Antimicrobial Stewardship For Ventilator Associated Pneumonia in Intensive Care (ASPIC)

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.

Study Overview

• Status: Recruiting
• Conditions: Ventilator Associated Pneumonia
• Intervention / Treatment: Drug: Antimicrobial Stewardship; Drug: Standard management

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.

• Study Type: Interventional
• Enrollment (Estimated): 590
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Arnaud Foucrier; Phone Number: +33 1 40 87 52 33; Email: arnaud.foucrier@aphp.fr
• Study Contact Backup: Name: Emmanuel Weiss; Phone Number: +33 1 40 87 59 11; Email: emmanuel.weiss@aphp.fr

Study Locations

• France
  • Clichy-sous-Bois, France
    • Recruiting
    • Foucrier
    • Contact: Arnaud Foucrier; Phone Number: 33 140875911; Email: arnaud.foucrier@aphp.fr

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group; Antimicrobial stewardship based on daily clinical assessment of clinical cure (experimental group). Discontinuation of antibiotic therapy antibiotics if criterions of clinical cure (regression of tracheal secretions, regression of temperature, improvement of PaO2/FiO2 ratio, absence of hemodynamic failure) of confirmed VAP are met. In the intervention group, intensivists will perform clinical assessment daily in order to decide on the pursuit or discontinuation of antibiotic therapy.	Drug: Antimicrobial Stewardship; Antimicrobial stewardship based on daily clinical assessment of clinical cure. Discontinuation of appropriate antibiotic therapy antibiotics if criteria of clinical cure of confirmed pneumonia are met. Intensivists will perform clinical assessment daily in order to decide on the pursuit or discontinuation of antibiotic therapy.
Other: Control group; Standard management: duration of appropriate antibiotic therapy for confirmed VAP according to guidelines. In the control group, intensivists will perform clinical assessment daily, but a minimum duration of 7 days, as highly recommended of antibiotic therapy will be mandatory whatever the clinical cure.	Drug: Standard management; Standard management: duration of appropriate antibiotic for confirmed pneumonia fixed for 7 days according to guidelines. In the control group, intensivists will perform clinical assessment daily, but the antibiotic will not be discontinued until 7 days whatever the clinical cure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	The primary endpoint is a composite endpoint with non-inferiority criteria including: 1. all-cause mortality (ACM) measured at day 28 after initiation of therapy	28 days
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	The primary endpoint is a composite endpoint with non-inferiority criteria including: 2. Treatment failure defined by new signs of pneumonia within 72 hours after the end antibiotic treatment at the test of cure visit	28 days
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	The primary endpoint is a composite endpoint with non-inferiority criteria including: 3. New episode of microbiologically confirmed VAP from 72H after the end of antibiotic treatment to day 28 after initiation of VAP antibiotic treatment	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Rate of all-cause mortality	28 days after inclusion
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	Rate of treatment failure	28 days after inclusion
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	Rate of new episode of VAP	28 days after inclusion
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	Number of antibiotic free alive-days	28 days after inclusion
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	Global score constructed with the DOOR and RADAR	28 days after inclusion
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	Duration of invasive MV	28 days after inclusion
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	Length of ICU stay	28 days after inclusion
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	Rate of VAP recurrence	28 days after inclusion
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	Rate of antibiotic related side effects	28 days after inclusion
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	Rate of acquisition of MDR bacteria	28 days after inclusion
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	Rate of subsequent infection of MDR bacteria	28 days after inclusion
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	Rate of death	28 and 90 days after inclusion
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	Adherence to AMS strategy	28 days after inclusion
Assess the medico-economic impact of antimicrobial stewardship applied to VAP at day 28 after inclusion	Total cumulative costs	28 days after inclusion

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Arnaud Foucrier, APHP

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2022
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: November 15, 2021
• First Submitted That Met QC Criteria: November 15, 2021
• First Posted (Actual): November 18, 2021

Study Record Updates

• Last Update Posted (Actual): May 25, 2025
• Last Update Submitted That Met QC Criteria: May 23, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Healthcare-Associated Pneumonia; Pathologic Processes; Disease Attributes; Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Cross Infection; Iatrogenic Disease; Pneumonia; Pneumonia, Ventilator-Associated; Anti-Bacterial Agents; Anti-Infective Agents
• Other Study ID Numbers: APHP200011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No