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
Resistant Candida auris*
Candida auris – Fungus, similar to C. albicans (thrush)
Only first identified in 2009 in Japanese hospital patient
Growing threat as most isolates have multi-drug resistance (e.g. fluconazole). Mostly found in hospital setting and more vulnerable patients.
Can cause invasive candidiasis – such as blood stream infections (fungemia) and large number of those cases are fatal
First seen in UK in 2016 but has since been found in many NHS trusts and growing number of patients
Dermatophytosis
type
symptom
diagnosis
treatment
Types: Three species filamentous fungi: Epidermophyton,
Microsporum and Trichophyton
Symptoms:
red scaly patch-like lesions (skin)
nail discoloration + thickening (nails)
hair loss and scarring (scalp)
Can be itchy but rarely painful
Clinical diagnosis based on the site of infection:
tinea capitis (head/scalp), corporis (trunk), pedis (athlete’s foot)
Diagnosis: culture from skin scrapings, nail clippings or hair samples
Treatment:
Head/scalp systemic griseofulvin or terbinafine often + topical imidazole or selenium sulfide shampoo or imidazole cream
Skin (corporis): topical imidazoles (clotrimazole, econazole, ketoconazole, miconazole),
Nails: See Candida nail infections for topical treatment options (same)
If not appropriate or fails, first line oral therapy is terbinafine (allylamine) 250mg OD for 6w-3mo (finger) or 3-6mo (toes). Itraconazole is an alternative
Aspergillosis
causes
symptom
diagnosis
treatment
Cause: Aspergillus spp. affects respiratory tract.
Severe – can be heart/brain/skin (immunocompromised)
Symptoms: wheezing, breathlessness, fatigue, cough (mucus/plugs), feel unwell
Diagnosis:
sputum culture limited value
bronchoalveolar lavage
antigen detection, NAAT detection
Treatment:
Typically Voriconazole but can use liposomal Amphotericin (i.v.)
Itraconazole/caspofungin/posaconazole are alternatives
+ bronchodilators and steroids if needed
Surgery – can be beneficial in some cases of pulmonary infection
Isolation for neutropenic patients associated with aggressive treatment
Avoid further exposure
Pityriasis versicolor
what
cause
symptom
diagnosis
treatmenr
Skin infection, common
Cause: Malassezia (yeast normally found on skin but overgrows)
Symptoms: changes to colour of patches of skin, can be itchy
Diagnosis: possibly skin scraping, examination
Treatment: topical antifungal creams if only small areas for 2-3 weeks (e.g. clotimazole, ketoconazole) or for larger areas anti-fungal shampoo (e.g. ketoconazole 2% once daily for 5 days)
Oral antifungals (e.g. itraconazole or fluconazole) only if more widespread and on treatment failure
See guidance summary here
Histoplasmosis
cause
transmission
symptoms
diagnosis
treatment
Cause: Histoplasma capsulatum
Transmission: inhalation of spores
Symptoms:
Lung infections: cough or flu-like symptoms
Chronic infection resembles TB
Can disseminate
Diagnosis: lab diagnostics e.g. blood antibodies, cultures, etc.
Treatment: oral itraconazole, if severe i.v. amphotericin B
Rare in temperate climates like UK. Can be life-threatening, e.g. HIV
Cryptococcal Infection
cause
symptom
diagnosis
treatment
Cause: Cryptococcus neoformans (by inhalation)
normally lung infections (pneumonia)
Cryptococcal meningitis in HIV/AIDS
Uncommon. Serious infection in immunocompromised
such as HIV patients with low CD4 count
Symptoms: includes (but not limited to) fever, fatigue, dry cough, headache, blurred vision, confusion, nausea, chest pain, skin rash
Diagnosis: include history plus e.g. blood, CSF, sputum, urine screening/culture
Treatment: amphotericin B + flucytosine (both i.v., 2 weeks) then oral fluconazole 8 weeks
what are the 4 main mechanisms of resistance
Some fungi have resistance to drugs, esp. Candida spp.
Some resistance is natural, some acquired
Four Main Mechanisms of resistance:
altered drug metabolism
efflux pumps (MDR or CDR genes)
change in protein target
prevention of drug entry
