Re-evaluation of the Role of Broad-Spectrum Cephalosporins Against Staphylococci by Applying Contemporary In-Vitro Results and Pharmacokinetic- Pharmacodynamic Principles

Abstract

The potency of cefepime, ceftriaxone, and ceftazidime was assessed by CLSI broth microdilution methods against 41,644 S. aureus (63.2% oxacillin-susceptible) and 14,266 coagulase-negative staphylococci (CoNS; 22.2% oxacillin-susceptible) through the SENTRY Antimicrobial Surveillance Program database (1998-2004). Using normal volunteer pharmacokinetic data and a linear intermittent intravenous infusion model, and an animal-derived pharmacokinetic/pharmacodynamic (PK-PD) target of ≥40% time above MIC, expected probabilities of target attainment (PTA) for cephems were evaluated using Monte Carlo simulation. Current CLSI breakpoints would rank the tested agents cefepime ≥ ceftriaxone > ceftazidime and by PK-PD PTA cefepime > ceftazidime > ceftriaxone. Cefepime has a potency advantage over ceftazidime (four- to eight-fold) and superiority at the usual dosing over ceftriaxone (22.7-66.1%) for oxacillin-susceptible staphylococci. Ceftazidime pharmacokinetic overcomes by-weight activity disadvantages, while a low proportion (<5%) of active free-drug penalizes ceftriaxone in the PTA calculations. PTA remained at ≥0.9 to a breakpoint of 8 mg/L for cefepime (1 g q8 or 12 hours) and ceftazidime and to a breakpoint of 2 mg/L for ceftriaxone. Regardless of applied breakpoint (CLSI or PKPD), cefepime has the widest and most potent anti-staphylococcal activity among commonly used “third- or fourth-generation” cephems. When used at doses ≥3 g/day, cefepime assures maximal coverage of oxacillin-susceptible staphylococci whether using existing (CLSI) or modified (PK-PD) breakpoints. Ceftriaxone should be used with caution.