Vancomycin Dosing for Serious MRSA Infections: A Non-inferiority Randomized Trial of Trough Level Versus AUC/MIC

MRSA Clinical Trial

Official title:

Vancomycin Dosing for Serious MRSA Infections: A Non-inferiority Randomized Trial of Trough Level Versus AUC/MIC

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04793152
• Other study ID #: 13327
• Status: Recruiting
• Phase: N/A
• Start date: March 20, 2023
• Est. completion date: March 1, 2026

Study information

• Verified date: May 2023
• Source: McMaster University
• Contact: Anthony D Bai, MD
• Phone: 613-793-8577
• Email: anthony.bai[@]medportal.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Intravenous vancomycin is considered first line therapy for serious methicillin-resistant Staphylococcus aureus (MRSA) infections including bacteremia, central nervous system infection, pneumonia, pleural space infection, bone or joint infection, prosthetic joint infection and deep abscesses. The effectiveness and toxicity of vancomycin depend on its dosing and chosen target. The most recent guidelines suggest targeting area under the curve over 24 hours over minimum inhibitory concentration (AUC/MIC) of 400 to 600. Implementation of AUC/MIC requires Bayesian software that can be variable, costly, complicated and time consuming. Ideally, AUC/MIC dosing would also require susceptibility testing by broth microdilution, which is not commonly done. It is recommended to target AUC of 400 to 600 assuming a MIC of 1ug/mL when MIC by broth microdilution is not known. Targeting a trough level of 10 to 15mg/L may be a reasonable and more practical alternative without compromising effectiveness. We will be conducting a randomized controlled non-inferiority trial to compare intravenous vancomycin dosing strategy targeting a trough level of 10 to 15mg/L versus AUC of 400 to 600 assuming a MIC of 1ug/mL by broth microdilution for serious MRSA infections. The primary outcome will be treatment failure, which is a composite of mortality and microbiologic failure at 90 days. We hypothesize that targeting a trough level of 10 to 15mg/L is non-inferior to targeting a AUC of 400 to 600 in terms of treatment failure. The criterion for non-inferiority is that a two-sided 95% confidence interval for difference in risk of treatment failure will lie within the non-inferiority margin of 10%.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 700
• Est. completion date: March 1, 2026
• Est. primary completion date: January 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult patients with serious MRSA infections based on culture results including bacteremia, pneumonia, pleural space infection, central nervous system infection, bone infection, septic arthritis, prosthetic joint infection, and deep abscess

• Enrolment within 4 days from date of MRSA culture collection

• Patient either currently not on vancomycin or has received vancomycin for 4 days or less

Exclusion Criteria:

• Vancomycin minimum inhibitory concentration (MIC) =2ug/mL

• Patient is palliative or expected to die in the next 48 hours, or requires critical care resources but will not receive it due to advanced care directives

• History of type 1 hypersensitivity reaction to vancomycin

• Patients on intermittent hemodialysis or peritoneal dialysis

Related Conditions & MeSH terms

• Infections
• MRSA

Intervention

Drug:
• Vancomycin
Administration as outlined

Locations

Country	Name	City	State
Canada	Hamilton Health Sciences	Hamilton	Ontario
Canada	St. Joseph's Healthcare Hamilton	Hamilton	Ontario
Canada	Kingston Health Sciences Centre	Kingston	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
McMaster University	The Physicians' Services Incorporated Foundation

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Treatment failure	Treatment failure is defined as death due to any cause or microbiologic failure based on demonstration of MRSA on repeated culture from the original site or another sterile site more than 1 week from randomization. Treatment failure will be determined by an independent committee of physicians after reviewing the clinical, laboratory and microbiologic data.	90 days
Secondary	Major adverse kidney events	New and persistent renal-replacement therapy, or serum creatinine that is 200% or more than the baseline value during the follow-up period	90 days
Secondary	Vancomycin associated nephrotoxicity	Increase in serum creatinine by =26.4mmol/L or =50% since starting vancomycin when compared to baseline	90 days
Secondary	Renal replacement therapy	Need for initiation of renal replacement therapy at any time during follow-up	90 days
Secondary	Time to target	Time in days to reach target level (trough of 10 to 15mg/L in the intervention group and AUC/MIC of 400 to 600 in the comparison group)	90 days
Secondary	Day 3 AUC	AUC as calculated using Bayesian modeling on day 3 from randomization	3 days
Secondary	Vancomycin cost	Direct cost of vancomycin monitoring and dosing from perspective of hospital system	90 days