The aim of this study is to compare the efficacy of daptomycin treatment versus vancomycin treatment in the treatment of methicillin resistant staphylococcus aureus (MRSA) bloodstream infections (BSI) due to isolates with high vancomycin minimum inhibitory concentrations (MIC) (i.e. \> or equal to 1.5 ug/ml) in terms of reducing all-cause mortality. Our secondary aim is to compare clinical failure rates of daptomycin treatment versus vancomycin treatment and to compare time to microbiological clearance in patients treated with daptomycin versus those treated with vancomycin. Our primary hypothesis is that Daptomycin treatment is superior to vancomycin treatment in reducing mortality from BSIs due to MRSA with high vancomycin MIC from 25% to 10%.
Introduction/Clinical Significance Vancomycin is the standard first-line treatment for methicillin resistant Staphylococcus aureus (MRSA) bacteremia. In recent years however, there has been an increase in the number of MRSA isolates with high vancomycin minimum inhibitory concentrations (MIC). Recent consensus guidelines recommend clinicians consider using alternative agents such as daptomycin for MRSA infection when the vancomycin MIC is greater than 1 ug/ml. To date however, there has been no head to head randomized trial comparing the safety and efficacy of daptomycin and vancomycin in the treatment of blood stream infections (BSIs) due to MRSA with high vancomycin MICs. Specific Aims: Our primary aim is to compare the efficacy of daptomycin treatment versus vancomycin treatment in the treatment of MRSA BSIs due to isolates with high vancomycin MICs (i.e. \> or equal to 1.5 ug/mL) in terms of reducing all-cause mortality. Our secondary aim is to compare clinical failure rates of daptomycin treatment versus vancomycin treatment and to compare time to microbiological clearance in patients treated with daptomycin versus those treated with vancomycin. Hypothesis: Daptomycin treatment is superior to vancomycin treatment in reducing mortality from BSIs due to MRSA with high vancomycin MIC from 25% to 10%. Methodology We will conduct a prospective open label randomized controlled phase 2B pilot study in 3 major Singaporean hospitals, with balanced treatment assignments within each hospital achieved by permuted block randomization. There will be 21 subjects per arm, with the control arm receiving vancomycin and the experimental arm receiving daptomycin. The primary objective is to compare the efficacy of daptomycin treatment versus vancomycin treatment in the treatment of MRSA BSIs due to isolates with high vancomycin MICs (i.e. \> or equal to 1.5 ug/mL) in terms of reducing all-cause mortality 60 days from positive index blood culture. Secondary outcomes include rates of clinical failure, time to microbiological clearance, and rates of nephro- and muscular toxicities in both arms. If the pilot study proves our hypothesis that indeed , we aim to proceed with a larger scale trial
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
14
Duration of treatment will be determined based on the type of bacteremia. Patients with uncomplicated bacteremia will receive a minimum of 14 days antibiotics and those with complicated bacteremia or infective endocarditis will receive a minimum of 28 to 42 days antibiotics from the date that microbiological clearance is achieved.
Duration of treatment will be determined based on the type of bacteremia. Patients with uncomplicated bacteremia will receive a minimum of 14 days antibiotics and those with complicated bacteremia or infective endocarditis will receive a minimum of 28 to 42 days antibiotics from the date that microbiological clearance is achieved.
Singapore General Hospital
Singapore, Singapore
All cause mortality
To compare the efficacy of daptomycin treatment versus vancomycin treatment in the treatment of MRSA BSIs due to isolates with high vancomycin MICs (i.e. \> or equal to 1.5 ug/L) in terms of reducing all-cause mortality 60 days from the time of index blood culture.
Time frame: 60 days
Rates of clinical failure
Our secondary aims are: 1.To compare the rates of 'clinical failure' as per the following definitions: i.To compare clinical failure rates of daptomycin treatment versus vancomycin treatment defined as a composite of all-cause mortality 60 days from index blood culture, microbiologic failure and/or a recurrence of MRSA BSI. ii.To compare clinical failure rates of daptomycin treatment versus vancomycin treatment defined as microbiologic failure and/or a recurrence of MRSA BSI. iii.To compare clinical failure rates of daptomycin treatment versus vancomycin treatment defined as a composite of all-cause mortality 60 days from index blood culture and/or microbiologic failure.
Time frame: 60 days
Time to microbiological clearance
To compare time to microbiological clearance. Microbiological clearance is defined as two consecutive MRSA negative blood cultures.
Time frame: 60 days
Rates of nephrotoxicity
To evaluate nephrotoxicity in both treatment arms. Nephrotoxicity will be defined as an increase in the serum creatinine level of 50umol/L from baseline or 50% above baseline throughout the course of the study, in the absence of an alternative explanation.
Time frame: 60 days
Rates of musculoskeletal toxicity
To evaluate musculoskeletal toxicity in both treatment arms as defined by a rise in creatine kinase (CK) of 5 times the upper limit of normal during the course of the study.
Time frame: 60 days
The need to stop the study drug due to toxicity
To evaluate the need to stop the study drug due to toxicity (as defined by Common Terminology Criteria for Adverse Events version 4.03 \[CTCAE\])
Time frame: 60 days
The need to discontinue study drug due to worsening infection
To evaluate the need to discontinue study drug due to worsening infection while on study treatment.
Time frame: 60 days
The need for an additional anti-MRSA agent due to worsening infection while on study treatment.
To evaluate the need for an additional anti-MRSA agent due to worsening infection while on study treatment.
Time frame: 60 days
Adverse events in both treatment arms up to 60 days from index culture or 30 days post last study dose if later than the 60 day visit.
To compare adverse events in both treatment arms up to 60 days from index culture or 30 days post last study dose if later than the 60 day visit.
Time frame: 90 days
Serious adverse events at any time during the study period, whether or not they are thought to be related to the investigation drug.
To assess the occurrence of serious adverse events at any time during the study period, whether or not they are thought to be related to the investigation drug.
Time frame: 60 days
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