Introduction

  • Vancomycin and piperacillin-tazobactam are combined for broad-spectrum 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 the literature based on the 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.

Pharmacology

VancomycinPiperacillin-tazobactam4
DoseDepends on infection and PK/PD target
General dosing for systemic infections: 15–20 mg/kg IV Q8–12H		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
AdministrationAdminister IV over ≥60 minutes at concentrations ≤5 mg/mL to reduce the risk of vancomycin infusion reactionStandard infusion: infuse over 30 min
Extended infusion: infuse loading dose over 30 min, start maintenance dose four hours later infused over 4 hours
PK/PDNegligible oral bioavailability
T1/2 = 4–6 hours
Renally eliminated (40–100% unchanged)
AUC:MIC-dependent kinetics; PK/PD target AUC/MIC ≥400; 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 EffectsNephrotoxicity
Ototoxicity
Vancomycin infusion reaction (flushing, hypotension, tachycardia)		GI upset (diarrhea, nausea, constipation)
Headache
Rash, pruritus
Drug Interactions & WarningsSubstrate of OAT1/3 ± inducer of OAT1/3
↑ nephrotoxicity: aminoglycosides, aspirin		Piperacillin: substrate and inhibitor of OAT1/3Δ
Tazobactam: substrate of OAT1/3
Interactions: probenecid (↑ piperacillin-tazobactam), methotrexate (↑ methotrexate)
CompatibilityCompatible with dextrose, NS, LR
Incompatible with lipid emulsion		LR: only the EDTA-containing formulation is compatible for Y-site administration
Not chemically stable in solutions containing sodium bicarbonate or solutions that significantly alter pH
Cannot be added to blood products or albumin hydrolysates
CommentsSerum troughs are a poor proxy of 24-hour AUC; trough-guided regimens have been shown to exceed the target AUC in 60% of adults10Useful in the ED for anaerobic coverage in Grade III open fractures, pneumonia with lung abscess or empyema, and empiric antipseudomonal coverage in patients with risk factors

Δ = meropenem is also a substrate of OAT1/3 but not an inhibitor.

