Antibiotic Durations for Gram-negative Bacteremia

Not Applicable

Completed

• Conditions: Bacteraemia Caused by Gram-Negative Bacteria
• Interventions: Other: "Fixed short" antibiotic course of 7 days; Other: "Fixed long" antibiotic course of 14 days; Other: "Individualized duration" of antibiotic therapy

• Registration Number: NCT03101072
• Lead Sponsor: 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.

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.

Study Timeline

• Study First Submitted: 2017-03-29
• Study First Submitted QC: 2017-03-29
• Study First Posted: 2017-04-04
• Study Start: 2017-04-27
• Primary Completion: 2019-06-11
• Study Completion: 2019-08-26
• Status Verified: 2019-11
• Last Update Submitted: 2019-11-18
• Last Update Posted: 2019-11-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 504

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
"Fixed short" antibiotic course	"Fixed short" antibiotic course of 7 days	Patients randomized to this group will receive a "fixed short" antibiotic course of 7 days.
"Fixed long" antibiotic course	"Fixed long" antibiotic course of 14 days	Patients randomized to this group will receive a "fixed long" antibiotic course of 14 days.
"Individualized" antibiotic course	"Individualized duration" of antibiotic therapy	"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%

Primary Outcome Measures

Name	Time	Method
Incidence of clinical failure in all arms	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

Name	Time	Method
Incidence of clinical failure in all arms	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
Incidence of Clostridium difficile infection in all arms	day 90	incidence of symptomatic C. difficile infection in all arms
Incidence of all-cause mortality in all arms	day 90	incidence of all-cause mortality
Incidence of emergence of resistance to the study antibiotic in all arms	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

Trial Locations

Locations (3)

Geneva University Hospitals; 🇨🇭 Geneva, Switzerland

Cantonal Hospital St Gallen; 🇨🇭 St. Gallen, Saint Gallen, Switzerland

Lausanne University Hospital; 🇨🇭 Lausanne, Vaud, Switzerland