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Antimicrobial Agents and Chemotherapy, January 2005, p. 302-308, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.302-308.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pharmacodynamics of Cefepime Alone and in Combination with Various Antimicrobials against Methicillin-Resistant Staphylococcus aureus in an In Vitro Pharmacodynamic Infection Model

Vanthida Huang1,2,{dagger} and Michael J. Rybak1,2,3*

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences,1 School of Medicine,3 Wayne State University, Detroit Receiving Hospital, Detroit, Michigan2

Received 24 May 2004/ Returned for modification 16 August 2004/ Accepted 12 September 2004

Treatment options for gram-positive resistant bacteria are limited; therefore, efforts to evaluate therapy options in the critical care population are warranted. Cefepime has broad-spectrum activity against gram-negative and gram-positive organisms. We have previously demonstrated that the combination of cefepime with vancomycin, linezolid, or quinupristin-dalfopristin had an improved or enhanced effect against methicillin-resistant Staphylococcus aureus (MRSA). We investigated various regimens of cefepime alone and in combination against two clinical MRSA isolates (R2481 and R2484) in an established in vitro pharmacodynamic model. Human pharmacokinetic regimen simulations were as follows: cefepime, 2 g every 8 h (q8h) (C8) and 12 h (C12), continuous-infusion 2-g loading dose followed by 4 g alone or in combination with gentamicin and tobramycin (1.0 or 2.0 [G1 and G2 or TB1 and TB2] mg/kg of body weight q12h and 5.0 [G5 or TB5] mg/kg q24h), arbekacin (ARB) (100 mg q12h), linezolid (LIN) (600 mg q12h), tigecycline (TIG) (100 mg q24h), or daptomycin (DAP) (6 mg/kg q24h) for 48 h. The MICs for cefepime, gentamicin, tobramycin, ARB, LIN, TIG, and DAP for the two clinical MRSA isolates (R2481 and R2484) were 4 and 4, 0.25 and 0.5, 128 and 0.5, 0.5 and 0.125, 2 and 4, 0.25 and 0.25, and 0.0625 and 0.125 µg/ml, respectively. At 48 h, combinations of C12 and C8 plus ARB, G1, or G5 (range, –2.05- to –4.32-log10 decrease) demonstrated enhanced lethality against R2481 (resistant to tobramycin) (P < 0.05). A similar relationship was demonstrated against R2484 with cefepime plus ARB, gentamicin, or tobramycin (range, –2.05- to –3.63-log10 decrease) (P < 0.05). A 99.9% kill was achieved with cefepime plus aminoglycoside combinations as early as 2 h and maintained throughout the 48-h period. TIG was antagonistic when combined with C12 against both isolates. DAP alone achieved 99.9% kill for up to 48 h for both isolates and was the most active agent against R2481 and R2484 (–2.89- and –3.61-log10 decrease at 48 h); therefore, combination therapy did not enhance lethality. Overall, the most potent combinations noted were cefepime in combination with low- and high-dose aminoglycosides. Further investigations with combination therapies are warranted.

* Corresponding author. Mailing address: Anti-Infective Research Laboratory, Pharmacy Practice-4148, Eugene Applebaum College of Pharmacy and 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: Department of Clinical and Administrative Sciences, Southern School of Pharmacy, Mercer University, Atlanta, GA 30341.

Antimicrobial Agents and Chemotherapy, January 2005, p. 302-308, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.302-308.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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