AUGMENTED RENAL CLEARANCE IMPLIES A NEED FOR INCREASED AMOXICILLIN-CLAVULANATE DOSING IN CRITICALLY ILL CHILDREN

BackgroundAmoxicillin/clavulanate is commonly used to treat community-acquired infections on the pediatric intensive care unit. Few data are available to guide dosing in this vulnerable population.MethodsThis prospective pharmacokinetic study enrolled patients admitted to the pediatric intensive care unit in whom intravenous amoxicillin-clavulanate was indicated (25-35mg/kg q6h). Serial blood samples were obtained following the first and steady-state doses and amoxicillin/clavulanate concentrations were measured by a validated high-pressure liquid chromatography (HPLC)-tandem mass spectrometry method. Population pharmacokinetic analysis and Monte Carlo simulations were conducted using NONMEM' 7.3.ResultsThree hundred twenty-five amoxicillin and 151 clavulanate blood samples were collected from 50 patients with a median age of 2.58 years (range: 0.08-15 years). A 3-compartment model for amoxicillin and a two-compartment model for clavulanate best described the data, in which allometric weight scaling and maturation functions were added a priori to scale for size and age. In addition, serum Cystatin C (sCysC) 'as a marker for renal function' and concomitant treatment with vasopressors were identified to have a significant influence on amoxicillin clearance. The typical population values of clearance for amoxicillin and clavulanate were 17.97L/H/70kg (95% CI:15.33-21.30L/H/70kg) and 12.20L/H/70kg (95% CI:10.54-14.55L/H/70kg), respectively. Four hourly dosing of 25mg/kg (based on the amoxicillin component) was required to achieve 40% of the dosing interval for amoxicillin concentrations to be above MIC, and for clavulanate levels to be maintained above 2mg/L. For patients with augmented renal function a 1hour infusion was preferable to bolus dosing to achieve the therapeutic target.ConclusionsCurrent dosing regimens result in subtherapeutic concentrations in the early period of sepsis due to augmented renal clearance, which risks treatment failure in critically ill children.