Clinical trial NCT04291768: Shortened Antibiotic Treatment of 5 Days in Gram-negative Bacteremia
Official title: Short Course Antibiotic Treatment of Gram-negative Bacteremia: A Multicenter, Randomized, Non-blinded, Non-inferiority Interventional Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Gram-negative Bacteremia
Urinary Tract Infection Bacterial
Keywords: Gram-negative bacteremia
Urinary tract infection
Shortened antibiotic treatment
Bacterial infection
Lead sponsor: Hvidovre University Hospital
Sponsor class: OTHER
First posted: 2020-03-02
Enrollment: 380
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: GNB5 is an investigator-initiated multicentre non-inferiority randomized controlled trial which aims to assess the efficacy and safety of shortened antibiotic for patients hospitalized with a Gram negative bacteremia with a urinary tract source of infection (GNB).

Five days after initiation of antimicrobial therapy for GNB, participants are randomized 1:1 to parallel treatment arms: 5 days (intervention) or minimum 7 days (control) of antibiotic treatment. The intervention group discontinues antibiotics at day 5 if clinically stable and afebrile. The control group receives antibiotics for a duration of 7 days or longer at the discretion of the treating physician.

The primary outcome is 90-day survival without clinical or microbiological failure to treatment, which will be tested with a non inferiority margin of 10%.

Detailed description: Introduction: Prolonged use of antibiotics is closely related to antibiotic-associated infections, anti-microbial resistance and adverse drug events. The optimal duration of antibiotic treatment for Gram-negative bacteremia (GNB) with a urinary tract source of infection is poorly defined.

Methods and analysis: Investigator initiated multicenter, non-blinded, non-inferiority randomized controlled trial with two parallel treatment arms. One arm will receive shortened antibiotic treatment of 5 days and the other arm will receive standard antibiotic treatment of 7 days or longer. Randomization will occur in equal proportion (1:1) no later than day 5 of efficacious antibiotic treatment as determined by antibiogram. Immunosuppressed patients and those with GNB due to non-fermenting bacilli (Acinetobacter spp, Pseudomonas spp), Brucella spp, Fusobacterium spp or polymicrobial growth are ineligible.

Primary endpoint is 90-day survival without clinical or microbiological failure to treatment. Secondary endpoints include all-cause mortality, total duration of antibiotic treatment, hospital re-admission and Clostridioides difficile infection. Interim safety analysis will be performed after the recruitment of every 100 patients. Given an event rate of 12%, a margin of 10% and 90% power, the required sample size to determine non-inferiority is 380 patients. Analyses will be performed on both intention-to-treat and per-protocol populations.

Ethics and dissemination: Approval by Ethics Committee and National Competent Authorities will be obtained before initiation of the trial. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

Impact: Demonstration of non-inferiority will provide needed evidence to safely shorten antibiotic treatment duration in GNB with a urinary tract source of infection and thereby reduce the risk of adverse events and development of resistance associated with use of antibiotics

Eligibility criteria: Inclusion Criteria:

* Age \>18 years
* Blood culture positive for Gram-negative bacteria
* Evidence of urinary tract source of infection (positive urine culture or at least one clinical symptom compatible with urinary tract infection)
* Antibiotic treatment with antimicrobial activity to Gram-negative bacteria administrated within 12 hours of first blood culture
* Temperature \<37.8°C at randomization
* Clinically stabile at randomization (systolic blood pressure \> 90 mm Hg, heart rate \<100 beats/min., respiratory rate \<24/minute, peripheral oxygen saturation \> 90 %)
* Oral and written informed consent

Exclusion Criteria:

* Antibiotic treatment (\>2 day) with antimicrobial activity to Gram-negative bacteria within 14 days of inclusion
* Gram-negative bacteremia within 30 days of blood culture
* Immunosuppression (Untreated HIV-infection, Neutropenia (absolute neutrophil count \< 1.0 x 109/l), Untreated terminal cancer, Receiving immunosuppressive agents (ATC-code L04A), Corticosteroid treatment (≥20 mg/day prednisone or the equivalent for \>14 days) within the last 30 days, Chemotherapy within the last 30 days, Immunosuppressed after solid organ transplantation, Asplenia)
* Polymicrobial growth in blood culture
* Bacteremia with non-fermenting Gram-negative bacteria (Acinetobacter spp, Burkholderia spp, Pseudomonas spp), Brucella spp, or Fusobacterium spp
* Failure to remove source of infection within 72 hours of first blood culture (e.g. change of catheter á demeure)
* Pregnancy or breastfeeding

Primary outcomes:
measure: 90-day survival without clinical or microbiological failure to treatment
timeFrame: 90 days
Secondary outcomes:
measure: Mortality
timeFrame: 14, 30 and 90 days
measure: Total duration of antibiotic treatment
timeFrame: 90 days
measure: Type of antibiotic treatment
timeFrame: 90 days
measure: Duration of antibiotic treatment
timeFrame: 90 days
measure: Total length of hospital stay
timeFrame: 90 days
measure: Hospital re-admission
timeFrame: 30 and 90 days
measure: Antibiotic adverse events
timeFrame: 90 days
measure: Use of antimicrobials after discharge
timeFrame: 90 days
measure: Severe adverse events
timeFrame: 90 days
measure: Acute kidney injury
timeFrame: 90 days
measure: Clostridioides difficile infection
timeFrame: 90 days
measure: Multidrug-resistance organism
timeFrame: 90 days
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: University Hospital of Aalborg
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital
city: Hellerup
country: Denmark
facility: Gentofte Hospital
city: Herlev
country: Denmark
facility: Herlev Hospital
city: Herning
country: Denmark
facility: Herning Hospital
city: Hillerød
country: Denmark
facility: Nordsjaellands Hospital
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital
city: Kolding
country: Denmark
facility: Kolding Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Roskilde
country: Denmark
facility: Roskilde Hospital
city: Silkeborg
country: Denmark
facility: Regionshospitalet Silkeborg
city: Århus
country: Denmark
facility: University Hospital of Aarhus
Study officials:
affiliation: Hvidovre University Hospital
name: Sandra Tingsgård, MD
role: PRINCIPAL_INVESTIGATOR
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