AAC Accepts, published online ahead of print on 14 April 2008

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Antimicrob. Agents Chemother. doi:10.1128/AAC.01046-07
Copyright (c)2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Activity of Clindamycin Inducible Resistant Community Associated Methicillin Staphylococcus aureus versus Clindamycin, Daptomycin, Doxycycline, Linezolid, Trimethoprim/sulfamethoxazole and Vancomycin in Murine Thigh-Infection and In Vitro Pharmacodynamic Models

Kerry L. LaPlante, Steven N. Leonard, David R. Andes, William A. Craig, and Michael J. Rybak^*

Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, and School of Medicine, Wayne State University, Detroit, MI 48201, Univ. of Wisconsin and VA Hospital, Madison, WI

^* To whom correspondence should be addressed. Email: m.rybak{at}wayne.edu.

Controversy exists about the most effective treatment options for community associated methicillin resistant Staphylococcus aureus (CA-MRSA) and the ability of these strains to develop inducible resistance to clindamycin during therapy. Using both in vitro pharmacodynamic and murine thigh-infection models we evaluated and compared several antimicrobial compounds against CA-MRSA. Inducible Macrolide lincosamide-streptogramin type B (iMLS_B) resistant strains and non-inducible resistant strains were evaluated. Two inocula (10⁵ and 10⁷) were evaluated for clindamycin activity in the in vivo model. In both models, the antimicrobial evaluation was performed in triplicate and bacterial quantification occurred over 72 h with drug doses that were designed to simulate fAUCs obtained in humans. When evaluating the activity of clindamycin against the iMLSb strains, constitutive resistance was noted at 24h (MIC > 256) and failure was noted at an inoculum 10⁶ in the in vivo models. However, at low inoculum (10⁵) in the murine thigh-infection model, clindamycin demonstrated modest activity reducing CFU/thigh for clindamycin inducible strains at 72h (0.45- 1.3 logs). Overall, daptomycin followed by vancomycin demonstrated the most significant kill against all strains in both models. Against the clindamycin non-inducible strain, clindamycin and doxycycline demonstrated significant kill. Doxycycline, linezolid and TMP/SMX (not run in murine model) demonstrated bacteriostatic activity against clindamycin inducible resistant isolates. This study demonstrates that clindamycin's activity against the iMLSb strains tested is partially impacted by inoculum size. At present, there are several alternatives that appear promising in treating clindamycin inducible resistance strains of CA-MRSA.

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