Piperacillin-tazobactam plus Vancomycin and Acute Kidney Injury by Caroline Rosario

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.

Pharmacology

	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 minAntipseudomonal: 4.5 g IV Q6-8H over 30 minExtended 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 Rash, pruritis
Drug Interactions and warnings	Substrate of OAT1/3 +/- Inducer of OAT1/3 ↑ nephrotoxicity: aminoglycosides, aspirin	Piperacillin: substrate and inhibitor of OAT1/3^∆, Tazobactam: substrate of OAT1/3 Interactions: Probenecid (↑ piperacillin-tazobactam), Methotrexate (↑ methotrexate)
Compatibility	Compatible with dextrose, NS, LR Incompatible with lipid emulsion	LR: only the formulation containing EDTA 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
Comments	Serum troughs are a poor proxy of 24-hour AUC, trough-guided regimens have been shown to exceed the target AUC in 60% of adults¹⁰	Useful 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

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

Overview of 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	↑ 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 criteriaAKIN criteriaVancomycin consensus guideline definition	AKI occurred in 33% of patients receiving vancomycin+piperacillin-tazobactamUse of extended infusion piperacillin-tazobactam did not increase risk of AKI Highest daily incidence of AKI occurred on day 5 of combination therapy
Hammond et al., 2017	Meta-analysis of 14 observational studies (n = 3549)	Vancomycin+piperacillin-tazobactam vs. vancomycin+any β-lactam or vancomycin alone	All included studies used one of the following: RIFLE criteriaAKIN criteria↑ SCr ≥100% or >0.5 mg/dL	Vancomycin+piperacillin-tazobactam greater association with AKI (aOR, 3.11; 95% CI, 1.77–5.47) Highest incidence of AKI in patients admitted to the ICU (OR 3.83 95% CI, 1.67-8.78)
Rutter et al., 2017	Retrospective matched cohort (n = 4103)	Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime	RIFLE criteria	Vancomycin+piperacillin-tazobactam 2.18 times more likely to cause AKI vs. vancomycin+cefepime (95% CI, 1.64–2.94) Vancomycin doses between 3 and 4 g daily used,
Peyko et al., 2017	Prospective observational cohort (n = 85)	Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime or vancomycin+meropenem	KDIGO	Incidence of AKI was higher in with vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime or meropenem (37.3% vs. 7.7% P = .005)
Rutter and Burgess et al., 2017	Retrospective matched cohort (n = 2448)	Vancomycin+piperacillin-tazobactam vs. Vancomycin+ampicillin-sulbactam	RIFLE criteria	Increased risk of AKI with vancomycin+piperacillin-tazobactam (aOR, 1.77; 95% CI, 1.26–2.46), no increased rate of AKI with vancomycin+ampicillin-sulbactamRates of AKI similar for piperacillin-tazobactam and ampicillin-sulbactam without vancomycin
Jeon et al., 2017	Retrospective matched cohort (n = 5335)	Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime	↑ SCr ≥0.3 mg/dL or ≥50% from baseline	Vancomycin+piperacillin-tazobactam associated with a higher risk of AKI vs. vancomycin-cefepime (aHR, 1.25; 95% CI, 1.11–1.42.)
Mousavi et al., 2017	Retrospective matched cohort (n = 280)	Vancomycin+piperacillin-tazobactam standard infusion vs. Vancomycin+piperacillin-tazobactam extended-infusion	RIFLE criteriaAKIN criteria	Similar rate of AKI between vancomycin+piperacillin-tazobactam standard infusion vs. vancomycin+piperacillin-tazobactam extended-infusionHigher vancomycin troughs were observed in the extended infusion group
Miano et al., 2022	Prospective, observational	Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime for ≥48 hours	↑ SCr vs. ↑ Cystatin C vs. ↑ BUN	Vancomycin + piperacillin-tazobactam ➡️ ↑ serum creatinine-defined AKI, but no change in cystatin C, BUN, or AKI outcomes (dialysis/mortality).Indicates vancomycin + piperacillin-tazobactam AKI may be pseudotoxicity.
Qian et al, 2023 (ACORN Trial)	Randomized controlled Trial N=2511	Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime	KDIGO ↑ SCr ≥0.3 mg/dL or ≥50% from baseline	The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam groupThe incidence of major adverse kidney events at day 14 did not differ between groups (124 patients [10.2%] in the cefepime group vs 114 patients [8.8%] in the piperacillintazobactam group~77% of each concurrently received vancomycin

RIFLE, AKIN and KDIGO definitions of AKI are based upon ↑ in serum creatinine or ↓ in urine output

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.

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: 10.1016/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: 10.1152/ajprenal.00013.2012. Epub 2012 Feb 15. PMID: 22338083; PMCID: PMC3362066.
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.
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.
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.
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.
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.
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.
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.
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.
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. E
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.
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.
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.