Abstract
This study analyzes the pharmacokinetic variability of piperacillin in non-critically ill patients with Enterobacteriaceae bloodstream infections (EBSI) and explores predicted clinical outcomes and piperacillin-related neurotoxicity under different renal conditions. Hospitalized, non-critically ill patients treated with piperacillin–tazobactam for EBSI were included. Four serum samples per patient were collected and analyzed. A population pharmacokinetic model was developed using the Pmetrics package for R. Monte Carlo simulations of various dosage regimens of 4 g piperacillin, administered q8 h or q12 h by short (0.5 h) or long (4 h) infusion, following the different glomerular filtration rate (GFR) categories used to classify chronic kidney disease (Kidney Disease: Improving Global Outcomes, KDIGO) to determine the probability of target attainment (PTA) using a free drug concentrations above the minimal inhibitory concentration (fT > MIC) of 50% for efficacy and targets for piperacillin-associated neurotoxicity. Twenty-seven patients (102 samples) were included. Extended piperacillin infusions reached a PTA > 90% (50%fT > MIC) within the susceptibility range, although a loading dose did not greatly improve the expected outcome. Long infusions reduced the expected toxicity in patients with severe renal impairment. The study supports the use of extended infusions of piperacillin in non-critically ill patients with EBSI. No benefits of a loading dose were expected in our population. Finally, extended infusions may reduce the risk of toxicity in patients with severe renal impairment.
Highlights
Enterobacteriaceae infections are associated with increased morbidity and mortality [1,2,3], which is mainly related to delay in providing active therapy, together with the lower efficacy of certain alternative drugs compared with first-line antibiotics
Most studies included in systematic reviews and meta-analyses across a wide range of severely ill patients admitted to intensive care units (ICU) found significant benefits in terms of mortality and clinical cure associated with prolonged versus intermittent infusions of piperacillin–tazobactam (TZP) [8,9]
While there is an extensive published literature on piperacillin pharmacokinetics (PK) concerning variability in plasma concentrations and strategies aimed at optimizing efficacy in critically ill patients [11,12,13], there is scant information relating to non-critically ill patients
Summary
Enterobacteriaceae infections are associated with increased morbidity and mortality [1,2,3], which is mainly related to delay in providing active therapy, together with the lower efficacy of certain alternative drugs compared with first-line antibiotics. Most studies included in systematic reviews and meta-analyses across a wide range of severely ill patients admitted to intensive care units (ICU) found significant benefits in terms of mortality and clinical cure associated with prolonged versus intermittent infusions of piperacillin–tazobactam (TZP) [8,9]. Despite these obvious benefits, a survey on antimicrobial dosing in the ICU found wide variability in reported practices for TZP dosing and monitoring [10]. Quinton et al found that a serum concentration threshold of 157.2 mg/L is predictive of the occurrence of piperacillin neurotoxicity, [15] while Imani et al found that a piperacillin Cmin > 361.4 mg/L or > 452.65 mg/L was associated with a 50% risk of developing a neurotoxicity or nephrotoxicity event, respectively [16]
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