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Duration of Antibiotics for the Treatment of Gram-negative Bacilli Bacteremia

Primary Purpose

Gram Negative Bacteremia

Status
Completed
Phase
Not Applicable
Locations
International
Study Type
Interventional
Intervention
short-course antibiotic treatment
accepted prolonged antibiotic treatment
Sponsored by
Rabin Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Gram Negative Bacteremia focused on measuring gram negative bacteremia, Duration of antibiotic treatment, safety, efficacy, short-course

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • patients with gram-negative aerobic bacilli bacteremia, defined as growth of a single gram-negative microorganism in one or more blood cultures, associated with evidence of infection (hyper- or hypothermia, a localized infection, sepsis or septic shock).
  • We will include patients receiving appropriate antibiotic treatment for 7 days and are afebrile / not hypothermic for the last 48 hours. Both community and hospital acquired gram-negative bacteremias will be included, regardless of antibiotic susceptibility patterns. We will allow the inclusion of patients receiving less than 7 days if clinically stable and discharge from hospital is considered. We will then recruit the patient before discharge, if stable at least for 48 hours before randomization.

We will include the following sources of bacteremia:

  1. Primary bacteremia / unknown source
  2. Urinary tract
  3. Abdominal
  4. Respiratory tract
  5. Central venous catheter(CVC), when the catheter was removed before randomization
  6. Skin and soft tissue, including surgical site infection

Exclusion Criteria:

  1. Gram-negative bacteremia due to specific infections as detailed here:

    1. Endocarditis / endovascular infections
    2. Necrotizing fasciitis
    3. Osteomyelitis
    4. Abdominal abscesses and other unresolved abdominal sources requiring surgical intervention (e.g., cholecystitis)
    5. Central nervous system infections
    6. Empyema
    7. CVC- related or CVC-associated bloodstream infections when the catheter is retained. We will permit the inclusion of patients with retained CVCs in whom the source of the bacteremia is not the CVC.
  2. Polymicrobial growth in blood cultures involving gram-positive or anaerobes in addition to gram-negatives (defined as either growth of two or more different species of microorganisms in the same blood culture, or growth of different species in two or more separate blood cultures within the same episode (< 48 h) and with clinical or microbiological evidence of the same source).
  3. Specific pathogens including:

    1. Salmonella spp.
    2. Brucella spp.
  4. Immunosuppression, including:

    1. HIV infection
    2. Hematopoietic stem-cell transplantation
    3. Neutropenia on day of randomization or in the 48 hours prior to randomization. Patients with neutropenic fever at presentation that are afebrile and non-neutropenic in the 48 hours before randomization will be included.
  5. Clinical instability during the 48 hours before randomization, defined as mean blood pressure<60 mmHg despite adequate fluid resuscitation or vasopressors support.
  6. Repeated positive blood cultures for the same organism separated by at least 24 hours, regardless of antibiotic treatment. Patients with repeated isolates on the first 24 hours will be included.
  7. Uncontrolled focus of infection: e.g. an abscess that was not drained sufficiently; non-drained moderate to severe hydronephrosis in a patient with bacteremia of urinary source; deep seated intra-abdominal infections that were not drained properly.
  8. Fever > 38.0C measured at least twice in the 48 h prior to recruitment; or > 38.5C once during the 48 h; or hypothermia <35.5C measured once during the 48 h.
  9. Previous enrollment in this trial
  10. Concurrent participation in another clinical trial

Sites / Locations

  • Rambam Health Care Center
  • Rabin medical center, Beilinson Hospital
  • Policlinico di Modena, Italy

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

short-course

accepted prolonged antibiotic treatment

Arm Description

antibiotic treatment stopped on day 7 if the patient has been afebrile for 48 hours and clinically stable. Continued hospitalization will be left to the discretion of the treating physician. Antibiotics will be restarted if fever recurs in at least 2 consecutive measurements above 38 or in cases of clinically or microbiologically documented infections.

antibiotic treatment continued for 14 days according to accepted hospital local guidelines. Duration of hospital stay will also be left to the discretion of the treating physician. Type of empiric antibiotic treatment and later, specific antibiotic treatment, will be chosen by the treating physicians in consultation with the infectious diseases unit. The decision on timing of switch to oral antibiotic therapy will also be left to the discretion of the treating physician.

