Safety and Efficacy of Strategy to Prevent Drug-Induced Nephrotoxicity in High-Risk Patients

Study Overview
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Brief Summary
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For more than fifty years, vancomycin has been cited as a nephrotoxic agent. Reports of vancomycin induced kidney injury (a.k.a vancomycin induced nephrotoxicity or VIN), have waxed and waned throughout the years for various reasons. Recently, VIN has reemerged as a clinical concern. This may be due to various reasons, including new dosing recommendations as well as an increased prevalence of risk factors associated with vancomycin induced nephrotoxicity. This study aims to evaluate a strategy which attempts to reduce kidney damage from vancomycin use.

Official Title
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Safety and Efficacy of Strategy to Prevent Drug-Induced Nephrotoxicity in High-Risk Patients

Conditions
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Health Care Associated Pneumonia, Osteomyelitis/Septic Arthritis, Endocarditis, Bacteremia, Acute Bacterial Skin and Skin Structure Infections

Intervention / Treatment
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* Drug: Vancomycin
* Drug: Ceftaroline
* Drug: Daptomycin
* Drug: Linezolid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years or older Receiving intravenous vancomycin for the treatment of healthcare associated pneumonia, osteomyelitis/septic arthritis, endocarditis/bacteremia, or acute bacterial skin and skin structure infections Expected to receive vancomycin for at least 72 hours and are within the first 72 hours of therapy Have at least two or more of the following risk factors for drug-induced nephrotoxicity: a) receipt high-dose vancomycin therapy (greater than or equal to four grams per day) b) receipt of vasopressors c) receipt of nephrotoxic drugs (i.e. aminoglycosides, furosemide, acyclovir, amphotericin b, colistin, and intravenous contrast dye) d) pre-existing renal dysfunction (i.e. SCr greater than or equal to 1.5 mg/dL). Exclusion Criteria: Pregnancy End-stage renal disease Receipt of more than 4 grams of vancomycin prior to enrollment on current admission Absolute neutrophil count < 1000/mm3

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vancomycin<br> | Drug: Vancomycin<br>* Dose optimized vancomycin. Target trough: 15 - 20 mg/L for Health Care Associated Pneumonia, Osteomyelitis, Septic Arthritis, Endocarditis and Bacteremia; Target trough: 10 - 20 mg/L for Acute Bacterial Skin and Skin Structure Infections;<br>|
| Active Comparator: Comparator<br> | Drug: Ceftaroline<br>* Dose based on package insert labeling CrCL > 50 mL/min: 600 mg IV q12h CrCL 31-50 mL/min: 400 mg q12h CrCL 15-30 mL/min: 300 mg q12h CrCL < 15mL/min: 200 mg q12h;<br>* Other names: Teflaro;Drug: Daptomycin<br>* Dose based on renal function and literature dosing recommendations CrCL ≥ 30 mL/min: 6 - 10 mg/kg IV q24h CrCL < 30 mL/min: 6 - 10 mg/kg IV q48h<br>* Other names: Cubicin;Drug: Linezolid<br>* 600 mg IV/PO q12h<br>* Other names: Zyvox;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Individuals With Nephrotoxicity | Increase in SCr of 0.5 mg/dL or 50% above baseline for at least two consecutive days while on the study drug and through discharge from hospital. This measure will be reported as proportion of patients with nephrotoxicity within each group in relation to the number of patients in each group. | Day 1 and daily serum creatinine assessment up to date of discharge from hospital, and a median of 7 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Individuals With Acute Kidney Injury Network Modified Definition of Nephrotoxicity | An abrupt (within 48 hour) reduction in kidney function with one or more of the following 1) Increase in SCr ≥ 0.3 mg/dL 2) Increase SCr ≥ 50% or 3) Decreased urine output (< 0.5 ml/kg/hr x 6 hrs) while on the study drug. This measure will be reported as proportion of patients with acute kidney injury within each group in relation to the number of patients in each group. | Day 1 and daily serum creatinine assessment up to date of discharge, and a median of 7 days. | 
| Proportion of Individuals With Clinical Success | Clinical success is a composite endpoint of those patients with clinical cure or improvement in clinical signs and symptoms of infection (i.e. SIRS criteria, and microbiology) while on the study drug. This measure will be reported as the proportion of patients with clinical success in each group compared to the the total number of patients in the group. | Daily assessment of signs and symptoms of infection, and a median of 7 days. |