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Antimicrobial Agents and Chemotherapy, July 2007, p. 2564-2573, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.00354-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Ampicillin-Resistant Non-β-Lactamase-Producing Haemophilus influenzae in Spain: Recent Emergence of Clonal Isolates with Increased Resistance to Cefotaxime and Cefixime{triangledown}

Silvia García-Cobos,1 José Campos,1,2* Edurne Lázaro,3 Federico Román,1 Emilia Cercenado,4 César García-Rey,5 María Pérez-Vázquez,1 Jesús Oteo,1 and Francisco de Abajo3

Antibiotic Laboratory, Bacteriology Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain,1 Consejo Superior de Investigaciones Científicas, Madrid, Spain,2 División de Farmacovigilancia, Agencia Española del Medicamento, Madrid, Spain,3 Microbiology Department, Hospital Gregorio Marañón, Madrid, Spain,4 GlaxoSmithKline S.A., Madrid, Spain5

Received 16 March 2007/ Returned for modification 7 April 2007/ Accepted 20 April 2007

The sequence of the ftsI gene encoding the transpeptidase domain of penicillin-binding protein 3 (PBP 3) was determined for 354 nonconsecutive Haemophilus influenzae isolates from Spain; 17.8% of them were ampicillin susceptible, 56% were β-lactamase nonproducing ampicillin resistant (BLNAR), 15.8% were β-lactamase producers and ampicillin resistant, and 10.4% displayed both resistance mechanisms. The ftsI gene sequences had 28 different mutation patterns and amino acid substitutions at 23 positions. Some 93.2% of the BLNAR strains had amino acid substitutions at the Lys-Thr-Gly (KTG) motif, the two most common being Asn526 to Lys (83.9%) and Arg517 to His (9.3%). Amino acid substitutions at positions 377, 385, and 389, which conferred cefotaxime and cefixime MICs 10 to 60 times higher than those of susceptible strains, were found for the first time in Europe. In 72 isolates for which the repressor acrR gene of the AcrAB efflux pump was sequenced, numerous amino acid substitutions were found. Eight isolates with ampicillin MICs of 0.25 to 2 µg/ml showed changes that predicted the early termination of the acrR reading frame. Pulsed-field gel electrophoresis analysis demonstrated that most BLNAR strains were genetically diverse, although clonal dissemination was detected in a group of isolates presenting with increased resistance to cefotaxime and cefixime. Background antibiotic use at the community level revealed a marked trend toward increased amoxicillin-clavulanic acid consumption. BLNAR H. influenzae strains have arisen by vertical and horizontal spread and have evolved to adapt rapidly to the increased selective pressures posed by the use of oral penicillins and cephalosporins.

* Corresponding author. Mailing address: Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Pozuelo a Majadahonda, 28220 Majadahonda, Madrid, Spain. Phone: (34) 91-822-3650. Fax: (34) 91-509-7966. E-mail: jcampos{at}isciii.es

{triangledown} Published ahead of print on 30 April 2007.

Antimicrobial Agents and Chemotherapy, July 2007, p. 2564-2573, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.00354-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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