Re-evaluation of the role of broad-spectrum cephalosporins against staphylococci applying contemporary in vitro results and pharmacokinetic-pharmacodynamic principals

Abstract number: p1553

Sader  H., Bhavnani  S.M., Ambrose  P.G., Jones  R.


To re-evaluate the current in vitro activity and to assess the PK-PD target attainment of cefepime (CPM), ceftriaxone (CRO) and ceftazidime (CAZ) against Staphylococcus spp.


The potency of CPM, CRO and CAZ against staphylococci was accessed through the SENTRY Antimicrobial Surveillance Program database, worldwide. During the 1998–2004 period 41,883 S. aureus (SA; 63% oxacillin [OXA]-susceptible [S]) and 14,349 coagulase-negative staphylococci (CoNS; 22% OXA-S) were S tested against CPM, CRO, CAZ and numerous comparators by CLSI broth microdilution methods. Using volunteer PK data and a linear intermittent intravenous infusion model, and an animal-derived PK-PD target of 25% time above MIC, expected probabilities of target attainment (PTA) for cephems were evaluated using Monte Carlo simulation. PTA were determined for the following dosing regimens: CPM 1gm q12 and q8 hours, CAZ 1 gm q8 hours and CRO 1 gm q24 hours, each representing the most common dosing patterns applied clinically. Cephem susceptibility (%S) was calculated based on the current CLSI (2006) breakpoints (BKPs) and also on BKPs derived from a PTA >90%.


Against OXA-S SA, MIC50/90 values were (in mg/L): 2/4 for CPM, 4/4 for CRO and 8/16 for CAZ, respectively; and against OXA-S CoNS MIC50/90 values were (in mg/L) 0.5/2 for CPM, 2/4 for CRO, and 4/8 for CAZ, respectively. The calculated %S of these cephems are summarized in the Table: Twenty year-old CLSI BKPs would rank the tested agents CPM >= CRO > CAZ and by PK-PD PTA CPM >= CAZ > CRO. CPM has a potency advantage over CAZ (4- to 8-fold) and superiority at the usual dosing over CRO (22.7–66.1%) for OXA-S staphylococci. CAZ PK overcomes by-weight activity disadvantages, while a low proportion (<5%) of active free-drug penalizes CRO in the PTA calculations. PTA remained at >90% to a BKP of 16 mg/L for CPM (1 gm q8) and CAZ and to a BKP of 2 mg/L for CRO.


Regardless of applied BKP (CLSI or PK-PD), CPM has the widest and more potent anti-staphylococcal activity among commonly used "third- or fourth-generation" cephems. When used at doses >= 3 gm/day, CPM assures maximal coverage of OXA-S staphylococci whether using existing (CLSI) or modified (PK/PD) BKPs. CRO should be used with caution.

Session Details

Date: 01/08/2007
Time: 00:00-00:00
Session name: XXIst ISTH Congress
Location: Oxford, UK
Presentation type:
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