Week 8 Flashcards
3 yeasts
Candida
Cryptococcus
Pneumocystis
Hyaline Mould (1)
Aspergillus
Dimorphic fungus (6)
Blastomyces Histoplasma Coccidioides Candida Sporothrix Paracoccidioides
Mucorales (3)
Mucor, Rhizopus, Rhizomucor
Key features of fungi
- Eukaryotic organisms
- Consume oxygen via oxidative phosphorylation in mitochondria
- Cell membrane and external cell wall
_______ makes up the cell wall of fungal membranes
2 enzymes important in the synthesis and drugs that mess with them
Ergosterol = major sterol of fungal cell membranes
Synthesis:
-Squalene epoxidase: squalene → oxidosqualene (targeted by allylamines)
-14 a-demethylase: lanosterol → ergosterol (targeted by azoles)
Polyenes
bind to synthesized ergosterol and disrupt interactions within cell membrane → increases membrane permeability
Fungal cell wall
external to cell membrane, made up of proteins and polysaccharides (mannan, glucan chitin)
Fungal cell wall contains _________ which interferes with DNA and RNA synthesis
cytosine deaminase
Mold
multicellular fungal colonies → HYPHAE = long tubular structures formed by multiple fungal cells lined up end to end
Hyphae grow towards a food source
Griseofulvin
inhibit fungal cell mitotic spindle → inhibition of mitosis and hyphae growth
Echinocandins
Glucan synthesized by 1,3 B-glucan synthase → inhibited by Echinocandins → cell wall instability
Yeast
single-celled fungus, replicate by budding
Pseudohyphae
Pseudohyphae
formed when buds fail to break off original yeast cell, forming long chains that resemble hyphae
present in yeast
Dimorphic fungi have what characteristics in the heat vs. cold?
mold in the cold, yeast in the heat (except Candida)
Cryptococcus: Main features (4)
Thick capsule, round
NOT dimorphic
Urease +
Yeast
Cryptococcus: Transmission
Transmission via inhalation - form soil and pigeon droppings
→ infect respiratory tract then disseminate hematogenously → localizes in CNS
Cryptococcus:
Host risk factors:
Opportunistic infection, but can cause disease occasionally in “normal” hosts
**AIDS
prolonged glucocorticoids, organ transplant, malignancy, sarcoid
**impaired cellular immunity*
Cryptococcus:
disease? (2)
1) Meningoencephalitis
2) Pulmonary cryptococcus
Meningoencephalitis
Due to hematogenous spread (typically from lungs)
Cryptococcus is NON INFLAMMATORY → many organisms, few PMNs→ obstruct CSF flow and increased intracranial pressure
Indolent course - 2 weeks of fever, malaise, headache
“Soap bubble” intraparenchymal lesions due to gelatinous pseudocysts that contain fungi
Pulmonary cryptococcus
asymptomatic or present with nonspecific symptoms (cough, hemoptysis, dyspnea, chest pain)
Cryptococcus:
Diagnosis (6)
1) Latex agglutination
2) India ink stain of CSF - shows polysaccharide capsule CLEAR under microscopy
3) Mucicarmine stain - specific for cryptococcus, appear pink
4) Culture on Sabouraud agar
5) Grows on Birdseed agar
6) CRAG = cryptococcal antigen test
cryptococcal antigen test (CRAG)
detects capsular polysaccharide
Highly sensitive, specific, cheap and fast
TEST OF CHOICE for cryptococcus
Treatment of cryptococcus
High mortality
Amphotericin B + Flucytosine (fungicidal) for meningitis + Fluconazole (fungistatic) for long term suppression in immunosuppressed patients
Cryptococcus: Appearance
narrow-based yeast with unequal budding
Cryptococcus:
Virulence factors (2)
Capsule: inhibits phagocytosis
Melanin: strains without melanin production can’t cause disease → contributes to NEUROTROPISM
Candida:
Main features:
Opportunistic dimorphic fungus
Grows as budding yeast cells, pseudohyphae, true hyphae or spores
Mold at 37C, yeast (pseudohyphae + budding yeast) at 20 C
