Comparing the Safety of Cefepime and Piperacillin-Tazobactam: The ACORN Trial
December 1, 2023
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By Jake Scott, MD
Clinical Assistant Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley
SYNOPSIS: Qian and colleagues conducted a pragmatic, open-label, randomized clinical trial to determine whether the empiric use of piperacillin-tazobactam or cefepime affects the risk of acute kidney injury (AKI) or neurological dysfunction in patients hospitalized for sepsis. The study showed no significant difference in the incidence of AKI between groups, but rates of neurological dysfunction were slightly higher in patients treated with cefepime.
SOURCE: Qian ET, Casey JD, Wright A, et al. Cefepime vs piperacillin-tazobactam in adults hospitalized with acute infection: The ACORN randomized clinical trial. JAMA 2023;330:1557-1567.
To address concerns about potential differences in renal toxicity, Qian and colleagues conducted a randomized clinical trial that compared the effect of cefepime vs. piperacillin-tazobactam on the incidence of acute kidney injury (AKI) among patients treated empirically for sepsis.1 This was a pragmatic, open-label, single-center study conducted at Vanderbilt University Medical Center. Patients 18 years of age or older were enrolled in the emergency department (ED) or medical intensive care unit (ICU) if an order for cefepime or piperacillin-tazobactam was initiated within 12 hours of presentation to the hospital. The trial was embedded within routine care by using a software application in the electronic health record (EHR) that immediately assessed whether a patient for whom a clinician ordered one of these two antibiotics was eligible for the study. Patients were excluded if they had previously received more than one dose of an anti-pseudomonal cephalosporin or anti-pseudomonal penicillin, had a documented allergy to penicillin or cephalosporins, were incarcerated, or if the treating clinician determined that one of the two drugs was more optimal than the other. Informed consent was waived since the interventions were used emergently as a part of routine care and since the study posed minimal risk.
Participants were randomized in a 1:1 ratio to receive either cefepime or piperacillin-tazobactam, and the order for the assigned antibiotic was facilitated by a clinical decision support tool (best-practices advisor) embedded in the EHR. Treatment assignment was unblinded to patients and clinicians after enrollment. Cefepime was administered as a 2-g intravenous (IV) push over five minutes every eight hours. No other anti-pseudomonal cephalosporins were available. Piperacillin-tazobactam was administered as a 3.375-g IV bolus over 30 minutes for the initial dose, followed by an extended infusion of 3.375 g every eight hours given over four hours for subsequent doses. The duration of therapy and whether to administer additional antibiotics, such as vancomycin and metronidazole, were decided by treating clinicians. During the first seven days after randomization, clinicians who ordered the unassigned antibiotic were reminded of the trial by an automated alert, but the orders were permitted.
The primary outcome was the highest stage of AKI or death within 14 days of randomization, measured on an ordinal scale. Stages of AKI were defined by the Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria: stage 0 (no AKI), stage 1 AKI (creatinine increased by 1.5-1.9 times baseline or an increase ≥ 0.3 mg/dL), stage 2 AKI (creatinine increase by 2.0-2.9 times baseline), stage 3 AKI (creatinine increased by ≥ 3.0 times baseline or an increase ≥ 4.0 mg/dL or requiring new renal replacement therapy [RRT]), and stage 4 (in-hospital mortality from any cause prior to hospital discharge). Secondary outcomes included the proportion of patients who experienced a major adverse kidney event at day 14 and the number of days alive and free of delirium and coma within 14 days.
A total of 2,511 patients were included in the primary analysis, 95% of whom had been enrolled in the ED. The median age of participants was 58 years (interquartile range [IQR], 43-69 years), and the median time between hospital presentation and enrollment was 1.2 hours (IQR, 0.4-3.5 hours). At baseline, 54% of patients were considered to have sepsis, according to the Sepsis-3 criteria, 13% were receiving vasopressors, and 8% were on mechanical ventilation.2 The most common suspected sources of sepsis included intra-abdominal, pulmonary, and skin and soft tissue. Baseline comorbidities were similar between the groups, as were their estimated degree of illness according to the Sequential Organ Failure Assessment (SOFA) score. Nine hundred forty-two patients (77.6%) in the cefepime group and 997 patients (76.9%) in the piperacillin-tazobactam group were given empiric vancomycin at the time of enrollment; the median duration of vancomycin was two days (IQR, 1-4 days). Crossover of antibiotic received was fairly common: 18.8% in the cefepime group and 17.2% in the piperacillin-tazobactam group received at least one dose of the unassigned antibiotic within 14 days of enrollment.
