Antifungals Flashcards
Name three challenges faced by the anti-fungal therapy
- Time taken for drugs to show effect
- Environmental fomites leading to reinfection cross infection
- Specificity issues/side effects
What are the key differences between fungal and eukaryotic cells
Chitin cell walls and different membrane lipids
How do cell walls in fungi differ from other
• Cell wall and associated glucans (sugars) are fungal specific
• Membranes have more subtle differences , the sterols are different hence:
o Binding properties
o Pathways to synthesis
Describe a membrane disrupting agent that acts on fungi and describe the side effects
Polyenes
Preferentially bind sterols especially ergosterol
Cause membrane leakage and loss of membrane function
Certain formulations can bind to host membranes = toxic side effects e.g. neuropathy, GI upset, Renal damage, liver failure
Name and describe the actions of two antifungal agents that affect ergosterol synthesis
Azoles
Purely fungistatic
Slow rate of action
Inhibit 14-alpha-demethylase depleting ergosterol
High systemic levels can be toxic
Works on dimorphic fungi and dermatophytes
Allylamines
Inhibit squalene epoxidase reducing ergosterol production and causing accumulations of squalene which is toxic
Broad spectrum activity
Particularly effective against dermatophytes
Describe an antifungal agent that inhibits glucan/chitin synthesis
Echinocandins
- Affect hyphae at growing tips and branching points
- Yeats buds fail to separate from mother cell
- Also lead to osmotically sensitive fungal cells
e. g. Nikkomycin
Describe the action of the nucleic acid inhibitors
Prymidine Analogues (Flucytosine)
- Deaminated in fungal cells by cytochrome deaminase
- Forms two products (FdUMP and FURTP)
- FURTP incorporates into fungal RNA leading to inhibition of protein synthesis
- FdUMP is a potentent inhibitor of thymidykate syththetase – inhibition of DNA syntheseis
Describe the treatment of fungal problems in horses
Equine Antifungals
• Dermatophytes normally self limiting
• Treatment rare due to cost but may be used to Reduce risk of spread, shorten infection time, where infection is not self limiting
• Most important aspect is removal and or cleaning of fomites
Describe treatment of cow, pig and sheep antifungals
Cow, Pig and Sheep Antifungals
• Ringworm in cows often self limiting only treat in cases where pathology is more serious (washes etc)
• Pigs ringworm is often not problematic
Describe the two methods that cab be used to control fungal infection
- Good infection control plans should be in place
* Crowded areas will increase the chance of contact and local environment acting as a fomite
Describe 4 potential mechanisms for azole resistance
- Increased efflux - leading to decreased drug concentration at target due to increased efflux.
- Altered target – so drug binds less well. This would develop slower than for equivalent effect in bacteria where growth dynamics are different.
- Up-regulation of target - hence more drug is required to inhibit.
- Development of bypass pathways / altered balance of pathways
Describe a potential mechanism for polyene resistance
• Fungi alter their balance of sterol types so impact of drug is less
Describe how resistance occurs in fungi
Modification of ERG 11 gene at the molecular level (mutation, conversion or overexpression)
What are three main overarching mechanisms in fungal resistance?
- Over expression of specific drug efflux pumps
- Alteration of sterol biosythesis
- Reduction of intracellular concentration of target enzymes
What other key points should you consider other than the primary therapy when dealing with ringworm cases?
- Potential spread (via contact)
- Secondary cases that may have already been infected
