Association between augmented renal clearance, antibiotic exposure and clinical outcome in critically ill septic patients receiving high doses of β-lactams administered by continuous infusion: a prospective observational study

This study assessed whether augmented renal clearance (ARC) impacts negatively on antibiotic concentrations and clinical outcomes in patients treated by high-dose beta-lactams administered continuously. Over a 9-month period, all critically ill patients without renal impairment treated by one of the monitored beta-lactams for a documented infection were eligible. During the first 3 days of antibiotic therapy, every patient underwent 24-h CLCr measurements and therapeutic drug monitoring. The main outcome was the rate of beta-lactam underdosing, defined as a free drug concentration < 4 x MIC of the known pathogen. Secondary outcomes were rates of subexposure for beta-lactams and therapeutic failure. The performance of CLCr in predicting underdosing was assessed by a ROC curve, and multivariable logistic regression was performed to determine risk factors for subexposure and therapeutic failure. A total of 79 patients were included and 235 samples were analysed. The rate of underdosing(<4xMIC) was 12%, with a significant association with CLCr (P < 0.0001). A threshold of CLCr >= 170 mL/min had a sensitivity and specificity of 0.93 (95% CI 0.77-0.99) and 0.65 (95% CI 0.58-0.71) for predicting beta-lactam underdosing(<4xMIC). Mean CLCr values >= 170 mL/min were significantly associated with subexposure(<4xMIC) [OR = 10.1 (2.4-41.6); P = 0.001]. Patients with subexposure(<4xMIC) presented higher rates of therapeutic failure [OR = 6.3 (1.2-33.2); P = 0.03]. Mean CLCr values >= 170 mL/min remain a risk factor for subexposure to beta-lactams despite high doses of beta-lactams administered continuously. beta-Lactam subexposure was associated with higher rates of therapeutic failure in septic critically ill patients. (C) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.