Combination Antibiotic Therapy for Methicillin Resistant Staphylococcus Aureus Infection
- Conditions
- Methicillin-Resistant Staphylococcus Aureus
- Interventions
- Drug: Beta-Lactam
- Registration Number
- NCT02365493
- Lead Sponsor
- Menzies School of Health Research
- Brief Summary
The aim of this clinical trial is to determine whether a novel combination antibiotic treatment (vancomycin/daptomycin + beta-lactam) is superior to the standard antibiotic treatment (vancomycin/daptomycin) for hospitalised adults with Methicillin Resistant Staphylococcus aureus bacteraemia. The hypothesis is that the addition of beta-lactam antibiotics (these are antibiotics from the penicillin family) to the standard therapy will lead to more efficient bacterial killing and hence lead to faster clearance of bacteria from the blood stream and other areas of infection, thereby reducing the risk of the spread of infection and death.
The study design is an investigator-initiated, multi-centre, open-label, randomised controlled trial. This will include 440 participants diagnosed with Methicillin Resistant Staphylococcus aureus bacteraemia recruited over a period of 4 years (July 2015 - June 2019) from within Infectious Diseases inpatient units across 21 hospital sites including 18 from within Australia and 3 located in Singapore. Participation will be voluntary and subject to informed consent. The participants will be randomised 1:1 to either the standard therapy group or combination therapy group. The combination therapy will include a treatment of intravenous beta-lactam for the first 7 days of treatment, in addition to the standard treatment (either vancomycin or daptomycin). The primary outcome measure will be complication-free survival 90 days post randomisation.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 358
- Age >= 18 years.
- ≥1 set of blood cultures positive for MRSA
- Able to be randomized within 72 hours of blood cultures being collected.
- Likely to remain as inpatient for 7 days following randomization
- Previous type 1 hypersensitivity reaction to ß-lactams
- Polymicrobial bacteraemia (not counting contaminants)
- Previous participation in the trial
- Known pregnancy
- Current β-lactam antibiotic therapy which cannot be ceased or substituted
- Participant's primary clinician unwilling to enrol patient
- Moribund (expected to die in next 48 hours with or without treatment)
- Treatment limitations which preclude the use of antibiotics Note that we are NOT planning to exclude participants with renal failure.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Standard therapy + Beta-Lactam Beta-Lactam In addition to standard treatment an intravenous Beta-Lactam (β-lactam) will be added for the first 7 calendar days following randomisation (randomisation is day 1 - hence patients will receive 6-7 days of β-lactam). This β-lactam will be intravenous flucloxacillin 2g every 6 hours in Australia and intravenous cloxacillin 2g every 6 hours in Singapore. For those with a history of minor allergy to any penicillin (rash or unclear history, but not anaphylaxis or angiooedema), it will be intravenous cefazolin 2g every 8 hours. For haemodialysis patients, it will usually be cefazolin 2g three times per week post dialysis, however clinicians are also free to choose intermittent (flu)cloxacillin, dosed as for glomerular filtration rate (GFR ) \<10, if they desire.
- Primary Outcome Measures
Name Time Method Complication-free 90 day survival Time period from randomisation (day 1) to day 90 Composite outcome at 90 days - any of:
1. All-cause mortality
2. Persistent bacteraemia at day 5 or beyond
3. Microbiological relapse - positive blood culture for MRSA at least 72 hours after a preceding negative culture
4. Microbiological treatment failure. Positive sterile site culture for MRSA at least 14 days after randomisation.
- Secondary Outcome Measures
Name Time Method All-cause mortality at days 14, 42 and 90 days Time period from randomisation (day 1) to day 90 Persistent bacteraemia at day 5 or beyond Time period from randomisation (day 1) to day 90 Acute kidney injury defined as ≥ stage 1 modified RIFLE criteria at any time within the first 7 days, OR new need for renal replacement therapy at any time from days 1 to 90. Excludes participants already on haemodialysis. Time period from randomisation (day 1) to day 90 \>=stage 1 modified RIFLE criteria (1.5-fold increase in the serum creatinine, or glomerular filtration rate (GFR) decrease by 25 percent). This endpoint does not apply to participants who were already on haemodialysis at randomisation.
Microbiological treatment failure. Positive sterile site culture for MRSA at least 14 days after randomisation Time period from randomisation (day 1) to day 90 Persistent bacteraemia at day 2 Time period from randomisation (day 1) to day 90 Microbiological relapse - positive blood culture for MRSA at least 72 hours after a preceding negative culture Time period from randomisation (day 1) to day 90 Duration of intravenous antibiotic treatment Time period from randomisation (day 1) to day 90 Direct health care costs Time period from randomisation (day 1) to day 90
Trial Locations
- Locations (30)
Blacktown Hospital
🇦🇺Blacktown, New South Wales, Australia
Concord Repatriation General Hospital
🇦🇺Concord, New South Wales, Australia
St Vincent's Hospital
🇦🇺Darlinghurst, New South Wales, Australia
John Hunter Hospital
🇦🇺New Lambton Heights, New South Wales, Australia
Nepean Hospital
🇦🇺Kingswood, New South Wales, Australia
Wollongong Hospital
🇦🇺Wollongong, New South Wales, Australia
Westmead Hospital
🇦🇺Westmead, New South Wales, Australia
Cairns Hospital
🇦🇺Cairns, Queensland, Australia
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
The Queen Elizabeth Hospital
🇦🇺Woodville South, South Australia, Australia
Flinder's Medical Centre
🇦🇺Bedford Park, South Australia, Australia
Western Health - Footscray
🇦🇺Footscray, Victoria, Australia
Dandenong Hospital
🇦🇺Dandenong, Victoria, Australia
Western Health - Sunshine Hospital
🇦🇺Sunshine, Victoria, Australia
Rambam Health Corporation
🇮🇱Haifa, Israel
Western Health - Williamstown Hospital
🇦🇺Williamstown, Victoria, Australia
Middlemore Hospital
🇳🇿Otahuhu, Auckland, New Zealand
Tan Tock Seng Hospital
🇸🇬Novena, Tan Tock Seng, Singapore
Royal Perth Hospital
🇦🇺Perth, Western Australia, Australia
Royal Prince Alfred Hospital
🇦🇺Camperdown, New South Wales, Australia
Liverpool Hospital
🇦🇺Liverpool, New South Wales, Australia
Royal Brisbane and Women's Hospital
🇦🇺Herston, Queensland, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
Fiona Stanley Hospital
🇦🇺Murdoch, Western Australia, Australia
Monash Medical Centre Clayton Campus
🇦🇺Clayton, Victoria, Australia
Beilinson Hospital
🇮🇱Petah Tikva, Israel
National University Hospital
🇸🇬Kent Ridge, Singapore
Austin Hospital
🇦🇺Heidelberg, Victoria, Australia
Singapore General Hospital
🇸🇬Outram Park, Singapore
Royal Darwin Hospital
🇦🇺Darwin, Northern Territory, Australia