Outcomes

Primary Outcome Measures

composite of the following
The primary outcome is a composite of the following outcome measures
All -cause mortality
All- cause mortality
Treatment Failure
Failure including any of the following: Relapse: a recurrent bacteraemia due to the same microorganism occurring from day of randomization and until day 9013 Local suppurative complication that was not present at infection onset (e.g. renal abscess in pyelonephritis, empyema in pneumonia) Distant complications of initial infection, defined by growth of the same bacteria as in the initial bacteremia
Hospital re-admissions or extended hospitalization
We will define re-admission as a new hospitalization for any cause occurring more than14 days from start of appropriate antibiotic treatment. Patients hospitalized after day 14 (were never discharged or 7-day regimen who were readmitted between days 7-14) will be counted as failures for this outcome. We will define re-admission as a new hospitalization for any cause occurring more than14 days from start of appropriate antibiotic treatment. Patients hospitalized after day 14 (were never discharged or 7-day regimen who were readmitted between days 7-14) will be counted as failures for this outcome.

Secondary Outcome Measures

Clostridium difficile associated diarrhea
Clostridium difficile associated diarrhea
Development of Antibiotic resistance
Development of resistance, defined as clinical isolates resistant to antibiotics previously used in the bacteremia episode. Surveillance sampling will not be conducted.
Carriage of carbapenem resistant Klebsiella pneumonia.
Carriage of carbapenem resistant Klebsiella pneumonia (screened routinely)
Total in hospital days
Total in hospital days within 30 and 90 days
Total antibiotic days
Total antibiotic days
Adverse events
Any diarrhea Liver function test abnormalities, defined as elevated bilirubin x 1.5 of upper limit of normal or transaminases x 2.5 of upper limit of normal Antibiotic rash Acute kidney injury - defined according to RIFLE criteria as increased creatinine level x 1.5 from baseline or glomerular filtration rate (GFR) decrease >25% or urine output of <0.5 ml/kg/h for 6 hours22
Infection caused by other than gram-negative bacteremia
Development of either clinically or microbiologically documented infection other than gram-negative bacteremia. We will use the 2008 CDC/NHSN surveillance definitions of health-care associated infections for bacterial infections
Number of hospital re-admissions
Number of hospital re-admissions until day 90
Functional capacity and time to return to baseline activity
Functional capacity and time to return to baseline activity

Full Information

First Posted
November 14, 2012
Last Updated
April 6, 2019
Sponsor
Rabin Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT01737320
Brief Title
Duration of Antibiotics for the Treatment of Gram-negative Bacilli Bacteremia
Official Title
Duration of Antibiotics for the Treatment of Gram-negative Bacilli Bacteremia - a Randomized Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
April 2019
Overall Recruitment Status
Completed
Study Start Date
January 2013 (undefined)
Primary Completion Date
March 2018 (Actual)
Study Completion Date
March 4, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Rabin Medical Center

4. Oversight

5. Study Description

Brief Summary
The investigators plan an open label randomized controlled trial to compare short-course antibiotic therapy (<=7 days) versus longer treatment (>7 days). The investigators will include hospitalized patients with gram-negative bacteremia. The investigators primary objective is to investigate the safety and efficacy of short-course antibiotics.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gram Negative Bacteremia
Keywords
gram negative bacteremia, Duration of antibiotic treatment, safety, efficacy, short-course

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
604 (Actual)

