Adequacy of cefepime concentrations in the early phase of critical illness: A case for precision pharmacotherapy

Study Objective: In critically ill patients, adequacy of early antibiotic exposure has been incompletely evaluated. This study characterized factors associated with inadequate cefepime exposure in the first 24 h of critical illness. Design: Prospective cohort study. Setting: Academic Medical Center. Patients: Critically ill adults treated with cefepime. Patients with acute kidney injury or treated with kidney replacement therapy or extracorporeal membrane oxygenation were excluded. Intervention: None. Measurements: A nonlinear mixed-effects pharmacokinetic (PK) model was developed to estimate cefepime concentrations for each patient over time. The percentage of time the free drug concentration exceeded 8 mg/L during the first 24 h of therapy was calculated (%ƒT>8; appropriate for the susceptible breakpoint for Pseudomonas aeruginosa). Factors predictive of low %ƒT>8 were explored with multivariable regression. Main Results: In the 100 included patients, a one-compartment PK model was developed with first-order elimination with covariates for weight and estimated glomerular filtration rate based on creatinine and cystatin C (eGFRSCr-CysC). The median (interquartile range) %ƒT>8 for cefepime in the first 24 h of therapy based on this model was 85% (66%, 100%). Less than 100% ƒT>8 during first 24 h of therapy occurred in 70 (70%) individuals. Lower Sequential Organ Failure Assessment score (p = 0.032) and higher eGFRSCr-CysC (p < 0.001) predicted a lower %ƒT>8. Central nervous system infection source was protective (i.e., associated with a higher %ƒT>8; p = 0.008). Conclusions: During early critical illness, cefepime concentrations were inadequate in a significant proportion of patients. Antimicrobial optimization is needed to improve the precision of pharmacotherapy in the critically ill patients.