Antibiotic Therapy in Viral Airway Infections (ATHENIAN)

Antibiotic Therapy in Viral Airway Infections: An Open Labeled Randomized Controlled Pragmatic Trial to Evaluate the Efficacy and Safety of Discontinuing Antibiotic Therapy in Adult Patients With Respiratory Viruses

Antimicrobial resistance is one of the most urgent health threats of our time, and Norwegian hospitals were required to reduce the use of broad-spectrum antibiotics with 30% by the end of 2020. In the current proposal, the investigators aim to assess the efficacy and safety of early discontinuation of antibiotic therapy in adult patients infected with respiratory viruses.

A general recommendation to treat all instances of community acquired pneumonia (CAP) patients with antibiotics leads to significant antibiotic overtreatment. In 2008, the US Food and Drug Administration approved the first multiplex polymerase chain reaction assay for the detection of multiple respiratory virus nucleic acids simultaneously. The wide availability of such nucleic acid amplification tests (NAAT) for rapid viral detection together with chest radiographs has the potential to define patients who can be managed without antibiotics.

Akershus University Hospital is one of the largest hospitals in Norway, with a catchment area of more than 550,000 people. In 2012 to 2013, the majority of patients admitted to Akershus University Hospital with suspected CAP and a positive viral NAAT were treated with antibiotics, a prescription pattern representing antibiotic overtreatment. The investigators accordingly hypothesize that discontinuation of antibiotic therapy in patients with moderately severe disease and airway sample positive for respiratory viruses is safe and non-inferior to continuation of antibiotic therapy.

Study Overview

• Status: Recruiting
• Conditions: Respiratory Tract Infections; Infectious Disease; Influenza; Respiratory Syncytial Virus (RSV)
• Intervention / Treatment: Other: Stop antibiotic therapy

Detailed Description

In patients with positive airway sample for respiratory viruses, the investigators hypothesize that discontinuation of antibiotic therapy is safe and non-inferior to continuation of antibiotic therapy. More specifically, the investigators hypothesize that the early clinical response assessed at 120 hours after randomization, defined as survival with symptom improvement without receipt of rescue antibacterial therapy, will be similar between patients who discontinue and continue antibiotic therapy. Furthermore, the investigators hypothesize that discontinuation of antibiotic therapy is associated with similar mortality rates, duration of hospital admission and reduced number of defined daily doses of antibiotics.

The primary aim is to assess whether discontinuation of antibiotic therapy in patients with positive airway sample for respiratory viruses is safe and associated with early clinical response assessed at 120 hours after randomization that is comparable to patients who continue antibiotic therapy.

The secondary aims are to assess whether discontinuation of antibiotic therapy in patients with positive airway sample for respiratory viruses is associated comparable (1) mortality rates, (2) duration of hospital admission, (3) defined daily doses of antibiotic therapy.

Specific objectives In patients with positive airway sample for respiratory viruses, assess the impact of discontinuing antibiotic therapy on early clinical response quantified as survival with symptom improvement without receipt of rescue antibacterial therapy. Early clinical response is defined as improvement of one or more levels relative to baseline in two or more symptoms of the investigator's assessment of symptoms of community-acquired bacterial pneumonia and no worsening of one or more levels in other symptoms.

• Study Type: Interventional
• Enrollment (Estimated): 380
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Olav Dalgard, MD PhD; Phone Number: +4792616800; Email: olav.dalgard@medisin.uio.no
• Study Contact Backup: Name: Magnus N Lyngbakken, MD PhD; Phone Number: +4793408837; Email: magnus.lyngbakken@medisin.uio.no