The primary outcome of highest stage of AKI or death by day 14 did not differ significantly between the two groups (odds ratio [OR], 95% confidence interval [CI], 0.80 to 1.13; P = 0.56). Nine hundred ten of 1,214 patients (75.0%) in the cefepime group and 952 of 1,297 patients (73.4%) in the piperacillin-tazobactam group did not die or experience AKI of any stage by day 14; 7.1% vs. 7.7%, respectively, experienced stage 1 AKI; 3.4% vs. 5.4% experienced stage 2 AKI; 7.0% vs. 7.5% experienced stage 3 AKI; and 7.6% vs. 6.0% died. Results were similar in the adjusted and prespecified sensitivity analyses.
There were no significant differences in the incidence of major adverse kidney events by day 14. Patients in the cefepime group had fewer days alive and free of delirium and coma within 14 days of enrollment as compared with patients in the piperacillin-tazobactam group (mean 11.9 vs. 12.2 days, respectively; OR, 0.79 [95% CI, 0.65 to 0.95]). Two hundred fifty-two patients (20.8%) in the cefepime group experienced delirium or coma within 14 days of enrollment, compared to 225 patients (17.3%) in the piperacillin-tazobactam group (absolute difference, 3.4% [95% CI, 0.3% to 6.6%]).
COMMENTARY
This trial by Qian and colleagues is remarkable for its clever leveraging of EHR software to enroll participants rapidly within a few hours of presentation to the hospital and for embedding the trial within routine care. A total of 3,806 patients were screened and 2,634 were randomized in less than one year, which is extraordinary. The investigators should be lauded for this novel trial design.
The study also provides quality clinical evidence that the risk of nephrotoxicity is unlikely higher with piperacillin-tazobactam than with another anti-pseudomonal beta-lactam antibiotic, even when the majority of patients received at least one dose of vancomycin, which is in contrast to findings from some prior observational studies. Previous meta-analyses of observational studies found that the particular combination of vancomycin with piperacillin-tazobactam was associated with an increased risk of AKI as compared with vancomycin combined with other beta-lactam antibiotics, including cefepime.3,4 These findings led the U.S. Food and Drug Administration (FDA) to issue a warning that the co-administration of piperacillin-tazobactam with vancomycin may result in additive nephrotoxicity, and to a shift in many hospitals away from the routine use of piperacillin-tazobactam combined with vancomycin for patients with sepsis.5
However, preclinical studies have not found this combination to cause additive nephrotoxicity.6 This discrepancy could be partly due to indication biases and unmeasured confounding in the retrospective studies, and also may be related to the clinical studies relying on estimated creatinine clearance as a proxy for kidney function rather than measuring glomerular filtration rates. A few studies have shown that piperacillin-tazobactam inhibits certain kidney proximal tubule cell transporters, leading to a decrease in the secretion of creatinine into the urine and an increase in creatinine levels in the blood, much like trimethoprim competes for potassium secretion, without actually affecting glomerular filtration rate when measured by cystatin C.7,8
In short, these studies and the ACORN trial suggest that the association between combination therapy with piperacillin-tazobactam and vancomycin and increased creatinine levels is artifactual and represents pseudotoxicity rather than true toxicity. The increased risk of neurotoxicity associated with cefepime, as found in this trial, has been less questionable, since it had been shown previously in preclinical and observational studies.9-11
There are several limitations to this trial. It was a single-center study, which may limit generalizability, and it was unblinded and open-label, which could lead to some degree of ascertainment bias (e.g., clinicians may have been more prone to investigate potential adverse effects previously associated with each study drug), although the number of clinical and laboratory assessments was similar between groups.
One important question is whether the duration of exposure was long enough to detect a significant difference. The median duration of therapy for each of the study drugs was only three days (IQR, 1-4 days), and patients only received vancomycin for a median duration of two days (IQR, 1-4 days). Although reports vary, one retrospective study found that the median time to onset of AKI for patients treated with vancomycin and piperacillin-tazobactam combination therapy was three days (IQR, 2-5 days), and the median time to onset of AKI with vancomycin and cefepime combination therapy was five days (IQR, 3-7 days).12 Another retrospective study found that the highest rates of AKI for patients treated with vancomycin plus piperacillin-tazobactam occurred on days 4 (10.7%) and 5 (19.3%).13
Although the authors of the ACORN trial noted that outcomes were similar among 1,798 patients who received longer courses, additional prospective investigations may be needed to elucidate whether there is a greater risk of AKI with longer courses. While it is ideal to minimize the unnecessary exposure to such broad-spectrum antibiotics, and to limit the duration of therapy to the first 24-48 hours while establishing a microbiologic diagnosis, these regimens often are prolonged in patients with undifferentiated sepsis. In addition to the relative duration of exposure to the study drugs, there also was significant crossover of antibiotics in each group for unclear reasons, which makes the distinction between interventions less clear.
