Fungal Flashcards
What patient groups get serious fungal infections? [6]
Chemo, bone marrow transplants. ITU patients. Central IV catheters. HIV/AIDS. Organ transplants. Long term corticosteroid use.
Where do we get information on how to manage invasive fungal infections?
(EORTC/MSG) (IDSA) (ESCMID) (BCSH)
European org for research and treatment of cancer/invasive fungal infections/mycoses study group.
Infectious disease society of america guidelines.
Euro society of clinical microbiology and infectious diseases.
Where do we get information on how to manage invasive fungal infections?
European org for research and treatment of cancer/invasive fungal infections/mycoses study group.
Infectious disease society of america guidelines.
Euro society of clinical microbiology and infectious diseases.
What are the main causative agents of invasive fungal infections? [4]
Candida, Aspergillus, Cryptococcus, Histoplasma.
What factors are important to know when treating candida infections? [2]
If previous azole therapy has been tried, what species is present.
What are the main types of candidiasis? [4]
Catheter related.
Acute disseminated.
Chronic disseminated.
Deep organ.
What is candidaemia?
Blood infection of candida. Can lead to dissemination of infection to acute/chronic deep organs. Endophthalmitis. fungal endocarditis.
What is aspergillus?
Type of mould. Common environmental pathogen which tends to cause pulmonary infections in immuno-compromised patients. Blood cultures are hard to obtain so must be diagnosed by using imaging, antibody detection etc.
What types of infection does aspergillus tend to cause?
Pulmonary in immuno-compromised patients (lung transplants).
How is an infection caused by aspergillus diagnosed?
Imaging, antibody detection etc. Blood cultures are hard to obtain.
What is aspergillosis?
An aspergillus infection which commonly originates in the lung and has become invasive. Can cause ABPA: allergic bronchopulmonary aspergillosis.
What is ABPA?
allergic bronchopulmonary aspergillosis can be caused by an aspergillosis infection.
What is an aspergilloma?
This is a fungal ball grown in a pre-existing cavity e.g. patient with previous TB. [Saprophytic]
What is the most common Cryptococcus?
Neoformans. Causes undetected pulmonary infections and invasive CNS disease in HIV/AIDS patients.
What types of infections are most commonly associated with Cryptococcus neoformans?
Undetected pulmonary infections and invasive CNS disease in HIV/AIDS patients.
What is Histoplasmosis?
Pulmonary disease caused by common environmental pathogen histoplasma capsulatum. Typically in AIDS/HIV patients.
How can fungal infections be diagnosed? [7]
With difficulty.
- Cultures of blood, respiratory, biopsy, material.
- Microscopy
- Imaging via X-ray or CT
- Mannan/anti-mannan
- Beta-D-glucan
- Galactomannam
- Serology for antibodies
What are the three diagnostic certainty levels?
Proven - fungal cause known.
Probable - 1x host, clinical + mycological
Possible - less criteria than probable
What diagnostic indicators are often present in the host? [5]
Neutropenia. Fever (unresponsive to broad spectrum antibiotics) Immunosuppressive therapy HIV/AIDS Recent prolonged use of corticosteroids.
What clinical diagnostics are there? [3]
Relevant imaging:
Resp: lesions, air-crescent sign or cavity.
CNS: lesions or meningeal enhancement.
Disseminated: lesions on liver or spleen.
What mycological indicators of a fungal infection are there? [3]
Galactomannan antigens
Beta-D-glucan in serum
MC&S, sputum, NBL.
What key characteristics are common across antifungals?
SPECIFICITY:
We need the drug to kill the fungi before us!
As fungi are eukaryotic we share many more similarities than with bacteria etc.
What are the main classifications of antifungals? [4]
Azoles (Imidazoles, triazoles)
Echinocandins (caspofungin, anidulafungin)
Polyenes (amphoterocin)
Nucleoside analogues (flucytosine)
How do azoles work? [3]
Inhibit fungal CYP450 enzymes causing decreased ergosterol biosynthesis.
Cause significant interactions via p450 enzymes.
Most are static and only kill actively dividing fungal cells.
What side effects do azoles cause?
They are orally active but cause hepatic and QT interval side effects. Cause significant interactions via p450 enzymes.
