M11b: Fungal Infections and Antifungal Drugs Flashcards
Aspergillus (mold):
Aspergillus is the most important pathogenic mold. Aspergillus is _ in nature and is found in large numbers in _.
Infection with this fungus may be associated with mortality rates of greater than 90% in some _ populations, such as transplant recipients.
_ is the most significant species and causes most severe infections.
_ rarely produces severe infections, but can produce chronic otitis externa.
ubiquitous
rotting plants
immunocompromised
Aspergillus fumigatus
Aspergillus niger
Aspergillus (mold):
Aspergillus has a broad spectrum of manifestations in the respiratory tract:
– _ colonization
– _: asthma, recurrent chest infiltrates, eosinophilia, and both type I and type III skin test hypersensitivity to Aspergillus antigen
– _: almost exclusive to lung transplant recipients, at the site of anastomosis
– _
– _: circumscribed “fungus ball”; occurs when inhaled conidia enter an existing cavity, germinate, and produce abundant hyphae in the abnormal pulmonary or sinus space
– Invasive _
– Disseminated _
Airway
Allergic bronchopulmonary aspergillosis (ABPA)
Tracheobronchitis
Sinusitis
Aspergilloma
pulmonary aspergillosis
aspergillosis
Aspergillus (mold):
Pathogenesis of invasive Aspergillus infections:
– Inhalation of _
– Evasion of pulmonary _ (affected by corticosteroids) or _ (decreased in number by chemotherapy)
– Local infection in the _
– Entry into _
– Dissemination to other sites (for example the brain) via the _
spores
macrophages
neutrophils
lung
blood vessels
blood
Aspergillus (mold):
Diagnosis:
– Detection of characteristic _ in resected tissue
– Growth on samples from _ specimens
– Detection of the _ antigen in blood and _ fluid
branching septate hyphae
respiratory
galactomannan
bronchoalveolar lavage
Aspergillus (mold):
Treatment options:
– _ formulations
– _, _, or _ (not _)
– _
Amphotericin
Voriconazole, posaconazole, or itraconazole (not fluconazole)
Echinocandins
Molds other than Aspergillus spp. that cause disease in humans:
Mucor, Absidia, Rhizopus, Rhizomucor (Zygomycoses):
– Belong to a class of fungi called _
– Grow in the environment and tissue as _
– Produce _ with thick walls that branch off nearly at right angles
– Cause infections in patients with (3)
– High affinity for _, causing thrombosis and infarction
– Gain entry into the body via the _
– _ are deposited in the nasal turbinates and may be inhaled into the pulmonary alveoli
– Most common form of mucormycosis is _ disease
– Presents with invasion of the _, _ and then the _
– (High / Low) mortality
– Therapy: _ is the agent of choice. Surgical resection is often necessary. _ is the only oral agent with activity against this mold
Zygomycetes
hyphae
broad, nonseptate hyphae
immune deficiencies, metabolic disorders (diabetes) and free iron rich states (hemochromatosis)
vascular structures
respiratory tract
Spores
rhinocerebral
nose, sinuses and then the brain
High
amphotericin B
Posaconazole
Molds other than Aspergillus spp. that cause disease in humans:
Sporotrichosis:
– Due to _, a thermally dimorphic fungus that lives on vegetation
– It grows as a (yeast / mold) at ambient temperatures and as small budding (yeast / mold) in tissue or in vitro at 35-37oC
– _ disease occurs as a result of inoculation of the fungus into the skin
– Most infections occur in persons who have exposure to _ or _, such as wood or thorned plants such as roses (such as may occur with rose gardeners)
– Common presentation is a _ that doesn’t respond to antibacterials
– May have local lymphatic spread causing a string of _ (other infectious cause of this sporotrichoid pattern is Mycobacterium marinum)
Sporothrix schenckii
mold
yeast
Cutaneous
soil or infected plant products
non-healing, inflamed nodule
red, nodular lesions
Molds other than Aspergillus spp. that cause disease in humans:
Others you should know:
– _ molds (a.k.a. black molds): usually cause skin and subcutaneous infections; have _ cell walls, imparting a brown or black pigment. Implicated in fungal _ outbreak in 2012
– _: endemic in Southeast Asia. Disease occurs in immunocompromised individuals, especially those with AIDS
– _: disseminated infection occurs particularly in patients with hematological malignancies and bone marrow transplantation
– _: infection in immunocompetent individuals is usually post-traumatic; disseminated infection occurs mostly in immunocompromised individuals
Dematiaceous
melanized
meningitis
Penicillium marneffei
Fusarium
Scedosporium
Geographically restricted, dimorphic fungi:
A number of fungal infections are found in the _ of specific regions of the country.
