Clinical trial NCT05124977: Antimicrobial Stewardship For Ventilator Associated Pneumonia in Intensive Care
Official title: Antimicrobial Stewardship For Ventilator Associated Pneumonia in Intensive Care
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Ventilator Associated Pneumonia
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2021-11-18
Enrollment: 590
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: Increasing emergence of multidrug resistant (MDR) bacteria worldwide is now considered one of the most urgent threats to global health. The association between increase of antibiotics consumption and resistance emergence has been well documented for all patients admitted to the Intensive care unit (ICU) who received antibiotic treatment and for patients treated for ventilator associated pneumonia (VAP).

Reduction of use of antibiotics is a major point in the war against antimicrobial resistance. VAP is the first cause of healthcare-associated infections in ICU and more than half of antibiotics prescriptions in ICU are due to VAP.

Once the diagnosis of pneumonia under MV has been made, initiation of antibiotic treatment must be prompt but there is no clear consensus on its duration. In the case of a good clinical response to treatment, it has been shown in some situations that short course antibiotics can be effective without side effects and antimicrobial stewardship initiatives can be applied successfully and effectively to the management of Community Acquired Pneumonia (CAP).

The hypothesis is that an antimicrobial stewardship is possible in the treatment of VAP with no increase in the rate of all-cause mortality, treatment failure or occurrence of new episode of pneumonia.

The objective is to investigate whether an antimicrobial stewardship for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would be non-inferior in terms of all-cause mortality, treatment failure or occurrence of new episode of pneumonia.

This study will be a prospective, national multicenter (31 centers), phase III, comparative randomized (1:1), single-blinded clinical trial comparing two management strategies of treatment of pneumonia on the basis of two parallel arms:

Experimental group: Antimicrobial stewardship based on daily clinical assessment of clinical cure.

Control group: standard management: duration of appropriate antibiotic therapy for confirmed VAP according to guidelines.

Detailed description: Increasing emergence of multidrug resistant (MDR) bacteria worldwide is now considered one of the most urgent threats to global health. The association between increase of antibiotics consumption and resistance emergence has been well documented for all patients admitted to the Intensive care unit (ICU) who received antibiotic treatment1 and for patients treated for ventilator associated pneumonia (VAP). Reduction of use of antibiotics is a major point in the war against antimicrobial resistance. VAP is the first cause of healthcare-associated infections in ICU and more than half of antibiotics prescriptions in ICU are due to VAP. Current international guidelines define VAP as a pneumonia occurring\>48 hours after endotracheal intubation and distinguishes early onset VAP occurring in the first five days after admission and late VAP, occurring after.

Once the diagnosis of pneumonia under MV has been made, initiation of antibiotic treatment must be prompt but there is no clear consensus on its duration. In the case of a good clinical response to treatment, it has been shown in some situations that short course antibiotics can be effective without side effects and antimicrobial stewardship initiatives can be applied successfully and effectively to the management of Community Acquired Pneumonia (CAP).

American guidelines strongly recommend a 7-day course of antibiotic therapy rather than a longer duration but remark that "there exist situations in which a shorter or longer duration of antibiotics may be indicated, depending upon the rate of improvement of clinical, radiologic, and laboratory parameters".

The hypothesis is that an antimicrobial stewardship is possible in the treatment of VAP with no increase in the rate of all-cause mortality, treatment failure or occurrence of new episode of pneumonia.

The objective is to investigate whether an antimicrobial stewardship for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would be non-inferior in terms of all-cause mortality, treatment failure or occurrence of new episode of pneumonia.

This study will be a prospective, national multicenter (31 centers), phase III, comparative randomized (1:1), single-blinded clinical trial comparing two management strategies of treatment of pneumonia on the basis of two parallel arms:

Experimental group: Antimicrobial stewardship based on daily clinical assessment of clinical cure.

Control group: standard management: duration of appropriate antibiotic therapy for confirmed VAP according to guidelines.

The primary endpoint is a hierarchical endpoint with a first non-inferiority criteria and a second efficacy criteria.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of microbiologically confirmed of first episode of VAP
* Initial appropriate antibiotic therapy (whether empirical or not)
* Written informed consent from the patient or a legal representative if appropriate. If absence of a legal representative the patient may be included in emergency procedure

Definitive diagnosis of pneumonia (in agreement with international guidelines) is defined by association:

* Patient under MV\>48 hours at the time of the microbiological sampling
* New pulmonary infiltrate of which an infectious origin is strongly suspected
* Worsening oxygenation
* Have the following clinical criteria within the 24 hours prior to the first dose of antibiotic therapy