Regarding the difference in rates of neurological dysfunction between patients treated with piperacillin-tazobactam compared to those treated with cefepime, the mean number of days alive and free of delirium and coma within 14 days of randomization only differed by 0.3 days (11.9 [standard deviation (SD), 4.6] days vs. 12.2 [SD, 4.3] days, respectively). The clinical significance of such a small difference may be minimal. Lastly, the extended dosing regimens for piperacillin-tazobactam varied from some other studies, and the data on cefepime administered as an IV push are limited, but there is some evidence that critically ill patients who receive cefepime as an IV push are more likely to experience treatment failure compared to those who receive cefepime via intermittent infusion.14
REFERENCES
- Qian ET, Casey JD, Wright A, et al. Cefepime vs piperacillin-tazobactam in adults hospitalized with acute infection: The ACORN randomized clinical trial. JAMA 2023;330:1557-1567.
- Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801-810.
- Luther MK, Timbrook TT, Caffrey AR, et al. Vancomycin plus piperacillin-tazobactam and acute kidney injury in adults: A systematic review and meta-analysis. Crit Care Med 2018;46:12-20.
- Giuliano CA, Patel CR, Kale-Pradhan PB. Is the combination of piperacillin-tazobactam and vancomycin associated with development of acute kidney injury? A meta-analysis. Pharmacotherapy 2016;36:1217-1228.
- Zosyn (piperacillin and tazobactam) highlights of prescribing information. Revised May 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/050684s88s89s90_050750s37s38s39lbl.pdf
- Chang J, Pais GM, Marianski S, et al. Iohexol-measured glomerular filtration rate and urinary biomarker changes between vancomycin and vancomycin plus piperacillin-tazobactam in a translational rat model. Antimicrob Agents Chemother 2023;67:e0030423.
- Wen S, Wang C, Duan Y, et al. OAT1 and OAT3 also mediate the drug-drug interaction between piperacillin and tazobactam. Int J Pharm 2018;537:172-182.
- Miano TA, Hennessy S, Yang W, et al. Association of vancomycin plus piperacillin-tazobactam with early changes in creatinine versus cystatin C in critically ill adults: A prospective cohort study. Intensive Care Med 2022;48:1144-1155.
- Payne LE, Gagnon DJ, Riker RR, et al. Cefepime-induced neurotoxicity: A systematic review. Crit Care 2017;21:276.
- Boschung-Pasquier L, Atkinson A, Kastner LK, et al. Cefepime neurotoxicity: Thresholds and risk factors. A retrospective cohort study. Clin Microbiol Infect 2020;26:333-339.
- Maan G, Keitoku K, Kimura N, et al. Cefepime-induced neurotoxicity: Systematic review. J Antimicrob Chemother 2022;77:2908-2921.
- Navalkele B, Pogue JM, Karino S, et al. Risk of acute kidney injury in patients on concomitant vancomycin and piperacillin-tazobactam compared to those on vancomycin and cefepime. Clin Infect Dis 2017;64:116-123.
- Karino S, Kaye KS, Navalkele B, et al. Epidemiology of acute kidney injury among patients receiving concomitant vancomycin and piperacillin-tazobactam: Opportunities for antimicrobial stewardship. Antimicrob Agents Chemother 2016;60:3743-3750.
- Smith SE, Halbig Z, Fox NR, et al. Outcomes of intravenous push versus intermittent infusion administration of cefepime in critically ill patients. Antibiotics (Basel) 2023;12:996.
Qian and colleagues conducted a pragmatic, open-label, randomized clinical trial to determine whether the empiric use of piperacillin-tazobactam or cefepime affects the risk of acute kidney injury (AKI) or neurological dysfunction in patients hospitalized for sepsis. The study showed no significant difference in the incidence of AKI between groups, but rates of neurological dysfunction were slightly higher in patients treated with cefepime.
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