Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Bacteremia, Intensive Care, Critically Ill, Sepsis, Mortality, Antimicrobial

Intervention / Treatment
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* Other: 7 days of adequate antibiotic treatment
* Other: 14 days of adequate antibiotic treatment.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is in ICU or non-ICU ward at the time the blood culture is drawn or reported as positive. Patient has a positive blood culture with pathogenic bacteria. Exclusion Criteria: Patient already enrolled in the trial 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 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) 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) 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. Patient has a positive blood culture with Staphylococcus aureus or Staphylococcus lugdunensis Patient has a positive blood culture with Candida spp. or other fungal species. Blood culture grows rare bacterial pathogens requiring prolonged treatment (e.g. Mycobacteria spp., Nocardia spp., Actinomyces spp., Brucella spp., Burkholderia pseudomallei)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Short duration (7 days)<br>Patients in 7 day arm will receive adequate antibiotics until the end of day 7 only | Other: 7 days of adequate antibiotic treatment<br>* 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<br>|
| Active Comparator: Long duration (14 days)<br>Patients in 14 day arm will receive adequate antibiotics until the end of day 14 only | Other: 14 days of adequate antibiotic treatment.<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital mortality | Recorded as alive or dead at hospital discharge following index positive blood culture | Expected average of 4 weeks assessed upto one year | 
| ICU mortality | Recorded as alive or dead at ICU discharge following index positive blood culture | Expected average of 2 weeks assessed upto one year | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 |