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

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.

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

Study Overview

• Status: Completed
• Conditions: Community-acquired Pneumonia
• Intervention / Treatment: Device: Antibiotic therapy according to the result of mPCR (device)

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 411
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jean-François TIMSIT, PU-PH; Phone Number: 0140257702; Email: jean-francois.timsit@aphp.fr
• Study Contact Backup: Name: Muriel FARTOUKH, PU-PH; Phone Number: 01 56 01 65 72; Email: muriel.fartoukh@aphp.fr

Study Locations

• France
  • Paris, France, 75018
    • Hôpital Bichat

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Antibiotic therapy according to the result of mPCR; 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); 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.; Other Names: Antibiotic therapy to be adapted according to the result of mPCR (device)
No Intervention: Antibiotic therapy at discretion of ICU physicians

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Jean-François TIMSIT, PU-PH, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Voiriot G, Fartoukh M, Durand-Zaleski I, Berard L, Rousseau A, Armand-Lefevre L, Verdet C, Argaud L, Klouche K, Megarbane B, Patrier J, Richard JC, Reignier J, Schwebel C, Souweine B, Tandjaoui-Lambiotte Y, Simon T, Timsit JF; MULTI-CAP study group. Combined use of a broad-panel respiratory multiplex PCR and procalcitonin to reduce duration of antibiotics exposure in patients with severe community-acquired pneumonia (MULTI-CAP): a multicentre, parallel-group, open-label, individual randomised trial conducted in French intensive care units. BMJ Open. 2021 Aug 18;11(8):e048187. doi: 10.1136/bmjopen-2020-048187.
• Kerneis S, Visseaux B, Armand-Lefevre L, Timsit JF. Molecular diagnostic methods for pneumonia: how can they be applied in practice? Curr Opin Infect Dis. 2021 Apr 1;34(2):118-125. doi: 10.1097/QCO.0000000000000713.

Study record dates

Study Major Dates

• Study Start (Actual): October 4, 2018
• Primary Completion (Actual): August 5, 2022
• Study Completion (Actual): March 1, 2023

Study Registration Dates

• First Submitted: February 26, 2018
• First Submitted That Met QC Criteria: February 26, 2018
• First Posted (Actual): March 2, 2018

Study Record Updates

• Last Update Posted (Actual): October 18, 2023
• Last Update Submitted That Met QC Criteria: October 17, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Pneumonia; Anti-Infective Agents; Antitubercular Agents; Anti-Bacterial Agents; Antibiotics, Antitubercular
• Other Study ID Numbers: P160928J; AO 1615-48 (Other Grant/Funding Number: PHRC)

Drug and device information, study documents

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