First dose target attainment with extended infusion regimens of piperacillin and meropenem

Abstract

Standard dosing regimens of meropenem and piperacillin-tazobactam frequently fail to achieve targeted plasma concentrations in critically ill patients. Extended or continuous regimens are often used to improve target attainment. Although prompt antibiotic initiation is a major determinant of survival, few studies have reported systemic concentrations early after treatment initiation. No prior study has reported concentrations immediately after the loading dose and first extended infusion. This study aimed to evaluate plasma target attainment during the first dosing interval with an extended infusion regimen in a general intensive care unit (ICU). Adult ICU patients were prospectively included in conjunction with the first administration of meropenem or piperacillin-tazobactam. Treatment was initiated with a 0.5 h loading dose immediately followed by a 3 h extended infusion; typically 4 + 4 g piperacillin or 1(− 2)g + 1(− 2)g meropenem, in line with the local ICU protocol. Patients requiring renal replacement therapy were excluded. Plasma concentrations were measured post-loading dose (Cmax), near the end of the first extended infusion, and at the end of the first dosing interval (Cmin). Samples were analyzed using validated tandem mass spectrometry (UHPLC-MS/MS) methods. The primary endpoint was the proportion of patients achieving 100% time above minimum inhibitory concentrations (fT > MIC) during the first dosing interval. This was evaluated using observed Cmin above 2 mg/L (meropenem) and 20 mg/L (piperacillin). Additionally, published pharmacokinetic models were applied to the observed data for %fT > MIC estimation, using an a posteriori Bayesian approach. We included 65 meropenem and 142 piperacillin measurements from 22 and 48 patients, respectively. Many patients (45% meropenem, 38% piperacillin) failed to reach 100% fT > MIC with the standard regimens used. Target non-attainment was associated with high estimated glomerular filtration rates (eGFR) and suspected augmented renal clearance (ARC). All meropenem patients that failed to reach target had eGFR > 90 mL/min/1.73 m2, as did 76% of corresponding piperacillin patients. Patients with suspected ARC frequently exhibited a tenfold or greater peak-to-trough decline (Cmin/Cmax < 0.1). Despite aggressive dosing, plasma concentrations often fail to reach 100% fT > MIC during the first dosing interval. Alternative regimens and early plasma concentration measurements followed by adaptive dose adjustments should be considered to improve target attainment.