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Antimicrobial Agents and Chemotherapy, July 2008, p. 2407-2414, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.00214-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Low β-Lactamase-Negative Ampicillin-Resistant Haemophilus influenzae Strains Are Best Detected by Testing Amoxicillin Susceptibility by the Broth Microdilution Method

Antibiotic Laboratory, Bacteriology Service, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain,¹ Consejo Superior de Investigaciones Científicas, Madrid, Spain²

Received 15 February 2008/ Returned for modification 21 March 2008/ Accepted 13 April 2008

Ampicillin resistance in Haemophilus influenzae due to alterations in penicillin-binding proteins (β-lactamase negative ampicillin resistant [BLNAR]) is acquiring increasing clinical and epidemiological importance. BLNAR strains with low ampicillin MICs (0.5 to 4 µg/ml) represent the majority of this population in Europe and the United States, but separating them from susceptible isolates is challenging. To investigate the best method to identify low-BLNAR strains, we studied the antibiotic susceptibilities of 94 clinical isolates of H. influenzae by microdilution, Etest, and disk diffusion: 25 had no resistance mechanisms (gBLNAS), 34 had mutations in the ftsI gene only (gBLNAR), 20 were β-lactamase producers only (gBLPAR), and 15 showed β-lactamase production and mutations in the ftsI gene (gBLPACR). By current CLSI breakpoints, most gBLNAR isolates were ampicillin susceptible by microdilution (76.5%) or by Etest (88.2%). Most gBLNAR strains (79.4%) were nonsusceptible to amoxicillin (the most widely used community antibiotic in the United States and Europe) when tested by microdilution. By Etest, 15% of β-lactamase-positive isolates were nonresistant to ampicillin or amoxicillin. The poorest agreement between Etest and microdilution results was for the gBLPAR isolates (25% for ampicillin, 15% for amoxicillin, and 10% for cefaclor). Low-strength disks of ampicillin and amoxicillin-clavulanic acid poorly identified low-BLNAR isolates and are not recommended as a screening method. We suggest new amoxicillin breakpoints for BLNAR isolates as follows: susceptible, MIC 0.5 µg/ml (no resistance mechanisms; pharmacokinetic/pharmacodynamic [PK/PD] data favorable); intermediate, MICs = 1 to 2 µg/ml (resistance mechanisms present but PK/PD data favorable), and resistant, MICs 4 µg/ml (resistance mechanisms present and PK/PD data unfavorable).

Published ahead of print on 28 April 2008.