Effect of Antibiotic Choice On ReNal Outcomes (ACORN)

Summary

Sepsis is one of the most common causes of acute illness and death in the United States. Early, empiric broad-spectrum antibiotics are a mainstay of sepsis treatment. Two classes of antibiotics with activity against Pseudomonas, anti-pseudomonal cephalosporins and anti-pseudomonal penicillins, are commonly used for acutely ill adults with sepsis in current practice. Recent observational studies, however, have raised concern that anti-pseudomonal penicillins may cause renal toxicity. Anti-pseudomonal cephalosporins, by comparison, may be associated with a risk of neurotoxicity. Rigorous, prospective data regarding the comparative effectiveness and toxicity of these two classes of medications among acutely ill patients are lacking. The investigator propose a randomized trial comparing the impact of anti-pseudomonal cephalosporins and anti-pseudomonal penicillins on renal outcomes of acutely ill patients.

Timeline

Start

2021-11-10

Primary completion

2022-10-21

Completion

2022-10-21

Publications

• Background Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. Lancet. 2018 Jul 7;392(10141):75-87. doi: 10.1016/S0140-6736(18)30696-2. Epub 2018 Jun 21.
• Background Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.1007/s00134-017-4683-6. Epub 2017 Jan 18.
• Background Liu VX, Fielding-Singh V, Greene JD, Baker JM, Iwashyna TJ, Bhattacharya J, Escobar GJ. The Timing of Early Antibiotics and Hospital Mortality in Sepsis. Am J Respir Crit Care Med. 2017 Oct 1;196(7):856-863. doi: 10.1164/rccm.201609-1848OC.
• Background Damiani E, Donati A, Serafini G, Rinaldi L, Adrario E, Pelaia P, Busani S, Girardis M. Effect of performance improvement programs on compliance with sepsis bundles and mortality: a systematic review and meta-analysis of observational studies. PLoS One. 2015 May 6;10(5):e0125827. doi: 10.1371/journal.pone.0125827. eCollection 2015.
• Background Thakar CV, Christianson A, Freyberg R, Almenoff P, Render ML. Incidence and outcomes of acute kidney injury in intensive care units: a Veterans Administration study. Crit Care Med. 2009 Sep;37(9):2552-8. doi: 10.1097/CCM.0b013e3181a5906f.
• Background Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005 Aug 17;294(7):813-8. doi: 10.1001/jama.294.7.813.
• Background Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, Edipidis K, Forni LG, Gomersall CD, Govil D, Honore PM, Joannes-Boyau O, Joannidis M, Korhonen AM, Lavrentieva A, Mehta RL, Palevsky P, Roessler E, Ronco C, Uchino S, Vazquez JA, Vidal Andrade E, Webb S, Kellum JA. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015 Aug;41(8):1411-23. doi: 10.1007/s00134-015-3934-7. Epub 2015 Jul 11.
• Background Gomez H, Kellum JA. Sepsis-induced acute kidney injury. Curr Opin Crit Care. 2016 Dec;22(6):546-553. doi: 10.1097/MCC.0000000000000356.
• Background Arnaud FCS, Liborio AB. Attributable nephrotoxicity of vancomycin in critically ill patients: a marginal structural model study. J Antimicrob Chemother. 2020 Apr 1;75(4):1031-1037. doi: 10.1093/jac/dkz520.
• Background Filippone EJ, Kraft WK, Farber JL. The Nephrotoxicity of Vancomycin. Clin Pharmacol Ther. 2017 Sep;102(3):459-469. doi: 10.1002/cpt.726. Epub 2017 Jun 5.
• Background Bellos I, Karageorgiou V, Pergialiotis V, Perrea DN. Acute kidney injury following the concurrent administration of antipseudomonal beta-lactams and vancomycin: a network meta-analysis. Clin Microbiol Infect. 2020 Jun;26(6):696-705. doi: 10.1016/j.cmi.2020.03.019. Epub 2020 Mar 25.
• Background Rutter WC, Burgess DR, Talbert JC, Burgess DS. Acute kidney injury in patients treated with vancomycin and piperacillin-tazobactam: A retrospective cohort analysis. J Hosp Med. 2017 Feb;12(2):77-82. doi: 10.12788/jhm.2684.