Evidence

Author, yearDesign / sample sizeIntervention & comparisonAKI definitionOutcome
Sanz et al., 2002Prospective, multi-center (n = 969)Amikacin + cefepime vs. amikacin + piperacillin-tazobactam↑ SCr ≥50% from baselineNo difference in severe nephrotoxicity between amikacin + piperacillin-tazobactam vs. amikacin + cefepime
Karino et al., 2016Retrospective cohort and nested case-control studies (n = 320)Vancomycin + piperacillin-tazobactam standard infusion vs. extended infusionRIFLE criteria
AKIN criteria
Vancomycin consensus guideline definition		AKI occurred in 33% of patients receiving vancomycin + piperacillin-tazobactam; extended-infusion piperacillin-tazobactam did not increase AKI risk; highest daily incidence of AKI on day 5 of combination therapy
Hammond et al., 2017Meta-analysis of 14 observational studies (n = 3549)Vancomycin + piperacillin-tazobactam vs. vancomycin + any β-lactam or vancomycin aloneRIFLE / AKIN criteria, or ↑ SCr ≥100% or >0.5 mg/dLGreater association with AKI for vancomycin + piperacillin-tazobactam (aOR 3.11; 95% CI 1.77–5.47); highest incidence in ICU patients (OR 3.83; 95% CI 1.67–8.78)
Rutter et al., 2017Retrospective matched cohort (4193 screened; 1633 vs. 578 matched)Vancomycin + piperacillin-tazobactam vs. vancomycin + cefepimeRIFLE criteriaVancomycin + piperacillin-tazobactam associated with 2.18× higher odds of AKI vs. vancomycin + cefepime (95% CI 1.64–2.94)
Peyko et al., 2017Prospective observational cohort (n = 85)Vancomycin + piperacillin-tazobactam vs. vancomycin + cefepime or meropenemKDIGOHigher AKI incidence with vancomycin + piperacillin-tazobactam vs. cefepime or meropenem (37.3% vs. 7.7%; P = .005)
Rutter & Burgess et al., 2017Retrospective matched cohort (n = 2448)Vancomycin + piperacillin-tazobactam vs. vancomycin + ampicillin-sulbactamRIFLE criteriaIncreased AKI with vancomycin + piperacillin-tazobactam (aOR 1.77; 95% CI 1.26–2.46); no increased AKI with vancomycin + ampicillin-sulbactam; AKI rates similar for piperacillin-tazobactam and ampicillin-sulbactam without vancomycin
Jeon et al., 2017Retrospective matched cohort (n = 5335)Vancomycin + piperacillin-tazobactam vs. vancomycin + cefepime↑ SCr ≥0.3 mg/dL or ≥50% from baselineVancomycin + piperacillin-tazobactam associated with higher AKI risk vs. vancomycin + cefepime (aHR 1.25; 95% CI 1.11–1.42)
Mousavi et al., 2017Retrospective matched cohort (n = 280)Vancomycin + piperacillin-tazobactam standard infusion vs. extended infusionRIFLE / AKIN criteriaSimilar AKI rate between standard- and extended-infusion piperacillin-tazobactam; higher vancomycin troughs observed in the extended-infusion group
Miano et al., 2022Prospective observational cohortVancomycin + piperacillin-tazobactam vs. vancomycin + cefepime for ≥48 hours↑ SCr vs. ↑ cystatin C vs. ↑ BUNVancomycin + piperacillin-tazobactam → ↑ creatinine-defined AKI, but no change in cystatin C, BUN, or hard AKI outcomes (dialysis/mortality) — suggests the AKI may be pseudotoxicity
Qian et al., 2023 (ACORN Trial)Randomized controlled trial (n = 2511)Cefepime vs. piperacillin-tazobactam (~77% of each also received vancomycin)KDIGO; ↑ SCr ≥0.3 mg/dL or ≥50% from baselineHighest stage of AKI or death not significantly different between groups; major adverse kidney events at day 14 did not differ (cefepime 10.2% vs. piperacillin-tazobactam 8.8%)
Recent Evidence (2024–2026)
Pan et al., 2025Systematic review & network meta-analysis (70 studies, n = 76,638)Vancomycin + piperacillin-tazobactam vs. vancomycin + cefepime, meropenem, or other β-lactamsCreatinine-based (RIFLE/AKIN/KDIGO across studies)Higher creatinine-defined AKI with piperacillin-tazobactam vs. cefepime (OR 2.55; 95% CI 2.00–3.28) and vs. meropenem (OR 2.26; 95% CI 1.71–3.02); association also seen for stage 2–3 AKI
Alshehri et al., 2025Systematic review & meta-analysis (17 studies, n = 80,595)Vancomycin + piperacillin-tazobactam vs. vancomycin + meropenemCreatinine-basedHigher AKI (OR 2.02; 95% CI 1.56–2.62) and higher renal replacement therapy (OR 1.55; 95% CI 1.23–1.96) with piperacillin-tazobactam, but no difference in mortality or hospital length of stay
Chen et al., 2025Pharmacovigilance disproportionality analysis (FDA FAERS)Vancomycin + piperacillin-tazobactam signal vs. comparator regimensCreatinine-defined AKI vs. other renal biomarkers, severe AKI, and RRTExcess signal for creatinine-defined AKI (ROR 1.23) but not for non-creatinine biomarkers (ROR 0.89, NS), severe AKI (ROR 0.82), or renal replacement therapy (ROR 1.08, NS) — supports pseudo-injury over true nephrotoxicity
Li et al., 2025Systematic review & meta-analysis, critically ill (20 studies, n = 28,243)Vancomycin + piperacillin-tazobactam vs. vancomycin + other β-lactamsCreatinine-based; stage 2–3AKI OR 1.66 (95% CI 1.42–1.94); severe stage 2–3 OR 1.63 (1.28–2.06); association larger in children (OR 3.16) than adults (OR 1.59)
Mohammad et al., 2026Systematic review & meta-analysis (5 cohorts, n = 908)Piperacillin-tazobactam + teicoplanin vs. piperacillin-tazobactam + vancomycinCreatinine-based~48% lower AKI odds with teicoplanin (OR 0.52; 95% CI 0.30–0.89) — a glycopeptide-substitution lever where vancomycin is the modifiable element

RIFLE, AKIN, and KDIGO definitions of AKI are based on a rise in serum creatinine or a fall in urine output.

