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D046915:Penicillin-Binding Proteins / Q000235:genetics*; D011159:Population Surveillance; D018440:beta-Lactam Resistance / Q000235:genetics*; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D046915:Penicillin-Binding Proteins; D047090:beta-Lactams