Cystic Fibrosis Infections

1,729 views
1,579 views

Published on

Published in: Health & Medicine
0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
1,729
On SlideShare
0
From Embeds
0
Number of Embeds
13
Actions
Shares
0
Downloads
0
Comments
0
Likes
2
Embeds 0
No embeds

No notes for slide

Cystic Fibrosis Infections

  1. 1. Bugs, biofilms and resistance in Cystic Fibrosis Davies et al Respiratory Care May 2009 Infectious Disease Journal Club 20 August 2009 Dr Preneshni R Naicker
  2. 2. Background <ul><li>CF is the most common lethal inherited disorder affecting Caucasians – autosomal recessive </li></ul><ul><li>Incidence  one in 2500 </li></ul><ul><li>Mutations in the CF transmembrane conductance regulator gene ( cftr ) </li></ul><ul><li>CFTR normally functions as a cAMP-regulated chloride channel </li></ul><ul><li>Defects in CFTR =  Cl secretion into airways </li></ul><ul><li> Na absorption from the airways </li></ul><ul><li>Multisystem disease - 90% of CF patients die of respiratory failure </li></ul>
  3. 3. <ul><li>Carriers in SA </li></ul><ul><li>1 in 27 in White population </li></ul><ul><li>1 in 50 in Coloured population </li></ul><ul><li>1 in 90 in Black population </li></ul><ul><li>Incidence </li></ul><ul><li>1 in 2800 (White population) </li></ul><ul><li>1 in 10 000 (Coloured population) </li></ul><ul><li>1 in 32 000 (Black population) </li></ul>
  4. 4. Why the propensity for bacterial infection? <ul><li>Lessons learned from Pseudomonas aeruginosa </li></ul><ul><li>Environmental pathogen, found in moist areas </li></ul><ul><li>1) Acquisition of Infection </li></ul><ul><li>Mechanisms underlying early acquisition: </li></ul><ul><li>a) ‘Low volume hypothesis’ </li></ul><ul><li>Impaired mucociliary clearance related to low airway surface liquid </li></ul><ul><li>volume </li></ul><ul><li>Defective CFTR doesn’t inhibit Na absorption through epithelial Na channels </li></ul><ul><li>Hyperabsorption of water </li></ul><ul><li>Depletes airway surface fluid </li></ul><ul><li>Impairs muco-ciliary clearance </li></ul><ul><li>Doesn’t explain the narrow range of pathogens </li></ul>
  5. 5. <ul><li>b) Adherence hypothesis </li></ul><ul><li>P. aeruginosa has several classes of adhesins eg pili </li></ul><ul><li>Receptor = GalNAc β 1-4Gal - ↑ on surface of CF respiratory epithelial cells </li></ul><ul><li>↑ adherence of P.aer to CF cells vs wild-type cells </li></ul><ul><li>Explains high prevalence of P.aer and S.aureus </li></ul><ul><li>c) Impaired ingestion of bacteria </li></ul><ul><li>by epithelial cells </li></ul><ul><li>Respiratory epithelial cells ingest </li></ul><ul><li>P.aeruginosa – but cells with mutant CFTR </li></ul><ul><li>are less capable </li></ul><ul><li>of ingestion </li></ul>
  6. 6. <ul><li>2) Establishing chronic infection </li></ul><ul><li>Armamentarium of immuno-evasive strategies </li></ul><ul><li>Secretion of exoproducts </li></ul>Break down intercellular tight juctions Slow ciliary beat functions Siderophores Inhibits phagocytosis Suppresses cell-mediated immunity Exotoxin A Cleave Immunoglobulins, complement components and cytokines Elastase Protease
  7. 7. <ul><li>Antibiotic resistance </li></ul><ul><li>Β -lactamases </li></ul><ul><li>Inducible resistance </li></ul><ul><li>Impermable outer membrane (porins) </li></ul><ul><li>Efflux pumps </li></ul><ul><li> P.aeruginosa strains in CF lungs are hypermutable </li></ul><ul><li>Switch genes on or off </li></ul><ul><li>Increased frequency of mutations in the genome </li></ul>
  8. 8. <ul><li> Phenotypic changes </li></ul><ul><li>In response to environmental triggers </li></ul><ul><li>Convert to mucoid phenotype - mutants that overproduce mucoid exopolysaccharide (alginate) are selected </li></ul>
  9. 9. Biofilm production
  10. 10. <ul><li>Initiation depends on ‘ quorum-sensing ’ </li></ul><ul><li>Molecules eg acyl homoserine lactones that diffuse across bacterial membrane  bacteria ‘sense’ other bacteria in the vicinity. </li></ul><ul><li>Once a critical mass in achieved  biofilm producing genes are expressed </li></ul><ul><li>Protects against phagocytosis and antibiotic penetration </li></ul><ul><li>Major role in the persistence of infection </li></ul><ul><li>Almost impossible to eradicate </li></ul>
  11. 11. Infection with other organisms
  12. 12. <ul><li>Burkholderia cepacia complex </li></ul><ul><li> 3-4% infected </li></ul><ul><li>currently 11 species </li></ul><ul><li>50 % = B. cenocepacia </li></ul><ul><li>unique cable pili </li></ul><ul><li>R to many abics </li></ul><ul><li>produce biofilms </li></ul><ul><li>invade systemically ‘ cepacia syndrome ’ </li></ul><ul><li>independent neg prognostic indicator </li></ul>
  13. 13. Virulence factors of Burkholderia cepacia complex