How is fluconazole used and at what doses?
IV/Oral.
400mg daily in severe infections, up to 800mg IV unlicensed.
Active against most candida with CNS penetration but many interactions via p450 inhibition (like all other azoles)
Why would itraconazole be used in preference to fluconazole?
Superior for prophylaxis of IFI but can cause heart failure (negative initrope) and increased hepatotoxicity.
What are the side effects of itraconazole?
Interactions with CYP3A4. Heart failure, hepatotoxicity. Tastes horrible but the oral liquid has better absorption.
Cannot be administered with statins.
Can statins and itraconazole be co-administered?
NO
Why would voriconazole be used instead of itra/fluconazole?
Superior CNS penetrations and active against both Candida and Aspergillus spp.
Good Oral and IV BA.
Use is restricted to CNS infections, or where patients cannot take other medication. Can cause dose associated visual disturbances?
Which antifungal is associated with dose related visual disturbances?
Voriconazole.
What is amphotericin?
A member of the polyene class of antifungals.
How does amphotericin function?
Binds to ergosterol in fungal cell membranes creating porins, increasing fungal cell permeability,
It is fungacidal, broad spectrum and poorly orally BA. (IV only) It can interact with many other nephrotic agents.
How is amphotericin given?
Iv only, Not orally BA.
What side effects are associated with Amphotericin use?[5]
Renal, cardiac, hepatic, electrolyte, infusion reactions.
A test dose must be given first with a crash trolley on standby. (test dose: 1mg over 10mins)
What is Ambisome/abelcet?
This is a lipid formulation of amphotericin developed to reduce renal toxicity and is now used 1st line instead of the non-lipid formulation.
What is caspofungin?
Member of the echinocandins.
Inhibits B-1,3-glucan synthesis in the cell wall.
Can be used in patients with renal impairment.
What is anidulafungin?
Member of the echinocandins. Inhibits B-1,3-glucan synthesis in the cell wall. Used only in invasive candidiasis.
Which echinocandin is only used to treat invasive candidiasis?
Anidulafungin.
What is flucytosine?
Nucleoside analogue. Synergises with Amphotericin.Converted to 5-FU intracellularly, preventing DNA synthesis. Can cause bone marrow suppression. Blood plasma levels need to be monitored. Resistance can occur if used as a single agent.
How does flucytosine function as an antifungal?
Converted to 5-FU intracellularly, preventing DNA synthesis. Can cause bone marrow suppression. Blood plasma levels need to be monitored. Resistance can occur if used as a single agent.
Which antifungal is used for most simple fungal infections?
Fluconazole. If it is candida and no previous azole therapy has been trialled.
Which antifungals are used for most serious infections?
Lipid-amphotericin (ambisome etc.) and/or echinocandins,
Which antifungal is used for invasive CNS infections?
Voriconazole, better CNS penetration.
What organisms give rise to tineas, athletes foot and ringworm?
The true dermatophytes: trichophyton spp. Epidermophyton spp. Microsporum spp.
What is the most common cause of oral and vaginal thrush?
Candida albicans.
What is a dermatophyte?
Fungi which requires keratin for growth.
What is tinea?
Name for a group of diseases caused by fungus: ringworm, athletes foot, jock itch.
What factors predispose to sporadic and recurrent vuvlovaginal candidiasis? [5]
Diabetes. Pregnancy. Oral Contraceptive use. Corticosteroid use. Immunosuppressive therapy in general.
What drug is the main choice to treat mild and uncomplicated vulvocandidiasis?
Triconazole vaginal ointment. Azoles are the drugs of choice. Clotrimazole, butoconazole, miconazole etc. as a single dose regimen or short course. Oral fluconazole (not in pregnancy) given as single dose.
What drug is the main choice to treat complicated vulvocandidiasis?
Longer duration of therapy, 7-14 days with intravaginal or oral azole antifungal generally is needed.
What is nystatin?
Polyene antibiotic from a bacterium. Can be used prophylactically.
How does nystatin function as an antifungal?
It is a polyene so mode of action is targeting of ergosterol in the cell wall, causing increased permeability due to porin formation. Increased oxidative damage.
