Kevin Downes
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania
Disclosure information not submitted.
Anna Sharova, MPH
Clinical Research Coordinator
Children's Hospital of Philadelphia, United States
Disclosure information not submitted.
Lauren Gianchetti, MPH
Clinical Research Coordinator
Children's Hospital of Philadelphia, United States
Disclosure information not submitted.
Julie Fitzgerald, MD, PhD, FCCM
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania
Disclosure information not submitted.
Athena Zuppa, MD
Director, Center for Clinical Pharmacology
Children's Hospital of Philadelphia
Medford, NJ, United States
Disclosure information not submitted.
Title: Attainment of Cefepime Therapeutic Targets in Critically Ill
Introduction: The recommended therapeutic target for cefepime (FEP) in critically ill patients is a time above MIC of 100% (100% fT >MIC). We hypothesized that this target is not attained in most critically ill children, especially for higher MICs, and that measures of augmented renal clearance are associated with sub-optimal FEP concentrations.
Methods: We performed a prospective observational pilot study in children (< 19y) in our PICU receiving FEP for suspected sepsis (≥2 SIRS criteria). All received FEP at 50 mg/kg/dose (max 2g) q8h (standard therapy). Three FEP concentrations were measured per subject after ≥3 doses. A urine sample was collected prior to PK sampling for measurement of urinary biomarkers (NGAL, KIM-1, clusterin, osteopontin, cystatin C). We used log linear regression to calculate the T >MIC for each subject across a range of MIC values (1-64); the free fraction of FEP was assumed to be 61%. We tested the association between clinical factors (age, dose, eGFR [bedside Schwartz], vasopressors, biomarkers) and 100% T >MIC using chi-squared and Wilcoxon rank sum tests; Spearman correlation was tested between covariates and FEP troughs.
Results: 21 subjects were enrolled (38% female). The median age was 10.6y (range: 0.7-18.7). Two (10%) and 7 (33%) subjects had an eGFR < 60 or >200 mL/min/1.73 m2 at PK sampling, respectively. Median number of FEP doses prior to PK sampling was 5 (range 3-9). 95% of subjects achieved 100% T >MIC for an MIC of 1 mg/L, decreasing to 52% for an MIC of 4 and 33% for an MIC of 16 (cut-point for susceptibility of Pseudomonas). Younger age and higher eGFR were associated with failure to attain 100% fT >MIC for MIC of 4 and 16 mg/L. Only 1/11 patients (9%) with an eGFR >200 mL/min/1.73 m2 attained 100% fT >MIC for MIC of 4 (p = 0.02). Urinary NGAL and KIM-1 were higher in subjects who failed to attain 100% T >MIC for MIC of 4. Age (r=.53), eGFR (r=-.58), urinary NGAL (r=.42) and KIM-1 (r=.50) were correlated with FEP troughs.
Conclusions: A significant proportion of children with suspected sepsis failed to attain target concentrations for FEP. Younger age, higher eGFR, and lower urinary NGAL and KIM-1 were associated with failure to attain T >MIC targets. Urinary biomarkers may be a non-invasive means to screen for patients at risk for subtherapeutic FEP concentrations.