Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness: A Pilot RCT

Bacteremia Clinical Trial

— BALANCE  

Official title:

Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness: A Pilot RCT

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02261506
• Other study ID #: 187-2014
• Status: Completed
• Phase: N/A
• First received: September 26, 2014
• Last updated: December 14, 2017
• Start date: October 16, 2014
• Est. completion date: October 5, 2017

Study information

• Verified date: December 2017
• Source: Sunnybrook Health Sciences Centre
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Bacteremia is a leading cause of mortality and morbidity in critically ill adults. Although bacteria in the bloodstream (bacteremia) may arise from variable infectious foci (most commonly central vascular catheter related, lung, urinary tract, intra-abdominal, or skin and soft tissue sources), because of the high attendant morbidity and mortality of bacteremia, these patients collectively represent a critically important group to study.

The consequences of the excessive antimicrobial use for individual patients, range from rash, gastrointestinal upset and diarrhea, to anaphylaxis, neutropenia, renal failure, toxic epidermal necrolysis, death, and a marked increase in ICU and hospital drug costs. One particularly concerning complication, Clostridium difficile infection, has increased in incidence and severity over the past decade. Much of this burden could be prevented through reduction in unnecessary antibiotic use.

Another major consequence of excessive antibiotic use is antimicrobial resistance. Antibiotic resistance is not only a concern for the patient who receives antibiotics, but also for neighbouring patients in the ICU, as well as future patients in the ICU and the hospital at large - through patient-to-patient transmission, and environmental contamination.

No previous randomized controlled trials have directly compared shorter versus longer durations of antimicrobial treatment in these patients. The investigators will conduct a multi-center randomized concealed allocation trial of shorter duration (7 days) versus longer duration (14 days) antibiotic treatment for critically ill patients with bacteremia admitted to ICU. Eligible, patients will be randomized to either 7 days or 14 days of adequate antimicrobial treatment. The selection of type, dose and route of antibiotics will be at the discretion of the treating physicians, but the duration of treatment (7 versus 14 days) will be determined by randomization group. The randomization assignment will not be communicated to the study research coordinator, study critical care or infectious diseases investigators or clinicians until day 8. The primary outcome for the main trial will be 90-day mortality.

The study will be initiated at Sunnybrook Health Sciences Centre in Toronto, Ontario, and then rolled out to a second site at Kingston General Hospital in Kingston, Ontario. These sites will be sufficient to meet the sample size goals for the pilot RCT, but if additional funds are obtained the investigators will also roll out to the other Canadian ICUs listed below. The goal of adding these additional sites will be to increase the generalizability of the findings with respect to trial feasibility

Recruitment information / eligibility

• Status: Completed
• Enrollment: 115
• Est. completion date: October 5, 2017
• Est. primary completion date: August 30, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patient is in the ICU at time the blood culture result reported as positive AND

• 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 syndrome with well-defined requirement for prolonged treatment:

• infective endocarditis

• osteomyelitis/septic arthritis

• undrainable/undrained abscess

• unremovable/unremoved prosthetic-associated infection

• 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.

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

Related Conditions & MeSH terms

• Bacteremia

Intervention

Other:
• 7 days of adequate antibiotic treatment durations
We will not be randomizing patients to any specific antibiotic regimen. Patients will be randomized to fixed durations of adequate treatment: 7 versus 14 days. The selection of antibiotic(s) will be at the discretion of the treating team, although the research team will check to ensure that the selected antibiotics have an 'adequate' spectrum of coverage for the bacterial pathogen(s) isolated in the blood culture.
• 14 days of adequate antibiotic treatment durations

Locations

Country	Name	City	State
Canada	Foothills Hospital	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Queen Elizabeth II Hospital	Halifax	Nova Scotia
Canada	Kingston General Hospital	Kingston	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	CHUM	Montreal	Quebec
Canada	The Ottawa Hospital	Ottawa	Ontario
Canada	Centre hospitalier affilié universitaire de Québec	Quebec
Canada	CSSS de Trois-Rivières	Quebec
Canada	Université de Sherbrooke	Sherbrooke	Quebec
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	Toronto Western Hospital	Toronto	Ontario
Canada	Royal Columbian Hospital	Vancouver	British Columbia
Canada	St. Paul's Hospital	Vancouver	British Columbia
Canada	St. Boniface Hospital	Winnipeg	Manitoba

