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Antimicrobial Agents and Chemotherapy, May 2004, p. 1509-1514, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1509-1514.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Rapidly Increasing Prevalence of ß-Lactamase-Nonproducing, Ampicillin-Resistant Haemophilus influenzae Type b in Patients with Meningitis

Keiko Hasegawa,1 Naoko Chiba,1 Reiko Kobayashi,2 Somay Y. Murayama,1 Satoshi Iwata,3 Keisuke Sunakawa,1 and Kimiko Ubukata1*

Kitasato Institute for Life Sciences & Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku,1 National Medical Center of Japan, Tokyo,3 Pharmaceutical Research Center, Meiji Seika Kaisha Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, Japan2

Received 23 May 2003/ Returned for modification 30 August 2003/ Accepted 30 December 2003

A total of 395 Haemophilus influenzae strains from 226 Japanese institutions participating in the Nationwide Surveillance Study Group for Bacterial Meningitis were received from 1999 to 2002. All strains were analyzed by PCR to identify the resistance genes, and their susceptibilities to ß-lactam agents were determined. Of these strains, 29.1% were ß-lactamase nonproducing and ampicillin (AMP) susceptible (BLNAS) and lacked all resistance genes; 15.4% were ß-lactamase producing and AMP resistant and had the blaTEM-1 gene; 30.6% were ß-lactamase nonproducing and AMP resistant (low-BLNAR) and had a Lys-526 or His-517 amino acid substitution in ftsI encoding PBP 3; 13.9% were ß-lactamase nonproducing and AMP resistant (BLNAR) and had an additional substitution of Thr-385 in ftsI; 9.1% were amoxicillin-clavulanic acid resistant (BLPACR I) and had the blaTEM-1 gene and a Lys-526 or His-517 amino acid substitution in ftsI; and 1.8% showed resistance similar to that of the BLPACR I group (BLPACR II) but had blaTEM-1 gene and ftsI substitutions, as was the case for the BLNAR strains. All but three strains were serotype b. The prevalence of BLNAR strains has increased rapidly: 0% in 1999, 5.8% in 2000, 14.1% in 2001, and 21.3% in 2002. The MICs at which 90% of BLNAR isolates were inhibited were as follows: AMP, 16 µg/ml; cefotaxime, 1 µg/ml; ceftriaxone, 0.25 µg/ml; and meropenem, 0.5 µg/ml. All of these values were higher than those for the BLNAS counterpart strains. The relatively wide distributions of the ß-lactam MICs for BLNAR strains presumably reflect variations in ftsI gene mutations. Pulsed-field gel electrophoresis suggested the rapid spread of specific H. influenzae type b strains throughout Japan. Expedited vaccination, rapid identification, and judicious antibiotic use could slow their spread.

* Corresponding author. Mailing address: Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Phone: 81-3-5791-6385. Fax: 81-3-5791-6386. E-mail: keiko{at}lisci.kitasato-u.ac.jp.

Antimicrobial Agents and Chemotherapy, May 2004, p. 1509-1514, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1509-1514.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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