They are typically acquired via the _ and cause _ or _ infections (especially in immunocompromised patients).
soil
respiratory tract
pneumonia
disseminated
Geographically restricted, dimorphic fungi:
Histoplasma capsulatum:
– Highly endemic in the _, but occurs worldwide
– Causes _
– Clinical presentations: o _: >90% of primary infections are unrecognized - asymptomatic or mild flu-like illness o _ and _ o _ or _ o _
– Detection of antigen in the _ and _ is a sensitive diagnostic tool
– Therapy depends on the severity of infection and is with _ or _
Ohio and Mississippi River valleys
histoplasmosis
o Acute primary infection
o Mediastinal granuloma and fibrosis
o Chronic pulmonary histoplasmosis or cavitary pulmonary histoplasmosis
o Disseminated histoplasmosis
urine and serum
amphotericin or itraconazole
Geographically restricted, dimorphic fungi:
Coccidioides immitis:
– C. immitis and C. posadasii are phenotypically _ and cause _ (“valley fever”)
– Occurs in _ United States
– Infection is usually self-limited, with an _ illness; dissemination is always (common / rare) but always serious and may be fatal
indistinguishable
coccidiodomycosis
southwest
influenza-like
rare
Geographically restricted, dimorphic fungi:
Blastomyces dermatitidis:
– Also occurs in the _ and _
– Causes _, a chronic infection with granulomatous and suppurative lesions that is initiated in the lungs. Dissemination may occur to any organ but preferentially to the _ and _
– Much (more / less) common than histoplasmosis
Ohio and Mississippi River valleys
blastomycosis
skin and bones
less
How do antifungals work?
Systemic antifungals:
Polyenes:
– Act by binding to _ in the fungal cytoplasmic membrane, thereby causing membrane permeability to (increase / decrease) – it is like penicillin to fungi
– Amphotericin B o _ o Active against _ o Frequent side effects (4) o New lipid preparations decrease but not eliminate this _
sterols
increase
Fungicidal
almost all fungi
nephrotoxicity
infusion-related side effects (rigors, fever)
hypokalemia
hypomagnesemia
toxicity
How do antifungals work?
Systemic antifungals:
Azoles:
– Disrupt _ biosynthesis
– (Fungistatic / Fungicidal)
– Usually (well / not well) tolerated
– Liver toxicity with elevation of _ may occur
– _: no longer used because of side effects
– _: oral and intravenous; used for surface and systemic mycoses
– _: oral; used in systemic and cutaneous mycoses; active against Aspergillus
– _: oral and intravenous; good activity against Candida and Aspergillus; not active against Mucorales
– _: oral; good activity against Candida, Aspergillus and Mucorales
– _: useful as topical agents for cutaneous infections. Examples: clotrimazole, miconazole
ergosterol
Fungistatic
well
transaminases
Ketoconazole
Fluconazole
Itraconazole
Voriconazole
Posaconazole
Imidazoles
How do antifungals work?
Systemic antifungals:
Echinocandins:
– New class of antifungal agents, these inhibit synthesis of _, which is one of the macromolecules that make up the fungal cell wall
– Active against _ and _ (used for serious infections)
– Not active against _ and the _
– Currently available as intravenous formulations only: _, _, and _
– _-like reactions can occur with rapid infusion
– Usually well tolerated. Most common side effects are _ and elevation of _ enzymes
– Largely metabolized by the _, so need to adjust dose based on _ function
1,3-β-D-glucan
Candida and Aspergillus
Cryptococcus and the Zygomycetes
caspofungin, micafungin and anidulafungin
Histamine
headache
liver
liver
hepatic
How do antifungals work?