• Background Carreno J, Smiraglia T, Hunter C, Tobin E, Lomaestro B. Comparative incidence and excess risk of acute kidney injury in hospitalised patients receiving vancomycin and piperacillin/tazobactam in combination or as monotherapy. Int J Antimicrob Agents. 2018 Nov;52(5):643-650. doi: 10.1016/j.ijantimicag.2018.08.001. Epub 2018 Aug 10.
• Background Downes KJ, Cowden C, Laskin BL, Huang YS, Gong W, Bryan M, Fisher BT, Goldstein SL, Zaoutis TE. Association of Acute Kidney Injury With Concomitant Vancomycin and Piperacillin/Tazobactam Treatment Among Hospitalized Children. JAMA Pediatr. 2017 Dec 4;171(12):e173219. doi: 10.1001/jamapediatrics.2017.3219. Epub 2017 Dec 4.
• Background Kalligeros M, Karageorgos SA, Shehadeh F, Zacharioudakis IM, Mylonakis E. The association of acute kidney injury with the concomitant use of vancomycin and piperacillin/tazobactam in children: A systematic review and meta-analysis. Antimicrob Agents Chemother. 2019 Sep 9;63(12):e01572-19. doi: 10.1128/AAC.01572-19. Epub 2019 Oct 7.
• Background O'Callaghan K, Hay K, Lavana J, McNamara JF. Acute kidney injury with combination vancomycin and piperacillin-tazobactam therapy in the ICU: A retrospective cohort study. Int J Antimicrob Agents. 2020 Jul;56(1):106010. doi: 10.1016/j.ijantimicag.2020.106010. Epub 2020 May 12.
• Background Hammond DA, Smith MN, Painter JT, Meena NK, Lusardi K. Comparative Incidence of Acute Kidney Injury in Critically Ill Patients Receiving Vancomycin with Concomitant Piperacillin-Tazobactam or Cefepime: A Retrospective Cohort Study. Pharmacotherapy. 2016 May;36(5):463-71. doi: 10.1002/phar.1738. Epub 2016 Apr 1.
• Background Kang S, Park J, Yu YM, Park MS, Han E, Chang MJ. Comparison of acute kidney injury and clinical prognosis of vancomycin monotherapy and combination therapy with beta-lactams in the intensive care unit. PLoS One. 2019 Jun 5;14(6):e0217908. doi: 10.1371/journal.pone.0217908. eCollection 2019.
• Background Buckley MS, Hartsock NC, Berry AJ, Bikin DS, Richards EC, Yerondopoulos MJ, Kobic E, Wicks LM, Hammond DA. Comparison of acute kidney injury risk associated with vancomycin and concomitant piperacillin/tazobactam or cefepime in the intensive care unit. J Crit Care. 2018 Dec;48:32-38. doi: 10.1016/j.jcrc.2018.08.007. Epub 2018 Aug 11.
• Background Hammond DA, Smith MN, Li C, Hayes SM, Lusardi K, Bookstaver PB. Systematic Review and Meta-Analysis of Acute Kidney Injury Associated with Concomitant Vancomycin and Piperacillin/tazobactam. Clin Infect Dis. 2017 Mar 1;64(5):666-674. doi: 10.1093/cid/ciw811. Epub 2016 Dec 10.
• Background Molina KC, Barletta JF, Hall ST, Yazdani C, Huang V. The Risk of Acute Kidney Injury in Critically Ill Patients Receiving Concomitant Vancomycin With Piperacillin-Tazobactam or Cefepime. J Intensive Care Med. 2020 Dec;35(12):1434-1438. doi: 10.1177/0885066619828290. Epub 2019 Feb 10.
• Background 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.
• Background Abanades S, Nolla J, Rodriguez-Campello A, Pedro C, Valls A, Farre M. Reversible coma secondary to cefepime neurotoxicity. Ann Pharmacother. 2004 Apr;38(4):606-8. doi: 10.1345/aph.1D322. Epub 2004 Feb 24.
• Background Balderia PG, Chandorkar A, Kim Y, Patnaik S, Sloan J, Newman GC. Dosing Cefepime for Renal Function Does Not Completely Prevent Neurotoxicity in a Patient With Kidney Transplant. J Patient Saf. 2018 Jun;14(2):e33-e34. doi: 10.1097/PTS.0000000000000225.
• Qian ET, Casey JD, Wright A, Wang L, Shotwell MS, Siemann JK, Dear ML, Stollings JL, Lloyd BD, Marvi TK, Seitz KP, Nelson GE, Wright PW, Siew ED, Dennis BM, Wrenn JO, Andereck JW, Han JH, Self WH, Semler MW, Rice TW; 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 Oct 24;330(16):1557-1567. doi: 10.1001/jama.2023.20583.
• Qian ET, Casey JD, Wright A, Wang L, Siemann J, Dear ML, Stollings J, Lloyd BD, Seitz K, Nelson G, Wright P, Siew ED, Dennis B, Wrenn J, Andereck J, Self WH, Semler MW, Rice TW; 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 Mar 10;13(3):e066995. doi: 10.1136/bmjopen-2022-066995.

Drugs

Indications