Higher than standard dosing regimen are needed to achieve optimal antibiotic exposure in critically ill patients with augmented renal clearance receiving piperacillin-tazobactam administered by continuous infusion.

PURPOSE: To determine whether augmented renal clearance (ARC) impacts negatively on piperacillin-tazobactam unbound concentrations in critically ill patients receiving 16 g/2 g/day administered continuously. MATERIAL AND METHODS: Fifty nine critically ill patients without renal impairment underwent 24-h creatinine clearance (CrCL) measurement and therapeutic drug monitoring during the first three days of antimicrobial therapy by piperacillin-tazobactam. The main outcome was the rate of piperacillin underexposure, defined by at least one of three samples under 16 mg/L. Monte Carlo simulation was performed to predict the distribution of piperacillin concentrations for various CrCL and minimal inhibitory concentration (MIC) values. RESULTS: The rate of piperacillin underexposure was 19%, significantly higher in ARC patients (0 vs. 31%, p = .003). A threshold of CrCL ≥ 170 mL/min had a sensitivity and specificity of 1 (95%CI: 0.79-1) and 0.69 (95%CI: 0.61-0.76) to predict piperacillin underexposure. In ARC patients, a 20 g/2.5 g/24 h PTZ dosing regimen was associated with the highest probability to reach the 16 mg/L empirical target, without risk of excessive dosing. CONCLUSIONS: When targeting a theoretical MIC at the upper limit of the susceptibility range, the desirable target (100%fT>16) may not be achieved in patients with CrCL ≥ 170 mL/min receiving PTZ 16 g/2 g/day administered continuously.

Association between augmented renal clearance, antibiotic exposure and clinical outcome in critically ill septic patients receiving high doses of ß-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 ß-lactams administered continuously. Over a 9-month period, all critically ill patients without renal impairment treated by one of the monitored ß-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 ß-lactam underdosing, defined as a free drug concentration <4 × MIC of the known pathogen. Secondary outcomes were rates of subexposure for ß-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<4×MIC 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 ß-lactam underdosing<4×MIC. 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<4×MIC 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 ß-lactams despite high doses of ß-lactams administered continuously. ß-Lactam subexposure was associated with higher rates of therapeutic failure in septic critically ill patients.