-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 g/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, fluoroquinoloneresistant H. influenzae isolates have recently been occasionally reported worldwide. To address these problems, we examined susceptibilities to -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 -lactamase-negative ampicillin-susceptible, -lactamase-positive ampicillinresistant, BLNAR, and -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 -lactams, piperacillin-tazobactam exhibited potent activity against all isolates of H. influenzae, with all MICs at <0.5 g/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 g/ml) and 31 ciprofloxacin-susceptible isolates (MICs, 0.06 to 0.5 g/ml) had amino acid changes in their QRDRs. Piperacillin-tazobactam was the most potent -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.
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