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Antibiotic Durations for Gram-negative Bacteremia (PIRATE)

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ClinicalTrials.gov Identifier: NCT03101072
Recruitment Status : Recruiting
First Posted : April 4, 2017
Last Update Posted : May 22, 2019
Sponsor:
Collaborators:
Centre Hospitalier Universitaire Vaudois
Cantonal Hospital of St. Gallen
Information provided by (Responsible Party):
Angela HUTTNER, University of Geneva, Switzerland

Brief Summary:
Gram-negative bacteremia (GNB) is a frequent hospital & community-acquired infection, yet there is as yet no evidence from randomized studies on the optimal duration of antibiotic therapy. This point-of-care, multicenter randomized controlled non-inferiority trial will randomize 500 patients with GNB on day 5 of appropriate antibiotic therapy to either (1) a total of 7 days of antibiotic therapy, (2) a total of 14 days of antibiotic therapy, or (3) an individualized duration of antibiotic therapy (guided by the patient's clinical course & C-reactive protein levels). The primary outcome is the incidence of clinical failure at day 30.

Condition or disease Intervention/treatment Phase
Bacteraemia Caused by Gram-Negative Bacteria Other: "Fixed long" antibiotic course of 14 days Other: "Fixed short" antibiotic course of 7 days Other: "Individualized duration" of antibiotic therapy Not Applicable

Detailed Description:

Antibiotic resistance continues to grow and is now considered to be one of the most serious global threats of the 21st century. The key driver of resistance is antibiotic overuse; long antibiotic courses select for resistance among the trillions of bacteria hosted by the human body. There is as yet no evidence from randomized studies on its optimal duration of antibiotic therapy. Traditionally, guidelines have somewhat arbitrarily recommended long courses of two weeks, even though patients with no structural complications may recover after only five days of therapy. Evidence is mounting that longer courses leave patients with multi-resistant organisms. Indeed, given rising concerns over resistance, many physicians have reduced antibiotic durations for GNB to 7 days with no apparent untoward consequences.

This point-of-care, multicenter randomized controlled non-inferiority trial will randomize 500 patients with GNB on day 5 of appropriate antibiotic therapy to either (1) a total of 7 days of antibiotic therapy, (2) a total of 14 days of antibiotic therapy, or (3) an individualized duration of antibiotic therapy (guided by the patient's clinical course & C-reactive protein levels). The primary outcome is the incidence of clinical failure at day 30. Patients will be followed through day 90; secondary outcomes will include the incidence of clinical failure on days 60 and 90, the total number of antibiotic days, the incidence of antibiotic-related adverse events (including Clostridium difficile infection), the emergence of bacterial resistance, length of hospital stay. Cost-effectiveness/health-economic analyses will also be performed.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

With day 1 defined as the first day of appropriate (microbiologically efficacious) antibacterial therapy, patients will be randomized 1:1:1 on day 5 (±1) to one of the following three arms:

  • "Fixed long" antibiotic course of 14 days (control arm)
  • "Fixed short" antibiotic course of 7 days (first intervention arm)
  • "Individualized" antibiotic course (second intervention arm): • Starting on day 5, therapy will be discontinued after the patient has been afebrile for 48 hours and the CRP level has decreased from its peak by at least 75% In all arms, the choice and mode of administration (IV vs. PO) of antibiotic(s) will be left to the patient's attending physician and consulting infectious disease specialist and thus will follow usual standards of care.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Participants, their care providers, and study investigators having contact with participants & their providers will be blinded until the antibiotic therapy is discontinued. Outcomes assessors and data analysts will be fully blinded.
Primary Purpose: Treatment
Official Title: The PIRATE PROJECT: a Point-of-care, Informatics-based Randomized Controlled Trial for Decreasing Over-utilization of Antibiotic ThErapy in Gram-negative Bacteremia
Actual Study Start Date : April 27, 2017
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : August 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antibiotics

Arm Intervention/treatment
Active Comparator: "Fixed long" antibiotic course
Patients randomized to this group will receive a "fixed long" antibiotic course of 14 days.
Other: "Fixed long" antibiotic course of 14 days
Only the duration of antibiotic therapy will be investigated in this study. (In all arms, the choice and mode of administration (IV vs. PO) of antibiotic(s) will be left to the patient's attending physician and consulting infectious disease specialist and thus will follow usual standards of care.)

Experimental: "Fixed short" antibiotic course
Patients randomized to this group will receive a "fixed short" antibiotic course of 7 days.
Other: "Fixed short" antibiotic course of 7 days
Only the duration of antibiotic therapy will be investigated in this study. (In all arms, the choice and mode of administration (IV vs. PO) of antibiotic(s) will be left to the patient's attending physician and consulting infectious disease specialist and thus will follow usual standards of care.)

Experimental: "Individualized" antibiotic course
"Individualized" antibiotic course: starting on day 5, therapy will be discontinued after the patient has been afebrile for 48 hours and the CRP level has decreased from its peak by at least 75%
Other: "Individualized duration" of antibiotic therapy
Only the duration of antibiotic therapy will be investigated in this study. (In all arms, the choice and mode of administration (IV vs. PO) of antibiotic(s) will be left to the patient's attending physician and consulting infectious disease specialist and thus will follow usual standards of care.)




