Antibiotic Durations for Gram-negative Bacteremia (PIRATE)

University of Geneva, Switzerland

Status: Completed

Conditions: Bacteraemia Caused by Gram-Negative Bacteria

Treatments: Other: "Individualized duration" of antibiotic therapy; Other: "Fixed short" antibiotic course of 7 days; Other: "Fixed long" antibiotic course of 14 days

Study type: Interventional

Funder types: Other

Identifiers

NCT03101072

2017-00108

Details and patient eligibility

About

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.

Full 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.

Enrollment: 504 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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504 participants in 3 patient groups

"Fixed long" antibiotic course

Active Comparator group

Description:

Patients randomized to this group will receive a "fixed long" antibiotic course of 14 days.

Treatment:

Other: "Fixed long" antibiotic course of 14 days

"Fixed short" antibiotic course

Experimental group

Description:

Patients randomized to this group will receive a "fixed short" antibiotic course of 7 days.

Treatment:

Other: "Fixed short" antibiotic course of 7 days

"Individualized" antibiotic course

Experimental group

Description:

"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%

Treatment:

Other: "Individualized duration" of antibiotic therapy