Prospective monitoring of cefepime in intensive care unit adult patients

Abstract

IntroductionCefepime 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 (for example, 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.MethodsPatients (median age 55.1 years, range 21.8 to 81.2) received intravenous cefepime at 2 g every 12 hours for creatinine clearance (CLCr) ≥ 50 ml/min, and 2 g every 24 hours or 36 hours for CLCr < 50 ml/minute. 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.ResultsSeventeen first-doses and 11 steady states (that is, four to six days after the first dose) were measured. Plasma levels varied greatly between individuals, from two- to three-fold at peak-concentrations to up to 40-fold at trough-concentrations. Nineteen out of 21 (90%) patients had PK/PD parameters comparable to literature values. Twenty-one of 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 to 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/minute) demonstrated accumulation of cefepime in the plasma (trough concentrations of 20 to 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.ConclusionsThese 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/minute 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.

Pharmacokinetics and Pharmacodynamics of Piperacillin-Tazobactam in 42 Patients Treated with Concomitant CRRT

“…Several groups have shown the feasibility of b-lactam therapeutic drug monitoring in the general ICU population (27)(28)(29), and our data suggest that this monitoring may be particularly important in patients on CRRT. Our data suggest that a piperacillin dose of 9 g/d (piperacillin/tazobactam=3.375 g every 8 hours) may result in failure to reach the PD goal, and practitioners should consider using doses above 9 g/d in practice.…”

Defining Clinical Exposures of Cefepime for Gram-Negative Bloodstream Infections That Are Associated with Improved Survival

“…These previous studies lacked PK/PD data, which could be highly useful in interpreting observed outcomes. Very few studies have analyzed patient outcomes according to fT ϾMIC in cefepime-treated patients (12)(13)(14). As such, the necessary fT ϾMIC to prevent mortality for cefepime-treated patients with GNBSI is not well defined.…”

Application of Antibiotic Pharmacodynamics and Dosing Principles in Patients With Sepsis

“…19 Cefepime is a fourth-generation cephalosporin commonly used for nosocomial infections for which prolonged and continuous infusions have been evaluated. [20][21][22][23][24][25][26] The concern about achieving appropriate T > MIC with traditional dosage regimens (eg, 1-2 g every 8-12 hours infused over 30 minutes) for cefepime is similar to the concerns for piperacillin/tazobactam in critically ill patients at risk for resistant pathogens. [21][22][23][24][25] Data suggest prolonged or continuous infusion strategies may provide higher T > MIC and increase the probability that the infection will be resolved.…”

“…[20][21][22][23][24][25][26] The concern about achieving appropriate T > MIC with traditional dosage regimens (eg, 1-2 g every 8-12 hours infused over 30 minutes) for cefepime is similar to the concerns for piperacillin/tazobactam in critically ill patients at risk for resistant pathogens. [21][22][23][24][25] Data suggest prolonged or continuous infusion strategies may provide higher T > MIC and increase the probability that the infection will be resolved. 22,23,26 Changing the duration of infusion to 6 hours or administering a single 2000-mg loading dose followed by 24-hour continuous infusion of 4000 mg increases the probability of optimal T > MIC by 30% across different levels of renal function and pathogen MICs.…”