Evaluation of model–informed precision dosing of cefepime in critically ill patients: a French before– after study

Cefepime is widely used in the intensive care unit (ICU) for the treatment of complicated Gram-negative infections. Cefepime is a candidate for therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD), especially in critically ill patients, notably because of its concentration-dependent neurological toxicity. In this study, we aimed to evaluate the impact of the implementation of cefepime MIPD on PK/PD targets attainment in intensive care. We performed a monocentric, retrospective, before‒after study, including all adult patients hospitalized in our ICU and for whom at least two cefepime plasma through concentrations (C _min ) were measured on separate days. The main endpoint was a C _min between 4×MIC (or 10mg/L if the MIC was unavailable) and 20mg/L. We modelled the odds of target attainment via a mixed-effect logistic model and the rate of target attainment with a spline of time.

A total of 281 patients were included, of whom 121 were in the MIPD group and 160 in the control group. Median age, weight and follow-up duration were 65 years, 76 kg and 3 days respectively. The two most common infections were pneumonia (n=239) and peritonitis (n=16). A total of 728 cefepime through concentrations were collected. MIPD was non-significantly associated with higher odds of being in the therapeutic range (aOR 1.40 [0.88 – 2.22]) and significantly associated with lower odds of being over-exposed (aOR 0.58 [0.35 – 0.96]). HR of target attainment was 1.1 [0.7 – 1.9] at day 1 and 1.6 [0.9 – 2.9] at day 7.

In summary, we demonstrated that cefepime MIPD in the ICU reduces the risk of over-exposure, and may be beneficial on the odds and on the rate of PK/PD targets attainment.

What is already known about this subject

• Cefepime is a candidate for TDM/MIPD programs, with established PK/PD targets for both antimicrobial efficacy and neurological toxicity (100% f T >4×MIC and C _min >20mg/L, respectively).

• Previous randomized controlled trials (RCT) of beta-lactams model-informed precision dosing (MIPD) versus standard dosing approaches failed to demonstrate a superiority of MIPD in clinical endpoints attainment, and provided conflicting results on pharmacokinetic target attainment.

What this study adds

• Cefepime MIPD in the intensive care units reduces the odds of being over-exposed, and thus, possibly, the risk of elicit dose-dependent neurological toxicity.

• Further RCT evaluating MIPD efficacy should focus on evaluating target attainment rate instead of probability alone.