Fungal Infections Flashcards
What are fungi?
Eukaryotic organisms with chitinous cell walls and ergosterol containing plasma membranes and 80s RNA
What is the difference between a yeast and a mould?
Yeasts – single celled, reproduce by budding
Moulds – multicellular hyphae, grow by branching and extension
Give some examples of yeasts
– Candida
– Cryptococcus
– Histoplasma (dimorphic- mould at low temp and yeast at high temp)
Give some examples of moulds
– Dermatophytes
– Aspergillus
– Agents of mucormycoses
What is the most common fungal infections in humans?
Candida spp
How many Candida species are there?
> 150 Candida spp., but < 10 are human pathogens
What are the clinical manifestations of candida?
– Acute, subacute, chronic, episodic
– Superficial or systemic/invasive
What are the superficial candida infections?
• Oral thrush • Candida oesophagitis • Vulvovaginitis • Cutaneous – Localised or generalised
What is the treatment of Oral thrush?
Topical nystatin
What is the treatment of vulvovaginitis?
Topical clotrimazole or oral fluconazole
What is the treatment of local cutaneous candida?
Topical clotrimazole
What is the treatment of oesophagitis?
Oral fluconazole
What are the risk factors for candidaemia?
– Malignancies, esp haematological
– Burns patients
– Complicated post-op courses (eg Tx or GIT Sx)
– Long lines
What is the management of candidaemia?
Source Control: Look for source and signs of dissemination: Imaging, Serology for beta-D-glucan, ECHO, Fundoscopy. REMOVE LINES AND PROSTHETICS
Systemic intervention: Antifungals for at least 2/52 (from date of first –ve BC) – Echinocandin eg anidulafungin (whilst a/w identification and susceptibilities)
•Blood Culture every 48 hours
How do you treat invasive CNS candida?
Ambisome/ voriconazole
How do you treat candida endocarditis (from valve issues/ long lines/ IVDU) and candida bone and joint infection?
Ambisome/ voriconazole and symptomatic treatment
How do you treat UTI with candida (vulvovaginitis/ catheter associated)?
Fluconazole
How do you treat intra abdominal candida?
Echinocandin/ Fluconazole
What is cryptococcus?
Encapsulated yeast
Serotypes A&D = neoformans
Serotypes B&C = gattis
Aerosol transmission
Chronic, subacute to acute pulmonary, meningitic or systemic disease
Which animal is cryptococcus associated with?
Pigeons
What are the risk factors for cryptococcosis?
• Impaired T-cell immunity
– E.g patients with HIV, who have reduced CD4 helper T-cell numbers (typically less than 200/ml)
• Patients taking T-cell immunosuppressants for solid organ transplant also have a 6%
lifetime risk
When does C gatti happen?
- Causes a meningitis in apparently immunocompetent individuals in tropical latitudes, esp. SE Asia and Australia
- Outbreak in Vancouver Island 2004
- High incidence of space-occupying lesions in brain and lung
- Increased resistance to amphotericin B clinically
What type of ink is used for a cryptococcal stain?
India ink
How do you diagnose cryptococcal disease?
- Typical clinical history/features – Immunosuppressed host
- Imaging
- India ink staining of CSF
- Serum/CSF cryptococcal Ag (CRAG)
- Can culture from blood/body fluids
How do you manage cryptococcal disease?
- Induction: Amphotericin B + flucytosine (at least 2/52)
- Consolidation: High dose fluconazole (at least 8/52)
- Maintenance: Low dose fluconazole (at least 1 year). Repeat LP for pressure management.
- Pulmonary disease: If mild, fluconazole alone
What is aspergillosis?
A mould with worldwide distribution
What diseases can aspergillus cause?
– Mycotoxicosis - ingestion of contaminated foods
– Allergy and sequelae - presence of conidia/transient growth of the organism in body orifices
– Colonization - in preformed cavities and debilitated tissues
– invasive, inflammatory, granulomatous, necrotizing disease of lungs, and other organs
– systemic and fatal disseminated disease
How do you diagnose an aspergilloma/ aspergillus disease in the lung?
- Imaging
- Sputum/BAL – MC&S, Ag testing
- Aspergillus Abs (precipitans)
- Galactomannan
- Bx – histology, MC&S
What is the management of aspergillus?
• Voriconazole • Ambisome • Duration based on host/radiological/mycological factors – At least 6/52 • Sx
What is pneumocystis jiroveci?
Why is it different to other fungi?
• Ubiquitous fungus in the environment and distributed worldwide
• Acquisition by airborne route
– Pneumonia
– Extrapulmonary disease = rare
• Lacks ergosterol in it’s cell wall
What are the risk factors for P jiroveci?
– Immunodeficiency
– Immunosuppressive drugs
– Debilitated infants
– Severe protein malnutrition
How do you diagnose P. jiroveci?
