Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness

Not Applicable

Completed

• Conditions: Bacteremia; Critically Ill; Mortality; Intensive Care; Sepsis; Antimicrobial
• Interventions: Other: 14 days of adequate antibiotic treatment.; Other: 7 days of adequate antibiotic treatment

• Registration Number: NCT03005145
• Lead Sponsor: Sunnybrook Health Sciences Centre

Brief Summary

The World Health Organization, U.S. Centers for Disease Control and Prevention, Association of Medical Microbiology and Infectious Diseases (AMMI) Canada, and Health Canada have all declared antimicrobial resistance a global threat to health, based on rapidly increasing resistance rates and declining new drug development. Up to 30-50% of antibiotic use is inappropriate, and excessive durations of treatment are the greatest contributor to inappropriate use. Shorter duration treatment (≤7 days) has been shown in meta-analyses to be as effective as longer antibiotic treatment for a range of mild to moderate infections. A landmark trial in critically ill patients with ventilator-associated pneumonia showed that mortality and relapse rates were non-inferior in patients who received 8 vs 15 days of treatment. Similar adequately powered randomized trial evidence is lacking for the treatment of patients with bloodstream infections caused by a wide spectrum of organisms.

Detailed Description

Bloodstream infections are a common and serious problem, increasing length of hospital stay by 2-3 weeks, adding $25,000-40,000 in excess hospital costs, and tripling the risk of death. At the same time, antibiotic overuse is also a common and serious problem, in that 30-50% of antibiotic use is unnecessary or inappropriate, and results in avoidable drug side effects such as kidney failure, Clostridioides difficile infection, increased costs, and spiralling antibiotic resistance rates. The greatest contributor to antibiotic overuse is excessive durations of treatment.

Extensive research has demonstrated that shorter duration antibiotic treatment (less or equal to 7 days) is as effective as longer duration treatment for a variety of infectious diseases, but this question has not been directly studied in the setting of bloodstream infection. BALANCE team's systematic review of the medical literature, national survey of Canadian infectious diseases and critical care physicians, multicentre retrospective study and BALANCE pilot RCT, all support the need for a randomized controlled trial comparing shorter (7 days) versus longer (14 days) antibiotic therapy for bloodstream infections. Prior to performing the main trial, Investigators completed a pilot trial in ICU patients to establish the feasibility of the research design, and to optimize the definitive trial. Investigators also completed a pilot trial of non-ICUs patients to test the feasibility, compare the patient population in two settings and to assess the reasonableness of expanding the main BALANCE Trial to non-ICU wards. The overall recruitment rate of the non-ICU ward pilot RCT exceeded the recruitment rate in the BALANCE ICU pilot RCT with a protocol adherence of 90%. The results of this pilot were used to estimate the necessary sample size recalculation, after merging the BALANCE ward trial with the BALANCE main trial, with the principle of maintaining an equal to smaller non-inferiority margin by the trial's completion. With the completion of this pilot RCT, the eligibility criteria for the BALANCE trial are also modified to broaden the inclusion of all bacteremic patients admitted to hospital. By defining the duration of treatment for bloodstream infections, BALANCE research program will help maximize the clinical cure of individual patients, while minimizing their risk of drug side effects, C. difficile, and antibiotic resistance. Since this intervention would require no new technology, and would reduce (rather than increase) health care costs, it would offer immediate benefits to patients and the healthcare system.

The BALANCE RCT will randomize hospitalized patients with bloodstream infection to 7 versus 14 days of adequate antibiotic treatment; the antibiotic drugs, doses, routes and interval will be left to the discretion of the treating team. Although placebo controls are not feasible, prolonged allocation concealment to day 7 will be used to mitigate selection bias. The primary analysis will assess whether 7 days is associated with non-inferior 90 day survival as compared to 14 days of treatment. Participants from the vanguard BALANCE pilot RCTs will be included in the BALANCE main RCT, and participating Canadian sites will continue to enrol patients. BALANCE international collaborators include New Zealand, Australia, Saudi Arabia, the United States, Israel and Switzerland.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2016-12-20
• Study First Submitted QC: 2016-12-22
• Study First Posted: 2016-12-29
• Study Start: 2017-02-24
• Primary Completion: 2023-05-05
• Study Completion: 2023-08-03
• Status Verified: 2023-11
• Last Update Submitted: 2024-02-28
• Last Update Posted: 2024-02-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 3622

Inclusion Criteria

1. Patient is in ICU or non-ICU ward at the time the blood culture is drawn or reported as positive.
2. Patient has a positive blood culture with pathogenic bacteria.

