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Multi-step selection of resistance in Haemophilus influenzae by amoxicillin/clavulanate, cefpodoxime, cefprozil, azithromycin, clarithromycin



Multi-step selection of resistance in Haemophilus influenzae by amoxicillin/clavulanate, cefpodoxime, cefprozil, azithromycin, clarithromycin



Abstracts of the Interscience Conference on Antimicrobial Agents & Chemotherapy 41: 198



Background: Widespread use of oral beta-lactams or macrolides in community-acquired respiratory tract infections caused by H. influenzae may lead to resistance. Objectives: Abilities of amoxicillin/clavulanate, cefpodoxime, cefprozil, azithromycin and clarithromycin to select R mutants of H. influenzae were tested by multi-step methodology. Methods: 5 random strains (3 beta-lactamase+) were tested. NCCLS microbroth MICs (mug/ml) in fresh Haemophilus Test Medium were: 0.5-2 (amox/clav); 0.03-0.06 (cefpodox); 4-256 (cefproz); 1-2 (azithro); 4-8 (clarithro). Serial subcultures of all drug/strain combinations except cefproz against 2 strains with MICs>128 mug/ml were done at subMIC in fresh HTM a maximum of 50 times (amox/clav; cefpodox) or until MICs rose at least 4X (cefproz, azithro, clarithro). R clones were subcultured 10X without drug: MICs of resultant clones to all drugs were done, and identity to parents confirmed by pulse field. Results: After 50 subcultures in amox/clav, MICs did not rise more than 2X (highest MIC 2 mug/ml). For cefpodox after 50 days, MICs (mug/ml) rose 4X to 0.25 in 1 strain and 2X to 0.125 mug/ml in 1 strain. For cefproz, 3 strains yielded a 2->4 fold increase after 32-50 days. Azithro gave a 4X increase in all 5 strains after 23-50 days and clarithro a 4X increase in 4/5 strains after 14-46 days. All R clones were identical to S parents by pulse-field. MICs of azithro-R clones were 16 mug/ml and those of clarithro-R clones 32-128 mug/ml. Strains selected by azithro had high clarithro MICs and vice versa, but strains selected by beta-lactams had azithro and clarithro MICs of parents. No parent or macrolide/azalide R strain had erm, mef or ereA genes. Conclusions: After 50 subcultures in presence of drugs, MICs of amox/clav against H. influenzae did not rise, in contrast to cefpodox, cefproz, azithro, clarithro, whose MICs rose to variable degrees.

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