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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
504
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.)
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.)
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.)
Cantonal Hospital St Gallen
Sankt Gallen, Canton of St. Gallen, Switzerland
Lausanne University Hospital
Lausanne, Canton of Vaud, Switzerland
Geneva University Hospitals
Geneva, Switzerland
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
Time frame: day 30 (with day 1 being the first day of microbiologically efficacious antibiotic therapy)
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
Time frame: day 60
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
Time frame: day 90
Incidence of all-cause mortality in all arms
incidence of all-cause mortality
Time frame: day 90
Incidence of Clostridium difficile infection in all arms
incidence of symptomatic C. difficile infection in all arms
Time frame: day 90
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
Time frame: day 90
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