Systemic antifungals:
Antimetabolite:
– _ interferes with fungal DNA synthesis by noncompetitive inhibition of _
– Most widely used as combination therapy with amphotericin to treat _ or _
– Use as monotherapy rapidly induces _
– Side effects are more common in patients with impaired _ function and include (3)
5-flucytosine
thymidylate synthetase
cryptococcosis or candidiasis
resistance
renal
bone marrow suppression, rash and diarrhea
How do antifungals work?
Systemic antifungals:
Allylamines:
– Inhibition of _ biosynthesis
– _: oral and topical; treatment of dermatophytes
ergosterol
Terbinafine
How do antifungals work?
Systemic antifungals:
Griseofulvin:
– Used to treat _ and must be given for long periods
– (Well / Poorly) absorbed, accumulates in the _ tissues
– Interacts with _ and disrupts _ function
– Only actively growing _ are affected
dermatophytoses
Poorly
keratinized
microtubules
mitotic spindle
hyphae
How do antifungals work?
Topical antifungals:
Nystatin:
– _ antifungal, similar mode of action to amphotericin B
– Used to treat local _ infections of the mouth and vagina, may also suppress subclinical esophageal _ and gastrointestinal overgrowth of _
– No _ absorption
Polyene
Candida
candidiasis
Candida
systemic
How do antifungals work?
Topical antifungals:
Clotrimazole, miconazole and other azoles:
– A variety of antifungal azoles too _ for systemic use are available for topical administration
– (Broad / Narrow) spectrum of activity
toxic
Broad
Candida albicans, other Candida sp.:
Disease(s) (5)
Comments
Oral thrush, esophagitis, vaginitis, bloodstream infection, abscesses
Endogenous infection. Primary infection of the mucosa and skin with secondary dissemination
Aspergillus fumigatus, other Aspergillus sp.
Disease(s) (5)
Comments
Aspergilloma, sinusitis, invasive pulmonary aspergillosis, tracheobronchitis, disseminated aspergillosis
It has the ability to invade blood vessels and disseminate to other sites
Cryptococcus neoformans:
Disease(s) (2)
Comments
Pneumonia, meningoencephalitis
Dissemination from the respiratory focus to other foci usually occurs in the setting of AIDS and steroid therapy
Zygomecete (Mucor, Absidia, Rhizopus):
Disease(s) (3)
Comments
Sinusitis, brain abscess, pneumonia
High mortality; patients with immune deficiency or diabetes
Sporothrix schenckii:
Disease(s) (1)
Comments
Cutaneous disease with lesions in the extremities
Dimorphic fungus
Histoplasma capsulatum:
Disease(s) (1)
Comments
Pulmonary infection
Ohio and Mississippi River valleys
Coccidioides immitis:
Disease(s) (2)
Comments
Pulmonary infection, meningitis
Southwestern US and South America
Blastomyces dermatitidis:
Disease(s) (2)
Comments
Pulmonary infection, spread to skin
Mississippi River valley, eastern and northern US
Pneumocystis jiroveci (PJP):
Disease(s) (1)
Comments
Pneumonia
Patients with defective cellular immunity
Tricophyton spp., Microsporum spp.:
Disease(s) (1)
Comments
Superficial fungal infections
Transmitted by direct or indirect contact
Constituents of the fungal cell wall (3)
Mannan
Glucans
Chitin
General aspects of fungal disease:
Fungal infections are called _.
Mycoses can be classified as (5)
mycoses
superficial cutaneous subcutaneous systemic opportunistic.
General aspects of fungal disease:
Fungal toxicoses:
Aflatoxin B1 is the most potent carcinogen known to man and causes _.
This is especially a problem in countries with high prevalence of _ and where food shortages encourage consumption of _.
primary hepatocellular carcinoma
chronic viral hepatitis (Hepatitis B and C)
tainted grains and nuts
