Shortened Antibiotic Treatment of 5 Days in Gram-negative Bacteremia

Gram-negative Bacteremia Clinical Trial

— GNB5  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04291768
• Other study ID #: 190801
• Secondary ID: 2019-003282-17H-
• Status: Recruiting
• Phase: Phase 4
• Start date: March 11, 2020
• Est. completion date: October 1, 2026

Study information

• Verified date: February 2023
• Source: Hvidovre University Hospital
• Contact: Sandra Tingsgård, MD
• Phone: +4520544094
• Email: sandra.tingsgaard[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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%.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 380
• Est. completion date: October 1, 2026
• Est. primary completion date: October 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Bacteremia
• Bacterial Infections
• Gram-negative Bacteremia
• Infections
• Urinary Tract Infection Bacterial
• Urinary Tract Infections

Intervention

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.
• 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.

Locations

Country	Name	City	State
Denmark	University Hospital of Aalborg	Aalborg
Denmark	University Hospital of Aarhus	Århus
Denmark	Bispebjerg Hospital	Copenhagen
Denmark	Rigshospitalet	Copenhagen
Denmark	Gentofte Hospital	Hellerup
Denmark	Herlev Hospital	Herlev
Denmark	Herning Hospital	Herning
Denmark	Nordsjaellands Hospital	Hillerød
Denmark	Hvidovre Hospital	Hvidovre
Denmark	Kolding Hospital	Kolding
Denmark	Odense University Hospital	Odense
Denmark	Roskilde Hospital	Roskilde
Denmark	Regionshospitalet Silkeborg	Silkeborg

Sponsors (1)

Lead Sponsor	Collaborator
Thomas Benfield

Country where clinical trial is conducted

Denmark, 

References & Publications (25)

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Chotiprasitsakul D, Han JH, Cosgrove SE, Harris AD, Lautenbach E, Conley AT, Tolomeo P, Wise J, Tamma PD; Antibacterial Resistance Leadership Group. Comparing the Outcomes of Adults With Enterobacteriaceae Bacteremia Receiving Short-Course Versus Prolonged-Course Antibiotic Therapy in a Multicenter, Propensity Score-Matched Cohort. Clin Infect Dis. 2018 Jan 6;66(2):172-177. doi: 10.1093/cid/cix767. — View Citation

Corey GR, Stryjewski ME, Everts RJ. Short-course therapy for bloodstream infections in immunocompetent adults. Int J Antimicrob Agents. 2009;34 Suppl 4:S47-51. doi: 10.1016/S0924-8579(09)70567-9. — View Citation

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Corona A, Wilson AP, Grassi M, Singer M. Prospective audit of bacteraemia management in a university hospital ICU using a general strategy of short-course monotherapy. J Antimicrob Chemother. 2004 Oct;54(4):809-17. doi: 10.1093/jac/dkh416. Epub 2004 Sep 16. — View Citation

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DANMAP 2017 - Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, food and humans in Denmark. 2017

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. — View Citation

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Huttner A, Albrich WC, Bochud PY, Gayet-Ageron A, Rossel A, Dach EV, Harbarth S, Kaiser L. PIRATE project: point-of-care, informatics-based randomised controlled trial for decreasing overuse of antibiotic therapy in Gram-negative bacteraemia. BMJ Open. 2017 Jul 13;7(7):e017996. doi: 10.1136/bmjopen-2017-017996. — View Citation

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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. — View Citation

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Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med. 2008 Mar 1;177(5):498-505. doi: 10.1164/rccm.200708-1238OC. Epub 2007 Dec 20. — View Citation

Pollack LA, Srinivasan A. Core elements of hospital antibiotic stewardship programs from the Centers for Disease Control and Prevention. Clin Infect Dis. 2014 Oct 15;59 Suppl 3(Suppl 3):S97-100. doi: 10.1093/cid/ciu542. — View Citation

Rice LB. The Maxwell Finland Lecture: for the duration-rational antibiotic administration in an era of antimicrobial resistance and clostridium difficile. Clin Infect Dis. 2008 Feb 15;46(4):491-6. doi: 10.1086/526535. — View Citation

Schroeder S, Hochreiter M, Koehler T, Schweiger AM, Bein B, Keck FS, von Spiegel T. Procalcitonin (PCT)-guided algorithm reduces length of antibiotic treatment in surgical intensive care patients with severe sepsis: results of a prospective randomized study. Langenbecks Arch Surg. 2009 Mar;394(2):221-6. doi: 10.1007/s00423-008-0432-1. Epub 2008 Nov 26. — View Citation

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. — View Citation

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Yahav D, Franceschini E, Koppel F, Turjeman A, Babich T, Bitterman R, Neuberger A, Ghanem-Zoubi N, Santoro A, Eliakim-Raz N, Pertzov B, Steinmetz T, Stern A, Dickstein Y, Maroun E, Zayyad H, Bishara J, Alon D, Edel Y, Goldberg E, Venturelli C, Mussini C, Leibovici L, Paul M; Bacteremia Duration Study Group. Seven Versus 14 Days of Antibiotic Therapy for Uncomplicated Gram-negative Bacteremia: A Noninferiority Randomized Controlled Trial. Clin Infect Dis. 2019 Sep 13;69(7):1091-1098. doi: 10.1093/cid/ciy1054. — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	90-day survival without clinical or microbiological failure to 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)	90 days
Secondary	Mortality	Number of deaths by any cause	14, 30 and 90 days
Secondary	Total duration of antibiotic treatment	Days that the participant receives antibiotic treatment for Gram-negative bacteremia, adding intravenous and oral therapy	90 days
Secondary	Type of antibiotic treatment	Antibiotic treatment for Gram-negative bacteremia given by antibiogram	90 days
Secondary	Duration of antibiotic treatment	Duration of antibiotic treatment for Gram-negative bacteremia given by antibiogram	90 days
Secondary	Total length of hospital stay	Days from the date of hospital admission for Gram-negative bacteremia to the date of discharge	90 days
Secondary	Hospital re-admission	Number of participants with readmissions for reasons related to or unrelated to Gram-negative bacteremia	30 and 90 days
Secondary	Antibiotic adverse events	Number of participants with adverse events with possible relation to the antibiotic treatment of Gram-negative bacteremia	90 days
Secondary	Use of antimicrobials after discharge	Days of antibiotic treatment for any reason after hospital discharge	90 days
Secondary	Severe adverse events	Number of participants with serious adverse events according to International Council of Harmonisation-Good Clinical Practice (ICH-GCP) guidelines	90 days
Secondary	Acute kidney injury	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.	90 days
Secondary	Clostridioides difficile infection	Number of participants with Clostridioides difficile infection	90 days
Secondary	Multidrug-resistance organism	Multidrug-resistance organism defined as identification of resistant bacteria in a clinical specimen obtained only from a clinical infection.	90 days