Part of our normal flora - mucous membranes of respiratory, GI, and female genital tracts
Candida:
Host risk factors:
Intensive medical care (indwelling catheters), TPN, abdominal surgery, broad spectrum abx
Immunocompromised hosts (premature infants, neutropenia, chemotherapy)
Candida:
Treatment: (3)
1) Nystatin mouthwash and oral fluconazole → thrush and esophagitis
2) Topical azoles or oral fluconazole for vaginitis
3) Oral fluconazole or IV echinocandins for disseminated (can also use Amphotericin B)
Candida:
1) Oral thrush
2) Vaginitis
3) Cutaneous candidiasis
4) Immunocompromised disease
Cutaneous candidiasis
beefy red rash with satellite pustular lesions in moist intertriginous areas (e.g. diaper rash)
Candida Vaginitis
(itching, copious cottage cheese clumps)
-Normal vaginal pH (pH<4.5)
Candida in immunocompromised patients
Disseminated candidiasis (can lead to endocarditis)
Candidemia → visceral disease (EYE**, kidney, brain, lung, skin, etc.)
**Endophthalmitis: fungal infection of eye typically
Esophagitis
Significant problem for nosocomial bloodstream infections (via catheters)
Candida: Diagnosis (3)
Blood cultures
Germ tube test: POSITIVE test strongly indicative of Candida
1,3-Beta-D Glucan Test
1,3-Beta-D Glucan Test
antigen present in most fungal cell walls
Sensitive, NOT specific to candida
Only effective when applied to select patients
Cross reacts with other environmental factors
Can also be used to identify Aspergillus infection
Aspergillus fumigatus (Aspergillosis):
Main features:
Usually does not cause disease
Very common in the environment
NOT dimorphic - only occurs as a mold (mats of hyphae, not a single-celled yeast)
Aspergillus fumigatus produces what toxin?
Produces Aflatoxin → carcinogen that causes hepatocellular carcinoma (found in peanuts, rice, cereal, grains)
Aspergillus fumigatus
Host risk factors:
NEUTROPENIA (e.g AML**), prolonged glucocorticoid use, advanced HIV, CGD, abnormal lung (e.g. COPD, old cavitary lung disease)
Aspergillus fumigatus
Disease
1) Allergic bronchopulmonary aspergillosis
2) Aspergilloma
3) Invasive aspergillosis
4) Sino-orbital aspergillosis
Sino-orbital aspergillosis
can present identical to mucormycosis, but occurs in neutropenic hosts (not diabetics)
Aspergilloma
fungus ball that develops in preexisting cavity in the lung (old TB site)
Can invade blood vessels → massive hemoptysis
Allergic bronchopulmonary aspergillosis
IgE mediated type I/IV hypersensitivity reaction → eosinophilia → inflammation of airways, mucus plugs in terminal bronchioles
Typically in patients with asthma or CF
Repeated attaches can lead to bronchiectasis
TX: corticosteroids
Invasive aspergillosis
invasion of lung tissue and bloodstream in immunocompromised host
Can occlude blood vessels and lead to PULMONARY INFARCTION
Can occur in patients with CGD
TX: voriconazole (mild) and Amphotericin B (Severe)
Aspergillosis Appearance
Narrow septate hyphae with acutely angled (45 degree) branching → differentiate with Mucormycosis (wide angled 90 degree non-septate hyphae)
Diagnosis of Aspergillosis (3)
1) Direct microscopy showing narrow hyphae septate that branch at 45-degree angles
- Angioinvasion and necrosis prominent
Serologic tests:
2) Aspergillus galactomannan antigen
3) B-D-Glucan antigen test (same one used for candida)
Mucormycosis:
Main features:
Ubiquitous fungi (bread mold) - found nature on decaying vegetation and in the soil BUT human infection is rare
Non-septate hyphae with broad angle branching (90 degrees)
Germinate in nasal passages → invade and proliferate in blood vessel walls → penetrate cribriform plate → enter brain
Growth stimulated in presence of high glucose and acid
Mucormycosis
Appearance?
microscopic hyphae, broad, ribbon-like nonseptate with 90 degree branching
Mucormycosis: Host risks for infection (6)
1) Diabetes mellitus (particularly with ketoacidosis)
2) AIDS
3) Neutropenic
4) Immunosuppressed (e.g. glucocorticoids)
5) Use of deferoxamine (chelates iron and aluminum - acts as siderophore, enhances Rhizopus growth and pathogenicity)
6) Iron overload
Diseases caused by Mucormycosis? (2)
Rhinocerebral mucormycosis
Pulmonary mucormycosis
Rhinocerebral mucormycosis
necrotic ulcer on palate, orbit invasion, extension to cavernous sinus and brain
Almost only happens in patients with diabetes
Can cause cavernous sinus thrombosis
Can move extremely quickly
Pulmonary mucormycosis
can present as slowly progressive nodule (looks like cancer) in “normal” hosts or rapid onset in IC hosts
Treatment of Mucormycosis?
surgical debridement and high dose antifungal therapy (amphotericin B)
EMERGENCY
Manage underlying problems
Pneumocystis Jiroveci
Main features
Opportunistic fungi - cysts containing dark oval bodies on microscopy
Fungal organism that lacks ergosterol
Transmission through inhalation of cysts
Pneumocystis Jiroveci
Host risk factors:
HIV, solid organ transplant, stem cell transplants, ALL, lymphomas, chronic glucocorticoids
Pneumocystis Pneumonia (PCP)
seen in HIV patients with CD4 < 200
Asymptomatic in immunocompetent
Pneumocystis Jiroveci
Diagnosis
1) Silver stain of: induced sputum, bronchoalveolar lavage, lung biopsy
2) CXR: diffuse, bilateral infiltrates extending from perihilar region, “ground glass”
Pneumocystis Jiroveci
Treatment and prophylaxis?
TMP/SMX or pentamidine
Prophylaxis: TMP/SMX, dapsone, atovaquone
Blastomyces Dermatitidis:
Location?
Mississippi and Ohio River basins
Blastomyces Dermatitidis:
Main features?
Dimorphic fungi (mold in the cold, yeast in the heat)
**Broad based budding organism on wet smear
Blastomyces Dermatitidis:
Transmission?
Transmitted via inhalation of spores (conidia) typically from moist soil
→ spores phagocytosed and brought to RES → converted to yeast in tissue → survive and infect
Blastomyces Dermatitidis:
Disease (2)
Pulmonary blastomycosis
Extrapulmonary disseminated disease
Pulmonary blastomycosis
Acute pneumonia (uncommon) or chronic pneumonia (most common)
Acute or chronic pneumonia → granulomas in lung
Extrapulmonary disseminated disease
(skin, bones)
Skin = verrucous lesion with irregular borders (mimics squamous cell carcinoma)
Bone = osteomyelitis, soft tissue swelling, chronic draining sinus tract
Blastomyces Dermatitidis:
Diagnosis
culture with visualization of broadly based budding yeast cells in clinical specimens
Blastomyces Dermatitidis:
Treatment
azoles, or amphotericin B
Coccidioidomycosis
Main features
Dimorphic fungi
Yeast→ Large spherule containing endospores at body temperature
Mold → barrel-shaped arthroconidia
Coccidioidomycosis
Transmission
inhalation of spores after dust exposure (e.g. after earthquakes, archeological excavations, desert military maneuvers)
Coccidioidomycosis
Disease (2)
Pulmonary coccidioidomycosis
Extrapulmonary disease
Coccidioidomycosis
Location
desert regions of western hemisphere (Arizona, CA, NM, Texas)
Coccidioidomycosis
Risk factors
occupation, ethnicity, immune status
Coccidioidomycosis
Diagnosis (2)
1) Spherules + alternating arthroconidia
2) Serology: antibodies indicate active disease
Early = immunodiffusion
> 1 month = complement fixation
Can be used to follow if someone is responding to treatment or predict extrapulmonary disease
Pulmonary coccidioidomycosis
→ nodule or granuloma formation, possible erythema nodosum
Extrapulmonary disease
due to disseminated disease or direct inoculation
Skin or subcutaneous soft tissue
Meninges
Skeleton
Paracoccidioidomycosis: paracoccidioides brasiliensis
Main features
Thermally dimorphic fungus
Large, round or oval yeast cell surrounded by multiple, attached, narrow-necked budding daughter yeast cells that resemble a CAPTAIN’S WHEEL
paracoccidioides brasiliensis
Location
Central and South America
paracoccidioides brasiliensis
disease
Typically causes asymptomatic pulmonary infection (dry cough, dyspnea, fibrosis)
Classic triad: edentulous, cervical lymphadenopathy, chronic pulmonary disease
Can cause painful ulcer i
Histoplasmosis
Main features:
DIMORPHIC yeast: mold at ambient temperature (20C) and yeast at body temperature (37C)
Mold → yeast conversion occurs in phagosomes after phagocytosis by macrophages
Facultative intracellular yeast inside macrophages
Hyaline septate hyphae with spherical thick-walled conidia and smaller microconidia
Histoplasmosis: Location
endemic to Ohio, Missouri, and Mississippi River valleys
Lives in soil near bird and bat droppings
Pulmonary histoplasmosis
Immunocompetent → granulomas appear as calcifications on XR
Immunocompromised → no granuloma formation
“SHOTGUN PNEUMONIA” = characteristic of histoplasmosis
histoplasmosis
diagnosis (2)
Takes a long time to grow → blood culture not effective
Antigen detection test (some cross-reactivity)
Sporotrichosis: sporothrix schenckii
Main features
DIMORPHIC yeast
CIGAR-SHAPED
Unequal budding yeast (human tissue) and mold form (plants - typically ROSE THORNS)
sporothrix schenckii
causes what disease? (4)
“Rose Gardener’s disease”
1) Primary nodule that becomes necrotic and ulcerates
- -> Forms granulomas made up of histiocytes and giant cells
2) Lymphocutaneous sporotrichosis
3) Pulmonary sporotrichosis
4) Disseminated sporotrichosis → joint, bone, lung meninges
Treatment of sporothrix schenckii
itraconazole, oral potassium iodide
MOA amphotericin
Polyene
Bind plasma sterols (ergosterol) and form membrane pores → leakage of electrolytes
Fungicidal
Mechanism of fungal resistance to amphotericin
Fungi produces less ergosterol or have thicker membranes that don’t form pores as easily
Spectrum of use of amphotericin (6)
broad spectrum antifungal reserved for fungal meningitis, and serious, systemic mycoses
Cryptococcus Blastomyces Coccidioides Histoplasma Candida Mucor
Pharmacokinetics of amphotericin
- NOT absorbed orally - IV only
- Good distribution but does NOT enter CSF or bone
- Liver and renal excretion
Toxicities of amphotericin
“amphoterrible”
1. Infusion reaction - Fever/Chills, Hypotension
2. NEPHROTOXICITY
3. ANEMIA (decreased EPO synthesis due to nephrotoxicity)
4. ELECTROLYTE ABNORMALITIES (hypomagnesemia, hypokalemia,
hypocalcemia)
5. ARRHYTHMIAS (from hypokalemia)
6. IV PHLEBITIS
7. **Hydration can decrease nephrotoxicity
8. **K+ and Mg2+ should be supplemented due to alteration of renal
tubule permeability with amphotericin B
MOA azoles
inhibit cytochrome P450 enzyme sterol
14-demethylase → block ergosterol production (essential for fungal plasma
membrane)
1. → hyperpermeability of fungal plasma membrane → cell lysis and
