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

Abstract

Study ObjectiveIn 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.DesignProspective cohort study.SettingAcademic Medical Center.PatientsCritically ill adults treated with cefepime. Patients with acute kidney injury or treated with kidney replacement therapy or extracorporeal membrane oxygenation were excluded.InterventionNone.MeasurementsA 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 ResultsIn 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).ConclusionsDuring 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.

A New Dosing Frontier: Retrospective Assessment of Effluent Flow Rates and Residual Renal Function Among Critically Ill Patients Receiving Continuous Renal Replacement Therapy

“…This pragmatic dose escalation approach within the first 24 hours of CRRT initiation is similar to other dose optimization strategies geared toward the critically ill population (25–28). One noteworthy study was by Crass et al (26) regarding renal dosing of patients with AKI but not requiring dialysis.…”

Impact of Various Estimated Glomerular Filtration Rate Equations on the Pharmacokinetics of Meropenem in Critically Ill Adults

“…No samples were obtained during drug infusion. As has been previously described by our group (24), residual blood samples for this study were stored at 4°C for no more than 4 days before being pulled and frozen at –80°C for this study. Samples were thawed in batches approximately monthly, aliquoted, and serum was processed for meropenem, creatinine, and cystatin C concentrations.…”

Precision medicine in the ICU: One size fits one patient

“…[1][2][3][4][5][6][7][8] Additionally, original research manuscripts aimed toward optimizing dosing strategies provide valuable insight for bedside clinicians when crafting drug regimens. [9][10][11][12] The vast heterogeneity encountered with ICU patients provides the optimal setting to showcase thevalueofprecisionmedicine.Asclinicians,wemustembracethis step forward to better identify the right therapy for the right patient at the right time.…”

“…Contributions from an international team of thought leaders and experts provide a detailed overview of ICU topics in a systems‐based approach 1–8 . Additionally, original research manuscripts aimed toward optimizing dosing strategies provide valuable insight for bedside clinicians when crafting drug regimens 9–12 . The vast heterogeneity encountered with ICU patients provides the optimal setting to showcase the value of precision medicine.…”