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Cefepime or Piperacillin/tazobactam Empirically for Gram-negative Infections in the Hospital settings

Given the overlapping efficacy of cefepime and piperacillin-tazobactam against a broad spectrum of gram-negative bacteria, the decision to choose one over the other often hinges on the variance in their safety profiles, specifically concerning their adverse effects. Let's start by getting your opinion on the choice of antibiotics between these two options:

What is your preferred empiric antibiotic coverage for gram-negative infections in the hospital setting?

  • Cefepime

  • Piperacillin/tazobactam

  • Either one!

Piperacillin/tazobactam has been increasingly associated with acute kidney injury (AKI), particularly when used in conjunction with vancomycin. Since 2011, studies have shown that patients treated with this combination have higher rates of AKI compared to those treated with vancomycin and other beta-lactams. The risk of AKI is significantly greater when vancomycin is combined with piperacillin-tazobactam, compared to vancomycin monotherapy, vancomycin combined with cefepime or carbapenem, or piperacillin-tazobactam monotherapy [1, 2].

On the other hand, cefepime is known to cause neurotoxicity, particularly in critically ill patients. The primary mechanism of cefepime's neurotoxic effects is attributed to its ability to penetrate the blood-brain barrier and antagonize γ-aminobutyric acid (GABA). This action leads to various neurotoxic symptoms including depressed consciousness, encephalopathy, aphasia, myoclonus, seizures, and coma. The risk of cefepime-induced neurotoxicity is significantly elevated in patients with chronic kidney disease, especially in those receiving higher doses or with severe renal dysfunction. While not fully understood, the neurotoxic effects are believed to be caused by the inhibition of GABA-A receptors [3].

The comparative risks of AKI or neurological dysfunction associated with cefepime versus piperacillin-tazobactam have been recently addressed in a new study titled "The Antibiotic Choice on Renal Outcomes (ACRON)" This research represents a significant step towards understanding the differential impact of these antibiotics, specifically in the context of their neurotoxic and nephrotoxic potential in a clinical setting.

 The Antibiotic Choice on Renal Outcomes (ACRON)
The Antibiotic Choice on Renal Outcomes (ACRON)

The ACORN study is a randomized clinical study at a U.S. academic medical center from November 2021 to October 2022, compared the safety of cefepime and piperacillin-tazobactam in 2511 hospitalized adults. Participants, presenting to the emergency department or medical intensive care unit, were evenly randomized to receive either cefepime or piperacillin-tazobactam. The primary outcome evaluated was the highest stage of acute kidney injury or death by day 14. Secondary outcomes included the incidence of major adverse kidney events by day 14 and days alive without delirium and coma within 14 days. The results revealed no significant difference in acute kidney injury or death between the two groups, with 7.0% in the cefepime group (stage 3 kidney injury) and 7.6% deaths compared to 7.5% (stage 3 kidney injury) and 6.0% deaths in the piperacillin-tazobactam group. Major adverse kidney events were similar in both groups, occurring in 10.2% of the cefepime group and 8.8% of the piperacillin-tazobactam group. Notably, the cefepime group had more neurological dysfunction, evidenced by fewer days alive without delirium and coma (mean 11.9 days) compared to the piperacillin-tazobactam group (mean 12.2 days) [4].

From an intensivist's perspective, this study provides valuable insights into the safety profiles of two commonly used antibiotics in critical care settings. The findings suggest that neither cefepime nor piperacillin-tazobactam significantly increases the risk of acute kidney injury or death, offering flexibility in antibiotic selection based on patient-specific factors other than renal outcomes. However, the increased incidence of neurological dysfunction associated with cefepime is noteworthy. This underscores the importance of careful neurological monitoring in patients receiving cefepime, particularly in critical care where patients may be more vulnerable to such complications. The study's outcomes can guide intensivists in making informed decisions about antibiotic therapy, balancing the need for effective antipseudomonal treatment against the risk of adverse effects in critically ill patients.

Based on this review, how would answer the same question presented at the beginning of the post:

What is your preferred empiric antibiotic coverage for gram-negative infections in the hospital setting?

  • 0%Piperacillin/tazobactam

  • 0%Cefepime

  • 0%Either one!

  1. Navalkele B, Pogue JM, Karino S, Nishan B, Salim M, Solanki S, Pervaiz A, Tashtoush N, Shaikh H, Koppula S, Koons J, Hussain T, Perry W, Evans R, Martin ET, Mynatt RP, Murray KP, Rybak MJ, Kaye KS. Risk of Acute Kidney Injury in Patients on Concomitant Vancomycin and Piperacillin-Tazobactam Compared to Those on Vancomycin and Cefepime. Clin Infect Dis. 2017 Jan 15;64(2):116-123. doi: 10.1093/cid/ciw709. Epub 2016 Oct 20. PMID: 27986669.

  2. Luther MK, Timbrook TT, Caffrey AR, Dosa D, Lodise TP, LaPlante KL. Vancomycin Plus Piperacillin-Tazobactam and Acute Kidney Injury in Adults: A Systematic Review and Meta-Analysis. Crit Care Med. 2018 Jan;46(1):12-20. doi: 10.1097/CCM.0000000000002769. PMID: 29088001.

  3. Payne LE, Gagnon DJ, Riker RR, Seder DB, Glisic EK, Morris JG, Fraser GL. Cefepime-induced neurotoxicity: a systematic review. Crit Care. 2017 Nov 14;21(1):276. doi: 10.1186/s13054-017-1856-1. PMID: 29137682; PMCID: PMC5686900.

  4. 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(16):1557–1567. doi:10.1001/jama.2023.20583

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