8. Arms, Groups, and Interventions

Arm Title
short-course
Arm Type
Experimental
Arm Description
antibiotic treatment stopped on day 7 if the patient has been afebrile for 48 hours and clinically stable. Continued hospitalization will be left to the discretion of the treating physician. Antibiotics will be restarted if fever recurs in at least 2 consecutive measurements above 38 or in cases of clinically or microbiologically documented infections.
Arm Title
accepted prolonged antibiotic treatment
Arm Type
Active Comparator
Arm Description
antibiotic treatment continued for 14 days according to accepted hospital local guidelines. Duration of hospital stay will also be left to the discretion of the treating physician. Type of empiric antibiotic treatment and later, specific antibiotic treatment, will be chosen by the treating physicians in consultation with the infectious diseases unit. The decision on timing of switch to oral antibiotic therapy will also be left to the discretion of the treating physician.
Intervention Type
Drug
Intervention Name(s)
short-course antibiotic treatment
Intervention Description
On day 7 of appropriate intravenous or oral antibiotic treatment for the bacteremic episode (day 1 is the first day of appropriate antibiotic therapy), patients will be randomized to: Intervention group - antibiotic treatment stopped on day 7 Control group - antibiotic treatment continued for 14 days according to accepted hospital local guidelines.
Intervention Type
Drug
Intervention Name(s)
accepted prolonged antibiotic treatment
Primary Outcome Measure Information:
Title
composite of the following
Description
The primary outcome is a composite of the following outcome measures
Time Frame
Until day 90 after randomization
Title
All -cause mortality
Description
All- cause mortality
Time Frame
Until day 90 after randomization
Title
Treatment Failure
Description
Failure including any of the following: Relapse: a recurrent bacteraemia due to the same microorganism occurring from day of randomization and until day 9013 Local suppurative complication that was not present at infection onset (e.g. renal abscess in pyelonephritis, empyema in pneumonia) Distant complications of initial infection, defined by growth of the same bacteria as in the initial bacteremia
Time Frame
Until day 90 after randomization
Title
Hospital re-admissions or extended hospitalization
Description
We will define re-admission as a new hospitalization for any cause occurring more than14 days from start of appropriate antibiotic treatment. Patients hospitalized after day 14 (were never discharged or 7-day regimen who were readmitted between days 7-14) will be counted as failures for this outcome. We will define re-admission as a new hospitalization for any cause occurring more than14 days from start of appropriate antibiotic treatment. Patients hospitalized after day 14 (were never discharged or 7-day regimen who were readmitted between days 7-14) will be counted as failures for this outcome.
Time Frame
Until day 90 after randomization
Secondary Outcome Measure Information:
Title
Clostridium difficile associated diarrhea
Description
Clostridium difficile associated diarrhea
Time Frame
Until day 30 after randomization
Title
Development of Antibiotic resistance
Description
Development of resistance, defined as clinical isolates resistant to antibiotics previously used in the bacteremia episode. Surveillance sampling will not be conducted.
Time Frame
Until day 30 after randomization
Title
Carriage of carbapenem resistant Klebsiella pneumonia.
Description
Carriage of carbapenem resistant Klebsiella pneumonia (screened routinely)
Time Frame
Until day 30 after randomization
Title
Total in hospital days
Description
Total in hospital days within 30 and 90 days
Time Frame
Until day 90 after randomization.
Title
Total antibiotic days
Description
Total antibiotic days
Time Frame
Until day 30 after randomization
Title
Adverse events
Description
Any diarrhea Liver function test abnormalities, defined as elevated bilirubin x 1.5 of upper limit of normal or transaminases x 2.5 of upper limit of normal Antibiotic rash Acute kidney injury - defined according to RIFLE criteria as increased creatinine level x 1.5 from baseline or glomerular filtration rate (GFR) decrease >25% or urine output of <0.5 ml/kg/h for 6 hours22
Time Frame
Until day 30 after randomization
Title
Infection caused by other than gram-negative bacteremia
Description
Development of either clinically or microbiologically documented infection other than gram-negative bacteremia. We will use the 2008 CDC/NHSN surveillance definitions of health-care associated infections for bacterial infections
Time Frame
Until day 90 after randomization
Title
Number of hospital re-admissions
Description
Number of hospital re-admissions until day 90
Time Frame
Until day 90 after randomization
Title
Functional capacity and time to return to baseline activity
Description
Functional capacity and time to return to baseline activity
Time Frame
Until day 30 after randomization