Study Locations

• Norway
  • Bergen, Norway, 5021
    • Not yet recruiting
    • Haukeland University Hospital
    • Contact: Dagfinn L Markussen, MD; Phone Number: +4799270071; Email: dagfinn.lunde.markussen@helse-bergen.no
  • Drammen, Norway, 3004
    • Not yet recruiting
    • Drammen Hospital, Vestre Viken Hospital Trust
    • Contact: Karl Erik Müller, MD PhD; Phone Number: +4797501475; Email: kamull@vestreviken.no
  • Grålum, Norway, 1714
    • Not yet recruiting
    • Sykehuset Østfold HF
    • Contact: Sara F Debes, MD PhD; Email: Sara.Foss.Debes@so-hf.no
  • Lørenskog, Norway, 1478
    • Recruiting
    • Akershus University Hospital
    • Contact: Magnus N Lyngbakken, MD PhD; Phone Number: +4793408837; Email: magnus.lyngbakken@medisin.uio.no
  • Oslo, Norway, 0424
    • Recruiting
    • Oslo University Hospital, Ullevål
    • Contact: Kristian Tonby, MD PhD; Phone Number: +4741550565; Email: kritonby@ous-hf.no
  • Stavanger, Norway, 4068
    • Recruiting
    • Stavanger University Hospital
    • Contact: Åse G Riis, MD; Phone Number: +4745217123; Email: ase.garlov.riis@sus.no
  • Tromsø, Norway, 9038
    • Not yet recruiting
    • University Hospital of North Norway
    • Contact: Vegard Skogen, MD PhD; Phone Number: +4791364541; Email: vegard.skogen@unn.no
  • Trondheim, Norway, 7006
    • Not yet recruiting
    • St. Olavs Hospital
    • Contact: Jan Kristian Damås, MD PhD; Phone Number: +4791112046; Email: jan.k.damas@ntnu.no
  • Tønsberg, Norway, 3103
    • Recruiting
    • Sykehuset i Vestfold HF
    • Contact: Asgeir Johannessen, MD PhD; Phone Number: +4797983264; Email: asgeir.johannessen@siv.no

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Hospitalized
• Adults 18 year or older
• Moderately severe disease (CRB65 ≤ 2 at time of inclusion)
• Nasopharyngeal swab positive for influenza virus, parainfluenza virus, respiratory syncytial virus (RSV) or human metapneumovirus (hMPV)
• On antibiotic therapy as instituted by the receiving physician from the emergency department
• Signed informed consent must be obtained and documented according to ICH GCP, and national/local regulations.

Exclusion Criteria:

• Requiring ICU admission at screening
• Requiring high-flow oxygen therapy or non-invasive ventilation at screening
• Signs of severe pneumonia (abscesses, massive pleural effusion, a well-defined lobar infiltrate on chest X-ray strongly suggestive of bacterial etiology)
• Not immunocompetent (i.e. on active chemotherapy, corticosteroid therapy equaling ≥ 20 mg prednisolone daily for ≥ 4 weeks, chronic immunosuppression due to solid organ transplant)
• SARS-CoV-2 positive
• Bacteremia
• Urine antigen test positive for legionella
• Any other infection necessitating antibiotic treatment
• Antibiotic use for assumed airway infection within the last 24 hours before admission to hospital
• Time from initiation of antibiotic therapy to screening >48 hours

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
Experimental: Intervention; Stop antibiotic therapy as instituted by admitting physician	Other: Stop antibiotic therapy; Stop antibiotic therapy instituted by the admitting physician
No Intervention: Control; Continue antibiotic therapy at the discretion of the treating physician (no change in ongoing treatment)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early clinical response	Survival with symptom improvement without receipt of rescue antibacterial therapy	120 hours after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
In-hospital mortality	Mortality during hospital admission	Untill hospital discharge (commonly 3-5 days)
30-day mortality	Mortality at 30 days after hospital discharge	30 days after hospital discharge
Duration of hospital admission	Duration of hospital admission	Untill hospital discharge (commonly 3-5 days)
Antimicrobial days of therapy	Number of days on antibiotic therapy	Untill hospital discharge (commonly 3-5 days)
Rescue antibiotic therapy during hospital admission	Rescue antibiotic therapy given to patients randomized to intervention	Untill hospital discharge (commonly 3-5 days)
New antibiotic therapy for presumed airway infection	New antibiotic therapy instituted after hospital discharge	30 days after hospital discharge
30-day readmission rate	Hospital readmissions up to 30 days after hospital discharge	30 days after hospital discharge

Collaborators and Investigators

• Sponsor: University Hospital, Akershus
• Collaborators: University of Oslo
• Investigators: Principal Investigator: Magnus N Lyngbakken, MD PhD, University Hospital, Akershus

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2022
• Primary Completion (Estimated): May 1, 2025
• Study Completion (Estimated): November 1, 2029

Study Registration Dates

• First Submitted: September 7, 2021
• First Submitted That Met QC Criteria: September 7, 2021
• First Posted (Actual): September 16, 2021

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 5, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: antibiotic stewardship; pragmatic trial; viral respiratory tract infection
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease Attributes; Infections; Communicable Diseases; Respiratory Tract Infections; Anti-Infective Agents; Anti-Bacterial Agents
• Other Study ID Numbers: 213847; 2021-004248-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No