Azithromycin as a Quorum-Sensing Inhibitor for the Prevention of Pseudomonas Aeruginosa Ventilator-Associated Pneumonia

Proof of Concept Study to Investigate the Impact of Azithromycin Administered iv Versus Placebo on the Prevention of Pneumonia in Ventilated Patients Colonized by Pseudomonas Aeruginosa

The purpose of this study is to assess the clinical efficacy of azithromycin, used as a quorum-sensing blocker, when compared to placebo for preventing or delaying the occurrence of pneumonia in ventilated patients colonized with Pseudomonas aeruginosa.

Study Overview

• Status: Terminated
• Conditions: Pneumonia, Ventilator-Associated; Pseudomonas Infections
• Intervention / Treatment: Drug: azithromycin; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Liège, Belgium, B-4000
    • General Intensive Car Unit, Centre Hospitalier Universitaire de Liège
  • Louvain
    • Ottignies, Louvain, Belgium, 1340
      • Intensive Care Unit, Clinique Saint-Pierre
• Former Serbia and Montenegro
  • Belgrade, Former Serbia and Montenegro
    • Surgical Intensive Care Unit, Clinical Center of Serbia, Institut of Neurosurgery
  • Belgrade, Former Serbia and Montenegro
    • Surgical Intensive Care Unit, Clinical Center of Serbia
• France
  • Besancon, France, 25030
    • Intensive Care Unit, Jean Minjoz University Hospital
  • Lille, France, 59037
    • Intensive Car Unit, Calmette University Hospital of Lille
  • Limoges, France, 8700
    • Medical-surgical intensive car unit, Dupuytren Teaching Hospital
  • Montauban, France, 82013
    • General Intensive Care Unit, Montauban City Hospital
  • Paris, France, 75018
    • Medical Intensive Car Unit, Hospital Bichat
  • Paris, France, 75018
    • Surgical Intensive Car Unit; University Hospital Bichat
  • Paris, France, 75674
    • General Intensive Care Unit, Hospital Saint-Joseph
  • Paris, France, 75679
    • Medical Intensive Care Unit, Cochin Hospital
• Poland
  • Krakow, Poland
    • Intensive Care Unit, Wojewodzki Hospital
  • Sosnowiec, Poland
    • Intensive Care Unit, Wojewodzki Hospital
  • Warsaw, Poland
    • Intensive Care Unit, Central Hospital
• Spain
  • Barcelona, Spain, 08003
    • Intensive Care Unit, Hospital del Mar
  • Barcelona, Spain, 08035
    • Internal Medicine, Vall d'Hebron Hospital
  • Palma de Mallorca, Spain, 07014
    • Intensive Care Unit, San Dureta University Hospital
  • Tarragona, Spain, 43007
    • Intensive Care Unit, Joan XXIII University Hospital
• Switzerland
  • Vaud
    • Lausanne, Vaud, Switzerland
      • Surgical and Medical Intensive Care Units, University Hospital Lausanne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and non pregnant female aged 18 to 75 years
• Patients hospitalized in ICU, under mechanically assisted ventilation expected to be mandatory for 3 days or more
• Reasonable survival chance within next few days with an Apache score 10-25
• Tracheal aspirate found positive for P. aeruginosa
• The subject (or a close family member in case of incompetence) understands the procedure, agrees to participate, and is willing to give written informed consent
• Informed consent must be obtained for all subjects before enrollment in the study, by patient or by a close family member

Exclusion Criteria:

• Poor prognosis as judged by Apache score II score >25
• Pregnant female
• Grossly under-or overweight (BMI<18or >29)
• Ongoing therapy with a macrolide
• Known allergy to any macrolide
• Proven P. aeruginosa pneumonia
• Ongoing anti-pseudomonal therapy with a proven susceptible colonizing strain
• Anticipated short duration of mechanical ventilation (<3 days)
• Known drug interaction that could either decrease efficacy or raise safety concerns
• Severe hepatic failure (type C, score >10 on Child Pugh scale)
• Sick sinus syndrome or long QT syndrome
• Recent donation of blood or participation in another clinical trial within 3 months
• Any situation exposing the patient to higher risk or possibly confounding results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 2; Placebo	Drug: placebo; once per day, IV from day 1 to 20
Experimental: 1; azithromycin iv 300 mg/day	Drug: azithromycin; 300 mg/day, IV from day 1 to 20; Other Names: Zithromax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Occurrence of and time to Pseudomonas aeruginosa pneumonia	daily

Secondary Outcome Measures

Outcome Measure	Time Frame
occurrence of and time to death	daily
time to extubation	daily
overall outcome	daily
duration of hospitalization and ICU stay	daily
occurrence of infections to other bacterial strains	daily
cost assessment	daily
demonstrate using in vitro and in vivo parameters that azithromycin can be used as a quorum-sensing blocker against P. aeruginosa	daily
determine whether prolonged treatment with azithromycin may induce resistance to any of 11 anti-pseudomonal antibiotics	daily
determine whether P. aeruginosa can develop resistance to the quorum-sensing effect of azithromycin	daily

Collaborators and Investigators

• Sponsor: Anbics Management-Services Ag
• Collaborators: Swiss National Science Foundation
• Investigators: Principal Investigator: Christian Van Delden, MD, Service of Infectious Diseases, University Hospital Geneva, Switzerland; Study Chair: Jean Carlet, MD, General Intensive Care Unit, Hospital Saint-Joseph, Paris, France

Publications and helpful links

General Publications

• Kohler T, Perron GG, Buckling A, van Delden C. Quorum sensing inhibition selects for virulence and cooperation in Pseudomonas aeruginosa. PLoS Pathog. 2010 May 6;6(5):e1000883. doi: 10.1371/journal.ppat.1000883.

Study record dates

Study Major Dates

• Study Start: April 1, 2003
• Primary Completion (Actual): October 1, 2005
• Study Completion (Actual): October 1, 2005

Study Registration Dates

• First Submitted: January 24, 2008
• First Submitted That Met QC Criteria: January 28, 2008
• First Posted (Estimate): February 8, 2008

Study Record Updates

• Last Update Posted (Estimate): February 8, 2008
• Last Update Submitted That Met QC Criteria: January 28, 2008
• Last Verified: January 1, 2008

More Information

Terms related to this study

• Keywords: Pneumonia; Pseudomonas aeruginosa; Ventilator-Associated; Quorum Sensing
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Cross Infection; Iatrogenic Disease; Healthcare-Associated Pneumonia; Pneumonia; Pneumonia, Ventilator-Associated; Pseudomonas Infections; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: Anb006#2001