Conclusions

  • Since 2011, observational evidence has indicated that combined vancomycin + piperacillin-tazobactam may be nephrotoxic; most of these studies were retrospective and defined nephrotoxicity by creatinine-based AKI.
  • More recent biomarker, randomized, and pharmacovigilance data question whether this creatinine-based signal consistently reflects true tubular injury or hard kidney outcomes — though several meta-analyses still report increased stage 2–3 creatinine-defined AKI.
  • Non–tubular-secretion biomarkers (cystatin C, BUN) did not show the same AKI increase.
  • Despite >50 studies linking the combination with AKI, some experts judge the true renal risk to be minimal.
  • Large 2024–2026 meta-analyses (e.g., Pan 2025 network meta-analysis, n≈77,000; Alshehri 2025, n≈81,000) continue to find a consistent association with creatinine-defined AKI — including more severe stage 2–3 AKI — versus cefepime or meropenem. Mortality and length of stay were not increased, but the hard-outcome picture is mixed: one meta-analysis found higher rates of renal replacement therapy (Alshehri 2025), whereas FAERS pharmacovigilance (Chen 2025) and the randomized ACORN trial found no excess in renal replacement therapy or major adverse kidney events.
  • Pharmacovigilance and biomarker data (Chen 2025 FAERS analysis; Miano 2022 cystatin C cohort) increasingly support that much of the creatinine rise reflects competitive inhibition of tubular creatinine secretion (pseudotoxicity) rather than true tubular injury; the randomized ACORN trial (2023) found no difference in major adverse kidney events.
  • The association appears larger in children than in adults (Li 2025); where vancomycin is the modifiable element, substituting teicoplanin (Mohammad 2026) or a non–piperacillin-tazobactam β-lactam may lower creatinine-defined AKI, though a hard-outcome benefit is unproven.
  • In emergencies, timely antibiotic therapy is vital; concern about creatinine-defined nephrotoxicity should not delay this combination, especially for short courses.

