Nebulized and Intravenous Colistin in Ventilator Associated-pneumonia
Nebulized and Intravenous Colistin in Ventilator Associated-pneumonia
Few antimicrobials are available to treat ventilated associated pneumonia (VAP) caused by
 Gram negative multi-resistant (MDR) bacteria. Colimycin often remains the only active
 antibiotic. The aim of the study is to demonstrate the superiority of nebulized colimycin
 over intravenous colimycin to treat VAP caused by Gramnegative MDR bacteria.
VAP is the most frequent nosocomial infection in critically ill patients and affects length
 of stay and cost in Intensive Care Unit. The increased incidence of nosocomial infections
 caused by MDR bacteria becomes a major health problem worldwide.

 Nowadays, few antimicrobials are available to treat Gram negative MDR VAP. Colimycin often
 remains the only active antibiotic. Treating VAP by intravenous (IV) colimycin has two main
 limitations: risk of renal toxicity and low tissue penetration. Nebulization of colimycin
 offers the possibility of generating high lung tissue concentrations, rapid bactericidal
 effects and low systemic accumulation in experimental models. To date however, there is no
 study comparing clinical effectiveness of nebulized and intravenous colimycin.

 We make the hypothesis that nebulized colimycin increases the clinical cure rate of VAP
 caused by Gram negative MDR bacteria compared to IV colimycin.

 Primary Objective: To demonstrate the superiority of nebulized colimycin over intravenous
 colimycin for treating VAP caused by Gram-negative MDR bacteria.

 Secondary Objectives:

 1. To compare the microbiological cure rate at end of treatment

 2. To compare the VAP recurrence rate after end of treatment

 3. To compare the lung superinfection rate after end of treatment

 4. To compare 28 day- and 90 day-mortality

 5. To compare duration of mechanical ventilation

 6. To compare length of ICU stay

 7. To compare renal function during colimycin administration

 8. To compare side effects resulting from colimycin nebulization and intravenous
 administration

 Ancillary study:

 In some centers, blood samples will be performed to measure colistin peak and trough plasma
 concentrations

 Study design:

 This is a randomized, multicenter, double-blind and phase III study

 1. Randomization:

 Patients are randomly assigned to experimental group or control group:

 Control group: patients receive simultaneously intravenous colimycin and nebulized
 placebo.

 Experimental group: patients receive simultaneously nebulized colimycin and intravenous
 infusion of placebo.

 Dosing adjustment is according to renal function for intravenous infusion of colimycin
 or placebo.

 2. Aerosol generation: Nebulization is performed with a vibrating plate nebulizer (Aeroneb®
 Solo) with following ventilator settings:

 -  Constant flow and volume-controlled mode

 -  Inspiratory/expiratory ratio of 1

 -  Tidal volume of 6-8 ml/kg

 -  Respiratory frequency of 12-18/min

 -  End-inspiratory pause of 20% To standardize nebulization procedure, a checklist
 form is completed by the nurse in charge of the patient.

 3. Duration of treatment:

 -  10 days in each group

 -  In intubated patients, weaning test is authorized after 4 days of treatment. If
 patient is extubated, aerosols are discontinued whereas intravenous infusions are
 continued (placebo or antibiotic) until day 10

 -  In tracheostomized patients: 10-day treatment for nebulized and intravenous therapy

 4. Combined intravenous administration of other antimicrobials are authorized

 5. Serum and microbiological samples

 -  Serum creatinine measured daily from baseline to day 11

 -  Lower respiratory tract specimens at day 5 and day 11 in intubated patients

 6. Survival follow-up at day 28 and 90 days

 Study population: Adult mechanical ventilated patients with VAP caused by Gram-negative MDR
 bacteria.

 Sample size and Power consideration: Data will be analyzed with triangular test. Assuming a
 clinical cure rate at day 11 of 65% in the group treated with nebulized colimycin and of 45%
 in the group treated with intravenous colimycin, a mean sample size of 134 patients is
 required to provide 80% power, with a two-sided type I error rate of 5%. The 90th percentile
 of the number of patients to include is 196.
Inclusion criteria

 -  Age older than 18 yr

 -  Invasive mechanical ventilation for more than 48 h Tracheostomized patients receiving
 intermittent mechanical ventilation can be included

 -  VAP caused by Gram-negative MDR bacteria resistant to all β-lactams and
 fluoroquinolones

 Exclusion criteria

 -  Extrapulmonary Gram-negative MDR infection requiring intravenous colimycin

 -  VAP associated with bacteremia requiring combined treatment by nebulized and
 intravenous colimycin

 -  Hypersensitivity to colistimethate, colistin base, polymyxins and/or their excipients

 -  Porphyria

 -  Severe hypoxemia defined as PaO2 / FiO2< 100; if veno-venous ECMO is initiated, the
 patient can be included

 -  Severe brain injury (initial Glasgow coma score < 8) during the first 7 days before
 randomization

 -  Myasthenia

 -  cystic fibrosis

 -  Refusal to participate in the study

 -  Participation in any clinical study of a therapeutic investigational product within 30
 days prior to the first day of inclusion

 -  No affiliation to social health insurance

 -  Patient under guardianship

 -  Pregnancy