Lecture 8: Applied - pathogens in the gut microflora, Clostridium difficile Flashcards
What do antibiotics target?
Antibiotics target essential processes like cell wall synthesis (vancomycin), DNA gyrase (fluoroquinolones) and DNA-directed RNA polymerase (fidaxomicin).
What is the difference between broad spectrum antimicrobials and narrow spectrum?
Broad spectrum targets many different organisms, narrow spectrum targets a specific (group of) organism(s).
When do you use a broad spectrum antibiotic and what are the effects?
Ciprofloxacin is a broad spectrum. If you don’t know the microorganism give broad spectrum so you have the biggest chance of cure. Broad spectrum antibiotics affect your gut ‘ecosystem’ and can cause diarrhea.
What is a Clostridium difficile infection (CDI)?
C. diff can outgrow when your gut microbiome has been disturbed and cause a lethal infection in the colon. They produce toxins which causes damage to the gut mucosa, and there are pseudomembranous coltis (yellowish plaques) formed over the damaged epithelium.
How is the diagnosis of CDI made?
Diagnosis is made by symptoms and patient material (PCR or enzyme immunoassay), and smell (it smells like horse manure).
What is typing?
Typing can be DNA based (PCR) or protein based (MALDI-TOF) and is important for diasease management and infection prevention and control. Typing is characterization beyond the species level and clustering of individual isolates in a meaningful way. It is used to compare strains or patient characteristics and study transmission routes.
How does Clostridium difficile transmission take place?
C.diff transmission is via the oral-fecal route. It forms endospores (dorment form of cell; dehydrated core, thick wall etc) which can survive oxygen. Spores are crucial for the transmission. When they enter a new host need to pass the stomach into the duodenum, where it will turn into a normal cell again under influence of bile salts.
What toxins does Clostridium difficile produce?
C. diff produces large toxins that are the primary cause of the symptoms. TcdA (toxin A) and TcdB (toxin B). They glycosylate rab/rho family GTPases and cause destruction of tight junctions between the cells (punch a hole in the gastrointestinal tract). This is investigated by exposing epithelial cells to purified toxins for instance.
Some strains produce an additional toxin that contributes to disease, CdtA and CdtB that together form CDT toxin (binary toxin). It ADP-ribosylates actin and is believed to increase adherence (like Velcro) and alter the immune response.
What is Trehalose and is it connected to Clostridium difficile?
Trehalose is a food additive that is used as sweetener or stabilizer (FDA approved in early 2000s). Some epidemic types are better at metabolizing low levels of trehalose.
How is Clostridium difficile treated?
Treatment of C.diff is with more antibiotics; metronidazole (mild), vancomycin (moderate to severe), fidaxomicin (recurrent) an some new drugs on the horizon.
Why is there commonly treatment failure for CDI?
Vancomycin has a higher efficacy than Metronidazole. But Metronidazole is cheaper, so is used first but fails commonly.
Clostridium difficile patients have a dysbiosis of the microbiome, how can you treat this?
With fecal microbiota transplantation. FMT restores diversity and is very effective for recurrent CDI.
Who is a good donor for fecal microbiota transplantation?
A ‘Flander’; a dull person with a 9-5 office job who isn’t obese, doesn’t use medicine/antibiotcs, has a healthy stool, doesn’t travel and isn’t older than 50.
Why does fecal microbiome transplantation work for CDI?
Primary bile acids induce C.diff, so by modulating the bacteria which produce bile acids there is a lower chance of recurrence.
What are risk factors for CDI?
Advanced age, antibiotic use, food additives and contact with pigs/lifestock.
