Aérosols d’antibiotiques et

maladies bronchiques

suppuratives

Patrice Diot, Tours

Problématiques de

l’antibiothérapie inhalée

Les molécules/dispositifs

Les indications

DCI / spécialitéVolumeunitaire

Classe thérapeutique

terbutaline (BRICANYL®) 2 ml bronchodilatateur

salbutamol (VENTOLINE®) 2,5 ml bronchodilatateur

ipratropium (ATROVENT®) 1 ou 2 ml bronchodilatateur

budésonide (PULMICORT®) 2 ml corticoïde

beclometasone (BECLOSPIN®) 1 ou 2 ml corticoïde

cromoglycate de sodium (LOMUDAL®) 2 ml anti-allergique

pentamidine (PENTACARINAT®) 6 ml antibiotique

tobramycine (TOBI®) 5 ml et poudre antibiotique

colistine (COLIMYCINE®) 3 ml et poudre antibiotique

aztreonam lysine (CAYSTON®) 1 ml antibiotique

dornase alfa (PULMOZYME®) 2,5 ml mucolytique

iloprost (VENTAVIS®) 2 ml traitement HTAP

melaleuca viridiflora (GOMENOL®) 5 ml décongestionnant ORL

Les molécules ayant l’AMM

Les molécules/dispositifs en

développement

Amikacine + liposomale (Transave)

Ciprofloxacine liposomale (Aradigm) ou poudre (Bayer)

Levofloxacine (MP-376) (MPEX)

Azithromycine (Int J Pharmaceutics 2010; 395: 205-214)

Telithromycine (Drug Dev Indust Pharmacy 2010; 36: 861-6)

Tobramycine/Fosfomycine (Gilead)

Gentamycine, Ceftazidime, Cefotaxime, Carbenicilline, Amoxicilline, Vancomycine

…

Aérosols d’antibiotiques

Domaines d’application en pratique clinique

•Mucoviscidose

•Bronchectasies hors mucoviscidose

•Pneumonies et ventilation assistée

•Pneumonies nosocomiales

TIP: poudre, 112 mg X 2

TIS: solution pour nébulisation, 300 mg X 2

L’antibiothérapie inhalée dans les DDB hors mucoviscodose: rationnel 1

L’antibiothérapie inhalée dans

les DDB hors mucoviscodose:

rationnel 2

ORIGINAL ARTICLE

Inhaled Colistin in Patients with Bronchiectasis and Chronic

Pseudomonas aeruginosa Infection

Charles S. Haworth1, Juliet E. Foweraker2, Peter Wilkinson3, Robert F. Kenyon4, and Diana Bilton5

1Cambridge Centre for Lung Infection and 2Department of Microbiology, Papworth Hospital, Cambridge, United Kingdom; 3WilkinsonAssociates, Radnage, Bucks, United Kingdom; 4Profile Pharma Ltd., Tangmere, Chichester, West Sussex, United Kingdom; and 5HostDefence Unit, Royal Brompton Hospital, London, United Kingdom

Abstract

Rationale: Chronic infection with Pseudomonasaeruginosa isassociated with an increased exacerbation frequency, amorerapiddecline in lung function, and increased mortality in patientswithbronchiectasis.

Objectives: To perform arandomized placebo-controlled studyassessing theefficacy and safety of inhaled colistin in patientswithbronchiectasis and chronic P. aeruginosa infection.

Methods: Patientswith bronchiectasis and chronic P. aeruginosainfection wereenrolled within 21 daysof completing acourseofantipseudomonal antibiotics for an exacerbation. Participants wererandomized to receivecolistin (1 million IU; n = 73) or placebo(0.45%saline; n = 71) via theI-neb twiceaday, for up to 6 months.

Measurements and Main Results: Theprimary endpoint wastimeto exacerbation. Secondary endpoints included timetoexacerbation basedonadherencerecorded bytheI-neb,P.aeruginosabacterial density, quality of life, and safety parameters. All analyseswereon theintention-to-treat population. Median time(25%quartile) to exacerbation was165 (42) versus111 (52) days in thecolistin and placebo groups, respectively (P= 0.11). In adherentpatients (adherencequartiles 2–4), themedian timeto exacerbationwas168 (65) versus103(37) daysin thecolistin and placebo groups,respectively (P= 0.038). P. aeruginosa density wasreduced after 4(P= 0.001) and 12weeks(P= 0.008) and theSt.George’sRespiratory

Questionnairetotal scorewasimproved after 26weeks(P= 0.006) inthecolistin versusplacebopatients, respectively. Therewerenosafetyconcerns.

Conclusions: Although theprimary endpoint wasnot reached, thisstudy showsthat inhaled colistin isasafeand effective treatment inadherent patientswith bronchiectasis and chronic P. aeruginosainfection.Clinical trial registered with http://www.isrctn.org/ (ISRCTN49790596)

Keywords: randomized controlled trial; nebulized antibiotics;adherence

At a Glance Commentary

Scientific Knowledge on the Subject: Chronic infectionwith Pseudomonas aeruginosa affects 12–27% of adultswith bronchiectasis and is associated with increasedexacerbation frequency and poor clinical outcomes. Theevidence base supporting the use of nebulized antibioticsin these patients is weak.

What This Study Adds to the Field: This randomizedcontrolled study showsimproved clinical and patient-reportedoutcomes with colistin administered through the I-nebadaptive aerosol delivery device in adherent patients withbronchiectasis and chronic P. aeruginosa infection.

(Received in original form December 17, 2013; accepted in final form March 8, 2014 )

Supported by Profile Pharma Ltd., Chichester, United Kingdom. The statistical analysis was performed by Wilkinson Associates. D.B. is supported by the NHIRRespiratory Disease Biomedical Research Unit at Royal Brompton and Harefield Hospital NHS Foundation Trust, United Kingdom

Author Contributions: C.S.H. and D.B. participated in the study conception. P.W. participated in the data analysis. C.S.H., J.E.F., P.W., R.F.K., and D.B.

participated in the study design, data interpretation, and writing of the manuscript, and have read and approved the final version for submission. C.S.H. andD.B., as the co-chief investigators, had unrestricted access to the data and had final responsibility for the manuscript.

Correspondence and requests for reprints should be addressed to Charles S. Haworth, M.D., Cambridge Centre for Lung Infection, Papworth Hospital,

Cambridge CB23 3RE, UK. E-mail: charles.haworth@papw orth.nhs.uk

This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org

Am J Respir Crit Care Med Vol 189, Iss 8, pp 975–982, Apr 15, 2014

Copyright © 2014 by the American Thoracic Society

Originally Published in Press as DOI: 10.1164/rccm.201312-2208OC on March 13, 2014

Internet address: www.atsjournals.org

Haworth, Foweraker, Wilkinson, et al.: Inhaled Colistin in Bronchiectasis 975

• 12 essais représentant 1264 patients adultes, dont 5 essais non publiés

• Molécules: amikacine, aztreonam, ciprofloxacine, gentamycine, colimycine, tobramycine

• Dispositifs: nébuliseur pneumatique 11inhalateur de poudre 1

• Endpoints: charge bactérienne, exacerbations (délai, nombre), qualité de vie, hospitalisations

Principaux résultats Réduction de la charge bactérienne

Eradication bactérienne

Réduction du risque d’exacerbation

Bronchospasme 10%