All Pharmacy Pearls

Introduction

  • Vancomycin and piperacillin-tazobactam are combined for broad-spectrum antibiotic coverage including

    • MRSA and Pseudomonas in hospitalized patients.

  • AKI, often as acute tubular necrosis, is a known complication of vancomycin, especially with higher doses and

    • co-administration of nephrotoxic drugs.

  • Piperacillin-tazobactam alone has minimal nephrotoxicity (<1%); its nephrotoxicity is usually due to acute

    • interstitial nephritis.

  • Reported AKI rates vary in literature based on AKI definition and target population.
  • Both drugs affect OAT1/3 transporters in the kidney, which are crucial for creatinine clearance and are

    • especially significant in patients with CKD.

Clinical Detail

    Vancomycin

    Piperacillin-tazobactam4

    Dose

    • Depends on infection and PK/PD target

    • General dosing for systemic infections: IV 15-

    20 mg/kg IV Q8-12H for systemic infections

    • Standard infusion: 3.375 g IV Q6H over 30 min

    • Antipseudomonal: 4.5 g IV Q6-8H over 30 min

    • Extended infusion: 4.5 g IV then 3.375-4.5 g over 4

    hours Q8H

    Administration

    Administer IV over >=60 minutes at concentrations

    <=5 mg/mL to reduce the risk of vancomycin

    infusion reaction

    Standard infusion: Infuse over 30 min

    Extended infusion: Infuse loading dose over 30 min, start

    maintenance dose four hours later infused over 4 hours

    PK/PD

    Negligible oral bioavailability

    T1/2 = 4-6 hours

    Renally eliminated (40-100% unchanged)

    AUC:MIC dependent kinetics, PK/PD target

    AUC/MIC >=400 µg/mL; surrogate serum trough

    concentrations often used

    T1/2 = 0.7-1.2 hours

    Renally eliminated (80% unchanged)

    Dose adjust at CrCl<40

    T>MIC dependent kinetics, prolonged infusions enhance

    efficacy

    Adverse

    Effects

    Nephrotoxicity

    Ototoxicity

    Vancomycin-infusion reaction (flushing,

    hypotension, tachycardia)

    GI upset (diarrhea, nausea, constipation)

    Headache

Evidence

    Author, year

    Design/ sample size

    Intervention &

    Comparison

    AKI definition

    Outcome

    Sanz et al.,

    2002

    Prospective, multi-center

    (n = 969)

    Amikacin+cefepime vs.

    amikacin+piperacillin-

    tazobactam

    • increased SCr >=50% from

    baseline

    • No difference in severe nephrotoxicity between

    amikacin+piperacillin-tazobactam vs.

    amikacin+cefepime

    Karino et al.,

    2016

    Retrospective cohort

    and nested case-control

    studies

    (n = 320)

    Vancomycin+piperacillin-

    tazobactam standard

    infusion vs.

    Vancomycin+piperacillin-

    tazobactam extended-

    infusion

    • RIFILE criteria

    • AKIN criteria

    • Vancomycin

    consensus

    guideline

    definition

Conclusions

    • Since 2011, evidence indicates combined vancomycin+ piperacillin-tazobactam may be nephrotoxic.

    • Most studies were retrospective, defining nephrotoxicity by creatinine-based AKI.

    • Recent data show this AKI definition doesn’t align with severe AKI outcomes (hemodialysis/mortality).

    • Non-tubular secretion biomarkers (Cystatin C, BUN) didn’t show the same AKI increase.

    • Despite >50 studies linking the drug combo with AKI, some expert report true renal risk is likely minimal.

    • In emergencies, timely antibiotic use is vital; nephrotoxicity concerns shouldn’t delay this combo, especially for short use.

    (Caroline Rosario & [email protected]

References

    • Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved October 4, 2023, from

    http://www.micromedexsolutions.com/

    • VANCOMYCIN HYDROCHLORIDE [package insert]. Rockford, IL: Mylan Institutional LLC; Jul, 2018.

    • Blair M, Côté JM, Cotter A, Lynch B, Redahan L, Murray PT. Nephrotoxicity from Vancomycin Combined with Piperacillin-Tazobactam: A

    Comprehensive Review. Am J Nephrol. 2021;52(2):85-97. doi: 10.1159/000513742.

    • Pill MW, O’Neill CV, Chapman MM, Singh AK. Suspected acute interstitial nephritis induced by piperacillin-tazobactam.

    Pharmacotherapy. 1997 Jan-Feb;17(1):166-9..

    • Li H, Yang Q, Gui M, Ding L, Yang L, Sun H, Li Z. Changes of renal transporters in the kinetic process of VCM-induced nephrotoxicity in

    mice. Toxicol Res (Camb). 2021 Jun 9;10(4):687-695. doi: 10.1093/toxres/tfab048. PMID: 34484661; PMCID: PMC8403606.

    • 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 Dec;36(12):1217-1228. doi: 10.1002/phar.1851.

    • Boucher, H. (2023) Piperacillin-tazobactam, Sanford Guide Web Edition. Available at: https://webedition.sanfordguide.com/en/drug-

    information/antibacterial-agents/penicillins/anti-pseudomonal-penicillins/piperacillin-tazobactam (Accessed: 12 October 2023).

    • Yang S, Liu Z, Wang C, Wen S, Meng Q, Huo X, Sun H, Ma X, Peng J, He Z, Liu K. Piperacillin enhances the inhibitory effect of tazobactam

    on β-lactamase through inhibition of organic anion transporter 1/3 in rats. Asian J Pharm Sci. 2019 Nov;14(6):677-686. doi:

  • 1016/j.ajps.2018.11.003.

    • Landersdorfer CB, Kirkpatrick CM, Kinzig M, Bulitta JB, Holzgrabe U, Sörgel F. Inhibition of flucloxacillin tubular renal secretion by piperacillin.

    Br J Clin Pharmacol. 2008 Nov;66(5):648-59. doi: 10.1111/j.1365-2125.2008.03266.x.

  • Neely MN, Youn G, Jones B, Jelliffe RW, Drusano GL, Rodvold KA, Lodise TP. Are vancomycin trough concentrations adequate for optimal

    • dosing? Antimicrob Agents Chemother. 2014;58(1):309-16. doi: 10.1128/AAC.01653-13.

  • Alvarez-Arango S, Ogunwole SM, Sequist TD, Burk CM, Blumenthal KG. Vancomycin Infusion Reaction – Moving beyond “Red Man

    • Syndrome”. N Engl J Med. 2021 Apr 8;384(14):1283-1286. doi: 10.1056/NEJMp2031891. Epub 2021 Apr 3.

  • Vallon V, Eraly SA, Rao SR, Gerasimova M, Rose M, Nagle M, Anzai N, Smith T, Sharma K, Nigam SK, Rieg T. A role for the organic anion

    • transporter OAT3 in renal creatinine secretion in mice. Am J Physiol Renal Physiol. 2012 May 15;302(10):F1293-9. doi:

  • 1152/ajprenal.00013.2012. Epub 2012 Feb 15. PMID: 22338083; PMCID: PMC3362066.
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    • L, Jarque I; Spanish PETHEMA Group. Cefepime plus amikacin versus piperacillin-tazobactam plus amikacin for initial antibiotic therapy in

    haematology patients with febrile neutropenia: results of an open, randomized, multicentre trial. J Antimicrob Chemother. 2002

    Jul;50(1):79-88. doi: 10.1093/jac/dkf087. PMID: 12096010.

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Tags:vancomycin piperacillin-tazobactam acute kidney injury cefepime

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