References

  1. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved October 4, 2023, from www.micromedexsolutions.com
  2. VANCOMYCIN HYDROCHLORIDE [package insert]. Rockford, IL: Mylan Institutional LLC; Jul, 2018.
  3. 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.
  4. 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..
  5. 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.
  6. 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.
  7. 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).
  8. 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: 10.1016/j.ajps.2018.11.003.
  9. 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.
  10. 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.
  11. 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.
  12. 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: 10.1152/ajprenal.00013.2012. Epub 2012 Feb 15. PMID: 22338083; PMCID: PMC3362066.
  13. Sanz MA, López J, Lahuerta JJ, Rovira M, Batlle M, Pérez C, Vázquez L, Julià A, Palau J, Gutiérrez M, Capote FJ, Ramos F, Benlloch L, Larrea 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.
  14. Watkins RR, Deresinski S. Increasing Evidence of the Nephrotoxicity of Piperacillin/Tazobactam and Vancomycin Combination Therapy-What Is the Clinician to Do? Clin Infect Dis. 2017 Nov 29;65(12):2137-2143. doi: 10.1093/cid/cix675.
  15. Karino S, Kaye KS, Navalkele B, Nishan B, Salim M, Solanki S, Pervaiz A, Tashtoush N, Shaikh H, Koppula S, Martin ET, Mynatt RP, Murray KP, Rybak MJ, Pogue JM. Epidemiology of Acute Kidney Injury among Patients Receiving Concomitant Vancomycin and Piperacillin-Tazobactam: Opportunities for Antimicrobial Stewardship. Antimicrob Agents Chemother. 2016 May 23;60(6):3743-50. doi: 10.1128/AAC.03011-15.
  16. 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. PMID: 27940946.
  17. Rutter WC, Cox JN, Martin CA, Burgess DR, Burgess DS. Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime. Antimicrob Agents Chemother. 2017 Jan 24;61(2):e02089-16. doi: 10.1128/AAC.02089-16. Erratum in: Antimicrob Agents Chemother. 2017 Mar 24;61(4): PMID: 27895019; PMCID: PMC5278703.
  18. Peyko V, Smalley S, Cohen H. Prospective Comparison of Acute Kidney Injury During Treatment With the Combination of Piperacillin-Tazobactam and Vancomycin Versus the Combination of Cefepime or Meropenem and Vancomycin. J Pharm Pract. 2017 Apr;30(2):209-213. doi: 10.1177/0897190016628960.
  19. Rutter WC, Burgess DS. Acute Kidney Injury in Patients Treated with IV Beta-Lactam/Beta-Lactamase Inhibitor Combinations. Pharmacotherapy. 2017 May;37(5):593-598. doi: 10.1002/phar.1918.
  20. Jeon N, Staley B, Klinker KP, Hincapie Castillo J, Winterstein AG. Acute kidney injury risk associated with piperacillin/tazobactam compared with cefepime during vancomycin therapy in hospitalised patients: a cohort study stratified by baseline kidney function. Int J Antimicrob Agents. 2017 Jul;50(1):63-67. doi: 10.1016/j.ijantimicag.2017.02.023.
  21. Mousavi M, Zapolskaya T, Scipione MR, Louie E, Papadopoulos J, Dubrovskaya Y. Comparison of Rates of Nephrotoxicity Associated with Vancomycin in Combination with Piperacillin-Tazobactam Administered as an Extended versus Standard Infusion. Pharmacotherapy. 2017 Mar;37(3):379-385. doi: 10.1002/phar.1901.
  22. Miano TA, Hennessy S, Yang W, Dunn TG, Weisman AR, Oniyide O, Agyekum RS, Turner AP, Ittner CAG, Anderson BJ, Wilson FP, Townsend R, Reilly JP, Giannini HM, Cosgriff CV, Jones TK, Meyer NJ, Shashaty MGS. Association of vancomycin plus piperacillin-tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study. Intensive Care Med. 2022 Sep;48(9):1144-1155. doi: 10.1007/s00134-022-06811-0.
  23. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, Schorr C, Simpson S, Wiersinga WJ, Alshamsi F, Angus DC, Arabi Y, Azevedo L, Beale R, Beilman G, Belley-Cote E, Burry L, Cecconi M, Centofanti J, Coz Yataco A, De Waele J, Dellinger RP, Doi K, Du B, Estenssoro E, Ferrer R, Gomersall C, Hodgson C, Møller MH, Iwashyna T, Jacob S, Kleinpell R, Klompas M, Koh Y, Kumar A, Kwizera A, Lobo S, Masur H, McGloughlin S, Mehta S, Mehta Y, Mer M, Nunnally M, Oczkowski S, Osborn T, Papathanassoglou E, Perner A, Puskarich M, Roberts J, Schweickert W, Seckel M, Sevransky J, Sprung CL, Welte T, Zimmerman J, Levy M. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021 Nov;47(11):1181-1247. doi: 10.1007/s00134-021-06506-y.
  24. 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. PMID: 37837651; PMCID: PMC10576861.
  25. Pan K, Li R, Li Y, Ding X, Li X, Lv Q. Vancomycin combined with piperacillin/tazobactam increases the risk of acute kidney injury compared with vancomycin plus other anti-pseudomonal beta-lactams: a systematic review and network meta-analysis. J Antimicrob Chemother. 2025;80(1):47-58. doi: 10.1093/jac/dkae410.
  26. Alshehri AM, Al Yami MS, Aldairem A, Alfehaid L, Almutairi AR, Almohammed OA, Badawoud AM. Evaluating the risk of acute kidney injury and mortality associated with concomitant use of vancomycin with piperacillin/tazobactam or meropenem in critically ill and non-critically ill patients: a systematic review and meta-analysis. BMC Infect Dis. 2025;25(1):36. doi: 10.1186/s12879-024-10227-0.
  27. Chen C, Zhou R, Fang J, Xiao J. Association of Vancomycin Plus Piperacillin-Tazobactam With Acute Kidney Injury: Differentiating Pseudo-Injury From True Nephrotoxicity. Clin Transl Sci. 2025;18(5):e70258. doi: 10.1111/cts.70258.
  28. Li R, Li Y, Xu C, Shen Z, Xu X, Ding X, Li X, Lv Q, Pan K. Incidence of Acute Kidney Injury in Critically Ill Patients Receiving Vancomycin With Concomitant Piperacillin-Tazobactam Versus Other Beta-Lactams: A Systematic Review and Meta-Analysis. J Pharm Technol. 2025;41(6):87551225251350894. doi: 10.1177/87551225251350894.
  29. Mohammad S, Ghazal H, Rahimeh W, Khan M, Al Balas M, El-Dahiyat F. Comparative Risk of Acute Kidney Injury with Piperacillin-Tazobactam Plus Teicoplanin Versus Piperacillin-Tazobactam Plus Vancomycin: A Systematic Review and Meta-Analysis. Drug Saf. 2026;49(3):291-302. doi: 10.1007/s40264-025-01611-z.
  30. Martin L, Pecar A, Baltaci Y, Simon A, Kohl S, Müller D, Förster J. Potentielle Nephrotoxizität der Kombinationstherapie von Vancomycin und Piperacillin-Tazobactam: Empfehlungen der AG ABS der DGPI unter Beteiligung von Experten der GPN. Klin Pädiatr. 2024;236(5):280-288. doi: 10.1055/a-2244-7698.
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