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Effects of an efflux mechanism and ribosomal mutations on macrolide susceptibility of Haemophilus influenzae clinical isolates.
Antimicrob Agents Chemother. 2003 Mar; 47(3):1017-22.AA

Abstract

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 micro g/ml, and these were defined as baseline strains. For 1.8% of the isolates, the azithromycin MICs were lower (<0.25 micro g/ml), and for 1.3% of the isolates, the MICs were higher (>4 micro g/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.

Authors+Show Affiliations

Department of Pathology, Hershey Medical Center, Pennsylvania 17033, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12604536

Citation

Peric, Mihaela, et al. "Effects of an Efflux Mechanism and Ribosomal Mutations On Macrolide Susceptibility of Haemophilus Influenzae Clinical Isolates." Antimicrobial Agents and Chemotherapy, vol. 47, no. 3, 2003, pp. 1017-22.
Peric M, Bozdogan B, Jacobs MR, et al. Effects of an efflux mechanism and ribosomal mutations on macrolide susceptibility of Haemophilus influenzae clinical isolates. Antimicrob Agents Chemother. 2003;47(3):1017-22.
Peric, M., Bozdogan, B., Jacobs, M. R., & Appelbaum, P. C. (2003). Effects of an efflux mechanism and ribosomal mutations on macrolide susceptibility of Haemophilus influenzae clinical isolates. Antimicrobial Agents and Chemotherapy, 47(3), 1017-22.
Peric M, et al. Effects of an Efflux Mechanism and Ribosomal Mutations On Macrolide Susceptibility of Haemophilus Influenzae Clinical Isolates. Antimicrob Agents Chemother. 2003;47(3):1017-22. PubMed PMID: 12604536.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of an efflux mechanism and ribosomal mutations on macrolide susceptibility of Haemophilus influenzae clinical isolates. AU - Peric,Mihaela, AU - Bozdogan,Bülent, AU - Jacobs,Michael R, AU - Appelbaum,Peter C, PY - 2003/2/27/pubmed PY - 2003/8/15/medline PY - 2003/2/27/entrez SP - 1017 EP - 22 JF - Antimicrobial agents and chemotherapy JO - Antimicrob Agents Chemother VL - 47 IS - 3 N2 - 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 micro g/ml, and these were defined as baseline strains. For 1.8% of the isolates, the azithromycin MICs were lower (<0.25 micro g/ml), and for 1.3% of the isolates, the MICs were higher (>4 micro g/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. SN - 0066-4804 UR - https://www.unboundmedicine.com/medline/citation/12604536/Effects_of_an_efflux_mechanism_and_ribosomal_mutations_on_macrolide_susceptibility_of_Haemophilus_influenzae_clinical_isolates_ L2 - https://journals.asm.org/doi/10.1128/AAC.47.3.1017-1022.2003?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -