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Antimicrobial Agents and Chemotherapy, July 2006, p. 2487-2492, Vol. 50, No. 7
0066-4804/06/$08.00+0     doi:10.1128/AAC.01316-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Molecular Evolution of ß-Lactam-Resistant Haemophilus influenzae: 9-Year Surveillance of Penicillin-Binding Protein 3 Mutations in Isolates from Japan

Pharmaceutical Research Center, Meiji Seika Kaisha Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567,¹ Laboratory of Infectious Agents Surveillance, Kitasato Institute for Life Sciences & Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan²

Received 7 October 2005/ Returned for modification 23 December 2005/ Accepted 23 April 2006

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, ß-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 ß-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 ß-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 ß-lactams. Although a significant change in the prevalence of ß-lactamase-producing strains was not observed, the proportions of those possessing both PBP 3 alterations and ß-lactamase production have slightly increased (from 1.4% to 5.0%). The ROB-1 ß-lactamase was rare, but this is the first report of this ß-lactamase in Japan.

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