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

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2015 by Rabin Medical Center
Sponsor:
Information provided by (Responsible Party):
dafna yahav, Rabin Medical Center
ClinicalTrials.gov Identifier:
NCT01737320
First received: November 14, 2012
Last updated: October 22, 2015
Last verified: October 2015
  Purpose
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.

Condition Intervention
Gram Negative Bacteremia
Drug: short-course antibiotic treatment
Drug: accepted prolonged antibiotic treatment

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Duration of Antibiotics for the Treatment of Gram-negative Bacilli Bacteremia - a Randomized Controlled Trial

Resource links provided by NLM:


Further study details as provided by Rabin Medical Center:

Primary Outcome Measures:
  • composite of the following [ Time Frame: Until day 90 after randomization ] [ Designated as safety issue: No ]
    The primary outcome is a composite of the following outcome measures

  • All -cause mortality [ Time Frame: Until day 90 after randomization ] [ Designated as safety issue: No ]
    All- cause mortality

  • Treatment Failure [ Time Frame: Until day 90 after randomization ] [ Designated as safety issue: No ]

    Failure including any of the following:

    1. Relapse: a recurrent bacteraemia due to the same microorganism occurring from day of randomization and until day 9013
    2. Local suppurative complication that was not present at infection onset (e.g. renal abscess in pyelonephritis, empyema in pneumonia)
    3. Distant complications of initial infection, defined by growth of the same bacteria as in the initial bacteremia

  • Hospital re-admissions or extended hospitalization [ Time Frame: Until day 90 after randomization ] [ Designated as safety issue: No ]

    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 [ Time Frame: Until day 30 after randomization ] [ Designated as safety issue: No ]
    Clostridium difficile associated diarrhea

  • Development of Antibiotic resistance [ Time Frame: Until day 30 after randomization ] [ Designated as safety issue: No ]
    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. [ Time Frame: Until day 30 after randomization ] [ Designated as safety issue: No ]
    Carriage of carbapenem resistant Klebsiella pneumonia (screened routinely)

  • Total in hospital days [ Time Frame: Until day 90 after randomization. ] [ Designated as safety issue: No ]
    Total in hospital days within 30 and 90 days

  • Total antibiotic days [ Time Frame: Until day 30 after randomization ] [ Designated as safety issue: No ]
    Total antibiotic days

  • Adverse events [ Time Frame: Until day 30 after randomization ] [ Designated as safety issue: No ]
    • 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 [ Time Frame: Until day 90 after randomization ] [ Designated as safety issue: No ]
    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 [ Time Frame: Until day 90 after randomization ] [ Designated as safety issue: No ]
    Number of hospital re-admissions until day 90

  • Functional capacity and time to return to baseline activity [ Time Frame: Until day 30 after randomization ] [ Designated as safety issue: No ]
    Functional capacity and time to return to baseline activity


Estimated Enrollment: 400
Study Start Date: January 2013
Estimated Study Completion Date: July 2017
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: short-course
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.
Drug: short-course antibiotic treatment

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:

  1. Intervention group - antibiotic treatment stopped on day 7
  2. Control group - antibiotic treatment continued for 14 days according to accepted hospital local guidelines.
Active Comparator: accepted prolonged antibiotic treatment

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.

Drug: accepted prolonged antibiotic treatment

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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:

  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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01737320

Contacts
Contact: Tanya Babich 972-3-9377380
Contact: Dafna Yahav, MD

Locations
Israel
Rambam Health Care Center Recruiting
Haifa, Israel
Contact: Mical Paul, MD         
Principal Investigator: Mical Paul, MD         
Rabin medical center, Beilinson Hospital Recruiting
Petah Tikvah, Israel
Contact: Tanya Babich    972-3-9377380    tanyanoaba@clalit.org.il   
Contact: Dafna Yahav, MD         
Sub-Investigator: Leonard Leibovici, MD         
Principal Investigator: Dafna Yahav, MD         
Italy
Policlinico di Modena, Italy Recruiting
Modena, Emilia Romagna, Italy
Contact: Erica Franceschini, MD    +393404962539    ericafranceschini0901@gmail.com   
Principal Investigator: Cristina Mussini, MD         
Sub-Investigator: Erica Franceschini, MD         
Sub-Investigator: Claudia Lazzaretti, MD         
Sponsors and Collaborators
Rabin Medical Center
Investigators
Principal Investigator: Dafna Yahav, MD Rabin Medical Center
  More Information

Responsible Party: dafna yahav, MD, a specialist in internal medicine and a specialist in the infectious disease unit, Principal investigator., Rabin Medical Center
ClinicalTrials.gov Identifier: NCT01737320     History of Changes
Other Study ID Numbers: 0258-12-RMC 
Study First Received: November 14, 2012
Last Updated: October 22, 2015
Health Authority: Israel: Ethics Commission

Keywords provided by Rabin Medical Center:
gram negative bacteremia
Duration of antibiotic treatment
safety
efficacy
short-course

Additional relevant MeSH terms:
Bacteremia
Bacterial Infections
Infection
Inflammation
Pathologic Processes
Sepsis
Systemic Inflammatory Response Syndrome
Anti-Bacterial Agents
Antibiotics, Antitubercular
Anti-Infective Agents
Antitubercular Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on April 27, 2016