Vancomycin Dosing for MRSA Infections

(TAUC Trial)

Recruiting at 3 trial locations

Overseen By Barbara Antuna Puente, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Anthony Bai

Disqualifiers: Vancomycin MIC ≥2ug/mL, Palliative, Dialysis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 90 days

700 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two ways of giving vancomycin to patients with serious MRSA infections. It aims to find out if a simpler dosing method is as effective as a more complex one. Vancomycin is the antibiotic with the most clinical experience for treating MRSA bacteremia.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that you can participate if you are not currently on vancomycin or have been on it for 4 days or less.

Is vancomycin generally safe for humans?

Vancomycin has been used for a long time to treat serious infections, but there are risks of drug toxicity (harmful effects) if not prescribed correctly. Recommendations exist to monitor its use carefully to minimize these risks. ^{1 2 3 4 5}

How is the drug Vancomycin unique in treating MRSA infections?

Vancomycin is unique in treating MRSA infections because it requires careful dosing to achieve specific drug concentration levels in the body, measured by the area under the concentration versus time curve (AUC) divided by the minimum inhibitory concentration (MIC) of the bacteria. This approach helps ensure the drug is effective, especially in critically ill patients, and differs from traditional dosing methods that focus only on trough concentrations. ^{3 6 7 8 9}

What data supports the effectiveness of the drug Vancomycin for MRSA infections?

Research shows that Vancomycin is effective for treating MRSA infections, especially when the drug concentration in the body is carefully monitored and adjusted. Studies suggest that achieving a specific drug concentration (AUC/MIC ratio of ≥400) is linked to better treatment outcomes, reducing the chance of treatment failure. ^{4 6 8 10 11}

Who Is on the Research Team?

Anthony D Bai, MD

Principal Investigator

Queen's University

Are You a Good Fit for This Trial?

Adults with serious MRSA infections confirmed by culture, including blood, lung, brain, bone infections and more. They must join within 4 days of the culture test and can be new to vancomycin treatment or have had it for up to 4 days. Not eligible if they're on dialysis, expected to die within 48 hours, allergic to vancomycin or if their infection resists higher doses of vancomycin.

Inclusion Criteria

I am not currently on vancomycin or have been on it for 4 days or less.

I have a serious MRSA infection confirmed by lab tests.

Enrolment within 4 days from date of MRSA culture collection

Exclusion Criteria

History of type 1 hypersensitivity reaction to vancomycin

Vancomycin minimum inhibitory concentration (MIC) ≥2ug/mL

You are receiving end-of-life care and are expected to pass away within the next two days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intravenous vancomycin with dosing strategy targeting either a trough level of 10 to 15mg/L or an AUC of 400 to 600 for serious MRSA infections

90 days

Regular monitoring visits for dose adjustments

Follow-up

Participants are monitored for treatment failure, defined as death or microbiologic failure, and other secondary outcomes such as nephrotoxicity and renal replacement therapy

90 days

What Are the Treatments Tested in This Trial?

Interventions

• Vancomycin

Trial Overview This study tests two ways of dosing vancomycin in treating serious MRSA infections: one targets drug levels in the blood (trough level) and the other focuses on how much drug stays in the body over time relative to the bacteria's resistance (AUC/MIC). It checks which method is just as good without being worse by more than a set margin.

How Is the Trial Designed?

Group I: Vancomycin targeting trough of 10 to 15mg/L Experimental Treatment 1 Intervention

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.

Group II: Vancomycin targeting AUC of 400 to 600 Active Control 1 Intervention

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.

Vancomycin is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Vancocin for:

• Severe infections caused by susceptible strains of methicillin-resistant staphylococci
• Enterocolitis caused by Staphylococcus aureus
• Staphylococcal endocarditis

Approved in European Union as Vancomycin for:

• Severe infections caused by Gram-positive bacteria
• Endocarditis
• Peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD)

Approved in Canada as Vancomycin for:

• Severe infections caused by susceptible strains of methicillin-resistant staphylococci
• Enterocolitis caused by Staphylococcus aureus

Approved in Japan as Vancomycin for:

• Severe infections caused by Gram-positive bacteria
• Endocarditis

Who Is Running the Clinical Trial?

