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 inad- equate 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 (%integral T > 8; appropriate for the susceptible breakpoint for Pseudomonas aeruginosa). Factors predictive of low %integral T > 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 (inter -quartile range) %integral T > 8 for cefepime in the first 24 h of therapy based on this model was 85% (66%, 100%). Less than 100% integral T > 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 %integral T > 8. Central nervous sys- tem infection source was protective (i.e., associated with a higher %integral T > 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.