– Microscopy
– PCR
– Beta-D-glucan
What is the management of P. jiroveci?
– High dose cotrimoxazole 2-3/52
– Alternatives: atovaquone, clindamycin + primaquine
– Steroids if hypoxia present
Why might antifungals targeting the cell membrane not work in PCP (P jiroveci)?
It lacks ergosterol in it’s cell wall
What is mucormycoses?
- Clinical syndrome caused by a number of fungal species belonging to the order Mucorales eg Rhizopus, Rhizomucor, Mucor
- Inoculation via inhalation of spores or primary cutaneous inoculation
- Favours immunosuppressed/diabetic patients
What are the clinical features of mucormycoses?
• Rhinocerebral => CNS
– Cellulitis of the orbit and face + black pus from the palate and nose.
– Eyes: proptosis, chemosis, ophthalmoplegias and blindness.
– Decreasing levels of consciousness.
- Pulmonary
- Cutaneous
How do you diagnose mucormycoses?
– Isolation from tissue Bx
What is the management of mucormycoses?
– Ambisome/Posaconazole
– Sx
– Rx guided by response
What are dermatophytes?
- A group of fungi capable of invading dead keratin of skin, hair and nails
- Classified by site infected e.g tinea capitis
- Spread via contact with desquamated skin scales
What are the risk factors for dermatophytes?
– Moisture
– Deficiencies in cell mediated immunity
– Genetic predisposition
Where do: Tinea cruris Tinea corporis Tinea pedis Tinea capitis Target?
Groin
Abdomen
Foot
Scalp
What is the diagnosis of dermatophytes?
– Skin scrapings, nail specimens and plucked hairs
• MC&S
What is the management of dermatophytes?
– Topical eg clotrimazole, ketoconazole
– Oral eg griseofulvin, terbinafine, itraconazole
What is the most associated side effect of: Azoles Polyenes Echinocandins Pyrimidine analogues
Abnormal LFTs
Nephrotoxicity
Relatively innocuous
Blood disorders
What are the targets for antifungal therapy?
Cell wall -Echinocandins (e.g. caspfungins)
Cell membrane - Polyene Abx, Azole antifungals
DNA synthesis - Pyramidine analogues (flucytosine)
What is in the fungal cell membrane?
Ergosterol rather than cholesterol
How may DNA synthesis be targeted by antifungal therapy?
Selective activation in fungi
How can the cell wall in fungi be targeted?
Mammalian cells do not have a cell wall
What do azoles do?
• In fungi, the cytochrome P450-enzyme lanosterol 14-a demethylase is responsible for
the conversion of lanosterol to ergosterol
• Azoles bind to lanosterol 14a-demethylase inhibiting the production of ergosterol
What is a caution with azoles?
Some cross-reactivity is seen with mammalian cytochrome p450 enzymes
• Drug Interactions
• Impairment of steroidneogenesis (ketoconazole, itraconazole)
What are polyenes?
Abx e.g. Amphotericin B
- Fermentation product of Streptomyces nodusus
- Binds sterols in fungal cell membrane
- Creates transmembrane channel and electrolyte leakage
- Active against most fungi except Aspergillus terreus, Scedosporium spp.
How do polyenes cause nephrotoxicity?
Delayed toxicity-
- Vascular-decrease in renal blood flow leading to drop in GFR, azotemia
- Tubular-distal tubular ischemia, wasting of potassium, sodium, and magnesium
WORSE IN PTS WHO ARE VOLUME DEPLETED/ OTHER NEPHROTOXIC DRUGS
Why is amphotericin B bad?
Classic amphotericin B deoxycholate (Fungizone™) formulation: serious toxic side effects
What are the less toxic formulations of amphotericin B?
1) Liposomal amphotericin B
2) Amphotericin B colloidal dispersion
3) Amphotericin B lipid complex
What are echinocandins?
• Cyclic lipopeptide antibiotics that interfere with fungal cell wall synthesis by
inhibition of ß-(1,3) D-glucan synthase
• Loss of cell wall glucan results in osmotic fragility
What is the spectrum of coverage for echinocandins?
• Spectrum:
– Candida species including non-albicans isolates resistant to fluconazole
– Aspergillus spp. but not activity against other moulds (Fusarium, Zygomycosis)
– No coverage of Cryptococcus neoformans
Why is flucytosine bad?
Restricted spectrum of activity
Resistance (rapid/ in monotherapy)
How does resistance occur to flucytosine?
– Decreased uptake (permease activity)
– Altered 5-FC metabolism (cytosine deaminase or UMP pyrophosphorylase activity)
What use is flucytosine?
Candida
Cryptococcus (with Ambisome/ fluconazole)
What are the side effects of flucytosine?
Infrequent – include D&V, alterations in liver function tests and blood disorders.
How do you monitor flucytosine?
Blood concentrations need monitoring when used in conjunction with Amphotericin B
