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.
調査の概要
詳細な説明
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.
研究の種類
入学 (推定)
連絡先と場所
研究連絡先
- 名前：Hakeam A Hakeam, MS Pharm., BCPS
- 電話番号：+966505494897
- メール：hakeam@kfshrc.edu.sa
研究場所
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Riyadh、サウジアラビア、11211
- King Faisal Specialist Hospital and Research Center-Riyadh
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コンタクト：
- A
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コンタクト：
- Hakeam Hakeam, MS Pharm
- 電話番号：38611 +9664647272
- メール：hakeam@kfshrc.edu.sa
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参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
サンプリング方法
調査対象母集団
説明
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
研究計画
研究はどのように設計されていますか？
デザインの詳細
コホートと介入
グループ/コホート |
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Vancomycin - Piperacillin Tazobactam
Patients who will be receiving a combination of vancomycin and piperacillin-tazobactam for treating various types of infections
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Vancomycin - Meropenem
Patients who will be receiving a combination of vancomycin and meropenem for treating various types of infections
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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To assess the incidence of developing true nephrotoxicity in patients receiving vancomycin + piperacillin-tazobactam versus vancomycin + meropenem.
時間枠：From enrollment until 72 hours from stopping vancomycin therapy
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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
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Difference in time to AKI onset based on serum creatinine and cystatin C between the two groups
時間枠：From enrollment until 72 hours from stopping vancomycin
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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
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Incidence of Transient and Persistent Acute Kidney Injury According to the 2026 KDIGO Criteria between the two study groups
時間枠：From enrollment until 72 hours from vancomycin therapy cessation
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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.
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From enrollment until 72 hours from vancomycin therapy cessation
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Recovery from AKI according to the 2026 KDIGO Criteria
時間枠：From AKI onset through 90 days after AKI onset.
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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.
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From AKI onset through 90 days after AKI onset.
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Severity of AKI staged according to the 2026 KDIGO criteria between the two groups
時間枠：From AKI onset through 7 days after AKI onset.
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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.
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From AKI onset through 7 days after AKI onset.
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協力者と研究者
出版物と役立つリンク
一般刊行物
- 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
研究記録日
主要日程の研究
研究開始 (推定)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- IRB#2261314
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