Differentiating True Nephrotoxicity From Pseudo-nephrotoxicity: A Prospective Comparative Study of Vancomycin Plus Piperacillin-Tazobactam vs. Meropenem Using Serum Creatinine and Cystatin-C

September 7, 2026 updated by: Hakeam Abdulaziz Hakeam, King Faisal Specialist Hospital & Research Center

This prospective comparative observational study will compare the incidence of true nephrotoxicity in adult patients receiving vancomycin in combination with either piperacillin-tazobactam or meropenem.

Vancomycin plus piperacillin-tazobactam has been associated with a higher incidence of kidney injury based mainly on increases in serum creatinine. However, it remains uncertain whether these increases represent true kidney injury or pseudo-nephrotoxicity, in which serum creatinine increases without a corresponding decline in kidney function.

To address this uncertainty, the study will prospectively assess kidney function using both serum creatinine and cystatin C. True nephrotoxicity will be identified when changes in both biomarkers meet the study criteria for acute kidney injury, while an increase in serum creatinine without a corresponding cystatin C increase will be considered pseudo-nephrotoxicity.

The study will compare true nephrotoxicity between patients receiving vancomycin plus piperacillin-tazobactam and those receiving vancomycin plus meropenem. It will also evaluate the timing, persistence, severity, and recovery of kidney injury. The results may help clarify whether the higher rates of nephrotoxicity reported with vancomycin plus piperacillin-tazobactam represent true renal injury and may help guide antibiotic selection when balancing antimicrobial coverage and kidney safety.

Study Overview

Status

Not yet recruiting

Conditions

Detailed Description

Vancomycin is commonly administered in combination with broad-spectrum beta-lactam antibiotics for empiric treatment of serious infections. Several studies have reported a higher incidence of nephrotoxicity in patients receiving vancomycin plus piperacillin-tazobactam compared with vancomycin combined with other antipseudomonal beta-lactams. However, most of these studies have defined kidney injury using serum creatinine alone. This has raised concern that the observed increase in nephrotoxicity may, at least in part, represent pseudo-nephrotoxicity caused by an increase in serum creatinine without a corresponding reduction in true kidney function.

This prospective, non-interventional, comparative two-arm cohort study will evaluate adult patients receiving vancomycin in combination with either piperacillin-tazobactam or meropenem. Treatment selection, antimicrobial dosing, vancomycin therapeutic drug monitoring, fluid management, hemodynamic management, and other clinical decisions will remain under the responsibility of the treating clinical team and will not be determined by the study investigators.

The primary objective is to compare the incidence of true nephrotoxicity between the two treatment groups. Kidney function will be assessed prospectively using both serum creatinine and cystatin C. True nephrotoxicity will be defined as fulfillment of the study criteria for acute kidney injury using both serum creatinine and cystatin C, whereas pseudo-nephrotoxicity will be defined as serum creatinine-based acute kidney injury without a corresponding increase in cystatin C.

Serum creatinine and cystatin C will be assessed at baseline and serially during combination antimicrobial therapy, with additional follow-up measurements after discontinuation when available according to the study protocol. This simultaneous biomarker assessment is intended to help distinguish functional changes in serum creatinine from kidney injury supported by a parallel change in cystatin C.

Secondary assessments will include the time to onset of acute kidney injury based separately on serum creatinine and cystatin C, the incidence of transient and persistent acute kidney injury, kidney recovery, and the severity of acute kidney injury. Kidney recovery and progression to acute kidney disease will also be assessed during follow-up when applicable.

Patients will be categorized into two observational exposure groups according to the beta-lactam prescribed by the treating team: vancomycin plus piperacillin-tazobactam or vancomycin plus meropenem. Relevant demographic, clinical, laboratory, antimicrobial exposure, and potential nephrotoxic risk factors will be prospectively collected.

The study is designed to clarify whether the higher incidence of nephrotoxicity reported with vancomycin plus piperacillin-tazobactam represents true renal injury or predominantly a serum creatinine-based phenomenon. The findings may improve interpretation of kidney function during antibiotic therapy and may help clinicians balance antimicrobial coverage with the risk of nephrotoxicity when selecting empiric antibiotic regimens.

Study Type

Observational

Enrollment (Estimated)

304

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Saudi Arabia
      • Riyadh, Saudi Arabia, 11211
        • King Faisal Specialist Hospital and Research Center-Riyadh
        • Contact:
          • A
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

Patients admitted to King Faisal Specialist Hospital and Research Center, and received vancomycin combined with either piperacillin-tazobactam or meropenem from August 2026 until achieving the pre-specified sample size will be screened for the inclusion and exclusion criteria

Description

Inclusion Criteria:

  • Age ≥18 years.
  • Receipt of vancomycin in combination with either piperacillin-tazobactam or meropenem, with both antimicrobial agents prescribed by the treating physician and expected to be administered concomitantly for >48 hours.

