Acute Kidney Injury
Conditions
Keywords
vancomycin, piperacillin-tazobactam, cefepime, acute kidney injury, nephrotoxicity, cystatin c, kidney injury molecule 1 (KIM1)
Brief summary
Hospitalized patients with suspected or confirmed infection are commonly treated with vancomycin (VN) in combination with either piperacillin-tazobactam (PT) or cefepime (CP). Although these regimens have similar effectiveness, recent observational evidence suggests they may differ in terms of the risk for acute kidney injury (AKI). Interpretation of existing evidence is complicated by the limitations of creatinine, the standard biomarker used to monitor kidney function, which has poor sensitivity and specificity for drug induced AKI. To address this important knowledge gap, the investigators propose to conduct a pragmatic, open-label, non-inferiority trial that will examine the comparative risk of AKI between these standard-of-care antibiotic combinations using sensitive and specific markers of drug-induced AKI. We hypothesize that the regimen of VN in combination with PT (VN+PT) is noninferior to the regimen of VN in combination with CP (VN+CP) in terms of AKI risk.
Interventions
DRUGVancomycin
Vancomycin is a glycopeptide antibiotic used to treat infections caused by Gram-positive bacteria, including those due to methicillin-resistant Staphylococcus aureus. Dosing of vancomycin will follow standard of care procedures, including the use of individualized dosing regimens developed in consultation with clinical pharmacists, based on participant body weight and renal function, and dosage titration guided by therapeutic drug monitoring. Vancomycin is administered via intermittent intravenous infusions of 60-90 minutes.
Piperacillin-tazobactam is an anti-pseudomonal penicillin with a dose range of 2.25 g or 4.5 g and frequency of every 6 or 8 hours based on a participant's body weight, renal function, and clinician discretion. Piperacillin-tazobactam is administered via extended-duration (4 hours) intravenous infusions
DRUGCefepime
Cefepime is an anti-pseudomonal cephalosporin with a dose range of 500 mg, 1,000 mg, or 2,000 mg, and frequency every 8, 12, or 24 hours based on a participant's body weight, renal function, and clinician discretion. Cefepime is administered via extended-duration (4 hours) intravenous infusions
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age of at least 18 years 2. Suspected or confirmed infection based on clinical criteria, for which vancomycin with piperacillin-tazobactam or vancomycin with cefepime was prescribed by the treating clinician, as evidenced by orders being placed in the electronic health record 3. The treating clinician considers both vancomycin with piperacillin- tazobactam or vancomycin with cefepime as acceptable treatment 4. The treating clinician anticipates at least 48 hours of antibiotic treatment
Exclusion criteria
1. Dialysis dependence or documented end stage kidney disease 2. AKI at baseline 3. Expected survival \<24 hours and/or presence of do not resuscitate orders 4. History of antibiotic-resistant organisms (microbiological culture results showing bacterial isolates with resistant or intermediate susceptibility to any study drug within the prior 90 days) 5. Documented allergy to vancomycin, cephalosporins, or penicillin 6. Suspected central nervous system infection 7. Inability to provide informed consent or lack of proxy for consent 8. Prisoners/incarcerated individuals 9. Known pregnancy or breastfeeding 10. Previous enrollment in this study 11. Receipt of vancomycin, piperacillin-tazobactam, or cefepime for \>24 hours within the preceding 7 days. At the time of screening, one-time doses of vancomycin, with or without piperacillin-tazobactam, or cefepime, will be allowed prior to randomization to avoid treatment delays; such patients must be enrolled within twelve hours of antibiotic administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Cystatin C Concentration | 5 days post enrollment | Change in serum cystatin c concentration through Day 5 after antibiotic initiation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kidney injury molecule 1 (KIM1) | 5 days post enrollment | Changes in urinary KIM1 concentration through Day 5 after antibiotic initiation. |
| Serum creatinine concentration | 5 days post enrollment | Change in serum creatinine concentration through Day 5 after antibiotic initiation. |
| Acute Kidney Injury | At 7 and 14 days | Acute kidney injury as defined by Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria: Stage 1 AKI (Creatinine increase by 1.5-1.9 times baseline OR increase by \>= 0.3 mg/dL) Stage 2 AKI (Creatinine increase by 2.0-2.9 times baseline) Stage 3 AKI (Creatinine increase by \>= 3.0 times baseline OR increase to \>= 4.0 mg/dL OR New renal replacement therapy (RRT)) |
| Major Adverse Kidney Events (MAKE) | 30 and 60 days | MAKE consists of death, need for RRT, or persistent kidney dysfunction (decrease in estimated glomerular filtration rate (GFR) to \<75% of baseline) |
Countries
United States
Contacts
CONTACTTodd Miano, PharmD, PhD
Outcome results
None listed