Thomas M Chapuis , Eric Giannoni , Paul A Majcherczyk , Rene Chiolero , Marie-Denise Schaller , Mette M Berger , Saskia Bolay , Laurent A Decosterd , Denis Bugnon and Philippe Moreillon. Critical Care 2010, 14:R51doi:10.1186/cc8941. Published: 1 April 2010
Abstract (provisional)
Introduction
Cefepime has been associated with a greater risk of mortality than other beta-lactams in patients treated for severe sepsis.
Hypotheses for this failure include possible hidden side-effects (e.g. neurological) or inappropriate pharmacokinetic/pharmacodynamic (PK/PD) parameters for bacteria with cefepime minimal inhibitory concentrations (MIC) at the highest limits of susceptibility (8 mg/l) or intermediate-resistance (16 mg/l) for pathogens such as Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. We examined these issues in a prospective non-interventional study of 21 consecutive intensive care unit (ICU) adult patients treated with cefepime for nosocomial pneumonia.
Methods
Patients (median age 55.1 years, range 21.8-81.2) received intravenous cefepime at 2 g every 12 hours for creatinine clearance (CLCr) > 50 ml/min, and 2g every 24 hours or 36 hours for CLCr < 50 ml/min. Cefepime plasma concentrations were determined at several time-points before and after drug administration by high-pressure liquid chromatography. PK/PD parameters were computed by standard non-compartmental analysis.
Results
17 first-doses and 11 steady states (i.e. 4-6 days after the first dose) were determined. Plasma levels varied greatly between individuals, from 2-3-fold at peak-concentrations to up to 40-fold at trough-concentrations. 19/21 (90%) patients had PK/PD parameters comparable to literature values. 21/21 (100%) patients had appropriate duration of cefepime concentrations above the MIC (T>MIC > 50%) for the pathogens recovered in this study (MIC < 4 mg/l), but only 45-65% of them had appropriate coverage for potential pathogens with cefepime MIC > 8 mg/l. Moreover, 2/21 (10%) patients with renal impairment (CLCr < 30 ml/min) demonstrated accumulation of cefepime in the plasma (trough concentrations of 20-30 mg/l) in spite of dosage adjustment. Both had symptoms compatible with non-convulsive epilepsy (confusion and muscle jerks) that were not attributed to cefepime-toxicity until plasma levels were disclosed to the caretakers and symptoms resolved promptly after drug arrest.
Conclusions
These empirical results confirm the suspected risks of hidden side-effects and inappropriate PK/PD parameters (for pathogens with upper-limit MICs) in a population of ICU adult patients. Moreover, it identifies a safety and efficacy window for cefepime doses of 2 g every 12 hours in patients with a CLCr > 50 ml/min infected by pathogens with cefepime MICs < 4 mg/l. On the other hand, prompt monitoring of cefepime plasma levels should be considered in case of lower CLCr or greater MICs.
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