AAC Accepts, published online ahead of print on 2 November 2009

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Antimicrob. Agents Chemother. doi:10.1128/AAC.01123-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

IN VITRO ACTIVITY OF CEM-101 AGAINST STREPTOCOCCUS PNEUMONIAE AND STREPTOCOCCUS PYOGENES WITH DEFINED MACROLIDE RESISTANCE MECHANISMS

Pamela McGhee, Catherine Clark, Klaudia Kosowska-Shick, Kensuke Nagai, Bonifacio Dewasse, Linda Beachel, and Peter C. Appelbaum^*

Hershey Medical Center, Hershey, PA 17033; and Kurume University School of Medicine, Kurume, Japan

^* To whom correspondence should be addressed. Email: pappelbaum{at}psu.edu.

CEM-101 had an MIC range against macrolide-susceptible pneumococci of 0.002-0.016 μg/ml and of 0.004-1 μg/ml against macrolide-resistant phenotypes. Only 3 strains with erm(B) ± mef(A) had CEM-101 MICs of 1 μg/ml and 218/221 strains had CEM-101 MICs 0.5 μg/ml. CEM-101 MICs were up to 4-fold lower than those of telithromycin against all strains. Against Streptococcus pyogenes, CEM-101 MICs ranged between 0.008-0.03 μg/ml against macrolide-susceptible, and 0.015-1 μg/ml against -resistant strains. Against erm(B) strains, erythromycin, azithromycin, clarithromycin MICs were 32->64 μg/ml while 17/19 strains had telithromycin MICs of 4 -16 μg/ml; CEM-101 MICs were 0.015-1 μg/ml. By comparison, erm(A) and mef(A) strains had CEM-101 MICs of 0.015-0.5 μg/ml, clindamycin and telithromycin MICs 1 μg/ml, with erythromycin, azithromycin and clarithromycin MICs of 0.5->64 μg/ml. Pneumococcal multistep resistance studies showed that although CEM-101 yielded clones with higher MICs in all 8 strains tested, 7 of 8 strains had clones with CEM-101 MICs which rose from 0.004-0.03 μg/ml (parents) to 0.06-0.5 μg/ml (resistant clones); in only 1 erm(B) + mef(A) strain with a parental MIC of 1 μg/ml was there a resistant clone with an MIC of 32 μg/ml with no detectable mutations in L4, L22, or 23S rRNA sequences. Among 2 of 5 S. pyogenes strains tested, CEM-101 MICs rose from 0.03– 0.25 μg/ml, and only in the 1 strain with erm(B) did CEM-101 MICs rise from 1 to 8 μg/ml with no changes occurring in any macrolide resistance determinant. CEM-101 had low MICs as well as low potential for selection of resistant mutants independent of bacterial species or resistance phenotypes in pneumococci and S.pyogenes.