Abstract
BACKGROUND: Critically ill children are at risk for subtherapeutic antibiotic concentrations. The frequency of target attainment and risk factors for subtherapeutic concentrations of cefepime in children have not been extensively studied. METHODS: We performed an observational study in critically ill children receiving a new prescription of standard dosing of cefepime for suspected sepsis (≥2 systemic inflammatory response syndrome criteria within 48 hours of cefepime start). Three plasma cefepime concentrations were measured at steady state and, a urine sample was collected prior to pharmacokinetics (PK) sampling for measurement of urinary biomarkers. Bayesian analysis determined cefepime PK for each individual, and simulations were used to estimate time above minimum inhibitory concentration ( f T > MIC) for 8 µg/mL (breakpoint for Pseudomonas ). Clinical factors and urinary biomarkers were compared between patients who did and did not achieve 100% f T > MIC. Correlations between covariates and cefepime PK parameters, as well as optimal cut points to identify <100% f T > MIC, were evaluated. RESULTS: Twenty-one subjects were enrolled and PK sampling occurred after a median of 5 doses (range, 3-9); 43% of children achieved 100% f T > MIC for an MIC of 8 µg/mL. Younger age and lower urinary biomarkers (neutrophil gelatinase-associated lipocalin and kidney injury molecule-1) were significantly associated with failure to attain 100% f T > 8 µg/mL. Urinary neutrophil gelatinase-associated lipocalin (<122.1-ng/mg creatinine) best identified individuals who failed to attain this putative target (positive predictive value, 91.7%). CONCLUSIONS: A large proportion of critically ill children failed to attain target concentrations for empiric treatment of Pseudomonas aeruginosa with cefepime. Urinary biomarkers may be a noninvasive means to identify those at higher risk for increased cefepime clearance and subtherapeutic concentrations.