  14. 14. <ul><li>S. aureus </li></ul><ul><li>common in early childhood </li></ul><ul><li>SCVs described </li></ul><ul><li>? Poorer prognosis with MRSA suggested </li></ul><ul><li>H. influenza </li></ul><ul><li>common in early disease & childhood </li></ul><ul><li>v. little research </li></ul><ul><li>S. maltophilia </li></ul><ul><li>Prevalence 4-30% </li></ul><ul><li>Related to antibiotic exposure history (IMI, CAZ) </li></ul>
  15. 15. <ul><li>Achromobacter (Alcaligenes) xylosoxidans </li></ul><ul><li>2% chronically infected (Tan et al) </li></ul><ul><li>Does not contribute to clinical deterioration </li></ul><ul><li>Pandoraea, Ralstonia, Inquilinus </li></ul><ul><li>Pathogenic role uncertain </li></ul><ul><li>NTM </li></ul><ul><li>Patients with CF have  predisposition for NTM </li></ul><ul><li>Prevalence 2-20% </li></ul><ul><li>M. abscessus , M. avium intracellulare, M. chelonae </li></ul>
  16. 16. Prevention <ul><li>Prevent cross-infection (Handwashing, disposable equipment) </li></ul><ul><li>Cohorting based on airway culture ? </li></ul><ul><li>Most separate B. cepacia complex and MRSA </li></ul>
  17. 17. Treatment – basic principles <ul><li>Role of prophylaxis for S. aureus is unclear </li></ul><ul><li> Incidence in S. aureus infection but no benefit on lung function </li></ul><ul><li>?  incidence of P.aeruginosa </li></ul><ul><li>P. aeruginosa can clearly be eradicated in identified early </li></ul><ul><li>Benefits of early id and aggressive Rx </li></ul><ul><li>Long term suppressive Rx of P. aeruginosa is Advantageous </li></ul><ul><li>Maintains lung function in patients with chronic infection </li></ul><ul><li>In vitro sensitivity testing has limitations </li></ul><ul><li>Difference in growth mode in airway vs culture plates </li></ul><ul><li>Attempts to perform AST on in vitro biofilms - disappointing </li></ul>
  18. 18. <ul><li>Different dosage </li></ul><ul><li>Higher doses are required </li></ul><ul><li>Avoid monotherapy with IV drugs </li></ul><ul><li>Organisms are prone to becoming multi-resistant </li></ul><ul><li>Use combinations of  2 antibiotics from different classes </li></ul><ul><li>Benefits of Synergy testing for MRO unproven </li></ul><ul><li>Antibiotics may be synergistic in vitro but evidence for translating into clinical benefit is lacking </li></ul>
  19. 19. Eradication of early Pseudomonas infection in Cystic Fibrosis TWR Lee Chronic Respiratory Disease Journal, May 2009
  20. 20. Introduction <ul><li>Chronic P. aeruginosa is preceded by a period of intermittent growth </li></ul><ul><li>Antibiotic regimens can eradicate the organism, delaying or preventing the development of chronic infection </li></ul><ul><li>Once chronic infection is established, eradication is almost impossible </li></ul>
  21. 21. Definitions
  22. 23. How to detect P.aeruginosa in CF pts <ul><li>OP cultures (Oropharyngeal) – in non-expectorating patients </li></ul><ul><li>Neg OP Culture reasonable predictor that LRT free of P. aeruginosa (NPV 85-95%) </li></ul><ul><li>Pos OP culture – not as good an indicator of LRTI (PPV 44-69%) </li></ul><ul><li>2 OP cultures 3 months apart NPV = 97% and PPV 83% </li></ul><ul><li>If OP culture Neg BUT S+S = LRTI – use hypertonic saline to induce sputum or BAL </li></ul><ul><li>P. aeruginosa antibody levels – If performed regularly, may alert clinician to early evidence of infection. </li></ul>
  23. 24. What is the evidence that early eradication is effective? <ul><li>Is there complete elimination or temporary suppression? </li></ul><ul><li>74% new strain </li></ul><ul><li>26% same strain (Munck et al) </li></ul>
  24. 25. What agents should be used in eradication regimes?
  25. 26. <ul><li>Early eradication regimes should consist of </li></ul><ul><li>Either Ciprofloxacin and colistin (3 months) OR </li></ul><ul><li>Tobramycin (1 month) – with or without ciprofloxacin </li></ul><ul><li>IV antibiotics should be considered an adjunct and may offer additional benefit </li></ul>
  26. 27. Any adverse effects of early eradication? <ul><li>P. aeruginosa antibiotic sensitivity is high on initial isolation and remains high </li></ul><ul><li>? Emergence of other pathogens following eradication therapy </li></ul><ul><li>no significant rise in prevalence of A. fumigatus, Burkholderia, Steno </li></ul><ul><li>Significant increase in Aspergillus fumigatus (Australasian BAL study) </li></ul>
  27. 28. Practical aspects <ul><li>Compliance with eradication regimens (1-3 months) </li></ul><ul><li>Ciprofloxacin – photosensitivity (minimize exposure to strong sunlight, sun-block) </li></ul><ul><li>Bronchospasm (supervise initial test dose) </li></ul><ul><li>Nebulizers – mouthpiece more effective than mask – poorly tolerated in small children </li></ul>
  28. 29. Thank you

×