Is the use of piperacillin/tazobactam associated with risk of acute kidney injury?

Introduction
The combination β-lactam/ β-lactamase inhibitor piperacillin/tazobactam is among a handful of indispensable agents for empiric antimicrobial therapy in seriously ill patients due to its broad spectrum of activity, including against Pseudomonas aeruginosa, low cost, and wide range of tissue penetration.1 Many patients in this setting also receive vancomycin empirically to cover methicillin-resistant Staphylococcus aureus. Vancomycin is well known to carry risk of renal injury due to direct renal tubular toxicity.2 While β-lactams, including piperacillin/tazobactam, have potential to precipitate immune-mediated interstitial nephritis, evidence suggesting piperacillin/tazobactam may be associated with direct nephrotoxicity emerged only recently.3-5 The body of evidence supporting this notion is largely limited to retrospective studies suggesting risk of renal injury is increased with combined use of piperacillin/tazobactam with vancomycin compared with vancomycin monotherapy; these studies have led to cautions in guidelines and drug interaction databases regarding concomitant use of piperacillin/tazobactam and vancomycin.6-8

The inherent limitations of studies suggesting increased risk of renal toxicity with combined piperacillin/tazobactam and vancomycin use, as well as a lack of clinical data or mechanistic studies directly indicating that piperacillin/tazobactam has intrinsic propensity for nephrotoxicity, led some clinicians to question whether use of this combination truly increases the likelihood of kidney injury.9,10 This review summarizes key recent literature regarding the risk of nephrotoxicity with the use of piperacillin/tazobactam.

Literature review
Meta-analyses
Multiple recent meta-analyses have used other vancomycin-based combinations as comparators to elucidate the risk of nephrotoxicity with combined use of piperacillin/tazobactam and vancomycin. In a large network meta-analysis, Bellos and colleagues pooled data from over 56,000 patients across 47 studies in which treatment with vancomycin monotherapy or a vancomycin-antipseudomonal β-lactam combination was utilized for at least 24 hours and incidence of acute kidney injury (defined based on creatinine and/or urine output according to 1 of 4 major criteria standards) was included among reported outcomes.11-15 No randomized studies were identified. The median time to development of acute kidney injury was estimated to be approximately 4 days. Thirty-seven of the included studies evaluated adult populations, comprising most of the overall analysis population (over 53,000 patients). In this subset of patients, the likelihood of acute kidney injury was significantly higher with concurrent use of vancomycin with piperacillin/tazobactam than with vancomycin monotherapy (odds ratio [OR] 2.05; 95% confidence interval [CI] 1.17 to 3.46) or vancomycin with either meropenem (OR 1.84; 95% CI 1.02 to 3.10) or cefepime (OR 1.80; 95% CI 1.13 to 2.77). Similar findings were noted in the analysis of approximately 3500 pediatric patients.

Subgroup analysis did not suggest variability in the findings according to criteria set used to define acute kidney injury; however, rates of severe kidney injury did not appear to differ between regimens. Another recent meta-analysis limited to studies of adults who received vancomycin-based combinations in intensive care units (ICUs; approximately 30,000 patients) had similar findings.16

Randomized controlled trial
Debate over the retrospective studies suggestive of renal injury risk with piperacillin/tazobactam and vancomycin led to calls for prospective studies designed to address this question, which culminated in the recently-published randomized Antibiotic Choice on Renal Outcomes (ACORN) trial.17 In this pragmatic, single-center, open-label trial, adults who presented to an emergency department or were admitted to a medical ICU, were suspected to have an infection, and had an order for cefepime or piperacillin/tazobactam initiated within 12 hours of presentation were screened via an electronic health record-embedded tool, with an alert to the treating clinician for eligible patients. Patients who had received an antipseudomonal β-lactam within the preceding week or for whom the treating clinician determined that 1 of the 2 study antibiotics was a better option were excluded. Patients who enrolled were randomized 1:1 to receive cefepime 2 g via IV push every 8 hours or piperacillin/tazobactam 3.375 g via IV infusion over 4 hours every 8 hours (after an initial 30-minute bolus dose), or a standard renally-adjusted dose of the assigned agent. Use of additional antibiotics, including vancomycin, was at the discretion of the treating clinician. The primary outcome was a 5-level ordinal endpoint representing the highest stage of acute kidney injury (defined by Kidney Disease: Improving Global Outcomes serum creatinine criteria, with the highest stage [3] defined as creatinine ≥3 times the baseline level, creatinine ≥ 4.0 mg/dL, or new renal replacement therapy) or death between randomization and study day 14.14 Baseline creatinine was determined hierarchically with preference for creatinine values obtained prior to the index hospital admission followed by in-hospital, pre-enrollment values. For patients who had acute kidney injury at enrollment, the lowest creatinine level since enrollment was used as the baseline value, with new acute kidney injury defined as an increase of ≥ 0.3 mg/dL from baseline.