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Exclusion Criteria

1. Patient already enrolled in the trial

2. Patient has severe immune system compromise, as defined by: absolute neutrophil count <0.5x109/L; or is receiving immunosuppressive treatment for solid organ or bone marrow or stem cell transplant

3. Patient has a prosthetic heart valve or synthetic endovascular graft (post major vessel repair with synthetic material) (note: coronary artery stents are not an exclusion)

4. Patient has documented or suspected syndrome with well-defined requirement for prolonged treatment:

   i) infective endocarditis; ii) osteomyelitis/septic arthritis; iii) undrainable/undrained abscess; iv) unremovable/unremoved prosthetic-associated infection (e.g. infected pacemaker, prosthetic joint infection, ventriculoperitoneal shunt infection etc.) (note: central venous catheters, including tunneled central intravenous catheter, and urinary catheters are not excluded unless the treating clinical team does not have equipoise for enrollment and randomization to either group)

5. Patient has a single positive blood culture with a common contaminant organism according to Clinical Laboratory & Standards Institute (CLSI) Guidelines: coagulase negative staphylococci; or Bacillus spp.; or Corynebacterium spp.; or Propionobacterium spp.; or Aerococcus spp.; or Micrococcus spp.

6. Patient has a positive blood culture with Staphylococcus aureus or Staphylococcus lugdunensis

7. Patient has a positive blood culture with Candida spp. or other fungal species.

8. Blood culture grows rare bacterial pathogens requiring prolonged treatment (e.g. Mycobacteria spp., Nocardia spp., Actinomyces spp., Brucella spp., Burkholderia pseudomallei)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Long duration (14 days)	14 days of adequate antibiotic treatment.	Patients in 14 day arm will receive adequate antibiotics until the end of day 14 only
Short duration (7 days)	7 days of adequate antibiotic treatment	Patients in 7 day arm will receive adequate antibiotics until the end of day 7 only

Primary Outcome Measures

Name	Time	Method
90 day survival	90 days from index blood culture	Survival at 90-days recorded as alive or dead at day 90 following index positive blood culture

Secondary Outcome Measures

Name	Time	Method
Relapse rates of bacteremia with the same organism	Upto 30 days after adequate antibiotic treatment	Defined as the recurrence of bacteremia due to original infecting organism (same Genus and species) after documentation of negative blood cultures or clinical improvement and within 30 days after completing course of adequate antimicrobial therapy.
Mechanical ventilation duration	Expected for an average of 30 days	Defined as the number of consecutive days receiving invasive (via an endotracheal tube or tracheostomy), or non-invasive (via a facemask, nasal mask, or helmet) ventilation
Hospital mortality	Expected average of 4 weeks assessed upto one year	Recorded as alive or dead at hospital discharge following index positive blood culture
Antibiotic allergy and adverse events	Upto 30 days from start of antibiotic treatment	Effect of medication on body that produces the allergic reaction to a medication like: * Hives; * Itching of the skin or eyes; * Skin rash; * Swelling of the lips, tongue, or face; * Wheezing; * Organ toxicity
Rates of secondary nosocomial infection/colonization with antimicrobial resistant organisms in hospital	Upto 30 days after index blood culture collection date	Colonized or infected with at least one highly-resistant microorganism during their hospital stay
Rates of C. difficile infection in hospital	Upto 30 days after index blood culture collection date	Defined as a positive PCR or ELISA test for Clostridium difficile toxin in the context of diarrhea within hospital of bacteremia diagnosis.
Hospital length of stay	Expected for an average of 30 days assessed up to 1 year	Defined as the duration between index blood culture and discharge date from hospital
Antibiotic free days	Upto 30 days after adequate antibiotic treatment	Defined as the number of days during the 28 days after the start of adequate antibiotics in which patients did not receive any antibiotics.
ICU mortality	Expected average of 2 weeks assessed upto one year	Recorded as alive or dead at ICU discharge following index positive blood culture
ICU length of stay	Expected for an average of 30 days assessed up to 1 year	Defined as the duration between index blood culture and discharge from the ICU for a consecutive 48-hour period

Trial Locations

Locations (68)

Frankston Hospital; 🇦🇺 Frankston, Victoria, Australia

Dandenong Hospital- Monash Health; 🇦🇺 Dandenong, Victoria, Australia

Foothills Hospital; 🇨🇦 Calgary, Alberta, Canada

Peter Lougheed Centre; 🇨🇦 Calgary, Alberta, Canada

Queen Elizabeth II Hospital; 🇨🇦 Halifax, Nova Scotia, Canada

Peninsula Private Hospital; 🇦🇺 Langwarrin, Victoria, Australia

Vancouver General Hospital; 🇨🇦 Vancouver, British Columbia, Canada

Cabrini Health; 🇦🇺 Malvern, Victoria, Australia

Brantford General Hospital; 🇨🇦 Hamilton, Ontario, Canada

Hospital Maisonneuve-Rosemont; 🇨🇦 Montreal, Quebec, Canada

University of Manitoba; 🇨🇦 Winnipeg, Manitoba, Canada

Rotorua Hospital; 🇳🇿 Rotorua, New Zealand

Middlemore Hospital; 🇳🇿 Auckland, New Zealand

The Ottawa Hospital; 🇨🇦 Ottawa, Ontario, Canada

Taranaki Hospital; 🇳🇿 New Plymouth, New Zealand

Wellington Hospital; 🇳🇿 Wellington, New Zealand

Rabin Medical Center; 🇮🇱 Petah Tikva, Tel Aviv, Israel

Niagara Health System; 🇨🇦 St. Catharines, Ontario, Canada

Sheba Medical Center; 🇮🇱 Tel HaShomer, Tel Aviv, Israel

Waikato Hospital; 🇳🇿 Hamilton, New Zealand

Auckland City Hospital; 🇳🇿 Auckland, New Zealand

Christchurch Hospital; 🇳🇿 Christchurch, New Zealand

Fiona Stanley Hospital; 🇦🇺 Murdoch, Western Australia, Australia

William Osler Health System; 🇨🇦 Brampton, Ontario, Canada

Kingston General Hospital; 🇨🇦 Kingston, Ontario, Canada

Mount Sinai Hospital; 🇨🇦 Toronto, Ontario, Canada

Trillium Health Partners; 🇨🇦 Mississauga, Ontario, Canada

St. Michael's Hospital; 🇨🇦 Toronto, Ontario, Canada

Michael Garron Hospital; 🇨🇦 Toronto, Ontario, Canada

NYU School of Medicine; 🇺🇸 New York, New York, United States

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States

St. George Hospital; 🇦🇺 Kogarah, New South Wales, Australia

Bankstown Hospital; 🇦🇺 Bankstown, New South Wales, Australia

St Vincent's Hospital; 🇦🇺 Darlinghurst, New South Wales, Australia

John Hunter Hospital; 🇦🇺 New Lambton Heights, New South Wales, Australia

Westmead Hospital; 🇦🇺 Westmead, New South Wales, Australia

Wollongong Hospital ICU; 🇦🇺 Wollongong, New South Wales, Australia

Ballarat Hospital; 🇦🇺 Ballarat, Victoria, Australia

Sunshine Coast University Hospital; 🇦🇺 Birtinya, Queensland, Australia

Monash Medical Centre; 🇦🇺 Clayton, Victoria, Australia

Bendigo Hospital; 🇦🇺 Bendigo, Victoria, Australia

St John of God Hospital; 🇦🇺 Subiaco, Western Australia, Australia

Eastern Regional Health Authority; 🇨🇦 Saint John's, Newfoundland and Labrador, Canada

King Faisal Specialist Hospital & Research Centre; 🇸🇦 Jeddah, Saudi Arabia

King Abdulaziz Medical City; 🇸🇦 Riyadh, Saudi Arabia

Lions Gate Hospital; 🇨🇦 Vancouver, British Columbia, Canada

St. Paul's Hospital; 🇨🇦 Vancouver, British Columbia, Canada

Vancouver Island Health; 🇨🇦 Victoria, British Columbia, Canada

University hospital Bern; 🇨🇭 Bern, Switzerland

Hamilton General Hospital; 🇨🇦 Hamilton, Ontario, Canada

St. Joseph's Healthcare; 🇨🇦 Hamilton, Ontario, Canada

London Health Sciences Centre; 🇨🇦 London, Ontario, Canada

Sunnybrook Health Sciences Centre; 🇨🇦 Toronto, Ontario, Canada

North York General Hospital; 🇨🇦 Toronto, Ontario, Canada

Health Sciences North; 🇨🇦 Sudbury, Ontario, Canada

Toronto General Hospital; 🇨🇦 Toronto, Ontario, Canada

Toronto Western Hospital; 🇨🇦 Toronto, Ontario, Canada

Centre hospitalier de l'Université de Montréal (CHUM); 🇨🇦 Montreal, Quebec, Canada

Hospitalier Régional de Trois-Rivières; 🇨🇦 Montreal, Quebec, Canada

Montreal General Hospital; 🇨🇦 Montreal, Quebec, Canada

Institut universitaire de cardiologie et de pneumologie de Québec; 🇨🇦 Québec, Quebec, Canada

Royal Victoria Hospital; 🇨🇦 Québec, Quebec, Canada

Université de Sherbrooke; 🇨🇦 Sherbrooke, Quebec, Canada

Centre hospitalier affilié universitaire de Québec; 🇨🇦 Quebec, Canada

Casey Hospital; 🇦🇺 Berwick, Victoria, Australia

St. Joseph's Health Centre; 🇨🇦 Toronto, Ontario, Canada

University of Alberta Hospital; 🇨🇦 Edmonton, Alberta, Canada

Royal Columbian Hospital; 🇨🇦 Vancouver, British Columbia, Canada