Mechanism of action of anti-fungals Flashcards
What are the main yeasts that infect humans?
replicate by budding
- Candida spp.
- Cryptococcus neoformans
- Pityriasis versicolor
- Systemic yeasts e.g Histoplamsa capsulatum
What are the main filamentous fungi? (replicate via filamentus extensions)
- Aspergillus spp
- Dermatophytes
What are the 3 types of illness caused by aspergillosis?
- Inflammatory response (e.g hypersensitivity pneumonitis, allergic bronchopulmonary aspergillosis)
- Aspergilloma (normally form in individuals who have had some other lung
disease) - Invasive aspergillosis
How are aspergillomas usually treated?
Through surgical excision
Name 4 tri-azole drugs?
- Fluconazole
- Itraconazole
- Posaconazole
- Voriconazole
What tri-azole drug is achieves very good penetration into the CCF?
Fluconazole
What are the cautions of fluconazole?
- Hepatic impairment
- Suseptibility to QT interval prolongation
- Renal impairment
- Hepatic impairment
- Pregnancy
What pathway do tri-azole drugs target?
IMPORTANT
- Ergosterol biosynthetic pathway
- Mainly stops Lanosterol being converted into ergosterol
- Mainly inhibits 14 alpha-demethylase
- Stops the biosynthesis of the steroid component of the cell wall
Name a way in which resistance to fluconazole can develop?
Efflux pumps which pump the fluconazole out of the cell
What are the 2 main polyenes?
- Amphotericin and nystatin (can be used topically or by IV infusion NOT orally)
What can amphotericin be used to treat?
- Severe systemic fungal infections (IV)
What can standard amphotericin cause intravenously?
- Severe kidney problems (can lose a lot of electrolytes)
- Usually given in a liposomal form (can decrease the toxic effects)
How does amphotericin work?
Amphotericin embeds itself in the cell membrane causing a leakage (binds to ergosterol)
What is flucytosine used against?
Predominantly systemic yeast and fungal infections. Adjunct to amphotericin in cryptococcal or severe systemic candidiasis
Describe the mechanism of action of flucytosine when used with amphotericin
- Amphotericin B increases cell permeability (5-FC can pass through this)
- Flucytosine (5-FC) forms a false nucleotide (pyrimidine)
- Disrupts nucleic acid and protein synthesis
- Binds to thymidylate synthase and stops DNA syntheis and DNA division from occuring
Name 3 echinocandins?
Antidulafungin, caspofungin and micafungin
What do echinocandins inhibit (e.g anidulafungin)
Act by inhibiting beta-!,3)-D-glucan synthase
When are echinocandins used (e.g anidulafungin)?
- Fungicidal against Candida spp (bloodstream candida infections)
- Fungistatic against Aspergilus spp. but are not used in the treatment of aspergillosis
- Uneffective against fungal infections of the CNS
Describe the mode of action of echinocandins
- Inhibits the 1,3 beta glucan chain formation i cell wall
- Polysaccaride chain that forms across the top of the fungal cell membrane that prevents it from osmotic stress
When would terbinafine be used?
- Less severe infections
- Nail infection
- Ringworm infection
What is griseofulvin?
- Used against dermatophyte infections of the skin, scalp, hair and nails where topical therapy has failed or is inappropriate
- Fungistatic (causes disruption of the mitotic spindle, inhibiting mitosis)
- Induces hepatic CYP450 activity (prone to other drug-drug interactions)
What are the main mechanisms by which fungal cells can resist anti-fungal drugs?
- Target enzyme overproduced, so drug does not inhibit the biochemical reaction completely
- Drug target is altered so drug cannot bind
- Drug is pumped out by an efflux pump
- Entry of drug is prevented at the cell membrane/wall level
- cell has a bypass pathway that compensates for the loss-of-function inhibition due to the drug activity
- Sone fungal enzymes that convert an inactive drug to its active form are inhibited
- Cell secretes some enzymes to the extracellular medium, which degrade the drug
Who does invasive candidiasis mainly affect?
- ICU patients (esp. with CV catheter)
- Immunocompromised
- V. low birthweight infants
What does invasive endocarditis present with?
- Often non-specific fever
- Diagnosis is usually by blood culture
- Organ-seeding (endocarditis)
- Lines should be removed
- Prolonged echinocandin/-azole therapy required
What can be used against invasive candidiasis?
- Echinocandin
- Fluconazole
- Amphotericin (when fluconazole or echinocandin cannot be used)
- Voricanozole: fluconazole resistnat Candida spp, when oral therapy is required, or in patients intolerant of amphotericin or an echinocandin
- In refractory cases, flucytosine can be used with IV amphotericin
What is the treatment of choice for aspergillosis?
- Voriconazole
- Liposomal amphotericin (alternative)
What is the main risk factor for cryptococcosis infection?
Advanced HIV
How is cryptococcosis transmitted?
Aerosol
What kind of diseases cn cryptococcosis cause?
- Cutaneous, pulmonary and neurological disease (leading cause of meningitis in SSA)
What are the 2 cryptococcus species?
C neoformans and C gatti
How is cryptococcal meningitis treated?
Amphotericin and flucytosine (7-10% mortality)
What is the causitive organism(s) for Histoplasmosis?
H capsulatam (worldwide) H duboisii (africa)
How is histoplasmosis transmitted?
Inhalation from soil contaminated with bird/bat droppings
presents 3-17 days post-exposure
What can histoplasmosis progress to?
Pulmonary, pericardial, disseminated disease (high mortality in HIV infected persons)
What drugs are used to treat histoplasmosis?
- Itraconazole
- Amphotericin (preferred in patients with fulminant or severe infection)
- Itraconazole used as prophylaxis often against relapse
What can coccidioides (rare type of systemic mycoses) cause?
- May be asymptomatic
- can cause fever and acute respiratory illness
What can paracoccidiodes (rare tyoe of systemic mycoses) cause?
- Respiratory symptoms and fascial lesions
