We need to optimize piperacillin-tazobactam dosing in critically ill patients—but how?

Zander et al. [1] have recently conducted a prospective observational study to describe the variability of piperacillin (PIP) concentrations and target attainment in a heterogeneous cohort of 60 critically ill patients. An intermittent bolus dosing regimen of piperacillintazobactam (PIP-TAZ) was used 4.5 g three times daily (TID) or twice daily (BID), depending on renal function. As PIP-TAZ is largely renally excreted, it was unsurprising that the investigators found that no patient within the highest quartile of creatinine clearance (CrCl) attained specified pharmacokinetic/pharmacodynamic (PK/PD) targets (trough concentrations ≥22.5 mg/L) on days 1 or 4. These results are consistent with previous data showing that ‘augmented renal clearance’ (ARC), defined as a CrCl ≥130 mL/min [2], is frequently being associated with subtherapeutic PIP concentrations, even when dosing PIP-TAZ four times daily (QID) [2, 3]. Of more interest, however, was that the investigators found that 0 % and 55 % of patients with a CrCl >65 mL/min and 30–65 mL/min, respectively, attained the target PIP trough concentrations [1]. This is a very important finding as it highlights that initiating TID PIP-TAZ dosing as a blanket strategy in critically ill patients with ‘normal’ renal function or even mild to moderate renal impairment will not reliably attain PK/PD targets. In line with these findings, and perhaps reflective of the ongoing challenges with dose optimization in this group of patients, previous work has shown QID dosing of PIP-TAZ to be insufficient in achieving free PIP concentrations that are four times the target minimum inhibitory concentration (MIC) at 50 % of the dosing interval (50%fT>4xMIC), even in patients not displaying ARC [4, 5]. Solutions for target non-attainment of PIP-TAZ in intensive care unit (ICU) patients include use of prolonged infusions and therapeutic drug monitoring (TDM). Administering PIP-TAZ as a prolonged infusion—that is, either administering the antibiotic over half the dosing interval (e.g., over 3 h if given QID), or administering the total daily dose as a continuous infusion over 24 h after an initial loading dose—may help overcome subtherapeutic PIP concentrations in the critically ill [6]. There are now observational studies as well as randomized controlled trial (RCT) data that show increased likelihood of PIP concentrations being maintained above the MIC of pathogens using the prolonged infusion strategy [7–9]. Furthermore, there were higher rates of clinical cure associated with PIP-TAZ administered as a continuous infusion in the RCTs [7, 9]. Both of the RCTs included patients with mild to moderate renal impairment, and so, coupled with the results from the study by Zander et al. [1] showing PK/PD target attainment being problematic in these groups of patients via intermittent bolus dosing, the use of prolonged infusions may be a simple strategy that ICUs can employ. Notably, however, prolonged infusions may still not achieve therapeutic targets in certain groups of patients, such as those displaying ARC [10]. In these circumstances, dose uptitration may also be advisable, but can only be comfortably performed with use of TDM. To this end, a major challenge in determining optimal PIP-TAZ dosing for individual critically ill patients is the high inter-patient variability in serum PIP trough concentrations. Zander and investigators noted a 123-fold to >1785-fold range of PIP trough concentrations among their study patients, which was more pronounced in patients with higher creatinine clearances than those with * Correspondence: [email protected] Royal Brisbane and Women’s Hospital, Brisbane, Australia School of Medicine, The University of Queensland, Brisbane, Australia Full list of author information is available at the end of the article