Among 2511 ACORN participants who received at least 1 dose of assigned treatment, median age was 58 years and nearly all (approximately 95%) were enrolled in the emergency department.17 A majority of patients (approximately 54% in each group) had sepsis and the most common suspected infection sources were intra-abdominal and pulmonary. Most patients (approximately 77% in each group) received IV vancomycin on the day of enrollment; median duration of study treatment and vancomycin were 3 and 2 days, respectively. Approximately 18% of patients in each group received at least 1 dose of the other study antibiotic. Additionally, approximately 7% of patients in each group received at least 1 dose of other extended-spectrum Gram-negative agents. In the primary analysis, no difference was identified in the highest stage of acute kidney injury or death with cefepime vs piperacillin/tazobactam (OR 0.95; 95% 0.80 to 1.13). Among patients who survived through day 14 of the study, approximately 17% of those assigned to cefepime and 21% of those assigned to piperacillin/tazobactam experienced acute kidney injury of any stage, including 7.0% and 7.5% who experienced stage 3 kidney injury, respectively. Approximately 7.6% of patients assigned to cefepime and 6.0% of those assigned to piperacillin/tazobactam died by day 14.

Sensitivity analysis of the primary outcome indicated similar findings to the primary analysis when restricted to patients with sepsis, by infection source, whether patients were receiving vancomycin, or to patients who received at least 48, 72, or 96 hours of assigned treatment. A prespecified analysis of major adverse kidney events (a composite of death, new renal replacement therapy, or creatinine ≥2 times baseline) censored at the earlier of hospital discharge or study day 14 indicated no difference between groups (risk difference 1.4%; 95% CI -1.0 to 3.8).17 However, a prespecified analysis of delirium- and coma-free days favored patients assigned to piperacillin/tazobactam (OR 0.79; 95% CI 0.65 to 0.95).

Discussion
The meta-analyses described above support an association between combined use of piperacillin/tazobactam with vancomycin and risk of renal injury; however, they carry important limitations that highlight issues with their evidence base.11,16 Neither of these studies (performed prior to publication of the ACORN trial) identified randomized trials for inclusion, and the analysis in ICUs consisted entirely of retrospective studies. Most of the included studies in both meta-analyses were at moderate to high risk of bias, and substantial study heterogeneity was noted by the authors for both analyses. Of particular concern would be the presence of confounding factors that may protect or predispose patients to renal injury, as well as differences in indications for antimicrobial therapy. Additionally, while both analyses included studies that utilized standardized kidney injury definitions, nearly all of the included studies exclusively used creatinine-based criteria to determine the incidence of acute kidney injury. Although measuring serum creatinine is among the simplest methods of evaluating renal function in clinical practice, it is an indirect indicator of renal injury with numerous limitations and potential confounders.18,19 Moreover, mounting laboratory and clinical data indicate that piperacillin/tazobactam impedes renal tubular secretion of creatinine (likely via competitive and/or non-competitive inhibition of organic anion transporters), prompting suggestions that associated creatinine elevations may not reflect true renal injury and are inappropriate for assessing piperacillin/tazobactam’s potential for nephrotoxicity.20,21

The ACORN trial is the most robust evidence available addressing this question and indicated no difference in the risk of acute kidney injury between piperacillin/tazobactam and cefepime, with or without concomitant vancomycin.17 While these findings are encouraging and many aspects of the study support external validity, the trial nevertheless has important limitations. Although the pragmatic study design integrated enrollment into routine decision-making for selecting empiric antipseudomonal antimicrobial therapy, its conduct at a single US center may not reflect practices that are standard at other centers. Additionally, the lack of blinding may have increased the risk of detection bias, particularly for the prespecified analysis of delirium- and coma-free days. Assessment of acute kidney injury using primarily creatinine-based criteria carries the inherent limitations outlined above, although an apparent lack of translation of any difference in this endpoint to increased risk of death or renal replacement therapy is encouraging. The study also utilized IV push dosing for cefepime, which has been postulated to lead to worse outcomes relative to intermittent or extended infusion, and used a lower dose and less frequent schedule for piperacillin/tazobactam than is often recommended for certain key indications.22-25 Additionally, a relatively large proportion of patients crossed over from one study drug to the other, which may dilute differences in treatment effects. Finally, the duration of assigned treatment in ACORN was relatively short; while this may be reflective of real-world use of these agents, studies supporting the association of concomitant piperacillin/tazobactam and vancomycin with acute kidney injury suggest length of therapy is an important risk factor and many cases may take up to 8 days to onset.26,27

Summary
A large body of evidence suggests an association between concomitant use of piperacillin/tazobactam with vancomycin and risk of acute kidney injury but consists primarily of retrospective studies with significant limitations. The ACORN randomized trial is the first interventional study to address this question and suggests that routine empiric use of this combination does not increase risk of acute kidney injury over cefepime plus vancomycin, but also carries important limitations related to how these agents were used and the duration of therapy. Additional prospective studies are needed to confirm these findings, particularly in patients at higher baseline risk of adverse outcomes and with a longer duration of treatment.

References

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Prepared by:
Michael Buege, PharmD, BCOP
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

December 2023

The information presented is current as November 21, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.