Sponsors (2)

Lead Sponsor	Collaborator
Sunnybrook Health Sciences Centre	Kingston General Hospital

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adherence to treatment duration protocol (proportion of treatment courses)	We will consider the main trial to be feasible and worthy of embarking on a larger mortality-powered RCT 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.	15 days
Primary	Rate of recruitment (patients per site, per month)	We will consider the main trial to be feasible if we achieve recruitment rates of at least 1 patient per 4 weeks, on average, per participating site.	For up to 1 year
Secondary	ICU mortality		Recorded as alive or dead at ICU discharge following index positive blood culture for an expected average of 2 weeks assesses upto one year.
Secondary	Hospital mortality		recorded as alive or dead at hospital discharge following index positive blood culture for an expected average of 4 weeks assesses upto one year.
Secondary	90 day mortality		Recorded as alive or dead at 90 days following index positive blood culture
Secondary	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
Secondary	Antibiotic allergy	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	Up to 30 days from start of antibiotic treatment.
Secondary	Anaphylaxis	To be considered anaphylaxis, the patient must have had >=1 of the following 3 criteria that a medical team member attributed to an Antimicrobial; Acute onset of skin or mucosal tissue changes (hives, itching/flush, lip/tongue/uvula swelling) over minutes/hours, accompanied by; respiratory compromise (dyspnea, wheeze, stridor, hypoxemia), AND/OR; reduced blood pressure or symptoms/signs of end organ dysfunction from shock; Rapid onset of two or more of the following; involvement of the skin-mucosa (hives, itch//flush, swollen lips/tongue/uvula); respiratory compromise; reduced BP or associated symptoms/signs; persistent gastrointestinal symptoms/signs (crampy abdominal pain, vomiting); Reduced blood pressure after exposure to a known allergen for that patient	Up to 30 days from start of antibiotic treatment
Secondary	Antimicrobial-related acute kidney injury	To be considered Antimicrobial-associated renal injury, a medical team member must have attributed the renal injury to the Antimicrobial, and the severity of the renal injury must meet one of these (RIFLE criteria): Risk: GFR decrease >25%, serum creatinine increased 1.5 times or urine production of <0.5 ml/kg/hr for 6 hours; Injury: GFR decrease >50%, doubling of creatinine or urine production <0.5 ml/kg/hr for 12 hours; Failure: GFR decrease >75%, tripling of creatinine or creatinine >355 µmol/l (with a rise of >44) (>4 mg/dl) OR urine output below 0.3 ml/kg/hr for 24 hours; Loss: persistent AKI or complete loss of kidney function for more than 4 weeks; End-stage renal disease: need for renal replacement therapy (RRT) for more than 3 months	Up to 30 days from start of antibiotic treatment
Secondary	Antimicrobial-related hepatitis	To be considered Antimicrobial-associated hepatitis, a medical team member must have attributed the hepatitis to the Antimicrobial, and the severity of the hepatitis must meet this FDA criteria for hepatic adverse events: o ALT> 3x the upper limit of normal	Up to 30 days from start of antibiotic treatment
Secondary	Rates of Clostridium 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 with antimicrobial resistant organisms in hospital		Upto 30 days after index blood culture collection date
Secondary	ICU lengths of stay		For the duration of ICU stay, expected for an average of 30 days assessed up to 1 year.
Secondary	Hospital lengths of stay		For the duration of Hospital stay, 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. Durations will be calculated for all patients then separately for patients who died within hospital and those who did not die.	For the duration of ICU and Hospital stay, expected for an average of 30 days
Secondary	Vasopressor duration in ICU	Defined as the number of consecutive days receiving intravenous vasoactive medications (e.g. epinephrine, norepinephrine, vasopressin, dopamine, phenylephrine, dobutamine, milrinone). Durations will be calculated for all patients then separately for patients who died within hospital and those who did not die.	For the duration of ICU and Hospital stay, expected for an average of 30 days