fungal infections Flashcards
what is fungus
– a single-celled or a multicellular organism
true pathogens
opportunistic pathogens
strutcure :
Yeasts, single cell: Candida spp., Cryptococcus
Filamentous, mould, multicellular: Aspergillus spp., Dermatophytes
Infections
localized: skin, mucosae
systemic
why is fungal cells different
Fungal cells have a cell wall
Fungal cells have some key differences in their cell membrane
Some differences in metabolism
Some differences in target protein structures
what are the main antifungal drugs
Polyenes
Azoles – imidazoles, triazoles
Allylamines (and amorolfine)
Echinocandins
Flucytosine
Griseofulvin
what are examples of polyene
and their route and spectrum
Amphotericin B, polyene macrolide (from Streptomyces nodosus)
Route: Oral, not toxic. Used for oral candida
I,v., highly toxic. Used for life-threatening systemic infections e.g. cryptococcal meningitis
Spectrum: Broad, kills most fungi (fungicidal depending on conc.)
Typically only used IV (poor bioavailability orally)
Nystatin, polyene macrolide (from Streptomyces noursei)
Route: Local/topical (oral suspension) for oral infections and cream for candida of skin
Spectrum: Broad as amphotericin
what is the mechanism of action of polyenes
Bind to ergosterol
Form pores in plasma membrane
Leaks K+/Mg2+
Lysis (cell death)
Fungicidal (depending on concentration)
Azoles
example types and route and spectrum of each
Type: Imidazoles, triazoles
Imidazoles: e.g. miconazole (e.g. Daktarin), clotrimazole (e.g. Canesten
cream), ketoconazole (e.g. Nizoral cream/shampoo)
Route: generally topical for superficial mycoses
Spectrum: Dermatophytes, candidiasis
Miconazole can be used oromucosal gel
Triazoles: e.g. fluconazole (capsules, liquid or i.v. systemic, itraconazole (Sporanox, capsules, liquid, i.v.), voriconazole (tablet, suspension, i.v.), posaconazole (tablet or suspension)
Route: depends on infection site – oral, systemic (see above)
Spectrum: Broad (e.g. Candida, Cryptococcus, Aspergillus…),
vori/posaconazole better Aspergillus
More for invasive & life-threatening
mode of action of azole
Inhibit lanosterol 14 alpha-demethylase (Cytochrome P450)
Thus interferes with ergosterol biosynthesis
Disrupts plasma membrane - Fungistatic
Allylamines
type and spectrum
moa
e.g. Terbinafine (lamisil)
Spectrum: Mainly dermatophytes: nail infections, ringworm
Mechanism of Action
Inhibits squalene epoxidase, hence generation of lanosterol from squalene in ergosterol biosynthesis, Fungistatic/cidal
Morpholine:
type and spectrum
moa
e.g. Amorolfine (synthetic)
Spectrum: Broad dermatophytes and yeast
Mechanism of Action
Inhibits D14 reductase and D7-8 isomerase hence interferes with ergosterol biosynthesis, usually Fungicidal
Echinocandins
type
route
spectrum
moa
Type: Lipopeptides, e.g. Caspofungin
Route: i.v. (1x/day)
Spectrum: Broad. Serious systemic infections (Candida, Aspergillus)
Not for CNS/not Cryptococcus
Mechanism of Action:
Inhibit the production of β1-3 glucan
(part of cell wall) via 1-3 β-glucan synthase. Fungicidal (depending on concentration)
Flucytosine
type
route
spectrum
moa
Type: Fluoropyrimidine (synthetic)
Route: Oral or i.v. Well absorbed including CSF.
Spectrum: Used in combination with other drugs for severe cryptococcal or candida systemic infections
Mechanism of Action
Converted into 5-FU, where disrupts RNA/DNA synthesis (fungistatic)
Griseofulvin
type
route
spectrum
moa
side effects
From Penicilium patulum
Type: Benzofuran
Route: Oral (tablets or suspension)
Spectrum: Limited, dermatophytes, usually Tinea capitis
Mechanism of Action: Griseofulvin binds to polymerised microtubules, inhibits mitosis (cell division) halt growth – fungistatic
Side effects: Rash, urticaria, nausea, vomiting, anorexia
what is Candidiasis
types
causes
symptoms
diagnosis
treatment
Most common fungal infection in UK
Candida spp. are widely distributed in the environment
Part of the normal commensal population of the skin
Types:
C. albicans, C. tropicalis, C. glabrata C. pseudotropicalis etc
Cause/Infection due to:
Broad-spectrum antibiotics
Immunodeficiency
Modest capacity to invade, although they have adhesins and extracellular lipases and proteases
Symptoms: usually localised
(skin, mucosae (e.g. vaginal, oral thrush), nail (onchomycosis))
Pain, itching, creamy curd-like plaques on mucosal surface
could bleed when removed
Immunocompromised: systemic
Pharyngitis, oesophagitis, dysphagia with weight loss
disseminated disease and sepsis
Diagnosis:
clinical features, KOH and laboratory culture
Treatment: Azoles
Imidazoles e.g. clotrimazole (Canesten, topical)
Triazole e.g. fluconazole (Canesten, oral)
Polyenes: nystatin (oral-related infections, skin, local application), amphotericin (systemic, i.v.) or caspofungin (i.v.) if systemic. Flucytosine with amphotericin some indications
Vulvovaginal Candidiasis
symptoms
treatment
Symptoms: See Lecture 2 (BV vs ‘thrush’)
Treatment: Adults
Vulvitis – topical imidazole creams. Example: Clotrimazole* 1% or 2% cream 2-3 times per day or ketoconazole 2% 1-2 times per day
Vaginal/vulvovaginal – intravaginal cream or pessary (more usual than isolated vulvitis) - can be combined with topical cream if vulval symptoms
Options: econazole, miconazole, clotrimazole, fenticonazole
Examples: 10% clotrimazole cream 5g inserted at night, single dose or 500mg single dose pessary to be inserted at night (some options 3 or 6 nights)
OR
Oral: fluconazole 150mg single dose or itraconazole 200mg BD,1 day
Girls (12-15yrs): Oral/intravaginal options not used. Topical considered
Pregnant adults (16yrs+): Intravaginal clotrimazole or miconazole for at least 7 days. Oral treatment not recommended
See NICE guidance
Candidiasis of nail
symptoms
diagnosis
self care
treatment
alternative
Oncomycosis (see NICE guidelines here)
Symptoms: Nail looks abnormal and discoloured, symptoms overlap with infections caused by dermatophytes (see later). Some more associated with Candida
Diagnosis: recommended to confirm with microscopy and culture
Self-care: a range of measures including good hygiene, footwear, clipping nails, avoiding damp conditions and nail trauma
Treatment:
Initially (if required) topical use of 5% lacquer of amorolfine (OTC) for 6 months (nails) or 9-12 months (toes)
If topical not appropriate or fails, can offer oral antifungal. First line - pulsed therapy of itraconazole 200mg BD for 1 week (x2 or x3, 21 days apart) – fungicidal for Candida
Terbinafine is alternative but off-label for non-dermatophyte infections
