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Antimicrobial Agents and Chemotherapy, October 2009, p. 4225-4230, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00192-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Antimicrobial Activities of Piperacillin-Tazobactam against Haemophilus influenzae Isolates, Including β-Lactamase-Negative Ampicillin-Resistant and β-Lactamase-Positive Amoxicillin- Clavulanate-Resistant Isolates, and Mutations in Their Quinolone Resistance-Determining Regions{triangledown}

Yoichi Hirakata,1,2* Kaori Ohmori,4 Miwako Mikuriya,4 Takeshi Saika,4 Kaoru Matsuzaki,4 Miyuki Hasegawa,4 Masumitsu Hatta,1 Natsuo Yamamoto,1 Hiroyuki Kunishima,1 Hisakazu Yano,1,2 Miho Kitagawa,1 Kazuaki Arai,1,2 Kazuyoshi Kawakami,3 Intetsu Kobayashi,5 Ronald N. Jones,6 Shigeru Kohno,7 Keizo Yamaguchi,8 and Mitsuo Kaku1,2

Department of Infection Control and Laboratory Diagnostics,1 Department of Clinical Microbiology with Epidemiological Research & Management and Analysis of Infectious Diseases (C-MERMAID),2 Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8574, Japan,3 Mitsubishi Chemical Medience Corporation, Itabashi-ku, Tokyo 174-8555, Japan,4 Department of Infection Control and Prevention, Toho University School of Nursing, Ohtaku, Tokyo 143-0015, Japan,5 JMI Laboratories, North Liberty, Iowa 52317,6 Second Department of Internal Medicine, Nagasaki University School of Medicine and Dentistry, Nagasaki 852-8501, Japan,7 Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Ohtaku, Tokyo 143-8540, Japan8

Received 27 January 2009/ Returned for modification 14 April 2009/ Accepted 7 July 2009

β-Lactamase-negative ampicillin-resistant (BLNAR) isolates of Haemophilus influenzae have been emerging in some countries, including Japan. The Clinical and Laboratory Standards Institute has only a susceptible MIC breakpoint (≤1 µg/ml) for piperacillin-tazobactam and a disclaimer comment that BLNAR H. influenzae should be considered resistant, which was adapted without presentation of data. In addition, fluoroquinolone-resistant H. influenzae isolates have recently been occasionally reported worldwide. To address these problems, we examined susceptibilities to β-lactams, including piperacillin-tazobactam, and ciprofloxacin by microdilution and disk diffusion (only for piperacillin-tazobactam) methods, against a total of 400 recent H. influenzae clinical isolates, including 100 β-lactamase-negative ampicillin-susceptible, β-lactamase-positive ampicillin-resistant, BLNAR, and β-lactamase-positive amoxicillin-clavulanate-resistant (BLPACR) isolates each. BLNAR and BLPACR isolates were tested by PCR using primers that amplify specific regions of the ftsI gene. We also detected mutations in quinolone resistance-determining regions (QRDRs) by direct sequencing of the PCR products of DNA fragments. Among β-lactams, piperacillin-tazobactam exhibited potent activity against all isolates of H. influenzae, with all MICs at ≤0.5 µg/ml (susceptible). A disk diffusion breakpoint for piperacillin-tazobactam of ≥21 mm is proposed. We confirmed that all BLNAR and BLPACR isolates had amino acid substitutions in the ftsI gene and that the major pattern was group III-like (87.5%). One ciprofloxacin-resistant isolate (MIC, 16 µg/ml) and 31 ciprofloxacin-susceptible isolates (MICs, 0.06 to 0.5 µg/ml) had amino acid changes in their QRDRs. Piperacillin-tazobactam was the most potent β-lactam tested against all classes of H. influenzae isolates. It is possible that fluoroquinolone-resistant H. influenzae will emerge since several clinical isolates carried mutations in their QRDRs.

* Corresponding author. Mailing address: Department of Clinical Microbiology with Epidemiological Research & Management and Analysis of Infectious Diseases (C-MERMAID), Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba-ku, Sendai, Miyagi 980-8574, Japan. Phone: 81-22-717-7376. Fax: 81-22-717-7390. E-mail: hiraichi{at}mail.tains.tohoku.ac.jp

{triangledown} Published ahead of print on 3 August 2009.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4225-4230, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00192-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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