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

Overview

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

Interventions

• Other Shortened antibiotic treatment
  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.
• Other Standard 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.

Primary outcome measures

• 90-day survival without clinical or microbiological failure to treatment [Time frame: 90 days]

Secondary outcome measures (12)

• Mortality [Time frame: 14, 30 and 90 days]
• Total duration of antibiotic treatment [Time frame: 90 days]
• Type of antibiotic treatment [Time frame: 90 days]
• Duration of antibiotic treatment [Time frame: 90 days]
• Total length of hospital stay [Time frame: 90 days]
• Hospital re-admission [Time frame: 30 and 90 days]
• Antibiotic adverse events [Time frame: 90 days]
• Use of antimicrobials after discharge [Time frame: 90 days]
• Severe adverse events [Time frame: 90 days]
• Acute kidney injury [Time frame: 90 days]
• Clostridioides difficile infection [Time frame: 90 days]
• Multidrug-resistance organism [Time frame: 90 days]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Denmark · 13 centers

• University Hospital of Aalborg — Aalborg
• University Hospital of Aarhus — Aarhus
• Rigshospitalet — Copenhagen
• Bispebjerg Hospital — Copenhagen
• Gentofte Hospital — Hellerup
• Herlev Hospital — Herlev
• Herning Hospital — Herning
• Nordsjaellands Hospital — Hillerød
• … and 5 more centers

Publications

• Kang CI, Kim SH, Park WB, Lee KD, Kim HB, Kim EC, Oh MD, Choe KW. Bloodstream infections caused by antibiotic-resistant gram-negative bacilli: risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome. Antimicrob Agents Chemother. 2005 Feb;49(2):760-6. doi: 10.1128/AAC.49.2.760-766.2005. PMID 15673761
• Biedenbach DJ, Moet GJ, Jones RN. Occurrence and antimicrobial resistance pattern comparisons among bloodstream infection isolates from the SENTRY Antimicrobial Surveillance Program (1997-2002). Diagn Microbiol Infect Dis. 2004 Sep;50(1):59-69. doi: 10.1016/j.diagmicrobio.2004.05.003. PMID 15380279
• de Kraker ME, Jarlier V, Monen JC, Heuer OE, van de Sande N, Grundmann H. The changing epidemiology of bacteraemias in Europe: trends from the European Antimicrobial Resistance Surveillance System. Clin Microbiol Infect. 2013 Sep;19(9):860-8. doi: 10.1111/1469-0691.12028. Epub 2012 Oct 8. PMID 23039210
• Sogaard M, Norgaard M, Dethlefsen C, Schonheyder HC. Temporal changes in the incidence and 30-day mortality associated with bacteremia in hospitalized patients from 1992 through 2006: a population-based cohort study. Clin Infect Dis. 2011 Jan 1;52(1):61-9. doi: 10.1093/cid/ciq069. PMID 21148521
• DANMAP 2017 - Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, food and humans in Denmark. 2017
• Goossens H, Ferech M, Vander Stichele R, Elseviers M; ESAC Project Group. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet. 2005 Feb 12-18;365(9459):579-87. doi: 10.1016/S0140-6736(05)17907-0. PMID 15708101
• Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, Dunn JR, Farley MM, Holzbauer SM, Meek JI, Phipps EC, Wilson LE, Winston LG, Cohen JA, Limbago BM, Fridkin SK, Gerding DN, McDonald LC. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015 Feb 26;372(9):825-34. doi: 10.1056/NEJMoa1408913. PMID 25714160
• Cunha BA. Antibiotic side effects. Med Clin North Am. 2001 Jan;85(1):149-85. doi: 10.1016/s0025-7125(05)70309-6. PMID 11190350

Identifiers

NCT: NCT04291768 · 190801 · 2019-003282-17 · H-19085920

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