Antibiotic Durations for Gram-negative Bacteremia

Bacteraemia Caused by Gram-Negative Bacteria Clinical Trial

— PIRATE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03101072
• Other study ID #: 2017-00108
• Status: Completed
• Phase: N/A
• Start date: April 27, 2017
• Est. completion date: August 26, 2019

Study information

• Verified date: November 2019
• Source: University of Geneva, Switzerland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 504
• Est. completion date: August 26, 2019
• Est. primary completion date: June 11, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Bacteraemia Caused by Gram-Negative Bacteria
• Bacteremia

Intervention

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.)
• "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.)
• "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.)

Locations

Country	Name	City	State
Switzerland	Geneva University Hospitals	Geneva
Switzerland	Lausanne University Hospital	Lausanne	Vaud
Switzerland	Cantonal Hospital St Gallen	St. Gallen	Saint Gallen

Sponsors (3)

Lead Sponsor	Collaborator
University of Geneva, Switzerland	Cantonal Hospital of St. Gallen, Centre Hospitalier Universitaire Vaudois

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of clinical failure in all arms	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	day 30 (with day 1 being the first day of microbiologically efficacious antibiotic therapy)
Secondary	Incidence of clinical failure in all arms	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	day 60
Secondary	Incidence of clinical failure in all arms	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	day 90
Secondary	Incidence of all-cause mortality in all arms	incidence of all-cause mortality	day 90
Secondary	Incidence of Clostridium difficile infection in all arms	incidence of symptomatic C. difficile infection in all arms	day 90
Secondary	Incidence of emergence of resistance to the study antibiotic in all arms	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	day 90