Combination Antibiotic Therapy for Methicillin Resistant Staphylococcus Aureus Infection

NCT02365493 | Terminated Phase 3 DMC

• 1 other identifier: NHMRC1078930
• Study Type: interventional
• Target: 358
• Locations: 4 countries
• Sites: 30

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.

Conditions

Methicillin-Resistant Staphylococcus Aureus

Keywords

Methicillin-Resistant Staphylococcus aureus (MRSA)

Outcome Measures

Primary Outcomes (1)

• Complication-free 90 day survival

  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.

  Time period from randomisation (day 1) to day 90

Secondary Outcomes (8)

• All-cause mortality at days 14, 42 and 90 days

  Time period from randomisation (day 1) to day 90

• Persistent bacteraemia at day 2

  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

• 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

Study Arms (2)

Standard therapy

NO INTERVENTION

Intravenous vancomycin dosed as per Australian Therapeutic Guidelines (loading dose of 25 mg/kg followed by maintenance dose of 15-20 mg/kg every 12 hours) with subsequent adjustment to maintain trough levels at 15-20 mg/dL OR Intravenous daptomycin 6-10 mg/kg per day, adjusted for renal function (details of renally adjusted dosing provided in full protocol). The choice of daptomycin or vancomycin is clinician-determined and may be influenced by such factors as local practice, the vancomycin minimum inhibitory concentration (MIC) of the isolate and evidence emerging during the course of the study

Standard therapy + Beta-Lactam

EXPERIMENTAL

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.

Drug: Beta-Lactam

Interventions

Beta-Lactam DRUG

Also known as: flucloxacillin, cloxacillin, cephazolin

Standard therapy + Beta-Lactam

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Menzies School of Health Research: lead
• Australasian Society for Infectious Diseases: collaborator
• Singapore Infectious Diseases Clinical Research Network: collaborator
• The University of Queensland: collaborator
• Australasian Kidney Trials Network: collaborator

Study Sites (30)

Blacktown Hospital

Blacktown, New South Wales, 2148, Australia

Location

Royal Prince Alfred Hospital

Camperdown, New South Wales, 2050, Australia

Location

Concord Repatriation General Hospital

Concord, New South Wales, 2139, Australia

Location

St Vincent's Hospital

Darlinghurst, New South Wales, 2010, Australia

Location

Nepean Hospital

Kingswood, New South Wales, 2747, Australia

Location

Liverpool Hospital

Liverpool, New South Wales, 2170, Australia

Location

John Hunter Hospital

New Lambton Heights, New South Wales, 2305, Australia

Location

Westmead Hospital

Westmead, New South Wales, 2145, Australia

Location

Wollongong Hospital

Wollongong, New South Wales, 2500, Australia

Location

Royal Darwin Hospital

Darwin, Northern Territory, 0820, Australia

Location

Cairns Hospital

Cairns, Queensland, 4870, Australia

Location

Royal Brisbane and Women's Hospital

Herston, Queensland, 4029, Australia

Location

Princess Alexandra Hospital

Woolloongabba, Queensland, 4102, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

Flinder's Medical Centre

Bedford Park, South Australia, 5042, Australia

Location

The Queen Elizabeth Hospital

Woodville South, South Australia, 5011, Australia

Location

Monash Medical Centre Clayton Campus

Clayton, Victoria, 3168, Australia

Location

Dandenong Hospital

Dandenong, Victoria, 3175, Australia

Location

Western Health - Footscray

Footscray, Victoria, 3011, Australia

Location

Austin Hospital

Heidelberg, Victoria, 3084, Australia

Location

Western Health - Sunshine Hospital

Sunshine, Victoria, 3021, Australia

Location

Western Health - Williamstown Hospital

Williamstown, Victoria, 3016, Australia

Location

Fiona Stanley Hospital

Murdoch, Western Australia, 6150, Australia

Location

Royal Perth Hospital

Perth, Western Australia, 6000, Australia

Location

Rambam Health Corporation

Haifa, Israel

Location

Beilinson Hospital

Petah Tikva, Israel

Location

Middlemore Hospital

Otahuhu, Auckland, 1640, New Zealand

Location

Tan Tock Seng Hospital

Novena, Tan Tock Seng, 308433, Singapore

Location

National University Hospital

Kent Ridge, 119074, Singapore

Location

Singapore General Hospital

Outram Park, 168753, Singapore

Location

Related Publications (2)

• Tong SYC, Lye DC, Yahav D, Sud A, Robinson JO, Nelson J, Archuleta S, Roberts MA, Cass A, Paterson DL, Foo H, Paul M, Guy SD, Tramontana AR, Walls GB, McBride S, Bak N, Ghosh N, Rogers BA, Ralph AP, Davies J, Ferguson PE, Dotel R, McKew GL, Gray TJ, Holmes NE, Smith S, Warner MS, Kalimuddin S, Young BE, Runnegar N, Andresen DN, Anagnostou NA, Johnson SA, Chatfield MD, Cheng AC, Fowler VG Jr, Howden BP, Meagher N, Price DJ, van Hal SJ, O'Sullivan MVN, Davis JS; Australasian Society for Infectious Diseases Clinical Research Network. Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal beta-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial. JAMA. 2020 Feb 11;323(6):527-537. doi: 10.1001/jama.2020.0103.

  PMID: 32044943 DERIVED

• Tong SY, Nelson J, Paterson DL, Fowler VG Jr, Howden BP, Cheng AC, Chatfield M, Lipman J, Van Hal S, O'Sullivan M, Robinson JO, Yahav D, Lye D, Davis JS; CAMERA2 study group and the Australasian Society for Infectious Diseases Clinical Research Network. CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection: study protocol for a randomised controlled trial. Trials. 2016 Mar 31;17:170. doi: 10.1186/s13063-016-1295-3.

  PMID: 27029920 DERIVED

MeSH Terms

Interventions

beta-Lactams; Floxacillin; Cloxacillin; Cefazolin

Intervention Hierarchy (Ancestors)

Lactams; Amides; Organic Chemicals; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Oxacillin; Penicillins; Cephalosporins; Thiazines

Study Officials

• Joshua Davis, MBBS, FRACP

  Menzies School of Health Research

  PRINCIPAL INVESTIGATOR

• Steven Tong, MBBS, FRACP

  Menzies School of Health Research

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 11, 2015
• First Posted: February 19, 2015
• Study Start: August 26, 2015
• Primary Completion: October 24, 2018
• Study Completion: October 24, 2018
• Last Updated: December 19, 2018

Record last verified: 2018-12

Locations

IL (2); AU (24); NZ (1); SG (3)