Clinical trial NCT05463406: Procalcitonin and Lung Ultrasonography Guided Antibiotherapy in Emergency Departments
Official title: Procalcitonin and Lung Ultrasonography Based Antibiotherapy in Patients With Lower Respiratory Tract Infection in Swiss Emergency Departments: Pragmatic Stepped-wedge Cluster-randomized Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Lower Respiratory Tract Infection
Keywords: pneumonia
lung ultrasonography
procalcitonin
clinical prediction score
antimicrobial stewardship
Lead sponsor: Centre Hospitalier Universitaire Vaudois
Sponsor class: OTHER
Collaborators: name: Cantonal Hospital of St. Gallen
name: University Hospital, Basel, Switzerland
name: Kantonsspital Baden
name: Hôpital Intercantonal de la Broye, Payerne, Switzerland
name: Réseau Hospitalier Neuchâtelois
name: Hôpital Riviera-Chablais, Vaud-Valais
name: Luzerner Kantonsspital
name: Cantonal Hosptal, Baselland
name: St. Claraspital AG
First posted: 2022-07-19
Enrollment: 1440
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Pragmatic stepped-wedge cluster-randomized controlled clinical trial investigating a new algorithm combining a clinical score, LUS and PCT results (The PLUS algorithm) for the management of LRTIs among adults in EDs. The unit of randomization will be the ED.
Primary purpose: DIAGNOSTIC

Brief summary: Acute respiratory infections are a common reason of attendance at emergency departments. It is also the main reason of unnecessary antibiotic prescription. Antibiotics save lives, but can also directly harm patients by causing antibiotic-associated adverse events. Antibiotic use is directly related to resistance, which is one of the major threats of our century. In addition, some microorganisms live in and on the human body and promote many aspects of our health. Antibiotic treatment can disturb those microorganisms and therefore have long-lasting negative effects on our health.

Unfortunately, it is difficult to differentiate between viral infections, which usually heal spontaneously, and bacterial pneumonia, which needs antibiotics treatment. This is one of the reasons of this over-prescribing of antibiotics.

This project aims to reduce widespread use of antibiotics in the emergency department through a new diagnostic strategy of bacterial pneumonia. This strategy includes sequential use of well-known techniques: a clinical score, lung ultrasound and finally a biomarker, procalcitonin. The latter tends to be higher in bacterial infections. The combination of these different tests improves the diagnostic process and allows improved use of targeted antibiotics, with the ultimate goal of better patient management.

The study will compare the antibiotic prescription rate and the clinical course of patients managed using this new diagnostic approach with those managed as usual. The project will also evaluate the acceptability and feasibility of this strategy and its cost-effectiveness. These two aspects are essential for a wider implementation of this innovative diagnostic approach and decrease antibiotic resistance.

Detailed description: Background Community-acquired lower respiratory tract infections (LRTI) are one of the most common motivations for emergency department (ED) consultations and stands as the leading cause of inappropriate antibiotic prescription. Besides the side effects, antibiotic overuse alters the microbiome and generates antibiotic resistance. When assessing patients with LRTIs, the challenge for ED physicians is to identify those with community-acquired pneumonia (CAP) of bacterial origin, who will most likely benefit from antibiotics. The low diagnostic accuracy of existing tools, as well as the poor adherence of clinicians to test guidance are leading causes of inappropriate antibiotic use.

Several diagnostic tests can assist in identifying patients with LRTI who require antibiotics. Clinical prediction score can refine the probability of CAP. Lung ultrasound (LUS) has a better diagnostic performance than chest X-ray, the historic reference imaging modality to consolidation in ED. LUS is performed quickly at the bedside without radiation. Procalcitonin (PCT) is a host inflammatory biomarker which tends to be higher in bacterial infections. PCT can be used safely to guide antibiotics use, while its impact on prescription is controversial. None of these tools on its own is sufficient to optimize antibiotic prescription, while a combined approach could better guide clinicians.

Rationale The investigators propose to evaluate the use of a decision support tool to guide antibiotics use in the ED as the summative value of LUS with PCT remains unknown in this setting.

Pragmatic stepped-wedge cluster-randomized controlled clinical trial investigating a new algorithm combining a clinical score, LUS and PCT results (The PLUS algorithm) for the management of LRTIs among adults in EDs. The unit of randomization will be the ED.

Primary safety objective To demonstrate non-inferiority of the intervention in terms of clinical failure by day 28.

Co-primary efficacy objective To show a 15% reduction in the proportion of patients with LRTIs prescribed an antibiotic by day 28 in the intervention group compared with the usual care group.

