Combined Use of a Respiratory Broad Panel mPCR and Procalcitonin to Reduce Duration of Antibiotics Exposure in Patients With Severe Community-Acquired Pneumonia

Study Overview
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Brief Summary
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To assess the effectiveness of a management strategy combining a broad panel respiratory mPCR and an algorithm of early antibiotic de-escalation and discontinuation based on both the mPCR results and the procalcitonin (intervention) in severe CAP, as compared to a conventional strategy (control). A multicentre, parallel-group, open-label, randomized controlled trial. The primary assessment criterion est the number of antibiotic-free days at 28 days

Detailed Description
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Randomization is performed immediately after the inclusion. In the intervention arm, a broad panel respiratory mPCR is performed on a lower respiratory tract sample (bronchoalveolar lavage fluid or tracheal aspirate, otherwise sputum), collected before the 12th hour following inclusion. In both arms, an additional lower respiratory tract sample (bronchoalveolar lavage fluid or tracheal aspirate, otherwise sputum) is collected for biological studies and banking. In the intervention arm, an algorithm of early antibiotic de-escalation and discontinuation is based on the early microbiological results, including the mPCR results, and the procalcitonin value. This algorithm is applied as soon as possible (before the 24th hour following inclusion if possible). In the control arm, initial antibiotic therapy is maintained, according to guidelines. In both arms, after 72 hours of antibiotic therapy, ICU physicians are advised to use procalcitonin (values and kinetics) to guide antibiotic therapy discontinuation, with a recommended total duration of 7 days, unless otherwise indicated. In both arms, a switch to oral therapy is encouraged

Official Title
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Combined Use of a Respiratory Broad Panel MULTIplex PCR and Procalcitonin to Reduce Antibiotics Exposure in Patients With Severe Community-Acquired Pneumonia: a Multicentre, Parallel-group, Open-label, Randomized Controlled Trial.

Conditions
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Community-acquired Pneumonia

Intervention / Treatment
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* Device: Antibiotic therapy according to the result of mPCR (device)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (≥18 years) with CAP admitted to the ICU since 18 hours or less; the diagnosis of pneumonia includes two clinical criteria among a temperature > 37.8°C, tachypnea (respiratory rate > 25/min), chest pain, cough, expectoration, localized crackles, with or without signs of pleural effusion, pulse oximetry less than 92% while breathing room air, and a newly-appeared parenchymal infiltrate; the pneumonia is community-acquired if the time between hospital admission and ICU referral is below or equal to 48 hours. Informed consent or emergency procedure. Exclusion Criteria: Pregnancy; Congenital immunodeficiency; HIV infection with the lymphocyte CD4 count below 200/mm3 or unknown in the last year; Acute hematologic malignancy; Neutropenia (<1 leucocyte/mL or < 0.5 neutrophil/mL); Immunosuppressive drugs within the previous 30 days, including anti-cancer chemotherapy and anti-rejection drugs for organ/bone marrow transplant Corticosteroids ≥ 20 mg/d of prednisone equivalent for more than 14 days; chronic obstructive pulmonary disease (COPD) with previous history of colonization/infection with Pseudomonas aeruginosa; Tracheostomy; Diffuse bronchiectasis, cystic fibrosis; Aspiration pneumonia; Moribund patient or death expected from underlying disease during the current admission; Patient deprived of liberty or under legal protection measure; Participation in another interventional trial.

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Antibiotic therapy according to the result of mPCR<br>Combined use of a respiratory broad panel Multiplex polymerase chain reaction (mPCR) (performed on a lower respiratory tract sample : bronchoalveolar lavage fluid or tracheal aspirate, otherwise sputum) and procalcitonin. | Device: Antibiotic therapy according to the result of mPCR (device)<br>* Phone call at D28 and D90, unless the patient is still hospitalized; Collection of a respiratory tract sample (either distal, i.e. tracheal aspirate or bronchoalveolar lavage, or proximal, i.e. sputum) for broad panel respiratory mPCR in the intervention arm. Collection of an additional respiratory tract sample for biological banking in both arms.<br>* Other names: Antibiotic therapy to be adapted according to the result of mPCR (device);|
| No Intervention: Antibiotic therapy at discretion of ICU physicians<br>Antibiotic therapy at discretion of ICU physicians | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effectiveness of a management combining a broad panel respiratory mPCR and an algorithm of early antibiotic de-escalation and discontinuation based on both the mPCR results and the procalcitonin in severe CAP, as compared to a conventional strategy | the number of antibiotic free days at D28, which corresponds to the number of days alive without any at Day 28. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality at 28 (D28) and 90 days (D90); | Mortality rate at D28 and D90 | Day 28 and day 90 | 
| Number of defined daily dose (DDD) per 100 patient days of broad- and narrow-spectrum antibiotics | Number of defined daily dose (DDD) per 100 patient days of broad- and narrow-spectrum antibiotics | Day 28 | 
| Antibiotics duration at D28 | Antibiotics duration at D28 | Day 28 | 
| Number of organ-failure free days (based on SOFA) at D28 | Number of organ-failure free days (based on SOFA) at D28 | Day 28 | 
| Incidence rates of bacterial superinfections at D28 | Incidence rates of bacterial superinfections at D28 | Day 28 | 
| Incidence rates of colonization/infection with multidrug resistant bacteria and Clostridium difficile infections at D28 | Incidence rates of colonization/infection with multidrug resistant bacteria and Clostridium difficile infections at D28 | Day 28 | 
| Incidence rates of relapse (same pathogen) or reinfection (another pathogen) at D28 | Incidence rates of relapse (same pathogen) or reinfection (another pathogen) at D28 | Day 28 | 
| Duration of ICU and hospital stay | Duration of ICU and hospital stay | Day 90 | 
| Cost of the total hospital admissions (including 90-day repeated admissions), ICU costs, cost of the microbiological diagnostic workup; | Cost of the total hospital admissions (including 90-day repeated admissions), ICU costs, cost of the microbiological diagnostic workup; | Day 90 | 
| Incremental / decremental cost effectiveness ratio in cost per treatment success (90-day composite of all-cause death and infection recurrence). | Incremental / decremental cost effectiveness ratio in cost per treatment success (90-day composite of all-cause death and infection recurrence). | Day 90 | 
| Sensitivity, specificity, and likelihood ratios of the broad panel mPCR Film Array for the diagnosis of pneumonia, taking the conventional microbiological tests as reference | Sensitivity, specificity, and likelihood ratios of the broad panel mPCR Film Array for the diagnosis of pneumonia, taking the conventional microbiological tests as reference | Day 28 | 
| Euroquol questionary (EQ-5D-3L) | Euroquol questionary (EQ-5D-3L) | Day 90 | 
| To assess the operational values of the broad panel mPCR Film Array for the diagnosis of ventilator associated pneumonia (in the intervention group only). | Sensitivity, specificity, and likelihood ratios of the broad panel mPCR Film Array for the diagnosis of ventilator associated pneumonia (in the intervention group only), taking the conventional microbiological tests as reference. | Day 28 |