Aminoglycosides in Early Sepsis (AGES)

Aminoglycosides in Early Sepsis (AGES): A Randomized Pragmatic Clinical Trial Comparing Gentamicin and Narrow Spectrum Betalactams to Broad Spectrum Betalactams as Empirical Treatment in Patients With Suspected Sepsis

Norwegian guidelines for empirical antibiotic therapy in suspected community acquired sepsis recommend the combination of narrow spectrum betalactam and aminoglycoside as the first choice, but broad spectrum betalactams are considered equally appropriate, effective, and safe. However, fear of renal complications due to gentamicin and concern for lacking evidence for efficiency commonly leads to the use of broad spectrum betalactam therapy, a larger driver of antibiotic resistance.

In patients with suspected community acquired sepsis, the investigators hypothesize that empirical combination therapy with narrow spectrum betalactams and aminoglycosides is safe and non-inferior to empirical therapy with broad spectrum betalactams. More specifically, the investigators hypothesize that the proportion of patients with acute kidney injury or death will be similar between these two treatment groups. Furthermore, the investigators hypothesize that the aminoglycoside-based regimen has lesser impact on the gut microbiome. Antimicrobial resistance is one of the most urgent health threats of our time, and Norwegian hospitals were required but failed to reduce the use of broad-spectrum antibiotics with 30% by the end of 2020. In this context, novel initiatives aiming at reducing use of antibiotics are direly needed.

Study Overview

• Status: Recruiting
• Conditions: Sepsis
• Intervention / Treatment: Drug: Gentamicin + narrow spectrum betalactam; Drug: Cefotaxime; Drug: Piperacillin-tazobactam

• Study Type: Interventional
• Enrollment (Estimated): 1900
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Magnus N Lyngbakken, MD PhD; Phone Number: +4793408837; Email: magnus.lyngbakken@medisin.uio.no
• Study Contact Backup: Name: Kristian Tonby, MD PhD; Phone Number: +4741550565; Email: kristian.tonby@medisin.uio.no

Study Locations

• Norway
  • Lørenskog, Norway, 1478
    • Recruiting
    • Akershus University Hospital
    • Contact: Magnus N Lyngbakken, MD PhD; Phone Number: +4793408837; Email: magnus.lyngbakken@medisin.uio.no
    • Contact: Jan Erik Berdal, MD PhD; Phone Number: +4748205817; Email: Jan-Erik.Berdal@ahus.no
    • Principal Investigator: Magnus N Lyngbakken, MD PhD
    • Sub-Investigator: Olav Dalgard, MD PhD
    • Sub-Investigator: Jan Erik Berdal, MD PhD
    • Sub-Investigator: Kristian N Malme, MD
    • Sub-Investigator: Magrit J Hovind, MD
  • Oslo, Norway, 0450
    • Recruiting
    • Oslo University Hospital Ullevål
    • Sub-Investigator: Aleksander R Holten, MD PhD
    • Contact: Kristian Tonby, MD PhD; Phone Number: +4741550565; Email: kristian.tonby@medisin.uio.no
    • Contact: Aleksander R Holten, MD PhD; Phone Number: +4799275784; Email: aleksander.holten@gmail.com
    • Principal Investigator: Kristian Tonby, MD PhD
  • Bergen
    • Bergen, Bergen, Norway
      • Not yet recruiting
      • Haukeland University Hospital
      • Contact: Oddvar Oppegaard, MD PhD; Phone Number: +47 97 58 57 09; Email: oddvar.oppegaard@helse-bergen.no
  • Oslo
    • Oslo, Oslo, Norway
      • Not yet recruiting
      • Lovisenberg Diakonal Hospital
      • Contact: Hedda Hoel, MD PhD; Phone Number: +47 90 15 58 28; Email: HeddaBenedicte.Hoel@lds.no
  • Trondheim
    • Trondheim, Trondheim, Norway
      • Not yet recruiting
      • St. Olav's Hospital
      • Contact: Birgitta Ehrnström, MD PhD; Phone Number: +47 45 51 10 37; Email: birgitta.ehrnstrom@ntnu.no