Anthony Bai

Lead Sponsor

Hamilton Health Sciences Corporation

Lead Sponsor

Trials

380

Recruited

345,000+

McMaster University

Lead Sponsor

Trials

936

Recruited

2,630,000+

Physician Services Incorporated

Collaborator

Trials

2

Recruited

850+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

The Physicians' Services Incorporated Foundation

Collaborator

Trials

165

Recruited

31,700+

Published Research Related to This Trial

In a study of 125 critically ill trauma patients with MRSA ventilator-associated pneumonia (VAP), high-dose vancomycin (mean dose of 18.1 mg/kg) achieved a clinical cure rate of 88%, indicating its efficacy in treating this serious infection.

The study suggests that high-dose vancomycin is a viable treatment option for MRSA VAP, as it resulted in a microbiological success rate of 89% and an overall mortality rate of 20%, with deaths primarily due to VAP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia with high-dose vancomycin or linezolid. Hamilton, LA., Christopher Wood, G., Magnotti, LJ., et al.[2015]

In a study of 81 critically ill patients with MRSA pneumonia, the use of an initial loading dose of vancomycin (25-30 mg/kg) did not lead to better clinical outcomes compared to those who did not receive the loading dose, with similar rates of clinical cure (68.2% vs. 66.1%).

The study found no significant differences in microbiological cure, all-cause mortality, or the incidence of acute kidney injury between the loading dose and non-loading dose groups, suggesting that the current guidelines for vancomycin loading doses may need reevaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of vancomycin loading dose on clinical outcome in critically ill patients with methicillin-resistant Staphylococcus aureus pneumonia. Yoon, JG., Huh, K., Sohn, YM., et al.[2022]

Vancomycin dosing for treating MRSA infections should be guided by the area under the concentration versus time curve (AUC) divided by the minimum inhibitory concentration (MIC), rather than just trough concentrations, as this method better predicts therapeutic effectiveness.

In patients with lower respiratory tract infections, achieving an AUC/MIC of ≥400 is linked to better clinical outcomes, while those with MRSA bacteremia reaching an AUC/MIC of ≥320 within 48 hours have a 50% lower chance of treatment failure, highlighting the importance of optimizing dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vancomycin pharmacokinetic models: informing the clinical management of drug-resistant bacterial infections. Stockmann, C., Roberts, JK., Yu, T., et al.[2017]

In a study analyzing vancomycin dosing in 2,570 patients, only about 20% achieved therapeutic drug levels, with a significant number either subtherapeutic (56%) or toxic (23.8%).

The introduction of a new dosing nomogram improved the achievement of therapeutic levels from 23.1% to 45.0% for lower targets and from 13.8% to 36.2% for higher targets, indicating a more effective strategy for dosing based on individual patient factors like age, body weight, and creatinine clearance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Appropriateness of an Initial Dosing Regimen of Vancomycin and Development of a New Dosing Nomogram. Yoon, S., Park, KR., Lee, S., et al.[2019]

Vancomycin remains a crucial treatment for Gram-positive infections, including MRSA, and its effectiveness is best monitored using the AUC24/MIC ratio, with a target of ≥400, although trough and peak serum levels are also commonly used in practice.

The study found that patient factors such as weight and renal function significantly influence vancomycin plasma levels, emphasizing the need for careful therapeutic monitoring and the potential of physiologically based pharmacokinetic (PBPK) modeling to optimize dosing regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Silico Pharmacokinetic Study of Vancomycin Using PBPK Modeling and Therapeutic Drug Monitoring. Ferreira, A., Martins, H., Oliveira, JC., et al.[2021]

Vancomycin is regaining attention due to its effectiveness against resistant gram-positive bacteria and improvements in its drug purity, making it a valuable option in treating infections.

The review highlights vancomycin's antimicrobial activity, pharmacokinetics, clinical uses, dosing regimens, and potential side effects, providing a comprehensive overview for healthcare professionals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vancomycin. A new old agent. Ingerman, MJ., Santoro, J.[2013]

The implementation of a pharmacist-led clinical practice guideline for vancomycin dosing and monitoring in a teaching hospital led to a significant increase in the prescribing of loading doses from 9% to 28%, which is crucial for effective treatment of serious infections.

