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

• Published in: International journal of antimicrobial agents Vol. 51; no. 3; pp. 443 - 449
• Main Authors: Carrié, Cédric, Petit, Laurent, d'Houdain, Nicolas, Sauvage, Noemie, Cottenceau, Vincent, Lafitte, Melanie, Foumenteze, Cecile, Hisz, Quentin, Menu, Deborah, Legeron, Rachel, Breilh, Dominique, Sztark, Francois
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-03-2018
• Subjects: Augmented renal clearance; Critical illness; Sepsis; Therapeutic failure; β-Lactams; Critical illness; Sepsis; Therapeutic failure; β-Lactams; Augmented renal clearance
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2017.11.013

•In patients with augmented renal clearance, PK/PD targets may not be reached using high-dose continuous-infusion β-lactams.•Mean CLCr values ≥170 mL/min remain associated with higher rates of subexposure for β-lactams.•Subexposure<4×MIC is associated with higher rates of therapeutic failure.
This study assessed whether augmented renal clearance (ARC) impacts negatively on antibiotic concentrations and clinical outcomes in patients treated by high-dose β-lactams administered continuously. Over a 9-month period, all critically ill patients without renal impairment treated by one of the monitored β-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 β-lactam underdosing, defined as a free drug concentration <4 × MIC of the known pathogen. Secondary outcomes were rates of subexposure for β-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 β-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 β-lactams despite high doses of β-lactams administered continuously. β-Lactam subexposure was associated with higher rates of therapeutic failure in septic critically ill patients.