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Antimicrobial Agents and Chemotherapy, March 2003, p. 1017-1022, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.1017-1022.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Effects of an Efflux Mechanism and Ribosomal Mutations on Macrolide Susceptibility of Haemophilus influenzae Clinical Isolates

Mihaela Peric,1 Bülent Bozdogan,1* Michael R. Jacobs,2 and Peter C. Appelbaum1

Department of Pathology, Hershey Medical Center, Hershey, Pennsylvania 17033,1 Case Western Reserve University, Cleveland, Ohio2

Received 25 September 2002/ Returned for modification 18 November 2002/ Accepted 19 December 2002

This study investigated macrolide resistance mechanisms in clinical Haemophilus influenzae strains with different levels of susceptibility to macrolides. A total of 6,382 isolates were collected during the Alexander Project from 1997 to 2000. For 96.9% of these isolates, the azithromycin MICs were 0.25 to 4 µg/ml, and these were defined as baseline strains. For 1.8% of the isolates, the azithromycin MICs were lower (<0.25 µg/ml), and for 1.3% of the isolates, the MICs were higher (>4 µg/ml). These isolates were defined as hypersusceptible and high-level macrolide-resistant strains, respectively. To identify the mechanisms associated with these three susceptibility patterns, representative strains were studied for the presence of macrolide efflux pumps and for ribosomal alterations. Macrolide efflux was studied by measuring the accumulation of radioactive azithromycin and clarithromycin in the presence or absence of carbonyl cyanide m-chlorophenylhydrazone (CCCP), a protonophore. Treatment with CCCP increased the accumulation of macrolides in baseline as well as high-level resistant strains, demonstrating the presence of an efflux mechanism, but not in the 20 hypersusceptible strains tested. Among the 31 strains studied that showed high-level resistance to both azithromycin and clarithromycin, 28 had ribosomal alterations, 7 had mutations in ribosomal protein L4, 11 had mutations in L22, 2 had mutations in 23S rRNA, 8 had multiple mutations, and 3 had no mutations. From these results, we conclude that the vast majority (>98%) of H. influenzae strains have a macrolide efflux mechanism, with a few of these being hyperresistant (1.3%) due to one or several ribosomal mutations. Occasional hypersusceptible strains (1.8%) were found and had no macrolide resistance mechanisms and appeared to be the only truly macrolide-susceptible variants of H. influenzae.

* Corresponding author. Mailing address: Department of Pathology, Hershey Medical Center, mail code H083, 500 University Dr., Hershey, PA 17033. Phone: (717) 531-3910. Fax: (717) 531-7953. E-mail: bozdogan-b{at}psu.edu.

Antimicrobial Agents and Chemotherapy, March 2003, p. 1017-1022, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.1017-1022.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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