Post-implementation, the rate of potentially toxic vancomycin concentrations decreased from 32% to 21%, indicating improved safety in prescribing practices, while infection cure rates improved from 85% to 96%, suggesting enhanced efficacy of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacist-led implementation of a vancomycin guideline across medical and surgical units: impact on clinical behavior and therapeutic drug monitoring outcomes. Phillips, CJ., Gordon, DL.[2022]

In a study of 23 pediatric patients with MRSA infections, 52% experienced treatment failure, particularly in those with minimum inhibitory concentrations (MICs) of 1.5 µg/mL or higher, indicating a significant challenge in effectively treating these infections.

Only 18% of patients achieved the recommended vancomycin trough levels of >15 µg/mL, and none reached the optimal AUC24/MIC ratio of >400, suggesting that current dosing guidelines may be inadequate for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of clinical outcome in children and adolescents receiving vancomycin for invasive infections due to methicillin-resistant Staphylococcus aureus: impact of increasing vancomycin MICs. Arun, A., Swamy, S., Jacob, K., et al.[2018]

The article summarizes updated recommendations for vancomycin dosing and monitoring, particularly for patients with osteomyelitis, emphasizing the importance of appropriate loading and maintenance doses to ensure efficacy and minimize toxicity.

Key recommendations include specific guidelines for trough concentration monitoring and the frequency of monitoring to prevent potential toxic effects, addressing long-standing uncertainties in vancomycin use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Summary of ASHP/IDSA/SIDP vancomycin monitoring recommendations: a focus on osteomyelitis. Malloy, KM., Davis, GA.[2013]

In a study of 36 critically ill adult trauma patients with MRSA pneumonia, those receiving vancomycin at a dose of 1 g every 8 hours achieved significantly higher trough concentrations (11.1 mg/L) compared to those receiving 1 g every 12 hours (6.8 mg/L).

Only 23.5% of patients on the 1 g every 8 hours regimen reached the desired trough concentration of 15 mg/L, while none in the 1 g every 12 hours group did, indicating that more frequent dosing is necessary to effectively treat MRSA pneumonia in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vancomycin dosing for pneumonia in critically ill trauma patients. Patanwala, AE., Norris, CJ., Nix, DE., et al.[2022]

A study involving 20 neonates validated a pharmacokinetic model for vancomycin, showing that it can reliably predict drug clearance based on weight, postmenstrual age, and serum creatinine levels.

The newly developed vancomycin dosage regimen achieved target drug concentrations more effectively than existing institutional and NeoFax® regimens, indicating improved efficacy for treating MRSA infections in neonates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

External Validation of a Vancomycin Population Pharmacokinetic Model and Developing a New Dosage Regimen in Neonates. Lim, CP., Tseng, SH., Neoh, CCC., et al.[2022]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Treatment of methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia with high-dose vancomycin or linezolid. [2015]

2. China pubmed.ncbi.nlm.nih.gov

Effect of vancomycin loading dose on clinical outcome in critically ill patients with methicillin-resistant Staphylococcus aureus pneumonia. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Vancomycin pharmacokinetic models: informing the clinical management of drug-resistant bacterial infections. [2017]

4. England pubmed.ncbi.nlm.nih.gov

Assessment of Appropriateness of an Initial Dosing Regimen of Vancomycin and Development of a New Dosing Nomogram. [2019]

5. Netherlands pubmed.ncbi.nlm.nih.gov

In Silico Pharmacokinetic Study of Vancomycin Using PBPK Modeling and Therapeutic Drug Monitoring. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Vancomycin. A new old agent. [2013]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Pharmacist-led implementation of a vancomycin guideline across medical and surgical units: impact on clinical behavior and therapeutic drug monitoring outcomes. [2022]

8. Italy pubmed.ncbi.nlm.nih.gov

Evaluation of clinical outcome in children and adolescents receiving vancomycin for invasive infections due to methicillin-resistant Staphylococcus aureus: impact of increasing vancomycin MICs. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Summary of ASHP/IDSA/SIDP vancomycin monitoring recommendations: a focus on osteomyelitis. [2013]

10. United States pubmed.ncbi.nlm.nih.gov

Vancomycin dosing for pneumonia in critically ill trauma patients. [2022]

11. France pubmed.ncbi.nlm.nih.gov

External Validation of a Vancomycin Population Pharmacokinetic Model and Developing a New Dosage Regimen in Neonates. [2022]