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: patients with gram-negative aerobic bacilli bacteremia, defined as growth of a single gram-negative microorganism in one or more blood cultures, associated with evidence of infection (hyper- or hypothermia, a localized infection, sepsis or septic shock). We will include patients receiving appropriate antibiotic treatment for 7 days and are afebrile / not hypothermic for the last 48 hours. Both community and hospital acquired gram-negative bacteremias will be included, regardless of antibiotic susceptibility patterns. We will allow the inclusion of patients receiving less than 7 days if clinically stable and discharge from hospital is considered. We will then recruit the patient before discharge, if stable at least for 48 hours before randomization. We will include the following sources of bacteremia: Primary bacteremia / unknown source Urinary tract Abdominal Respiratory tract Central venous catheter(CVC), when the catheter was removed before randomization Skin and soft tissue, including surgical site infection Exclusion Criteria: Gram-negative bacteremia due to specific infections as detailed here: Endocarditis / endovascular infections Necrotizing fasciitis Osteomyelitis Abdominal abscesses and other unresolved abdominal sources requiring surgical intervention (e.g., cholecystitis) Central nervous system infections Empyema CVC- related or CVC-associated bloodstream infections when the catheter is retained. We will permit the inclusion of patients with retained CVCs in whom the source of the bacteremia is not the CVC. Polymicrobial growth in blood cultures involving gram-positive or anaerobes in addition to gram-negatives (defined as either growth of two or more different species of microorganisms in the same blood culture, or growth of different species in two or more separate blood cultures within the same episode (< 48 h) and with clinical or microbiological evidence of the same source). Specific pathogens including: Salmonella spp. Brucella spp. Immunosuppression, including: HIV infection Hematopoietic stem-cell transplantation Neutropenia on day of randomization or in the 48 hours prior to randomization. Patients with neutropenic fever at presentation that are afebrile and non-neutropenic in the 48 hours before randomization will be included. Clinical instability during the 48 hours before randomization, defined as mean blood pressure<60 mmHg despite adequate fluid resuscitation or vasopressors support. Repeated positive blood cultures for the same organism separated by at least 24 hours, regardless of antibiotic treatment. Patients with repeated isolates on the first 24 hours will be included. Uncontrolled focus of infection: e.g. an abscess that was not drained sufficiently; non-drained moderate to severe hydronephrosis in a patient with bacteremia of urinary source; deep seated intra-abdominal infections that were not drained properly. Fever > 38.0C measured at least twice in the 48 h prior to recruitment; or > 38.5C once during the 48 h; or hypothermia <35.5C measured once during the 48 h. Previous enrollment in this trial Concurrent participation in another clinical trial
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dafna Yahav, MD
Organizational Affiliation
Rabin Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Rambam Health Care Center
City
Haifa
Country
Israel
Facility Name
Rabin medical center, Beilinson Hospital
City
Petah Tikvah
Country
Israel
Facility Name
Policlinico di Modena, Italy
City
Modena
State/Province
Emilia Romagna
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
30535100
Citation
Yahav D, Franceschini E, Koppel F, Turjeman A, Babich T, Bitterman R, Neuberger A, Ghanem-Zoubi N, Santoro A, Eliakim-Raz N, Pertzov B, Steinmetz T, Stern A, Dickstein Y, Maroun E, Zayyad H, Bishara J, Alon D, Edel Y, Goldberg E, Venturelli C, Mussini C, Leibovici L, Paul M; Bacteremia Duration Study Group. Seven Versus 14 Days of Antibiotic Therapy for Uncomplicated Gram-negative Bacteremia: A Noninferiority Randomized Controlled Trial. Clin Infect Dis. 2019 Sep 13;69(7):1091-1098. doi: 10.1093/cid/ciy1054.
Results Reference
derived

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Duration of Antibiotics for the Treatment of Gram-negative Bacilli Bacteremia

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