Exclusion Criteria:

  • Known advanced chronic kidney disease (CKD), defined as a baseline estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m², or dialysis dependence..
  • Pregnancy.
  • Receipt of renal replacement therapy prior to enrollment.
  • Obstructive uropathy causing AKI.
  • Recipients of solid organ transplant or hematopoietic stem cell transplantation within one year of presentation
  • Concomitant receive of agents known to be nephrotoxins:

Amphotericin B Aminoglycosides Calcineurin inhibitors

  • Patients with AKI 30 days prior to vancomycin initiation
  • Admission to the ICU for indication other than postoperative care for > 72 hours
  • Receiving vancomycin therapy within 30 days before the index combination

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Vancomycin - Piperacillin Tazobactam
Patients who will be receiving a combination of vancomycin and piperacillin-tazobactam for treating various types of infections
Vancomycin - Meropenem
Patients who will be receiving a combination of vancomycin and meropenem for treating various types of infections

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To assess the incidence of developing true nephrotoxicity in patients receiving vancomycin + piperacillin-tazobactam versus vancomycin + meropenem.
Time Frame: From enrollment until 72 hours from stopping vancomycin therapy

True nephrotoxicity is defined as both serum creatinine and cystatin-C meet the AKI criteria on 2026 KDIGO criteria.

Serum creatinine-based AKI: defined as any of the following: Change in SCr≥0.3 mg/dL within 48 hours OR SCr≥1.5×baseline within 7 days.

Cystatin-C-Based AKI is defined as any of the following: ≥50% increase from baseline cystatin-C OR absolute increase ≥0.3 mg/L from baseline
From enrollment until 72 hours from stopping vancomycin therapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Difference in time to AKI onset based on serum creatinine and cystatin C between the two groups
Time Frame: From enrollment until 72 hours from stopping vancomycin

Time to AKI onset will be determined independently according to serum creatinine-based and cystatin C-based AKI criteria.

Time to AKI onset will be calculated from initiation of the study antibiotic regimen to the first time the participant meets the respective AKI criterion. The difference in time to AKI onset between serum creatinine-based and cystatin C-based assessments will be evaluated and compared between patients receiving vancomycin plus piperacillin-tazobactam and those receiving vancomycin plus meropenem.
From enrollment until 72 hours from stopping vancomycin
Incidence of Transient and Persistent Acute Kidney Injury According to the 2026 KDIGO Criteria between the two study groups
Time Frame: From enrollment until 72 hours from vancomycin therapy cessation
AKI will be classified as transient or persistent according to the 2026 KDIGO AKI/AKD criteria based on the duration of increased serum creatinine or cystatin C, or reduced urine output. The incidence of transient and persistent AKI will be compared between patients receiving vancomycin plus piperacillin-tazobactam and those receiving vancomycin plus meropenem.
From enrollment until 72 hours from vancomycin therapy cessation
Recovery from AKI according to the 2026 KDIGO Criteria
Time Frame: From AKI onset through 90 days after AKI onset.
Recovery from AKI will be assessed according to the 2026 KDIGO AKI/AKD criteria using serum creatinine-based and cystatin C-based assessments. The proportion of participants achieving recovery from AKI will be determined and compared between patients receiving vancomycin plus piperacillin-tazobactam and those receiving vancomycin plus meropenem.
From AKI onset through 90 days after AKI onset.
Severity of AKI staged according to the 2026 KDIGO criteria between the two groups
Time Frame: From AKI onset through 7 days after AKI onset.
The severity of acute kidney injury (AKI) will be assessed according to the 2026 Kidney Disease: Improving Global Outcomes (KDIGO) AKI/AKD criteria. Participants who develop AKI will be classified according to AKI severity (Stage 1, Stage 2, or Stage 3) based on serum creatinine and urine output criteria. The distribution of AKI severity stages will be compared between patients receiving vancomycin plus piperacillin-tazobactam and those receiving vancomycin plus meropenem.
From AKI onset through 7 days after AKI onset.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

King Faisal Specialist Hospital & Research Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

  • 1. Lewington AJ, Cerda J, Mehta RL. Raising awareness of acute kidney injury: a global perspective of a silent killer. Kidney Int. 2013;84:457-467. 2. Perazella MA, Rosner MH. Drug-Induced Acute Kidney Injury. Clin J Am Soc Nephrol. 2022;17:1220-1233. 3. Fresilli S, Labanca R, Losiggio R, et al. Long-Term Outcomes After Acute Kidney Injury During Hospitalization: A Systematic Review and Meta-Analysis of Matched Controls Studies. Crit Care Med. 2026;54:335-342. 4. 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;80:47-58. 5. Prescott HC, Antonelli M, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2026. Crit Care Med. 2026;54:725-812. 6. Kalil AC, Metersky ML, Klompas M, et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63:e61-e111. 7. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59:e10-52. 8. Chiu CY, Sarwal A. Evaluating the Nephrotoxicity of Area-under-the-Curve-Based Dosing of Vancomycin with Concomitant Antipseudomonal Beta-Lactam Antibiotics: A Systematic Review and Meta-Analysis. Medicina (Kaunas). 2023;59. 9. 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;61. 10. Miano TA, Hennessy S, Yang W, et al. Association of vancomycin plus piperacillin-tazobactam

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

September 15, 2026

Primary Completion (Estimated)

June 5, 2027

Study Completion (Estimated)

July 9, 2027

Study Registration Dates

First Submitted

September 7, 2026

First Submitted That Met QC Criteria

September 7, 2026

First Posted (Actual)

September 14, 2026

Study Record Updates

Last Update Posted (Actual)

September 14, 2026

Last Update Submitted That Met QC Criteria

September 7, 2026

Last Verified

September 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB#2261314

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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