5.46 Part B Flashcards
Antifungal Drugs
• fewer effective agents because of similarity
of
• easier to treat — mycoses than — infections
fungal cells and human cells
superficial, systemic
ergosterol
Sterol found in fungal cell membranes;
human cells have cholesterol instead of
ergostero
Antifungal treatments
Polyene compounds -
bind ergosterol in fungal membranes
Polyene compounds
examples (2)
Amphotericin B systemic disease
Nystatin topical disease
Polyene compounds - Drugs cause (3)
altered membrane
permeability,
leakage of cell constituents, and cell death
Polyenes also bind — in mammalian
cells, but less strongly than ergosterol
cholesterol
Polyenes also bind cholesterol in mammalian
cells, but less strongly than ergosterol
• this is basis for —
• — is toxic due to binding of cholesterol
drug toxicity
filipin
terbinafine (TFB) to
itraconazole (ITZ)
Allylamines-
block ergosterol synthesis by inhibiting
squalene epoxidase activity
Allylamines ex
terbinafine
Allylamines
mainly effective on the —
(2) formulations
dermatophytes
topical or tablet
Azoles
block ergosterol synthesis by inhibiting cytochrome
P450-dependent 14a-lanosterol demethylation
Azoles
First oral azole (significant number of
(2)).
side effect and drugs interactions
Supplants ketoconazole
Active against many fungi and has improved
safety profile. Active against Candida species,
Cryptococcus, Aspergillus, endemic (systemic)
fungi, and dermatophytes.
Echinocandins
inhibit synthesis of b-(1,3)-D-glucan, an
essential component of fungal cell walls.
More selective than agents that target cell
membrane components.
Echinocandins
Narrow spectrum:
active against Aspergillus and Candida species;
these fungi have larger amounts of b-(1,3)-D-glucan
Caspofungin (2)
- Intravenous use
- minimal toxicity
Pyrimidine inhibition -
interferes with fungal protein and
DNA synthesis
Pyrimidine inhibition Active against (2)
Candida species and Cryptococcus neoformans
Pyrimidine inhibition
Always used in combination with another antifungal because
resistance
develops quickly if used alone
High risk categories (5)
Immunocompromised individuals: Burn victims Long-term IV catheter users Broad-spectrum antibiotic therapy Diabetes mellitus
Immunocompromised individuals:
9
blood and marrow transplant solid organ transplant major surgery AIDS neutropenia neoplastic disease (cancer patients) immunosuppressive therapy (e.g. corticosteroids) advanced age premature birth
Candida albicans
predominant species colonizing humans
responsible for most infections
Candida glabrata
resistant to some antifungals
Candida parapsilosis
common cause of catheter-related infections
Candidiasis
local disease vs. systemic invasive disease
Adequate neutrophil function protects against invasive infection.
Local factors and T-cell mediated defense system protects against
mucosal candidiasis
Mucosal candidiasis on palate
of a patient with AIDS
Due to
decreased T-cell
mediated immunity (however,
no invasion of tissue here)
Other host factors associated with
protection against Candida infections:
(4)
salivary flow and constituents
blood group & secretor status
epithelial barrier
presence of normal bacterial flora
candida infection: acute pseudomembranous
acute erythematous
clinical presentation:
multiple removable white plaques
generalized redness of tissue (ab sore mouth, painful)
candida infection: chronic plaquelike/nodular
clinical presentation:
fixed white plaques on commissures
candida infection: chronic erthematous
clinical presentation:
generalized redness of tissue on fitting surface of upper denture
candida infection: candidia associated angular chelities
clinical presentation:
bilateral cracks, angles of mouth
Thrush
Pseudomembranous
candidiasis lesions on
palate
Angular chelitis at
commissures of the mouth,
involving skin
Frequently there is a — component
bacterial
Plaquelike/nodular candidiasis
• Also called (2)
chronic hyperplastic
candidiasis or candidal leukoplakia
Plaquelike/nodular candidiasis
• Up to –% of lesions develop into oral
cancer
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Candidiasis- diagnosis
Mucosal candidiasis
scrape and look under the microscope
culture
Candidiasis- diagnosis
Invasive candidiasis
(4)
blood culture not sensitive
biopsy of involved tissue
microscopy
culture
Staining methods to visualize fungi in clinical
samples:
(5)
periodic acid-Schiff (PAS) potassium hydroxide (KOH) Grocott-Gomori methenamine silver Gridleys method Calcofluor white
periodic acid-Schiff (PAS)
-surface carbohydrate
potassium hydroxide (KOH)
-tissue dissolves, fungi do not (chitin)
Grocott-Gomori methenamine silver
-surface carbohydrate
Gridleys method
-modification of PAS
Calcofluor white
-fluorescent probe for chitin
why is candida auris a problem? (5)
it causes serious infections its often resistant to medicines its becoming more common its difficult to identity it can spread in hospital and nursing homes
C. neoformans is found worldwide in
soil contaminated with bird excreta
–% of patients with cryptococcosis appear to be immunocompetent.
20
Cryptococcus neoformans
Yeast cells are inhaled in alveoli and begin to produce a polysaccharide capsule. (3)
capsule inhibits phagocytosis and intracellular killing (if cells phagocytosed)
T-cell immunity crucial to infection control
melanin production in cell wall enhances virulence
Cryptococcus neoformans
melanin production in cell wall enhances virulence
resists
free radicals and enzyme degradation
Cryptococcus neoformans
Primary pulmonary infection is usually —
asymptomatic
C. neoformans has a striking
neurotropism (basis is unknown)
minimal inflammatory response with CNS infection
Cryptococcus neoformans
Patients often present with —, which worsens
meningitis
Cryptococcus neoformans
Diagnosis (2)
cryptococcal meningitis - examine CSF for encapsulated budding yeast
latex agglutination test for capsular polysaccharide antigen (CSF fluid and serum)
Cryptococcus neoformans
tx
cryptococcal meningitis
sometimes lifelong therapy required
(patients with T cell defects)
Aspergillosis (2)
Aspergillus fumigatus and Aspergillus flavus
Aspergillosis
acquired from the environment by
inhalation of conidia
Aspergillosis
grow as — in immunosuppressed individuals
hyphae
usually a pulmonary or sinus infection
angioinvasive -
growth through
cause (3)
blood vessel walls
tissue infarction, hemorrhage, necrosis
Aspergillosis
Diagnosis
culture on Sabourauds agar (grows in a few days)
caution: contamination from environment can easily occur
Aspergillosis
tx
high mortality
expanded-spectrum azole voraconazole
decreased exposure (filtered air)
Zygomycosis
(2) are main genera in this group
Rhizopus and Mucor
Zygomycosis (3)
aseptate, broad hyphae
angioinvasive
in addition to standard risk groups, patients with diabetes mellitus with ketoacidosis
in addition to standard risk groups, patients with diabetes mellitus with ketoacidosis
- acidosis reduces neutrophil chemotaxis and phagocytosis
Rhinocerebral zygomycosis-
spread from nares/sinuses to palate, orbit, face then to brain
Zygomycosis
tx
amphotericin B and
aggressive surgical debridement
Pneumocystis jiroveci -
organism has never been grown in vitro
Pneumocystosis
most people likely are infected early in life, but disease only occurs due to
immunosuppression (T cell deficiency most common risk factor)
Pneumocystic pneumonia
most common opportunistic infection in AIDS patients
before effective antiviral therapy
Pneumocystosis
Organism rarely found outside —
lungs
Pneumocystosis
tx
- trimethoprim-sulfamethoxazole (also used prophylactically)
target folic acid synthesis and utilization
note: P. jiroveci lacks ergosterol
