Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness

NCT ID: NCT03005145

Last Updated: 2024-02-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 3622 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-02-24
• Study Completion Date: 2023-08-03

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.

Conditions

Bacteremia; Intensive Care; Critically Ill; Sepsis; Mortality; Antimicrobial

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Short duration (7 days)

Patients in 7 day arm will receive adequate antibiotics until the end of day 7 only

Group Type: ACTIVE_COMPARATOR

7 days of adequate antibiotic treatment

Intervention Type: OTHER

The choice of treatment including type, dose, route and interval of antibiotic will be left at the discretion of treating team as long as it is appropriate for the bacteremia

Long duration (14 days)

Patients in 14 day arm will receive adequate antibiotics until the end of day 14 only

Group Type: ACTIVE_COMPARATOR

14 days of adequate antibiotic treatment.

Intervention Type: OTHER

The choice of treatment including type, dose, route and interval of antibiotic will be left at the discretion of treating team as long as it is appropriate for the bacteremia

Interventions

7 days of adequate antibiotic treatment

The choice of treatment including type, dose, route and interval of antibiotic will be left at the discretion of treating team as long as it is appropriate for the bacteremia

Intervention Type: OTHER

14 days of adequate antibiotic treatment.

The choice of treatment including type, dose, route and interval of antibiotic will be left at the discretion of treating team as long as it is appropriate for the bacteremia

Intervention Type: OTHER

Eligibility Criteria

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.

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sunnybrook Health Sciences Centre

