Trial on a Strategy Combining Rapid Diagnostic Testing and Antimicrobial Stewardship to Improve Antibiotic Use in Patients With Hospital-acquired Pneumonia.

Study Overview
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Brief Summary
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Hospital-Acquired Pneumonia (HAP) is the second most frequent hospital-acquired infection in the US and Europe and accounts for a large proportion of antibiotics prescribed in hospitals. Conventional methods to identify causative microorganisms (virus, bacteria) are time-consuming and sometimes inaccurate, leading to inadequate treatment in a large proportion of HAP patients. The FILMARRAY® Pneumonia Panel (FA-PP, bioMérieux) is an automated diagnostic device, allowing detection of multiple pathogens and resistance markers in one hour. Strategies combining rapid diagnostic testing and intervention of specialists in infectious diseases (i.e. antimicrobial stewardship -AMS - experts) showed significant synergistic impact on antibiotic use, mortality and costs in bloodstream infections. The trial hypothesis is that a strategy combining antimicrobial stewardship and FA-PP improves quality of care in HAP patients, as compared to antimicrobial stewardship alone. The trial will include patients hospitalized for ≥ 48 hours, aged 18 years or older, who have criteria of pneumonia: new lung infiltrate on a chest-x ray, plus evidence that the infiltrate is of an infectious origin (i.e. new onset of fever and/or purulent sputum and/or leukocytosis and/or decline in oxygenation). After informed consent, participants will be randomly allocated to either the intervention or the control arm. In the control arm, management of HAP patients will include clinical examination and conventional microbiological tests. Antibiotic choice will be discussed between AMS experts and the physician in charge of the patient. In the intervention arm, in addition to the procedures above, the strategy will include rapid testing using the FA-PP on a respiratory specimen, obtained by either invasive or non-invasive sampling. No additional invasive procedures will be required for the study, and FA-PP will be performed on samples collected as part as routine care. Investigators will visit the patient at inclusion, on day 3 and on day 30 (or at hospital discharge) to collect data on comorbidities, clinical outcomes, results of microbiological tests and antibiotics. At the end of follow-up, we will compare the number of days on broad-spectrum antibiotics, the incidence of negative outcomes, the length of stay and costs in the two arms. The use of the FA-PP is expected to prompt early adjustment of antibiotic therapy, improve outcomes, decrease length of stay, and to reduce the use of broad-spectrum antibiotics. The antibiotic saving may reduce the selection pressure, incidence of colonization with multidrug-resistant bacteria and incidence of hospital-acquired superinfections, both at an individual and hospital level. Moreover, this trial relies on the intervention of multidisciplinary AMS teams that are currently being implemented in many health facilities. Their transversal position offers opportunities for recruitment of patients from a wide range of medical and surgical departments. This project evaluates the feasibility of clinical trials based on the intervention of these teams, and will provide a high level of evidence regarding their impact on the prognosis of patients, appropriate use of antibiotics, and antimicrobial resistance.

Official Title
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Impact of a Strategy Combining the Rapid Polymerase Chain Reaction Platform FilmArray® and the Intervention of an Antimicrobial Stewardship Team in Hospital-acquired Pneumonia in Non-mechanically Ventilated Patients: a Randomized Controlled Trial.

Conditions
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Hospital-acquired Pneumonia

Intervention / Treatment
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* Diagnostic Test: Rapid Diagnostic Testing
* Diagnostic Test: Antimicrobial stewardship


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any patient hospitalized for ≥ 48 hours aged 18 years or older not mechanically-ventilated at inclusion with criteria of pneumonia Dated and signed inform consent written informed consent of relative (trusted person, close family) in case of emergency procedure, by default emergency inclusion notified in medical file and pursuance consent sought Affiliation with a social security scheme Criteria of pneumonia: New lung infiltrate on a chest-x ray plus Evidence that the infiltrate is of an infectious origin, i.e. new onset of fever (> 38.5°C) and/or purulent sputum and/or leukocytosis and/or decline in oxygenation Exclusion Criteria: Patients with severe chronic bronchitis structural changes: very severe COPD (Global initiative for chronic Obstructive Lung Disease GOLD 4), tracheostomy, bronchiectasis, cystic fibrosis Radiological evidence of thoracic empyema, pulmonary abcess Patient life expectancy < 90 days

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Antimicrobial stewardship (= AMS)<br>Management of HAP according to current practice, including intervention of the AMS team. | Diagnostic Test: Antimicrobial stewardship<br>* After clinical examination, routine biological tests will be performed. This includes blood culture, direct examination and culture of invasive or noninvasive respiratory samples, urinary antigen tests for Legionella and Pneumococcus, Influenza PCR on nasopharyngeal swabs (during the influenza season).<br>* Other names: AMS;|
| Experimental: Antimicrobial Stewardship + Rapid Diagnostic Testing<br>Management of HAP including rapid diagnostic testing (FA-PP) and intervention of the AMS team. | Diagnostic Test: Rapid Diagnostic Testing<br>* Automated microbiological diagnostic device based on multiplex PCR analysis, allowing detection of multiple pathogens and resistance markers in one hour from invasive and non-invasive respiratory samples<br>* Other names: Filmarray® Pneumonia Panel (FA-PP);Diagnostic Test: Antimicrobial stewardship<br>* After clinical examination, routine biological tests will be performed. This includes blood culture, direct examination and culture of invasive or noninvasive respiratory samples, urinary antigen tests for Legionella and Pneumococcus, Influenza PCR on nasopharyngeal swabs (during the influenza season).<br>* Other names: AMS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of days on broad-spectrum antibiotics at day 30 or end-of follow-up for 100 patients-days | Number of days that a patient is on an antibiotic, regardless of dose. The list of broad-spectrum antibiotics was defined according to previous literature data. | Day 30 or hospital discharge (plus or minus 4 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall antibiotic use | Number of days on antibiotics per 100 patient-days | Day 30 or hospital discharge (plus or minus 4 days) | 
| Duration of antibiotics for the HAP episode | Number of days on any antibiotic for the HAP episode | up to 30 days | 
| Mortality |  | up to 30 days | 
| In-hospital length of stay | Number of days between admission and discharge | up to 24 weeks | 
| Incidence of Clostridium difficile colitis | Number of patients with documented Clostridium difficile colitis per 100 patient-days. Clostridium difficile colitis is defined by clinical evidence of colitis (unexplained and new-onset ≥3 unformed stools) and positive microbiological test relying on the multistep algorithm routinely used in each investigating center and compliant with national and international standards. | Day 30 or hospital discharge (plus or minus 4 days) | 
| Medical direct costs | Costs of the FILMARRAY® Pneumonia panel (labor and consumables), Antibiotic costs, Total admission costs | Day 30 or hospital discharge (plus or minus 4 days) | 
| Analytical performances of the FILMARRAY® Pneumonia panel compared to conventional methods | Number of discrepancies on Micro-organism identification and Antibiotic resistance | End of the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antimicrobial stewardship, hospital-acquired pneumonia, syndromic approach, rapid diagnostic testing