Pharmacodynamics of Cefepime Alone and in Combination with Various Antimicrobials against Methicillin-Resistant Staphylococcus aureus in an In Vitro Pharmacodynamic Infection Model
Open Access
- 1 January 2005
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 49 (1), 302-308
- https://doi.org/10.1128/aac.49.1.302-308.2005
Abstract
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-log 10 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-log 10 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-log 10 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.Keywords
This publication has 48 references indexed in Scilit:
- Antibiotic heterogeneity: Should we use it? *Critical Care Medicine, 2003
- Stability and Antibacterial Activity of Cefepime during Continuous InfusionAntimicrobial Agents and Chemotherapy, 2003
- Pharmacokinetics and Pharmacodynamics of Cefepime in Patients with Various Degrees of Renal FunctionAntimicrobial Agents and Chemotherapy, 2003
- In Vitro Activities of Quinupristin-Dalfopristin and Cefepime, Alone and in Combination with Various Antimicrobials, against Multidrug-Resistant Staphylococci and Enterococci in an In Vitro Pharmacodynamic ModelAntimicrobial Agents and Chemotherapy, 2002
- In Vitro and In Vivo Activities of Tigecycline (GAR-936), Daptomycin, and Comparative Antimicrobial Agents against Glycopeptide-IntermediateStaphylococcus aureusand Other Resistant Gram-Positive PathogensAntimicrobial Agents and Chemotherapy, 2002
- Emergence of Methicillin-Resistant Staphylococcus aureus with Intermediate Glycopeptide ResistanceDrugs, 2001
- Pharmacodynamics of Intermittent- and Continuous-Infusion Cefepime Alone and in Combination with Once-Daily Tobramycin against Pseudomonas aeruginosa in an in vitro Infection ModelChemotherapy, 1999
- In-vitro bactericidal activity of cefpirome in combination with vancomycin against Staphylococcus aureus and coagulase-negative staphylococciJournal of Antimicrobial Chemotherapy, 1996
- Combination Antimicrobial Therapy for Bacterial InfectionsDrugs, 1996
- Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporinsDiagnostic Microbiology and Infectious Disease, 1995