Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness

Sepsis Clinical Trial

— BALANCE  

Official title:

Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness: Randomized Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03005145
• Other study ID #: 0796
• Status: Completed
• Phase: N/A
• Start date: February 24, 2017
• Est. completion date: August 3, 2023

Study information

• Verified date: November 2023
• Source: Sunnybrook Health Sciences Centre
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3622
• Est. completion date: August 3, 2023
• Est. primary completion date: May 5, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Antimicrobial
• Bacteremia
• Critical Illness
• Critically Ill
• Intensive Care
• Mortality
• Sepsis

Intervention

Other:
• 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
• 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

Locations

Country	Name	City	State
Australia	Ballarat Hospital	Ballarat	Victoria
Australia	Bankstown Hospital	Bankstown	New South Wales
Australia	Bendigo Hospital	Bendigo	Victoria
Australia	Casey Hospital	Berwick	Victoria
Australia	Sunshine Coast University Hospital	Birtinya	Queensland
Australia	Monash Medical Centre	Clayton	Victoria
Australia	Dandenong Hospital- Monash Health	Dandenong	Victoria
Australia	St Vincent's Hospital	Darlinghurst	New South Wales
Australia	Frankston Hospital	Frankston	Victoria
Australia	St. George Hospital	Kogarah	New South Wales
Australia	Peninsula Private Hospital	Langwarrin	Victoria
Australia	Cabrini Health	Malvern	Victoria
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	John Hunter Hospital	New Lambton Heights	New South Wales
Australia	St John of God Hospital	Subiaco	Western Australia
Australia	Westmead Hospital	Westmead	New South Wales
Australia	Wollongong Hospital ICU	Wollongong	New South Wales
Canada	William Osler Health System	Brampton	Ontario
Canada	Foothills Hospital	Calgary	Alberta
Canada	Peter Lougheed Centre	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Queen Elizabeth II Hospital	Halifax	Nova Scotia
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	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	The Ottawa Hospital	Ottawa	Ontario
Canada	Centre hospitalier affilié universitaire de Québec	Quebec
Canada	Institut universitaire de cardiologie et de pneumologie de Québec	Québec	Quebec
Canada	Royal Victoria Hospital	Québec	Quebec
Canada	Eastern Regional Health Authority	Saint John's	Newfoundland and Labrador
Canada	Université de Sherbrooke	Sherbrooke	Quebec
Canada	Niagara Health System	St. Catharines	Ontario
Canada	Health Sciences North	Sudbury	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	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	Toronto General Hospital	Toronto	Ontario
Canada	Toronto Western Hospital	Toronto	Ontario
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
Israel	Rabin Medical Center	Petah Tikva	Tel Aviv
Israel	Sheba Medical Center	Tel HaShomer	Tel Aviv
New Zealand	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
Saudi Arabia	King Faisal Specialist Hospital & Research Centre	Jeddah
Saudi Arabia	King Abdulaziz Medical City	Riyadh
Switzerland	University hospital Bern	Bern
United States	Cleveland Clinic	Cleveland	Ohio
United States	NYU School of Medicine	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Sunnybrook Health Sciences Centre

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	90 day survival	Survival at 90-days recorded as alive or dead at day 90 following index positive blood culture	90 days from index blood culture
Secondary	Hospital mortality	Recorded as alive or dead at hospital discharge following index positive blood culture	Expected average of 4 weeks assessed upto one year
Secondary	ICU mortality	Recorded as alive or dead at ICU discharge following index positive blood culture	Expected average of 2 weeks assessed upto one year
Secondary	Relapse rates of bacteremia with the same organism	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.	Upto 30 days after adequate antibiotic treatment
Secondary	Antibiotic allergy and adverse events	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	Upto 30 days from start of antibiotic treatment
Secondary	Rates of C. difficile infection in hospital	Defined as a positive PCR or ELISA test for Clostridium difficile toxin in the context of diarrhea within hospital of bacteremia diagnosis.	Upto 30 days after index blood culture collection date
Secondary	Rates of secondary nosocomial infection/colonization with antimicrobial resistant organisms in hospital	Colonized or infected with at least one highly-resistant microorganism during their hospital stay	Upto 30 days after index blood culture collection date
Secondary	ICU length of stay	Defined as the duration between index blood culture and discharge from the ICU for a consecutive 48-hour period	Expected for an average of 30 days assessed up to 1 year
Secondary	Hospital length of stay	Defined as the duration between index blood culture and discharge date from hospital	Expected for an average of 30 days assessed up to 1 year
Secondary	Mechanical ventilation duration	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	Expected for an average of 30 days
Secondary	Antibiotic free days	Defined as the number of days during the 28 days after the start of adequate antibiotics in which patients did not receive any antibiotics.	Upto 30 days after adequate antibiotic treatment