M11b: Fungal Infections and Antifungal Drugs Flashcards Preview

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Flashcards in M11b: Fungal Infections and Antifungal Drugs Deck (33)
1

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

2

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

3

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

4

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

5

Aspergillus (mold):
Treatment options:

– _ formulations

– _, _, or _ (not _)

– _

Amphotericin

Voriconazole, posaconazole, or itraconazole (not fluconazole)

Echinocandins

6

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

7

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

8

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

9

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

10

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

11

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

12

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

13

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

14

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

15

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

16

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

17

How do antifungals work?
Systemic antifungals:
Allylamines:

– Inhibition of _ biosynthesis

– _: oral and topical; treatment of dermatophytes

ergosterol

Terbinafine

18

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

19

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

20

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

21

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

22

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

23

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

24

Zygomecete (Mucor, Absidia, Rhizopus):

Disease(s) (3)

Comments

Sinusitis, brain abscess, pneumonia

High mortality; patients with immune deficiency or diabetes

25

Sporothrix schenckii:

Disease(s) (1)

Comments

Cutaneous disease with lesions in the extremities

Dimorphic fungus

26

Histoplasma capsulatum:

Disease(s) (1)

Comments

Pulmonary infection

Ohio and Mississippi River valleys

27

Coccidioides immitis:

Disease(s) (2)

Comments

Pulmonary infection, meningitis

Southwestern US and South America

28

Blastomyces dermatitidis:

Disease(s) (2)

Comments

Pulmonary infection, spread to skin

Mississippi River valley, eastern and northern US

29

Pneumocystis jiroveci (PJP):

Disease(s) (1)

Comments

Pneumonia

Patients with defective cellular immunity

30

Tricophyton spp., Microsporum spp.:

Disease(s) (1)

Comments

Superficial fungal infections

Transmitted by direct or indirect contact

31

Constituents of the fungal cell wall (3)

Mannan
Glucans
Chitin

32

General aspects of fungal disease:

Fungal infections are called _.

Mycoses can be classified as (5)

mycoses

superficial
cutaneous
subcutaneous
systemic
opportunistic.

33

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