Cystic Fibrosis Infections

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