Clinical trial NCT01975662: Vancomycin Versus Daptomycin for the Treatment of Methicillin Resistant Staphylococcus Aureus (MRSA) Bacteremia
Official title: A Multi-centre Open Label Randomized Controlled Phase IIB Trial Comparing Vancomycin Versus Daptomycin for the Treatment of MRSA Bacteremia Due to Isolates With High Vancomycin Minimum Inhibitory Concentrations
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Bacteremia Due to Staphylococcus Aureus
Keywords: MRSA
bacteremia
vancomycin
daptomycin
Lead sponsor: Singapore General Hospital
Sponsor class: OTHER
Collaborators: name: Singapore Clinical Research Institute
First posted: 2013-11-05
Enrollment: 14
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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%.

Detailed description: 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

Eligibility criteria: Inclusion Criteria:

* Age \> 21 years.
* Inpatient at the time of enrolment.
* MRSA bacteremia due to MRSA isolates with a vancomycin MIC \> 1.5 ug/ml.
* Be prepared to undergo all treatments and procedures, and attend follow-ups as per the trial protocol.

Exclusion Criteria:

* Allergy to any of the study medications.
* Pregnant or breastfeeding females.
* Unable to provide consent or have no legally authorized representatives.
* Currently enrolled or within the past three months participated in an interventional antibiotic or vaccine trial.
* \>48 hours after MRSA vancomycin MIC \> or equal to1.5 ug/ml confirmation by the microbiology laboratory (assessed from time of lab report).
* Patients on palliative care or with less than 24 hours of life expectancy (as discussed with their primary physicians).
* Polymicrobial bacteremia \[see (a) below\].
* Pneumonia \[see (b) below\].
* On treatment with linezolid, tigecycline or ceftaroline immediately prior to enrolment.
* Previous blood cultures positive for MRSA in the preceding one month.
* On vancomycin or daptomycin treatment for more than 96 hours prior to enrolment.
* BSI due to MRSA with vancomycin MIC \> or equal to 4 ug/ml.
* Baseline serum creatine kinase more than 1.5 times the upper limit of normal.
* Patients with prosthetic heart valves
* Any other significant condition that would, in the opinion of the investigator, compromise the patient's safety or outcome in the trial.

  1. .Isolation of a significant organism other than MRSA from index blood cultures or blood cultures taken up to two weeks prior to enrolment and/or for which the patient is still on treatment.
  2. .Chest x-ray at baseline consistent with pneumonia AND at least 2 of the following signs and symptoms: New onset or worsening cough, purulent sputum or increased suctioning requirements, dyspnea/tachypnea or respiratory rate \> 30/min, hypoxemia or worsening gas exchange as determined by study investigator.)

Primary outcomes:
measure: All cause mortality
timeFrame: 60 days
Secondary outcomes:
measure: Rates of clinical failure
timeFrame: 60 days
measure: Time to microbiological clearance
timeFrame: 60 days
measure: Rates of nephrotoxicity
timeFrame: 60 days
measure: Rates of musculoskeletal toxicity
timeFrame: 60 days
measure: The need to stop the study drug due to toxicity
timeFrame: 60 days
measure: The need to discontinue study drug due to worsening infection
timeFrame: 60 days
measure: The need for an additional anti-MRSA agent due to worsening infection while on study treatment.
timeFrame: 60 days
measure: 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.
timeFrame: 90 days
measure: Serious adverse events at any time during the study period, whether or not they are thought to be related to the investigation drug.
timeFrame: 60 days
Other outcomes:
measure: All cause mortality in the different subtypes of bacteremia
timeFrame: 60 days
measure: Rates of clinical failure in the different subtypes of bacteremia
timeFrame: 60 days
Locations:
city: Singapore
country: Singapore
facility: Singapore General Hospital
Study officials:
affiliation: Singapore General Hospital
name: Thuan Tong Tan, MBBS, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kalimuddin S, Chan YFZ, Phillips R, Ong SP, Archuleta S, Lye DC, Tan TT, Low JGH. A randomized phase 2B trial of vancomycin versus daptomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia due to isolates with high vancomycin minimum inhibitory concentrations - results of a prematurely terminated study. Trials. 2018 Jun 1;19(1):305. doi: 10.1186/s13063-018-2702-8.
citation: Kalimuddin S, Phillips R, Gandhi M, de Souza NN, Low JG, Archuleta S, Lye D, Tan TT. Vancomycin versus daptomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia due to isolates with high vancomycin minimum inhibitory concentrations: study protocol for a phase IIB randomized controlled trial. Trials. 2014 Jun 19;15:233. doi: 10.1186/1745-6215-15-233.