Why would application of whitfields ointment to the vagina burn?
It contains benzoic acid 6%, salicyclic acid 3%.
What is the mechanism of action of 5-flucytosine?
Blocks fungal DNA/RNA synthesis, can cause bone marrow suppression in humans. Causes misincorporation.
How do imi and triazoles function as antifungals?
Fungastatic inhibition of ergosterol biosynthesis and accumulation of toxic sterol intermediates.
What is terbinafine?
Allylamine and thiocarbonate.
How does terbinafine function as an anti-fungal?
Targets ergosterol biosynthesis, squalene epoxidase, erg1p. Causes fungastatic inhibition of ergosterol biosynthesis.
What is the antifungal medicine of choice? Why?
Voriconazole + superior CNS penetration.
What drug is given to patients unresponsive to itraconazole + amphotericin?
Caspagunfin an echinocandin, inhibits cell wall synthesis by inhibiting B-1,3-glucan synthesis.
How can candida acquire azole resistance? [3]
- MFS multidrug transporter: failure of effective drug accumulation. (Cdr1p + Cdr2p, CaMdr1p)
- Alterations in the azole target protein caused by mutations to Erg11p gene.
- Upregulation of the Erg11p gene.
Mutations to what gene coding for the azole protein target can confer resistance?
Erg11p gene.
Upregulation of what gene can confer resistance to azoles?
Erg11p gene. Upregulation causes increased expression of azole target and a loss of effectiveness.
Multidrug transporters such as [Blank], [Blank] + [Blank] can confer resistance to azole therapy in Candida spp.
Cdr1p
Cdr2p
CaMdr1p
Why is clinical resistance to antifungals rare?
Fungi utilise sterols other than ergosterol as a major component in their cell walls, so survival pressure does not build up.
What is the mode of action of Griseofulvin?
Accumulates in precursor Keratin cells to prevent transmission of fungi to unexfolidated cells.
Interferes with tubulin proteins that are important for cilia, flagella and the internal architecture controlling mitosis.
Griseofulvin interferes with what proteins?
Tubulin proteins. Interferes with tubulin proteins that are important for cilia, flagella and the internal architecture controlling mitosis. Accumulates in precursor Keratin cells to prevent transmission of fungi to unexfolidated cells
What do nystatin and amphotericin have in common? [3]
- Both polyene antifungals dervied from Aspergillus nodosum.
- IV use in hospitals.
- Mode of action based on similarity to alpha-helix and structure of 7TM receptor.
Why is the ERG11 gene important with regard to antifungals?
Responsible for CP51A1. Upregulation of or mutation of this gene is responsible for resistance to azoles.
What is the mode of action of miconazole on yeasts?
Inhibits mitochondrial ATPase.
What is the mode of action of azoles?
Inhibit oxidative enzymes such as P450 14-demethylase the CYP51A1 (ERG11 gene product).
This normally converts lanosterol.
Azoles bind to the iron/heam in the P450.
Interfere with ergosterol biosynthesis.
How do allylamines act antifungally?
Non-competitive inhibitors of squalene epoxidase. Intracellular levels of squalene build up and steroid biosynthesis impairment occurs. Very selective as they have low affinity for mammalian squalene epoxidase.
What is milbemycin?
An efflux pump inhibitor.
Why might milbemycin be added to antifungal therapy regimens?
Resistance to antifungals can arise through active efflux of the anti-fungal agents. Milbemycin is a pump inhibitor.
What fungal specific targets may be exploited in the future? [3]
Asparginases: aid skin entry.
Keratinases: allow use of dead skin cells as food source.
Fungal cell wall components- chitin, mannans, glucans.
What antifungal agents interfere with ergosterol synthesis? [2]
- Azoles (fluconazole, itraconazole, voriconazole)
2. Naftifine + terbinafine
What antifungal agents interfere with fungal DNA/RNA synthesis?
5-fluorocytosine.
What antifungal agents interfere with fungal cell wall synthesis?
Echinocandins. Inhibition of B-1,3-glucan biosynthesis.
What antifungals function via causing disruption to membrane function? [2]
Polyenes:
Nystatin. Amphotericin.
Formation of pores. Binds to ergosterol.
