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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.

Objectives: 

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.

Methods: 

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%.

Results: 

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.

Conclusions: 

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
Subject:
Location: Oxford, UK
Presentation type:
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