Primary Outcome Measures :
  1. Incidence of clinical failure in all arms [ Time Frame: day 30 (with day 1 being the first day of microbiologically efficacious antibiotic therapy) ]

    Clinical failure is defined by the presence of at least one of the following:

    • Relapse: a recurrent bacteremia due to the same bacterium occurring from the day of treatment cessation and until day 30
    • Local suppurative complication that was not present/apparent at infection onset (e.g., renal abscess in pyelonephritis, empyema in pneumonia)
    • Distant complications of the initial infection, defined by growth of the same bacterium causing the initial bacteremia (as determined by antibiotic susceptibility profiling)
    • The restarting of Gram-negative-directed antibiotic therapy after its initial discontinuation due to clinical worsening suspected to be due to the initial infecting organism and for which there is no alternate diagnosis/pathogen suspected
    • Death due to any cause through day 30


Secondary Outcome Measures :
  1. Incidence of clinical failure in all arms [ Time Frame: day 60 ]

    Clinical failure is defined by the presence of at least one of the following:

    • Relapse: a recurrent bacteremia due to the same bacterium occurring from the day of treatment cessation and until day 30
    • Local suppurative complication that was not present/apparent at infection onset (e.g., renal abscess in pyelonephritis, empyema in pneumonia)
    • Distant complications of the initial infection, defined by growth of the same bacterium causing the initial bacteremia (as determined by antibiotic susceptibility profiling)
    • The restarting of Gram-negative-directed antibiotic therapy after its initial discontinuation due to clinical worsening suspected to be due to the initial infecting organism and for which there is no alternate diagnosis/pathogen suspected
    • Death due to any cause through day 30

  2. Incidence of clinical failure in all arms [ Time Frame: day 90 ]

    Clinical failure is defined by the presence of at least one of the following:

    • Relapse: a recurrent bacteremia due to the same bacterium occurring from the day of treatment cessation and until day 30
    • Local suppurative complication that was not present/apparent at infection onset (e.g., renal abscess in pyelonephritis, empyema in pneumonia)
    • Distant complications of the initial infection, defined by growth of the same bacterium causing the initial bacteremia (as determined by antibiotic susceptibility profiling)
    • The restarting of Gram-negative-directed antibiotic therapy after its initial discontinuation due to clinical worsening suspected to be due to the initial infecting organism and for which there is no alternate diagnosis/pathogen suspected
    • Death due to any cause through day 30

  3. Incidence of all-cause mortality in all arms [ Time Frame: day 90 ]
    incidence of all-cause mortality

  4. Incidence of Clostridium difficile infection in all arms [ Time Frame: day 90 ]
    incidence of symptomatic C. difficile infection in all arms

  5. Incidence of emergence of resistance to the study antibiotic in all arms [ Time Frame: day 90 ]
    The incidence of emergence of resistance in micro-organisms recovered in clinical specimens (whether colonizers or etiologic agents of the gram-negative bacteremia) in all arms



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years
  2. Presence of Gram-negative bacteria in at least one blood culture bottle
  3. Treatment with a microbiologically efficacious antibiotic

Exclusion Criteria:

  1. Immunosuppression (including HIV infection with CD4 cell count ≤500/µl, hematopoietic stem-cell transplantation in the first month after transplantation and at any time before engraftment, neutropenia in the 48 hours prior to randomization, receipt of high-dose steroids [>40 mg prednisone or its equivalent] daily for > 2 weeks) in the two weeks prior to randomization
  2. GNB due to the following complicated infections:

    • Endocarditis or other endovascular infection without a removable focus
    • Necrotizing fasciitis
    • Osteomyelitis or septic arthritis
    • Confirmed prostatitis
    • Undrainable abscess or other unresolved sources requiring surgical intervention (e.g., cholecystitis) at the time of enrollment
    • Central nervous system infections
    • Empyema
  3. GNB due to non-fermenting bacilli (Acinetobacter spp., Burkholderia spp., Pseudomonas spp.), Brucella spp., Fusobacterium spp., or polymicrobial growth with Gram-positive organisms
  4. Fever (≥38º C) or hemodynamic instability in the 24h prior to recruitment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03101072


Contacts
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Contact: Angela Huttner, MD 41795533396 angela.huttner@hcuge.ch
Contact: Werner Albrich, MD 41714942653 Werner.Albrich@kssg.ch

Locations
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Switzerland
Cantonal Hospital St Gallen Recruiting
St. Gallen, Saint Gallen, Switzerland
Contact: Werner Albrich, MD         
Lausanne University Hospital Recruiting
Lausanne, Vaud, Switzerland
Contact: Pierre-Yves Bochud, MD         
Geneva University Hospitals Recruiting
Geneva, Switzerland, 1205
Contact: Angela Huttner, MD         
Sponsors and Collaborators
University of Geneva, Switzerland
Centre Hospitalier Universitaire Vaudois
Cantonal Hospital of St. Gallen
Investigators
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Principal Investigator: Angela Huttner, MD University of Geneva

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Angela HUTTNER, Principal Investigator, University of Geneva, Switzerland
ClinicalTrials.gov Identifier: NCT03101072     History of Changes
Other Study ID Numbers: 2017-00108
First Posted: April 4, 2017    Key Record Dates
Last Update Posted: May 22, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: (There is no plan to share IPD.)

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Angela HUTTNER, University of Geneva, Switzerland:
Gram-negative bacteremia
antibiotic durations
point-of-care randomization

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