title: 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 > or = 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 > or = 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 > or = 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 > or = 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.
authors.affiliation: JMI Laboratories, North Liberty, Iowa 52317, USA.
authors.forename: H S
authors.initials: HS
authors.lastname: Sader
authors.forename: S M
authors.initials: SM
authors.lastname: Bhavnani
authors.forename: P G
authors.initials: PG
authors.lastname: Ambrose
authors.forename: R N
authors.initials: RN
authors.lastname: Jones
authors.forename: M A
authors.initials: MA
authors.lastname: Pfaller
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D011336:Probability; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins