Sepsis or septic shock are associated with significant mortality and mortality with mortality estimates ranging from 20% to 50%. Appropriate antibiotic therapy is essential as failure to meet bactericidal or bacteriostatic pharmacokinetic and pharmacodynamic targets has been associated with poorer outcomes. The purpose of this study was to compare clinical outcomes in critically ill patients with sepsis or septic shock who were managed with piperacillin/tazobactam therapeutic drug monitoring (TDM)–based dose optimization versus fixed dosing.

Investigators performed a randomized, multicenter, patient-blinded, controlled trial of adult patients with severe sepsis or septic shock who were started on piperacillin/tazobactam per their prescriber's preference. Sepsis, which was defined by Sepsis-2 criteria, had to be diagnosed no more than 24 hours prior to randomization. Patients were excluded from this study if they had a contraindication to piperacillin/tazobactam, had impaired liver function (Child-Pugh C), were in palliative care, were pregnant or lactating, were participating in another clinical trial, or if their piperacillin/tazobactam concentration could not be measured within 24 hours of randomization.

Clinical, microbiological, and laboratory data were obtained daily from 1 day prior to randomization to Day 14, at the end of therapy, at discharge from the ICU, and at Day 28. The use of antimicrobial combinations as well as deprescribing or dose adjustments were left to the discretion of the prescribing clinician. Antimicrobial susceptibility testing was performed using EUCAST breakpoints.

This study was conducted from January 2017 to December 2019 in 13 sites in Germany[DL1]. Patients were randomized 1:1 to the intervention and control groups. Following a 4.5-gram loading dose of piperacillin/tazobactam, patients in the TDM-monitoring group received a continuous infusion of piperacillin/tazobactam for a total daily dosage of 13.5 grams (or 9 grams for those with an estimated glomerular filtration rate [eGFR] <20 mL/min). TDM of piperacillin/tazobactam was conducted daily for 10 days to maintain drug concentrations four times above the minimum inhibitory concentration for the causative organism. Drug concentrations were adjusted manually to maintain this drug exposure. In the control group, piperacillin/tazobactam dosing was only adjusted based on eGFR.

The primary endpoint was sepsis-related organ dysfunction as measured by total Sequential Organ Failure Assessment (SOFA) scores. These scores were assessed daily for 10 days, upon discharge from the ICU, or upon death. Secondary outcomes were 28-day all-cause mortality, mean SOFA sub-scores, duration of ICU and hospital stay, clinical and microbiological treatment response, intervention-free days off a ventilator, vasopressors, dialysis or antibiotics, pharmacokinetic/pharmacodynamic indices, Intensive Care Delirium Screening Checklist (ICDSC) results, and adverse events.  

A total of 249 patients—125 in the TDM group and 124 in the control group—were included in the study. The mean age of the study population was 66.3 years, and 69% were male. The most common pathogens isolated were E coli (17%), Klebsiella species (11.7%), and methicillin-susceptible S aureus.

Investigators found that there were no statistically significant differences between the TDM and control groups in mean SOFA scores (7.9 points in the TDM group vs. 8.2 points in the control group, P = .39), all-cause mortality at 28 days (21.6% vs. 25.8%, respectively, P = .44), mean duration of piperacillin/tazobactam therapy (4.8 days for each group, P = .81), overall duration of antibiotic therapy (6.8 days vs. 6.6 days, respectively, P = .7), mean total daily dose of piperacillin/tazobactam (10.3 grams vs. 9.8 grams, respectively, P = .12), neurological outcomes based on ICDSC scores (P = .68), or in the rate of adverse events (15.7% vs. 21.3%, respectively, P = .24). There was evidence of a higher rate of clinical and microbiological cure in the TDM versus the control group, but these also did not reach statistical significance (P = .30 and P = .12, respectively).

In the era of healthcare cost containment, this paper provides one more tool for pharmacists to help decide how to allocate scarce resources since the use of TDM may not be appropriate under all circumstances.

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