Shortened Antibiotic Treatment of 5 Days in Gram-negative Bacteremia (GNB5)

Short Course Antibiotic Treatment of Gram-negative Bacteremia: A Multicenter, Randomized, Non-blinded, Non-inferiority Interventional Study

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

Gram-negative bacteremia, Urinary tract infection, Shortened antibiotic treatment, Bacterial infection

Shortened antibiotic treatment of 5 days. Participation in the study will only affect treatment duration and will have no influence on the choice of treatment in respect to type and dose of antibiotic treatment.

Standard antibiotic treatment of minimum 7 days at the discretion of treating physician. Participation in the study will only affect treatment duration and will have no influence on the choice of treatment in respect to type and dose of antibiotic treatment.

90-day survival without clinical or microbiological failure to treatment as defined: All-cause mortality from day of randomization and until day 90 Microbiological failure: Recurrent bacteremia due to the same microorganism as verified by sequence analysis occurring from day of randomization and until day 90 Clinical failure: Re-initiation of therapy against Gram-negative bacteremia for more than 48 hours due to clinical worsening suspected to be due to the initial infecting organism and for which there is no alternate diagnosis/pathogen suspected from the day of randomization and until day 90 Distant complications of initial infection, defined by growth of the same bacteria as in the initial bacteremia (e.g. endocarditis, meningitis) Local suppurative complication that was not present at infection onset (e.g. renal abscess in pyelonephritis)

Days that the participant receives antibiotic treatment for Gram-negative bacteremia, adding intravenous and oral therapy

Number of participants with readmissions for reasons related to or unrelated to Gram-negative bacteremia

Number of participants with adverse events with possible relation to the antibiotic treatment of Gram-negative bacteremia

Number of participants with serious adverse events according to International Council of Harmonisation-Good Clinical Practice (ICH-GCP) guidelines

Number of participants with acute kidney injury is defined according to RIFLE criteria as increased creatinine level x 1.5 from baseline or estimated glomerular filtration rate (eGFR) decrease >25% or urine output of <0.5 ml/kg/h for 6 hours.

Multidrug-resistance organism defined as identification of resistant bacteria in a clinical specimen obtained only from a clinical infection.

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

Demographics, medical history, and laboratory data will be preserved to validate and replicate described research. Study protocol and statistical analysis plan will be publicly available. Data will be collected in the electronic data capture system (REDCap) and analyzed using open-source statistical packages in R. Data will be available immediately following the publication of the primary outcome. Data will be preserved for 10 upon study start. Anonymized trial data will be made available through relevant public databases when the trial ends. On request, anonymized patient-level data, the statistical code, and other relevant supporting information will be made available by contact with the corresponding author. Study data will be published only in pseudonymous form. Compliance with the plan will be monitored by the primary investigator routinely.

Data will be available immediately following the publication of the primary outcome. Data will be preserved for 10 upon study start.

On request, anonymized patient-level data, the statistical code, and other relevant supporting information will be made available by contact with the corresponding author.

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