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nick Daneman, MD

Role: PRINCIPAL_INVESTIGATOR

Sunnybrook Health Sciences Centre

Locations

NYU School of Medicine

New York, New York, United States

Cleveland Clinic

Cleveland, Ohio, United States

Bankstown Hospital

Bankstown, New South Wales, Australia

St Vincent's Hospital

Darlinghurst, New South Wales, Australia

St. George Hospital

Kogarah, 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

Sunshine Coast University Hospital

Birtinya, Queensland, Australia

Ballarat Hospital

Ballarat, Victoria, Australia

Bendigo Hospital

Bendigo, Victoria, Australia

Casey Hospital

Berwick, Victoria, Australia

Monash Medical Centre

Clayton, Victoria, Australia

Dandenong Hospital- Monash Health

Dandenong, Victoria, Australia

Frankston Hospital

Frankston, Victoria, Australia

Peninsula Private Hospital

Langwarrin, Victoria, Australia

Cabrini Health

Malvern, Victoria, Australia

Fiona Stanley Hospital

Murdoch, Western Australia, Australia

St John of God Hospital

Subiaco, Western Australia, Australia

Foothills Hospital

Calgary, Alberta, Canada

Peter Lougheed Centre

Calgary, Alberta, Canada

University of Alberta Hospital

Edmonton, Alberta, Canada

Lions Gate Hospital

Vancouver, British Columbia, Canada

Royal Columbian Hospital

Vancouver, British Columbia, Canada

St. Paul's Hospital

Vancouver, British Columbia, Canada

Vancouver General Hospital

Vancouver, British Columbia, Canada

Vancouver Island Health

Victoria, British Columbia, Canada

University of Manitoba

Winnipeg, Manitoba, Canada

Eastern Regional Health Authority

St. John's, Newfoundland and Labrador, Canada

Queen Elizabeth II Hospital

Halifax, Nova Scotia, Canada

William Osler Health System

Brampton, Ontario, Canada

Health Sciences North

Greater Sudbury, Ontario, Canada

Brantford General Hospital

Hamilton, Ontario, Canada

Hamilton General Hospital

Hamilton, Ontario, Canada

St. Joseph's Healthcare

Hamilton, Ontario, Canada

Kingston General Hospital

Kingston, Ontario, Canada

London Health Sciences Centre

London, Ontario, Canada

Trillium Health Partners

Mississauga, Ontario, Canada

The Ottawa Hospital

Ottawa, Ontario, Canada

Niagara Health System

St. Catharines, Ontario, Canada

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Michael Garron Hospital

Toronto, Ontario, Canada

Mount Sinai Hospital

Toronto, Ontario, Canada

North York General Hospital

Toronto, Ontario, Canada

St. Joseph's Health Centre

Toronto, Ontario, Canada

St. Michael's Hospital

Toronto, 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

Hospital Maisonneuve-Rosemont

Montreal, Quebec, Canada

Hospitalier Régional de Trois-Rivières

Montreal, Quebec, Canada

Montreal General Hospital

Montreal, Quebec, Canada

Centre hospitalier affilié universitaire de Québec

Québec, 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

Rabin Medical Center

Petah Tikva, Tel Aviv, Israel

Sheba Medical Center

Tel Litwinsky, Tel Aviv, Israel

Auckland City Hospital

Auckland, , New Zealand

Middlemore Hospital

Auckland, , New Zealand

Christchurch Hospital

Christchurch, , New Zealand

Waikato Hospital

Hamilton, , New Zealand

Taranaki Hospital

New Plymouth, , New Zealand

Rotorua Hospital

Rotorua, , New Zealand

Wellington Hospital

Wellington, , New Zealand

King Faisal Specialist Hospital & Research Centre

Jeddah, , Saudi Arabia

King Abdulaziz Medical City

Riyadh, , Saudi Arabia

University hospital Bern

Bern, , Switzerland

Countries

United States; Australia; Canada; Israel; New Zealand; Saudi Arabia; Switzerland

References

Ong SWX, Pinto R, Rishu A, Tong SYC, Commons RJ, Conly JM, Evans GA, Fralick M, Kandel C, Lagace-Wiens PRS, Lee TC, Lother SA, MacFadden DR, Marshall JC, Martel-Laferriere V, Mayette M, McDonald EG, Neary JD, Prazak J, Raby E, Regli A, Rogers BA, Smith S, Taggart LR, Wang HT, Wuerz T, Yahav D, Young PJ, Fowler RA, Daneman N; BALANCE trial consortium. Identifying heterogeneity of treatment effect for antibiotic duration in bloodstream infection: an exploratory post-hoc analysis of the BALANCE randomised clinical trial. EClinicalMedicine. 2025 Apr 10;83:103195. doi: 10.1016/j.eclinm.2025.103195. eCollection 2025 May.

Reference Type: DERIVED

PMID: 40256773 (View on PubMed)

BALANCE Investigators, for the Canadian Critical Care Trials Group, the Association of Medical Microbiology and Infectious Disease Canada Clinical Research Network, the Australian and New Zealand Intensive Care Society Clinical Trials Group, and the Australasian Society for Infectious Diseases Clinical Research Network; Daneman N, Rishu A, Pinto R, Rogers BA, Shehabi Y, Parke R, Cook D, Arabi Y, Muscedere J, Reynolds S, Hall R, Dwivedi DB, McArthur C, McGuinness S, Yahav D, Coburn B, Geagea A, Das P, Shin P, Detsky M, Morris A, Fralick M, Powis JE, Kandel C, Sligl W, Bagshaw SM, Singhal N, Belley-Cote E, Whitlock R, Khwaja K, Morpeth S, Kazemi A, Williams A, MacFadden DR, McIntyre L, Tsang J, Lamontagne F, Carignan A, Marshall J, Friedrich JO, Cirone R, Downing M, Graham C, Davis J, Duan E, Neary J, Evans G, Alraddadi B, Al Johani S, Martin C, Elsayed S, Ball I, Lauzier F, Turgeon A, Stelfox HT, Conly J, McDonald EG, Lee TC, Sullivan R, Grant J, Kagan I, Young P, Lawrence C, O'Callaghan K, Eustace M, Choong K, Aslanian P, Buehner U, Havey T, Binnie A, Prazak J, Reeve B, Litton E, Lother S, Kumar A, Zarychanski R, Hoffman T, Paterson D, Daley P, Commons RJ, Charbonney E, Naud JF, Roberts S, Tiruvoipati R, Gupta S, Wood G, Shum O, Miyakis S, Dodek P, Kwok C, Fowler RA; The BALANCE Investigators, for the Canadian Critical Care Trials Group, the Association of Medical Microbiology and Infectious Disease Canada Clinical Research Network, the Australian and New Zealand Intensive Care Society Clinical Trials Group, and the Australasian Society for Infectious Diseases Clinical Research Network. Antibiotic Treatment for 7 versus 14 Days in Patients with Bloodstream Infections. N Engl J Med. 2025 Mar 13;392(11):1065-1078. doi: 10.1056/NEJMoa2404991. Epub 2024 Nov 20.

Reference Type: DERIVED

PMID: 39565030 (View on PubMed)

Rogers BA, Fowler R, Harris PNA, Davis JS, Pinto RL, Bhatia Dwivedi D, Rishu A, Shehabi Y, Daneman N. Non-inferiority trial of a shorter (7 days) compared with a longer (14 days) duration of antimicrobial therapy for the treatment of bacteraemic urinary sepsis, measured by microbiological success after the completion of therapy: a substudy protocol for the Bacteraemia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) multicentre randomised controlled trial. BMJ Open. 2023 Jun 26;13(6):e069708. doi: 10.1136/bmjopen-2022-069708.

Reference Type: DERIVED

PMID: 37369422 (View on PubMed)

Daneman N, Rishu AH, Pinto RL, Arabi YM, Cook DJ, Hall R, McGuinness S, Muscedere J, Parke R, Reynolds S, Rogers B, Shehabi Y, Fowler RA; Canadian Critical Care Trials Group. Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) randomised clinical trial: study protocol. BMJ Open. 2020 May 11;10(5):e038300. doi: 10.1136/bmjopen-2020-038300.

Reference Type: DERIVED

PMID: 32398341 (View on PubMed)

Other Identifiers

0796

Identifier Type: -

Identifier Source: org_study_id