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Antimicrobial Agents and Chemotherapy, December 2004, p. 4665-4672, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4665-4672.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Impact of High-Inoculum Staphylococcus aureus on the Activities of Nafcillin, Vancomycin, Linezolid, and Daptomycin, Alone and in Combination with Gentamicin, in an In Vitro Pharmacodynamic Model

Kerry L. LaPlante1,{dagger} and Michael J. Rybak1,2*

Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences,1 School of Medicine, Wayne State University, Detroit, Michigan2

Received 24 May 2004/ Returned for modification 22 July 2004/ Accepted 9 August 2004

We evaluated the impact of high (9.5 log10 CFU/g) and moderate (5.5 log10 CFU/g) inocula of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) on the activities of nafcillin, linezolid, vancomycin, and daptomycin, alone and in combination with gentamicin in an in vitro pharmacodynamic model with simulated endocardial vegetations over 72 h. Human therapeutic dosing regimens for nafcillin, daptomycin, vancomycin, linezolid, and gentamicin were simulated. At a moderate inoculum, nafcillin (MSSA only), vancomycin, and daptomycin demonstrated equivalent and significant (P < 0.01) bactericidal (99.9% kill) activities (decreases of 3.34 ± 1.1, 3.28 ± 0.4, and 3.34 ± 0.8 log10 CFU/g, respectively). Bactericidal activity was demonstrated at 4 h for nafcillin and daptomycin and at 32 h for vancomycin. Linezolid demonstrated bacteriostatic activity over the course of the study period. At a high inoculum, daptomycin exhibited bactericidal activity against both MSSA and MRSA by 24 h (decrease of 5.51 to 6.31 ± 0.10 log10 CFU/g). Nafcillin (versus MSSA), vancomycin, and linezolid (MSSA and MRSA) did not achieve bactericidal activity throughout the 72-h experiment. The addition of gentamicin increased the rate of 99.9% kill to 8 h for daptomycin (P < 0.01) and 48 h for nafcillin (MSSA only) (P = 0.01). The addition of gentamicin did not improve the activity of vancomycin or linezolid for either isolate for the 72-h period. Overall, high-inoculum Staphylococcus aureus had a significant impact on the activities of nafcillin and vancomycin. In contrast, daptomycin was affected minimally and linezolid was not affected by inoculum.

* Corresponding author. Mailing address: Anti-Infective Research Laboratory, Pharmacy Practice, 4148, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201. Phone: (313) 577-4376. Fax: (313) 577-8915. E-mail: m.rybak{at}wayne.edu.

{dagger} Present address: University of Rhode Island, Department of Pharmacy Practice, Kingston, RI 02881.

Antimicrobial Agents and Chemotherapy, December 2004, p. 4665-4672, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4665-4672.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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