Gram Negative Bacilli
Most common organism associated with cystic fibrosis
|A||Pseudomonas aeruginosa (non mucoid)|
a. Cystic fibrosis (CF) is a clinical syndrome that reflects an autosomal recessive genetic disorder characterized by a mutation in the CF gene located on the long arm of chromosome 7.
b. It is a large gene that codes for a 1480-amino acid polypeptide known as cystic fibrosis transmembrane regulator (CFTR) which is a cyclic AMP – regulated chloride channel in the plasma membrane that also regulates the activity of other ion channels in the plasma membrane.
c. The most common gene mutation is a 3-base pair deletion that leads to absence of phenylalanine in the CFTR protein at position 508. This leads to abnormal folding of the protein in the ER followed by its degradation, reflected as absence of protein at the relevant site in the plasma membrane.
Two major defects occur at the cellular level in CF:
A. Defective CFTR Chloride channel function has been detected in the airways, sweat ducts and small intestine.
B. Ion transport defect in the airways- rate of absorption of sodium ions from the airway lumen to the interstitium is raised three-fold.
Ion transport abnormalities appear to deplete the amount of water on airway surfaces which leads to:
a. Periciliary liquid layer is depleted, hence failure of cilia dependent mucus clearance and decrease in the lubricant that prevents the mucus layer from adhering to the airway surface
b. Mucins in the mucus are concentrated, making it adhere more tenaciously to airway surfaces.
The thickened, adherent mucus and plugs are not cleared by cough mechanisms and become the nidi for initial airway infection that characterize lung disease in CF. The most common bacteria associated are S. aureus (~30%), P. aeruginosa (~80%) and Burkholderia cepacia (~10%). The reason for the selective selection of these bacteria is not known.
a. Small-colony variants of S. aureus are increasingly been recognized in CF patients. These auxotrophic (thymidine-dependent), slow-growing and antimicrobial resistant are believed to evolve in the CF airway following long term antibiotic therapy and are believed to play a role in persistence of S. aureus. These strains grow well only on mannitol salt agar and poorly on routine bacteriological media.
b. In childhood or early adolescence, CF patients become chronically infected with P. aeruginosa, either by environmental strains or cross- infections from CF/ non-CF individuals. As this infection evolves, isolates produce large amounts of extracellular mucoid polysaccharide called alginate. The thickened mucus coat overlying the CF airway contains hypoxic regions (hostile for the bacterium), leading to adaptation of the strains to nonmotile, anaerobically respiring, mucoid variants growing as a biofilm that leads to formation of microcolonies. These are highly resistant to antimicrobials and immunological clearance. Mucoid colonies are rarely seen in P. areuginosa isolates with other airway diseases except older patients with primary ciliary dyskinesia.
c. As life expectancy of CF patients has increased, Burkholderia cepacia has emerged as an important pathogen and is recovered from ~10% of adults with CF. Some infected patients develop what is described as cepacia syndrome. In this, young adults with CF and relatively mild pulmonary disease become infected, have rapid deterioration of function and die within 6 months.