Secondary objectives

1. To compare the quality of life (bothersomeness of CAP-related symptoms) on day 7, day 28 and day 90 between patients in the intervention and control groups.
2. To evaluate the acceptability and feasibility of the intervention through the identification of barriers and facilitators in patients and physicians.
3. To assess the incremental cost-effectiveness of the intervention as compared to usual care using a within-trial (short-term), and a model-based (long-term) economic evaluation.
4. To develop an advanced automatic LUS image analysis method using machine learning to assist in LUS diagnosis and risk stratification.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent
* Patients aged 18 years or more
* Acute LRTI (acute illness, less than 21 days, with at least one lower respiratory tract symptom, i.e. cough, sputum, dyspnea, chest pain and no alternative explanation)
* At least one of the following clinical criteria:

  * Focal abnormal auscultation (decreased breath sounds, crackles, bronchial breath sounds)
  * Fever (documented temperature ≥ 38°C in the last 24 hours, including self-measured temperature ≥ 38°C)
  * Tachypnea (respiratory rate ≥ 22/minute)
  * Tachycardia (heart rate ≥ 100/minute)

Exclusion Criteria:

* Previous receipt of a quinolone, macrolide or ceftriaxone or, of more than one dose of any other antibiotic within 72h prior to enrolment (excepted prophylactic antibiotics or antibiotics given for urinary tract infection)
* Previous hospital stay in the last 14 days
* Cystic fibrosis
* Severe COPD (≥GOLD 3 or if not available, as a proxy: exacerbation treated with antibiotics during the last 6 months)
* Severe immunodeficiency (drug-induced neutropenia with \<500 neutrophils/mm3, HIV infection with CD4\<200 cells/mm3, solid organ or bone marrow transplant recipient, prednisone ≥ 20mg/day for \>28 days)
* Initial admission of the patient in the intensive care unit
* Microbiologically-documented SARS-CoV-2
* Incapacity of discernment

Primary outcomes:
measure: Safety outcome
timeFrame: Day 28
measure: Efficacy outcome
timeFrame: Day 28
Secondary outcomes:
measure: Quality of life measured with the community-acquired pneumonia symptom questionnaire
timeFrame: Day 7, Day 28, Day 90
measure: Hospitalisation
timeFrame: Day 0 to Day 90
measure: Efficacy endpoint
timeFrame: Day 90
measure: Antibiotic side effects and C. difficile infection
timeFrame: Day 0 to Day 28
measure: Emergency department stay
timeFrame: Day 0 to Day 28
measure: Qualitative evaluation
timeFrame: Day 90
measure: Machine learning of Lung ultrasonography (LUS) images and videos
timeFrame: Day 90
measure: Economic evaluation
timeFrame: Day 90
measure: Clinical gestalt
timeFrame: Day 0
Other outcomes:
Locations:
city: Baden
country: Switzerland
facility: Cantonal hospital of Baden
state: AG
city: Basel
country: Switzerland
facility: University Hospital of Basel
state: BS
city: Liestal
country: Switzerland
facility: Kantonsspital Baselland
state: BS
city: Luzern
country: Switzerland
facility: Luzerner Kantonsspital
state: LU
city: Neuchâtel
country: Switzerland
facility: Réseau Hospitalier Neuchâtelois
state: NE
city: Saint Gallen
country: Switzerland
facility: Cantonal Hospital of St. Gallen
state: SG
city: Lausanne
country: Switzerland
facility: Centre hospitalier universitaire vaudois (CHUV)
state: VD
city: Payerne
country: Switzerland
facility: Hôpital Intercantonal de la Broye
state: VD
city: Rennaz
country: Switzerland
facility: Hôpital Riviera-Chablais
state: VD
Study officials:
References:
citation: Lamping DL, Schroter S, Marquis P, Marrel A, Duprat-Lomon I, Sagnier PP. The community-acquired pneumonia symptom questionnaire: a new, patient-based outcome measure to evaluate symptoms in patients with community-acquired pneumonia. Chest. 2002 Sep;122(3):920-9. doi: 10.1378/chest.122.3.920.
citation: Lhopitallier L, Kronenberg A, Meuwly JY, Locatelli I, Mueller Y, Senn N, D'Acremont V, Boillat-Blanco N. Procalcitonin and lung ultrasonography point-of-care testing to determine antibiotic prescription in patients with lower respiratory tract infection in primary care: pragmatic cluster randomised trial. BMJ. 2021 Sep 21;374:n2132. doi: 10.1136/bmj.n2132.
citation: Lhopitallier L, Kronenberg A, Meuwly JY, Locatelli I, Dubois J, Marti J, Mueller Y, Senn N, D'Acremont V, Boillat-Blanco N. Procalcitonin and lung ultrasonography point-of-care testing to decide on antibiotic prescription in patients with lower respiratory tract infection in primary care: protocol of a pragmatic cluster randomized trial. BMC Pulm Med. 2019 Aug 6;19(1):143. doi: 10.1186/s12890-019-0898-3.