• 1.

    Ohnuma T, et al. Epidemiology, resistance profiles, and outcomes of bloodstream infections in community-onset sepsis in the United States. Crit Care Med 2023; 51:11481158. doi: 10.1097/CCM.0000000000005870

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Ohnuma T, et al. Association of appropriate empirical antimicrobial therapy with in-hospital mortality in patients with bloodstream infections in the US. JAMA Netw Open 2023; 6:e2249353. doi: 10.1001/jamanetworkopen.2022.49353

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Tamma PD, et al. Infectious Diseases Society of America 2023 guidance on the treatment of antimicrobial resistant gram-negative infections. Clin Infect Dis (published online July 18, 2023). doi: 10.1093/cid/ciad428

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Su G, et al. Piperacillin/tazobactam and risk of acute kidney injury in adults hospitalized with infection without vancomycin: A multi-centre real-world data analysis. Int J Antimicrob Agents 2023; 61:106691. doi: 10.1016/j.ijantimicag.2022.106691

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Tang Girdwood S, et al. Relationship between piperacillin concentrations, clinical factors and piperacillin/tazobactam-associated acute kidney injury. J Antimicrob Chemother 2023; 78:478487. doi: 10.1093/jac/dkac416

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Almutairi MS, et al. Acute kidney injury associated with piperacillin-tazobactam versus other antibiotics combined with vancomycin in critically ill patients: A retrospective cohort study. Saudi Pharm J 2023; 31:101844. doi: 10.1016/j.jsps.2023.101844

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Alshehri AM, et al. Comparative risk of acute kidney injury following concurrent administration of vancomycin with piperacillin/tazobactam or meropenem: A systematic review and meta-analysis of observational studies. Antibiotics (Basel) 2022; 11:526. doi: 10.3390/antibiotics11040526

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Maan G, et al. Cefepime-induced neurotoxicity: Systematic review. J Antimicrob Chemother 2022; 77:29082921. doi: 10.1093/jac/dkac271

  • 9.

    Behal ML, et al. Cefepime induced neurotoxicity following a regimen dose-adjusted for renal function: Case report and review of the literature. Hosp Pharm 2022; 57:385391. doi: 10.1177/00185787211046856

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Qian ET, et al.; Vanderbilt Learning Healthcare System Platform Investigators. Protocol and statistical analysis plan for the Antibiotic Choice on Renal Outcomes (ACORN) randomised clinical trial. BMJ Open 2023; 13:e066995. doi: 10.1136/bmjopen-2022-066995

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Qian ET, et al.; Vanderbilt Center for Learning Healthcare and the Pragmatic Critical Care Research Group. Cefepime vs piperacillin-tazobactam in adults hospitalized with acute infection: The ACORN randomized clinical trial. JAMA 2023; 330:15571567. doi: 10.1001/jama.2023.20583

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Ford I, Norrie J. Pragmatic trials. N Engl J Med 2016; 375:454463. doi: 10.1056/NEJMra1510059

  • 13.

    Luther MK, et al. Vancomycin plus piperacillin-tazobactam and acute kidney injury in adults: A systematic review and meta-analysis. Crit Care Med 2018; 46:1220. doi: 10.1097/CCM.0000000000002769

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Cefepime versus Piperacillin-Tazobactam in Adults Hospitalized with Acute Infection: The ACORN Randomized Clinical Trial

Aiman Ajaz Aiman Ajaz, MD, is a second-year fellow, and Medha Airy, MD, MBBS, MPH, is an associate professor at the Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX.

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Medha Airy Aiman Ajaz, MD, is a second-year fellow, and Medha Airy, MD, MBBS, MPH, is an associate professor at the Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX.

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Gram-negative infections continue to be one of the main reasons for in-patient morbidity and mortality (1). An appropriate choice of an empiric antibiotic treatment has been associated with improved short-term outcomes with reduced risk of in-hospital mortality and death (2). The selection of empiric antibiotics is often determined by their efficacy and adverse effect profile. The Infectious Diseases Society of America recommends use of beta-lactam antibiotics for pseudomonas infection (3). Piperacillin-tazobactam and cefepime are the mainstay for empiric treatment for gram-negative coverage, specifically pseudomonas, and are often combined with vancomycin to provide gram-positive coverage as well (3). Numerous anecdotal and in vitro studies have indicated risk of acute kidney injury (AKI) with the use of piperacillin-tazobactam (47) and have reported neurological toxicity associated with the use of cefepime (8, 9).

Qian and colleagues (10, 11) recently published Antibiotic Choice on Renal Outcomes (ACORN), a pragmatic open-label randomized clinical trial that compares the use of piperacillin-tazobactam with cefepime in a real-life setting in patients diagnosed with infection and needing anti-pseudomonal coverage. It also compares risk of AKI and neurologic dysfunction (10, 11). This trial is another exemplary illustration of the role of pragmatic trials in the current era of lack of funding and industry-driven explanatory trials.

Pragmatic trials have been adopted in the last decade as a method of trial that provides evidence for adopting the intervention into real-world clinical practice (12). These trials emphasize external validity by adapting to the current practice patterns so that the outcomes can be generalized as they influence clinical or policy decision-making. Specific guidance and scoring systems were made available originally by using the Pragmatic Explanatory Continuum Indicator Summary (PRECIS) tool and were subsequently revised in PRECIS-2 to have parameters for assessing the degree of pragmatism while addressing ethical and regulatory issues (12).

