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January 5, 2024

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

J

Jimmy

PharmD

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Introduction

  1. Vancomycin and piperacillin-tazobactam are combined for broad-spectrum antibiotic coverage including MRSA and Pseudomonas in hospitalized patients.
  2. AKI, often as acute tubular necrosis, is a known complication of vancomycin, especially with higher doses and co-administration of nephrotoxic drugs.
  3. Piperacillin-tazobactam alone has minimal nephrotoxicity (<1%); its nephrotoxicity is usually due to acute interstitial nephritis.
  4. Reported AKI rates vary in literature based on AKI definition and target population.
  5. 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

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