ACORN trial showed zosyn does not cause AKI

  • related: Nephrology
  • tags: #literature #nephrology

The patient has pneumonia and risk factors for drug-resistant organisms (recent IV antibiotic use), so he warrants empiric treatment with antipseudomonal agents. Long-standing debates in the literature have been argued over whether it is superior to use cefepime or piperacillin-tazobactam. Observational trials had suggested the possibility that piperacillin-tazobactam (particularly in the setting of vancomycin administration) was associated with acute kidney injury, whereas cefepime may be associated with neurological dysfunction, including impaired consciousness and seizures. Before 2023, data were largely limited to biased observational cohorts. The pragmatic ACORN trial, powered to detect an OR of 0.65, addressed the question in a randomized experiment. The trial was conducted among patients presenting to the emergency department or medical ICU within 12 h of hospital presentation, and the key findings in this trial in 2,511 patients (three-quarters of whom received concomitant vancomycin) were that there was no observable difference in acute kidney injury as tested using an ordinal scale that appropriately managed the competing risk of death. However, the group assigned to cefepime had lower odds of being free of death, coma, or delirium as measured using a delirium-free days score (OR, 0.79; 95% CI, 0.65-0.95). This finding was robust to multiple sensitivity analyses.

The correct answer is to substitute piperacillin-tazobactam for cefepime. This appears to be particularly true among patients who are experiencing impaired consciousness given the modest but statistically significant increase in coma and/or delirium observed with cefepime.

Long-standing debates about whether and when to add metronidazole or clindamycin for the treatment of patients with sepsis continue to this day. Metronidazole is sometimes recommended when serious Bacteroides infection is thought to be present, and metronidazole was commonly coadministered with cefepime in the ACORN trial. Most anaerobic bacteria are commensals and may even be protective on the basis of observational microbiome data, whereas Bacteroides (most notably Bacteroides fragilis) is not. Because there is no strong reason to suspect serious Bacteroides infection, and piperacillin-tazobactam has potent activity against anaerobes, metronidazole is not the best answer.

Linezolid is an oxazolidinone with activity (primarily bacteriostatic) against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). There is extensive controversy, backed by few if any randomized data (in large part due to the rarity of MRSA pneumonia), regarding whether linezolid should be substituted for vancomycin in MRSA pneumonias given superior lung penetration. Given the lack of high-quality randomized trial evidence and the lack of evidence in this patient for MRSA pneumonia, substituting linezolid for vancomycin is not the best answer.

Long-standing controversy and debate surround the practice of “double coverage” for Pseudomonas. Although it is true that in states associated with high biofilm burden (such as cystic fibrosis or bronchiectasis), complex multi-agent strategies may be required to combat resistant Pseudomonas aeruginosa infection, routine double coverage is not based in high-quality randomized evidence and is thus not the best answer.123456

Footnotes

  1. SEEK Questionnaires ↩

  2. Abanades S, Nolla J, Rodríguez-Campello A, et al. Reversible coma secondary to cefepime neurotoxicity. Ann Pharmacother. 2004;38(4):606-608. PubMed ↩

  3. Appa AA, Jain R, Rakita RM, et al. Characterizing cefepime neurotoxicity: a systematic review. Open Forum Infect Dis. 2017;4(4):ofx170. PubMed ↩

  4. Bellos I, Karageorgiou V, Pergialiotis V, et al. Acute kidney injury following the concurrent administration of antipseudomonal β-lactams and vancomycin: a network meta-analysis. Clin Microbiol Infect. 2020;26(6):696-705. PubMed ↩

  5. Blevins AM, Lashinsky JN, McCammon C, et al. Incidence of acute kidney injury in critically ill patients receiving vancomycin with concomitant piperacillin-tazobactam, cefepime, or meropenem. Antimicrob Agents Chemother. 2019;63(5):e02658-18. PubMed ↩

  6. Qian ET, Casey JD, Wright A, 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(16):1557-1567. PubMed ↩