BALANCE on the Wards: A Pilot RCT (BALANCE-Wards)

Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness- BALANCE on the Wards: A Pilot RCT

The burden of bloodstream infections is large and increasing over time. Antibiotic overuse continues to drive increased rates of antimicrobial-resistant pathogens across Canada. However, prospective audits have revealed that 30-50% of antibiotic utilization is unnecessary or inappropriate. If shorter duration therapy is as effective as longer duration therapy for these infections, antimicrobial consumption would be decreased. A pilot trial (approved by the Sunnybrook Research Ethics Board), is underway in critically ill patients at 17 Canadian ICUs. Investigators have successfully demonstrated feasibility with respect to protocol adherence and recruitment rates in the ICU. Investigators now aim to conduct a similar pilot RCT among non-ICU patients admitted to hospital wards with bloodstream infections to determine feasibility and protocol adherence of the same trial protocol.

Study Overview

• Status: Completed
• Conditions: Bacteremia
• Intervention / Treatment: Other: 7 days of adequate antibiotic treatment; Other: 14 days of adequate antibiotic treatment

Detailed Description

Bloodstream infections are a common and serious problem, and are associated with increased morbidity and mortality. 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, Clostridium difficile infection, increased costs, and spiraling 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. Our team's systematic review of the medical literature, national survey of Canadian infectious diseases and critical care physicians, and multicentre retrospective study 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, our pilot RCT in critically ill patients is near-completion.

In order to increase the generalizability to non-critically ill patients, Investigators want to conduct a similar pilot RCT in non-critically ill patients (BALANCE on the Wards) to establish the feasibility of the research design, and to optimize the definitive trial.

Investigators will conduct a randomized concealed allocation trial of shorter duration (7 days) versus longer duration (14 days) antibiotic treatment for patients with bloodstream infections across all non-ICU hospital wards in Sunnybrook Hospital (BALANCE on the Wards). Our ongoing BALANCE pilot RCT in ICU is approved by the Sunnybrook REB (PIN: 187-2014). The BALANCE on Wards pilot trial will use the same protocol, informed consent form and the case report forms that are approved by the Sunnybrook REB with minimal changes to make it ward specific. If the investigators are able to achieve the primary outcome of this trial in Sunnybrook hospital, the main BALANCE trial will potentially involve enrolment of non-ICU patients at all (or a subset of) participating sites.

If eligibility criteria and study procedures are substantially unchanged, results of the both the pilot BALANCE RCTs will be rolled into the dataset for the main BALANCE RCT.

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada
      • Hamilton General Hospital
    • Kingston, Ontario, Canada
      • Kingston General Hospital
    • Ottawa, Ontario, Canada
      • The Ottawa Hospital
    • Toronto, Ontario, Canada, M4N3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada
      • St. Joseph's Health Centre
    • Toronto, Ontario, Canada
      • North York General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patient is in the hospital ward and not in the intensive care units at time the blood culture result reported as positive AND
2. Patient has a positive blood culture with pathogenic bacteria

Exclusion Criteria:

1. Patient already enrolled in either of the BALANCE trials
2. Patient is admitted in the ICU at the time of enrollment
3. 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
4. Patient has a prosthetic heart valve or synthetic endovascular graft

5. Patient has documented or suspicion of 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

6. 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.
7. Patient has a positive blood culture with Staphylococcus aureus.
8. Patient has a positive blood culture with Candida spp. or other fungal species.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Shorter duration (7 days); Patients in 7 day arm will receive adequate antibiotics until the end of day 7 only	Other: 7 days of adequate antibiotic treatment
Active Comparator: Longer duration (14 days); Patients in 14 day arm will receive adequate antibiotics until the end of day 14 only	Other: 14 days of adequate antibiotic treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility	defined by: (a) the adherence to treatment duration protocol (proportion of treatment courses); and (b) the rate of recruitment (enrolled per month). Investigators will consider enrolling patients in hospital wards for the BALANCE main trial if 90% of antibiotic treatment courses are within 7± 2 days in the shorter duration treatment arm or 14 ± 2 days in the longer duration treatment arm; and, if recruitment rates of at least 4 patients per 4 weeks is achieved.	15 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital mortality rates		recorded as alive or dead at hospital discharge following index positive blood culture for an expected average of 4 weeks assesses upto one year.
90-day mortality rates		recorded as alive or dead at 90 days following index positive blood culture
Relapse rates of bacteremia	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
Antibiotic allergy and adverse events		up to 30 days from start of antibiotic treatment.
Rates of C. difficile infection in hospital		Upto 30 days after index blood culture collection date
Rates of secondary nosocomial infection with antimicrobial resistant organisms in hospital		upto 30 days after index blood culture collection date
Hospital length of stay		for the duration of Hospital stay, expected for an average of 30 days assessed up to 1 year
Antibiotic free days		no. of days patient remained without antibiotics for up to 30 days post index blood culture collection date

Collaborators and Investigators

• Sponsor: Sunnybrook Health Sciences Centre

Publications and helpful links

General Publications

• Daneman N, Rishu AH, Pinto R, Arabi Y, Belley-Cote EP, Cirone R, Downing M, Cook DJ, Hall R, McGuinness S, McIntyre L, Muscedere J, Parke R, Reynolds S, Rogers BA, Shehabi Y, Shin P, Whitlock R, Fowler RA; Canadian Critical Care Trials Group. A pilot randomized controlled trial of 7 versus 14 days of antibiotic treatment for bloodstream infection on non-intensive care versus intensive care wards. Trials. 2020 Jan 15;21(1):92. doi: 10.1186/s13063-019-4033-9.

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2016
• Primary Completion (Actual): November 30, 2019
• Study Completion (Actual): January 30, 2020

Study Registration Dates

• First Submitted: September 23, 2016
• First Submitted That Met QC Criteria: September 26, 2016
• First Posted (Estimate): September 28, 2016

Study Record Updates

• Last Update Posted (Actual): September 14, 2020
• Last Update Submitted That Met QC Criteria: September 10, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Bacteremia, duration, non-critically ill, non-ICU
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Bacteremia; Anti-Infective Agents; Antitubercular Agents; Anti-Bacterial Agents; Antibiotics, Antitubercular
• Other Study ID Numbers: 218-2016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No