Status: Funded - Open
H. Rhodes Hambrick, MD
BACKGROUND: Sepsis is a leading cause of acute kidney injury (AKI) requiring continuous kidney replacement therapy (CKRT). Antibiotics are the standard of care for sepsis, with beta-lactams comprising the antibiotic class most prescribed. Cefepime is the beta lactam used most often in children receiving CKRT at our institution. Appropriate dosing for beta-lactams in children receiving CKRT is unknown, placing patients at risk of under-exposure with consequent inadequate antibacterial effect or excessive exposures resulting in toxicity. GAP: Dosing recommendations for antibiotics in children receiving CKRT are based on expert opinion and predominantly adult pharmacokinetic/pharmacodynamic (PK/PD) studies. Moreover, most of these dosing regimens do not account for differences in the CKRT prescription, such as the filter size, blood flow rate, and effluent flow rates, which can impact drug PK/PD. HYPOTHESIS: We hypothesize that variation in CKRT effluent flows (Qef, the dialysis dose) will explain ≥50% of variation in the ratio of extracorporeal clearance (CLEC) to total cefepime clearance and that higher Qef will predict decreased PD target attainment, i.e., % time that free concentrations exceed bacterial minimum inhibitory concentrations (% fT>MIC). Furthermore, we hypothesize that the mean estimates of CLEC from the CKRT module we have designed in the precision dosing software MwPharm++ will fall within 20% of actual CLEC obtained using real-world data. METHODS: This is a two-part study comprising in silico simulations using the precision dosing software MwPharm++ alongside a prospective study of children receiving CKRT and cefepime that involves rich sampling of the blood before and after the CKRT filter and from the CKRT effluent (dialysis waste fluid) to determine CLEC. RESULTS: Preliminary results from simulations suggest that extended (4h) or continuous (24h) infusions are superior to intermittent dosing for achieving 100% fT>MIC, particularly when targeting high MICs or with high dialysis doses. Additional simulations are underway, as is the prospective study. IMPACT: These studies will facilitate comprehensive PK/PD analysis of commonly used drugs in children on CKRT to facilitate prompt development of dosing guidelines. We anticipate providing precision dosing recommendations for cefepime using these new models within 2 years of study completion, whereafter we will move to study other drugs.