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Antimicrobial Agents and Chemotherapy, June 2008, p. 2156-2162, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01046-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Activities of Clindamycin, Daptomycin, Doxycycline, Linezolid, Trimethoprim-Sulfamethoxazole, and Vancomycin against Community-Associated Methicillin-Resistant Staphylococcus aureus with Inducible Clindamycin Resistance in Murine Thigh Infection and In Vitro Pharmacodynamic Models

Kerry L. LaPlante,^1, Steven N. Leonard,¹ David R. Andes,³ William A. Craig,³ and Michael J. Rybak^1,2*

Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences,¹ School of Medicine, Wayne State University, Detroit, Michigan 48201,² University of Wisconsin and Veterans' Affairs Hospital, Madison, Wisconsin³

Received 8 August 2007/ Returned for modification 13 February 2008/ Accepted 6 April 2008

Controversy exists about the most effective treatment options for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and about 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. Strains with inducible macrolide lincosamide-streptogramin type B (iMLS_B) resistance and strains in which resistance was noninducible were evaluated. Two levels of 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 the free drug area-under-the-concentration-time curve values (fAUCs) obtained from human samples. When the activity of clindamycin against the iMLS_B strains was evaluated, constitutive resistance was noted at 24 h (MIC of >256), and failure was noted at an inoculum of 10⁶ in the in vivo models. However, at a low inoculum (10⁵) in the murine thigh-infection model, clindamycin demonstrated modest activity, reducing the CFU/thigh count for clindamycin resistance-inducible strains at 72 h (0.45 to 1.3 logs). Overall, administration of daptomycin followed by vancomycin demonstrated the most significant kill against all strains in both models. Against the clindamycin noninducible strain, clindamycin and doxycycline demonstrated significant kill. Doxycycline, linezolid, and trimethoprim-sulfamethoxazide (not run in the murine model) demonstrated bacteriostatic activity against clindamycin resistance-inducible isolates. This study demonstrates that clindamycin's activity against the iMLS_B strains tested is partially impacted by inoculum size. At present, there are several alternatives that appear promising for treating clindamycin resistance-inducible strains of CA-MRSA.

Published ahead of print on 14 April 2008.

Present address: University of Rhode Island, Department of Pharmacy Practice, Fogarty Hall, 41 Lower College Road, Kingston, RI 02881. E-mail: KerryTedesco{at}uri.edu.