Shortened Antibiotic Treatment of 5 Days in Gram-negative Bacteremia
Shortened Antibiotic Treatment of 5 Days in Gram-negative Bacteremia
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%.
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
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 (>1 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