  * Purulent tracheal secretions
  * And at least 1 of the following : documented fever (body temperature \>38,3°C) or hypothermia (body temperature \<35°C) or white blood cell (WBC) count \>10,000 cells/mm3 or \<4,000 cells/mm3
* Microbiological criteria (positive quantitative culture of a lower respiratory tract (LRT): bronchoalveolar lavage fluid (BAL) (significant threshold ≥10\^4 colony-forming units/mL) or plugged telescopic catheter (PTC) (significant threshold ≥ 10\^3 colony-forming units/mL) or quantitative endotracheal aspirate (ETA) distal pulmonary secretion samples (significant threshold ≥10\^5 colony-forming units/mL)

Exclusion Criteria:

* Patient under selective decontamination of the digestive tract
* Duration of antibiotic therapy prior to inclusion \> 72h (for any reason) appropriate to the germs found in the bacterial documentation of the first episode of VAP
* Inclusion in another interventional study concerning antimicrobial strategies
* Moribund (IGS II\>80)
* Thoracic trauma with Abbreviated Injury Scale (AIS) thorax ≥ 3
* Severely immunocompromised patients (such as congenital immunodeficiency, neutropenia (\<1leucocyte/ml or \<0.5 neutrophil/ml) or acute hematologic malignancy or stem cell transplant, HIV infection with CD4 count below 200/mm3
* Patients undergoing immunosuppressive therapy and long term corticotherapy \> 0.5 mg/kg
* VAP due to: Pseudomonas aeruginosa, Carbapenem-resistant Acinetobacter spp, Carbapenem-resistant Enterobacteriaceae
* VAP occurring in the context of co-infection of COVID-19 or other viral pneumonia (confirmed by RT-PCR)
* Patients with empyema, necrotizing and abscessed pneumonia
* Patients requiring extracorporeal oxygen therapy (ECMO), either veno-venous or veno-arterial
* Pregnant women
* No health insurance coverage

Primary outcomes:
measure: Investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would be non-inferior in terms of all-cause mortality, treatment failure or occurrence of new episode of pneumonia
timeFrame: 28 days
measure: Investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would be non-inferior in terms of all-cause mortality, treatment failure or occurrence of new episode of pneumonia
timeFrame: 28 days
measure: Investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would be non-inferior in terms of all-cause mortality, treatment failure or occurrence of new episode of pneumonia
timeFrame: 28 days
Secondary outcomes:
measure: Investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would be non-inferior in term of all-cause mortality
timeFrame: 28 days after inclusion
measure: Investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would be non-inferior in term of occurrence of treatment failure
timeFrame: 28 days after inclusion
measure: investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would be non-inferior in term of occurrence of new episode of pneumonia
timeFrame: 28 days after inclusion
measure: Investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would increase the number of antibiotic free-alive days, from initiation of VAP antibiotic therapy to day 28
timeFrame: 28 days after inclusion
measure: Investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would reduce at day 28 after inclusion of VAP antibiotic therapy the global DOOR score
timeFrame: 28 days after inclusion
measure: Investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would reduce at day 28 after inclusion the duration of invasive mechanical ventilation
timeFrame: 28 days after inclusion
measure: Investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would reduce at day 28 after inclusion the length of stay in intensive care unit
timeFrame: 28 days after inclusion
measure: To investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would reduce at day 28 after inclusion the rate of VAP recurrence
timeFrame: 28 days after inclusion
measure: Investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would reduce at day 28 after inclusion the rate of complications of antibiotic therapy
timeFrame: 28 days after inclusion
measure: Investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would reduce at day 28 after inclusion the rate of acquisition of carriage of MDR bacteria
timeFrame: 28 days after inclusion
measure: Investigate whether an AMS for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would reduce at day 28 after inclusion: The rate of subsequent infection due to : carbapenem-resistant Enterobacteriaceae
timeFrame: 28 days after inclusion
measure: Study if an AMS based on daily clinical assessment of clinical cure of VAP versus standard management would improve survival at days 28 and 90 after inclusion
timeFrame: 28 and 90 days after inclusion
measure: Study the adherence to the AMS strategy (in order to identify factors associated to this adherence) in the intervention group only at day 28 after inclusion
timeFrame: 28 days after inclusion
measure: Assess the medico-economic impact of antimicrobial stewardship applied to VAP at day 28 after inclusion
timeFrame: 28 days after inclusion
Other outcomes:
Locations:
city: Clichy-sous-Bois
country: France
facility: Foucrier
Study officials:
affiliation: APHP
name: Arnaud Foucrier
role: PRINCIPAL_INVESTIGATOR
References: