Vancomycin Dosing for Serious MRSA Infections: A Non-inferiority Randomized Trial of Trough Level Versus AUC/MIC
Study Details
Study Description
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. 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/MIC of 400 to 600 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/MIC 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%.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| N/A |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Vancomycin targeting trough of 10 to 15mg/L 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. Trough level will be done 30 minutes before the fourth dose. For patients on 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 infectious diseases pharmacist will adjust the dose based on an assumption of linear pharmacokinetics. The dose at each administration will be rounded to the nearest 250mg. Trough will be remeasured before the fourth dose of the new regimen. |
Drug: Vancomycin
Administration as outlined
|
| Active Comparator: Vancomycin targeting AUC/MIC of 400 to 600 The initial intravenous vancomycin dosing is the same as described above for the trough group. The initial AUC target will be 400 to 600, which assumes a MIC of 1mg/L. The microbiology lab will do susceptibility testing by broth microdilution to determine the vancomycin MIC for all isolates in both treatment groups. When the MIC by broth microdilution is known, then the target will be AUC/MIC of 400 to 600. 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. An infectious diseases pharmacist will use a Bayesian software to estimate the AUC and the optimal dose. |
Drug: Vancomycin
Administration as outlined
|
Outcome Measures
Primary Outcome Measures
- Treatment failure [90 days]
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. This committee will be blinded to the treatment assignment.
Secondary Outcome Measures
- Major adverse kidney events [90 days]
New and persistent renal-replacement therapy, or serum creatinine that is 200% or more than the baseline value during the follow-up period
- Vancomycin associated nephrotoxicity [90 days]
Increase in serum creatinine by ≥26.4mmol/L or ≥50% since starting vancomycin when compared to baseline
- Renal replacement therapy [90 days]
Need for initiation of renal replacement therapy at any time during follow-up
- Time to target [90 days]
Time in hours 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)
- Day 3 AUC [3 days]
AUC as calculated using Bayesian modeling on day 3 from randomization
- Vancomycin cost [90 days]
Direct cost of vancomycin monitoring and dosing from perspective of hospital system
Eligibility Criteria
Criteria
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
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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
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History of type 1 hypersensitivity reaction to vancomycin
-
Patients on intermittent hemodialysis
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Hamilton Health Sciences | Hamilton | Ontario | Canada | L8L 2X2 |
| 2 | St. Joseph's Healthcare Hamilton | Hamilton | Ontario | Canada | L8N 4A6 |
Sponsors and Collaborators
- Hamilton Health Sciences Corporation
Investigators
- Principal Investigator: Anthony D Bai, MD, Hamilton Health Sciences Corporation
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 13327