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Hospitalized
• Adults 18 year or older
• Clinical suspicion of community acquired sepsis with indication for empirical antibiotic therapy
• National Early Warning Score 2 (NEWS2) ≥ 5
• Signed informed consent must be obtained and documented according to ICH GCP, and national/local regulations

Exclusion Criteria:

• Established chronic kidney failure (eGFR < 30 ml/min/1.73m2)
• Presentation with septic shock with multiorgan failure
• Suspicion of condition necessitating specific antimicrobial therapy (e.g. atypical pneumonia, fungal infection, parasitic infection, mycobacterial infection)
• Current or recent use of nephrotoxic drugs (e.g cisplatin within previous 2 months)
• Suspected or confirmed carrier of extended spectrum betalactamase (ESBL) producing bacteria, methicillin-resistant Staphylococcus aureus (MRSA), or other drug-resistant microbes necessitating specific antimicrobial therapy
• Multiple myeloma
• Renal transplantation
• Renal replacement therapy
• Myasthenia gravis
• Known hypersensitivity to any of the study drugs
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Gentamicin + narrow spectrum betalactam; Empirical therapy for suspected community-acquired sepsis with gentamicin + narrow spectrum betalactam (either one of penicillin, ampicillin, or cloxacillin)	Drug: Gentamicin + narrow spectrum betalactam; Empirical therapy for suspected community-acquired sepsis with gentamicin + narrow spectrum betalactam (either one of penicillin, ampicillin, or cloxacillin)
Active Comparator: Cefotaxime or piperacillin-tazobactam; Empirical therapy for suspected community-acquired sepsis with broad spectrum betalactam (either one of cefotaxime or piperacillin-tazobactam)	Drug: Cefotaxime; Empirical therapy for suspected community-acquired sepsis with cefotaxime; Drug: Piperacillin-tazobactam; Empirical therapy for suspected community-acquired sepsis with piperacillin-tazobactam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
30-day mortality	All-cause mortality up to 30 days after randomization	Up to 30 days after randomization
30-day acute kidney injury	Any acute kidney injury up to 30 days after randomization	Up to 30 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
In-hospital mortality	All-cause mortality during index hospitalization	During index hospitalization (commonly up to 30 days)
Duration of hospital stay	Duration of index hospitalization (days)	During index hospitalization (commonly up to 30 days)
Duration of intensive care stay	Duration of stay in intensive care unit (days)	During index hospitalization (commonly up to 30 days)
Duration of ventilator therapy	Duration of therapy with invasive mechanical ventilation (days)	During index hospitalization (commonly up to 30 days)
Duration of vasopressor therapy	Duration of therapy with vasoactive (vasopressor) (days)	During index hospitalization (commonly up to 30 days)
Hospital readmissions	Readmission after discharge from index hospitalization	Up to 30 days after discharge from index hospitalization
Post-discharge mortality	All-cause mortality after discharge from index hospitalization	Up to 30 days after discharge from index hospitalization
Duration of antibiotic treatment	Duration of antibiotic therapy during index hospitalization (days of therapy, DOT)	During index hospitalization (commonly up to 30 days)

Collaborators and Investigators

• Sponsor: University Hospital, Akershus
• Collaborators: Ullevaal University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 23, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): May 1, 2033

Study Registration Dates

• First Submitted: November 27, 2024
• First Submitted That Met QC Criteria: November 27, 2024
• First Posted (Actual): December 2, 2024

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 23, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: sepsis; antibiotics; cephalosporins; aminoglycosides
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathological Conditions, Signs and Symptoms; Sepsis; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pharmaceutical Preparations; Carbohydrates; Glycosides; Amides; Aminoglycosides; Drug Combinations; Penicillin G; beta-Lactams; Lactams; Cephalosporins; Thiazines; Sulfones; Tazobactam; Penicillanic Acid; Piperacillin; Ampicillin; Penicillins; Cephacetrile; Piperacillin, Tazobactam Drug Combination; Cefotaxime; Gentamicins
• Other Study ID Numbers: 2024-519797-39-00

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The dataset used in this study is not publicly available, as the Data Protection Authority approval and patient consent do not allow for such publication. The study group welcomes initiatives for cooperation and data access may be granted upon application.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No