PRECIS-2 has nine dimensions for assessing the level of pragmatism, and the study by Qian et al. (10, 11) meets most of these requirements (Table 1). The study included recruiting patients with suspected infection, a condition commonly presented in numerous health care facilities, aligning with the PRECIS-2 framework. Despite this, the study’s exclusive execution at a single tertiary care hospital in the United States could potentially skew the findings. While the procedures implemented could be mirrored in comparable settings, it is important to note that the same might not hold true for less-equipped institutions, a factor that should be considered separately from the core objectives of the study. The nature of follow-up is not entirely objective and may introduce a confirmation bias, as there might have been a tendency to look for neurological endpoints in the group receiving cefepime. The between-group difference of 0.3 days for being free of delirium and coma and being alive would likely not lead to a change in clinical practice. The outcome for these patients was censored at hospital discharge, which can lead to information bias. Lastly, PRECIS-2 focuses on the relevance of the primary outcome to the participants, and in this case, it affects them directly and meets this requirement. However, as the authors state, comparing two safety outcomes increases the chances of type 1 error, and this needs to be considered while interpreting the results.

Table 1

ACORN trial strengths and limitations

Table 1

It must be underscored that in the context of diminishing funding options and industry-driven research, this approach is the sole, viable means to assess an established treatment protocol and gather relevant data. The pragmatic trial design allowed them to obtain a waiver of informed consent and permit enrollment comparable to a real-world situation. This is of utmost importance, as it overcomes the biggest hurdle of enlisting patients in the trial process. Qian and colleagues (10, 11) concluded that the highest stage of AKI or death was not significantly different in the piperacillin-tazobactam and the cefepime group (odds ratio, 0.95 [95% CI, 0.80–1.13]; p = 0.56). However, patients in the cefepime group experienced fewer days alive and free of delirium and coma within the 14 days than did the piperacillin-tazobactam group (mean [SD], 11.9 [4.6] days [cefepime group] vs 12.2 [4.3] days [piperacillin-tazobactam group]; odds ratio, 0.79 [95% CI, 0.65–0.95]). These findings should help reduce hesitation among prescribers to use piperacillin-tazobactam due to concern of kidney injury, an apprehension that had grown significantly since its combined use with vancomycin that led to the warning for AKI among its users. This was based on a review and meta-analysis of the observational studies that concluded a higher incidence of AKI with the use of vancomycin and piperacillin-tazobactam compared with vancomycin monotherapy (odds ratio, 3.40 [95% CI, 2.57–4.50]) (13). With the ACORN study, prescribers should be reassured about the use of piperacillin-tazobactam.

Footnotes

The authors report no conflicts of interest.

References

  • 1.

    Ohnuma T, et al. Epidemiology, resistance profiles, and outcomes of bloodstream infections in community-onset sepsis in the United States. Crit Care Med 2023; 51:11481158. doi: 10.1097/CCM.0000000000005870

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Ohnuma T, et al. Association of appropriate empirical antimicrobial therapy with in-hospital mortality in patients with bloodstream infections in the US. JAMA Netw Open 2023; 6:e2249353. doi: 10.1001/jamanetworkopen.2022.49353

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Tamma PD, et al. Infectious Diseases Society of America 2023 guidance on the treatment of antimicrobial resistant gram-negative infections. Clin Infect Dis (published online July 18, 2023). doi: 10.1093/cid/ciad428

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Su G, et al. Piperacillin/tazobactam and risk of acute kidney injury in adults hospitalized with infection without vancomycin: A multi-centre real-world data analysis. Int J Antimicrob Agents 2023; 61:106691. doi: 10.1016/j.ijantimicag.2022.106691

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Tang Girdwood S, et al. Relationship between piperacillin concentrations, clinical factors and piperacillin/tazobactam-associated acute kidney injury. J Antimicrob Chemother 2023; 78:478487. doi: 10.1093/jac/dkac416

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Almutairi MS, et al. Acute kidney injury associated with piperacillin-tazobactam versus other antibiotics combined with vancomycin in critically ill patients: A retrospective cohort study. Saudi Pharm J 2023; 31:101844. doi: 10.1016/j.jsps.2023.101844

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Alshehri AM, et al. Comparative risk of acute kidney injury following concurrent administration of vancomycin with piperacillin/tazobactam or meropenem: A systematic review and meta-analysis of observational studies. Antibiotics (Basel) 2022; 11:526. doi: 10.3390/antibiotics11040526

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Maan G, et al. Cefepime-induced neurotoxicity: Systematic review. J Antimicrob Chemother 2022; 77:29082921. doi: 10.1093/jac/dkac271

  • 9.

    Behal ML, et al. Cefepime induced neurotoxicity following a regimen dose-adjusted for renal function: Case report and review of the literature. Hosp Pharm 2022; 57:385391. doi: 10.1177/00185787211046856

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Qian ET, et al.; Vanderbilt Learning Healthcare System Platform Investigators. Protocol and statistical analysis plan for the Antibiotic Choice on Renal Outcomes (ACORN) randomised clinical trial. BMJ Open 2023; 13:e066995. doi: 10.1136/bmjopen-2022-066995

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Qian ET, et al.; Vanderbilt Center for Learning Healthcare and the Pragmatic Critical Care Research Group. Cefepime vs piperacillin-tazobactam in adults hospitalized with acute infection: The ACORN randomized clinical trial. JAMA 2023; 330:15571567. doi: 10.1001/jama.2023.20583

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Ford I, Norrie J. Pragmatic trials. N Engl J Med 2016; 375:454463. doi: 10.1056/NEJMra1510059

  • 13.

    Luther MK, et al. Vancomycin plus piperacillin-tazobactam and acute kidney injury in adults: A systematic review and meta-analysis. Crit Care Med 2018; 46:1220. doi: 10.1097/CCM.0000000000002769

    • PubMed
    • Search Google Scholar
    • Export Citation
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