Differentiating True Nephrotoxicity From Pseudo-nephrotoxicity: A Prospective Comparative Study of Vancomycin Plus Piperacillin-Tazobactam vs. Meropenem Using Serum Creatinine and Cystatin-C
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.
Aperçu de l'étude
Statut
Description détaillée
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.
Type d'étude
Inscription (Estimé)
Contacts et emplacements
Coordonnées de l'étude
- Nom: Hakeam A Hakeam, MS Pharm., BCPS
- Numéro de téléphone: +966505494897
- E-mail: hakeam@kfshrc.edu.sa
Lieux d'étude
-
-
-
Riyadh, Arabie Saoudite, 11211
- King Faisal Specialist Hospital and Research Center-Riyadh
-
Contact:
- A
-
Contact:
- Hakeam Hakeam, MS Pharm
- Numéro de téléphone: 38611 +9664647272
- E-mail: hakeam@kfshrc.edu.sa
-
-
Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
- Adulte
- Adulte plus âgé
Accepte les volontaires sains
Méthode d'échantillonnage
Population étudiée
La 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
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
Cohortes et interventions
Groupe / Cohorte |
|---|
|
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
|
Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
To assess the incidence of developing true nephrotoxicity in patients receiving vancomycin + piperacillin-tazobactam versus vancomycin + meropenem.
Délai: 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
|
Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Difference in time to AKI onset based on serum creatinine and cystatin C between the two groups
Délai: 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
Délai: 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
Délai: 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
Délai: 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.
|
Collaborateurs et enquêteurs
Publications et liens utiles
Publications générales
- 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
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude (Estimé)
Achèvement primaire (Estimé)
Achèvement de l'étude (Estimé)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Réel)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Mots clés
Termes MeSH pertinents supplémentaires
Autres numéros d'identification d'étude
- IRB#2261314
Plan pour les données individuelles des participants (IPD)
Prévoyez-vous de partager les données individuelles des participants (DPI) ?
Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .