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

NCT04793152 | Recruiting

• 1 other identifier: 13327
• Study Type: interventional
• Target: 700
• Locations: 1 country
• Sites: 4

Brief 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%.

Conditions

MRSA

Keywords

vancomycin; MRSA; trough; AUC

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Major adverse kidney events

  90 days

• Vancomycin associated nephrotoxicity

  90 days

• Renal replacement therapy

  90 days

• Time to target

  90 days

• Day 3 AUC

  3 days

Study Arms (2)

Vancomycin targeting trough of 10 to 15mg/L

EXPERIMENTAL

If the patient has not received intravenous vancomycin yet, a loading dose of 25mg/kg (maximum 2g) will be given if the patient is severely ill at the discretion of the physician and pharmacist. The initial dose is 15mg/kg with a maximum dose of 2g. The frequency would be based on creatinine clearance (CrCl) as per the Cockcroft-Gault equation: Q8H if CrCl is \>100mL/min, Q12H if CrCl is 50-100mL/min, Q24H if CrCl is 30- 49mL/min, and Q48H if CrCl is \<30mL/min. Pharmacists can change the initial dose at their own discretion. Trough level will be done 30 minutes before the 4th dose. For Q48H dosing, a trough level will be done before the second dose. Vancomycin dosing will be adjusted to target trough level of 10 to 15mg/L. If not at target, the pharmacist will adjust the dose based on an assumption of linear pharmacokinetics. Trough will be remeasured before the fourth dose of the new regimen.

Drug: Vancomycin

Vancomycin targeting AUC of 400 to 600

ACTIVE COMPARATOR

The initial intravenous vancomycin dosing is the same as described above for the trough group. The AUC target will be 400 to 600, which assumes a MIC of 1ug/mL by broth microdilution. After the first non-loading dose of vancomycin, patients will have vancomycin level 30 minutes before the next dose. As per the pharmacist's discretion, patient may have an additional vancomycin level one hour after infusion of vancomycin for more accurate estimates. A pharmacist will use a Bayesian software to estimate the AUC and the optimal dose.

Drug: Vancomycin

Interventions

Vancomycin DRUG

Administration as outlined

Vancomycin targeting AUC of 400 to 600; Vancomycin targeting trough of 10 to 15mg/L

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Physician Services Incorporated: collaborator
• Canadian Institutes of Health Research (CIHR): collaborator
• Anthony Bai: lead

Study Sites (4)

Hamilton Health Sciences

Hamilton, Ontario, L8L 2X2, Canada

RECRUITING

St. Joseph's Healthcare Hamilton

Hamilton, Ontario, L8N 4A6, Canada

RECRUITING

Kingston Health Sciences Centre

Kingston, Ontario, K7L 2V7, Canada

RECRUITING

McGill University Health Centre

Montreal, Quebec, H3H 2R9, Canada

RECRUITING

MeSH Terms

Interventions

Vancomycin

Intervention Hierarchy (Ancestors)

Glycopeptides; Glycoconjugates; Carbohydrates; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Anthony D Bai, MD

  Queen's University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anthony D Bai, MD

CONTACT

613-533-6000; tony.bai@queensu.ca

Barbara Antuna Puente, MD

CONTACT

(613) 533 2000; barbara.antunapuente@queensu.ca

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor - Dept of Medicine

Study Record Dates

• First Submitted: March 8, 2021
• First Posted: March 11, 2021
• Study Start: March 20, 2023
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): October 1, 2029
• Last Updated: January 23, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

CA (4)