Impact of Comprehensive Molecular Tests on Antimicrobial Stewardship in Community-acquired Pneumonia

Study Overview
=================
Brief Summary
-----------------
Background: Community-acquired pneumonia (CAP) continues to be a major health problem with significant mortality and it's one of the main causes of antibiotic prescription. Antibiotic overuse is a key driver of antimicrobial resistance and exposes patients to an increased risk of other antibiotic-related adverse events. The investigators aim to assess if rapid molecular tests are an effective tool to reduce antibiotic use in CAP compared to routine microbiological testing. Design: Randomized, controlled, open-label clinical trial with two parallel groups (1:1) settled in a two-year multicenter, two tertiary care hospitals, between 2019 and 2021. Eligible participants will be non-severely immunosuppressed adult patients hospitalized for CAP through the emergency department. Primary endpoint will be antibiotic consumption measured by days of antibiotic therapy (DOT) per 1000 patient-days. Secondary end points will be: de-escalation to narrower antibiotic treatment, time to switch from intravenous to oral antibiotics, antibiotic-related side effects, length of hospital stay, days until clinical stability, need for ICU admission, need for hospital readmission in the 30 days after randomization, death from any cause in the 30 days after randomization. Patients will be randomly assigned to receive experimental diagnosis (comprehensive molecular testing added to routine microbiological testing) or standard diagnosis (only microbiological routine testing). A total of 220 patients are estimated in the experimental arm (undergoing comprehensive molecular testing) and 220 control subjects (undergoing routine testing) to be able to reject the null hypothesis that experimental and control groups have equal DOT per 1000 patients-days with a probability above 0.8. Discussion: Comprehensive molecular tests could be a key tool in the optimization of etiological diagnostics in CAP and, therefore, a key element in antimicrobial stewardship programs developed to improve safety and antibiotic use in CAP.

Official Title
-----------------
Impact of Comprehensive Molecular Tests on Antimicrobial Stewardship in Community-acquired Pneumonia: an Open, Controlled and Randomized Clinical Trial

Conditions
-----------------
Community-acquired Pneumonia

Intervention / Treatment
-----------------
* Diagnostic Test: real-time multiplex PCR
* Diagnostic Test: Standard diagnostic procedures


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult patients (18 years of age or older), of both sexes, hospitalized with a diagnosis of CAP in the first 24 hours of the admission. Patient or his legal representative gives the informed consent Exclusion Criteria: Patient with acute infection by SARS-CoV-2 being this defined as: Clinic of COVID-19 compatible, PCR positive for SARS-CoV-2 and negative serology for SARS-CoV-2. OR COVID-19 clinic compatible, PCR positive for SARS-CoV-2 (in the last 60 days) and positive serology for SARS-CoV-2. Pregnancy and / or nursing. Severe immunocompromised patients (chemotherapy or radiotherapy in the previous 90 days, use of immunosuppressive drugs, chronic use of corticosteroids at a minimum dose of 15 mg / day in the last two weeks, transplantation of hematopoietic progenitors, solid organ transplant, patients with HIV and CD4 count ≤ 200 cells / mm3). Imminent death (life expectancy ≤ 24 hours). Participation in another clinical trial of pharmacological treatment during the previous 3 months.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Controlled, open-label clinical trial with two parallel groups (1:1) settled in two tertiary care hospitals
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard diagnostic tests<br>Patients who will undergo only the standard diagnostic procedures | Diagnostic Test: Standard diagnostic procedures<br>* Patients who will undergo only the standard microbiological diagnostic procedures: blood cultures, Gram stain and culture sputum when possible, Gram and pleural fluid culture when appropriate, urine determination of the pneumococcal and Legionella pneumophila serogroup antigens type 1. A serological study will be carried out for the etiological agents of atypical pneumonia in the acute and convalescent phases of the infection.<br>|
| Experimental: Experimental + standard diagnostic tests<br>Patients will undergo described standard diagnostic procedures and in addition, real-time multiplex Protein Chain Reaction (PCR, FilmArray Pneumonia panel Plus ™, Biofire, BioMérieux). | Diagnostic Test: real-time multiplex PCR<br>* Patients will be randomly assigned to receive experimental diagnosis (comprehensive molecular testing added to routine microbiological testing) AND standard diagnosis microbiological procedures<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of DOT | Number of days of antibiotic therapy | Up to 30±5 days after hospital discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of days with intravenous antibiotic treatment. | Number of days of intravenous antibiotic treatment | Up to 30±5 days after hospital discharge | 
| Number of days until de-escalation | Number of days until de-escalation of antibiotic treatment to another of narrower spectrum | Up to 30±5 days after hospital discharge | 
| Number of days until antimicrobial monotherapy | Number of days untilt antimicrobial monotherapy | Up to 30±5 days after hospital discharge | 
| Number of days until etiological diagnosis | Number of days until detection of the causal agent | Up to 30±5 days after hospital discharge | 
| Number of days of Oxygen treatment | Days of oxygen treatment | Up to 30±5 days after hospital discharge | 
| Number of days of non-invasive ventilation | Days of invasive or non-invasive mechanical ventilation | Up to 30±5 days after hospital discharge | 
| Number of days of hospital admission | Number of days of hospital admission | Up to hospital discharge - a medium of 5 days | 
| Rate of readmissions | Rate of patients who are readmitted after hospital discharge | Up to 30±5 days after hospital discharge | 
| Rate of complicated community-acquired pneumonia (CAP) | Rate of complications related to CAP | Up to 30±5 days after hospital discharge | 
| Rate of general complications | Patients with medical complications not directly related to CAP until the end of the clinical trial. | Up to 30±5 days after hospital discharge | 
| Number of adverse events | Number of total adverse events. | Up to 30±5 days after hospital discharge | 
| Number of adverse events related to antimicrobials | Number of adverse events related to antibiotic therapy. | Up to 30±5 days after hospital discharge | 
| Number of participants with Clostridium difficile infection | Number of patients diagnosed with Clostridium difficile infection during the clinical trial. | Up to 30±5 days after hospital discharge | 
| Phlebitis rate | Number of patients with phlebitis resulting from the use of intravenous drugs. | Up to 30±5 days after hospital discharge | 
| Early mortality rate | Number of patients deceased 5 days after the randomization | Up tp 5 days after randomization | 
| 30 day case-fatality rate | Number of patients deceased 30±5 days after randomization | Up to 30±5 days after randomization | 
| CAP-related fatality rate | Number of patients Deceased patients, related to CAP during the clinical trial | Up to 30±5 days after hospital discharge | 
| All-cause fatality rate | Number of patients who died from any cause during the clinical trial | Up to 30±5 days after hospital discharge | 
| Number of DOT per 1000 patients-day | Number of Days of antibiotic treatment per 1000 patients-day | Up to 30±5 days after hospital discharge | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
antimicrobial stewardship, point-of-care test, comprehensive molecular tests, multiple PCR