Affiliation:
1. Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences
2. University of Wisconsin and Veterans' Affairs Hospital, Madison, Wisconsin
3. School of Medicine, Wayne State University, Detroit, Michigan 48201
Abstract
ABSTRACT
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 (10
5
and 10
7
) 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 (
f
AUCs) 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 ≥10
6
in the in vivo models. However, at a low inoculum (10
5
) 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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
88 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献