death
2. Typically fungistatic
Mechanism of fungal resistance to azoles
resistance can develop rapidly with
mutations in targeted enzymes
Azoles spectrum of use
local and less serious systemic fungal infections
aspergillosis, candidiasis, candidemia
Two different subclasses of azoles
- Imidazoles
2. Triazoles
Imidazoles
Ketoconazole : used for topical fungal infections, Cushing
syndrome (inhibit GC synthesis), Prostate cancer
(antiandrogenic)
Clotrimazole, Miconazole : topical agents used for cutaneous fungal infections (e.g. pregnant women with vulvovaginitis)
Triazoles
newer and safer
a. Fluconazole → used for chronic suppression of cryptococcal
meningitis in AIDS patients and candidal infections of all types
i. *Drug of choice for Cryptococcal meningitis and
Coccidioidal meningitis
ii. Orally available
iii. Distributes well (EVEN CSF)
iv. Renal excretion
v. Most frequently used -azole
b. Itraconazole → local blastomycosis, coccidiomycosis, and
histoplasmosis infections
c. Posaconazole, Voriconazole
Azole toxicity
- Inhibition of P450 enzymes → many drug-drug interactions
- Inhibition of steroid synthesis ( gynecomastia )
- GI distress
- Hepatotoxicity → monitor liver function
- QT prolongation
- **Contraindicated in pregnancy = TERATOGENIC
3 echinocandins
Caspofungin , Micafungin, Anidulafungin
MOA echinocandins
inhibit fungal enzyme 1,3-B-D-glucan synthase →
prevent synthesis of B-glucan (part of fungal cell wall) → fungal cell loses
resistance to cell lysis → fungal cell death
Echinocandins spectrum of use
Aspergillus and Candida species
- Caspofungin : used for RACE
a. Refractory invasive aspergillosis
b. Azole-Resistant Candida strains
c. Candidemia
d. Empiric treatment in febrile neutropenic patient - Micafungin : used for candidemia, esophageal candidiasis, prophylaxis
for patients undergoing hematopoietic stem cell transplant - Anidulafungin : used for esophageal candidiasis and systemic Candida
infections
Echinocandins pharmacokinetics
- Metabolized by LIVER - DO NOT induce or inhibit CYP450
2. Given IV, not orally absorbed
Host factors and echinocandins
Must change dosage if pt taking drugs that induces/inhibits
CYP450
Toxicities of echinocandins (4)
- Infusion hypersensitivity reactions (histamine-mediated flushing and
delirium, hypotension, bronchospasm, phlebitis - GI symptoms
- Asymptomatic LFTs
- Fever
MOA Flucytosine (5-FC)
- 5-FC metabolized to 5-FU in fungal cells by cytosine deaminase
- 5-FU inhibits fungal DNA and RNA synthesis selectively → less toxicity
to humans - Synergistic with amphotericin
5-FC spectrum of use
- Systemic fungal infections in combination with amphotericin B (e.g.
cryptococcal meningitis) - Orally available, distributes in CSF
Toxicities of 5-FC
Bone marrow suppression
MOA terbinafine
interferes with ergosterol synthesis by inhibiting squalene epoxidase (fungicidal)
Terbinafine spectrum of use
systemic treatment of superficial skin, hair,
and nail infections (NOT deep infections)
1. Not absorbed well orally, but accumulates in keratin precursor cells
MOA griseofulvin
inhibits fungal growth by binding microtubules and
disrupting mitotic spindles
1. Human microtubules are less sensitive
Griseofulvin spectrum of use
systemic treatment of “superficial’ skin, hair, and nail
infections (NOT deep infections)
1. Not absorbed well orally, but accumulates in keratin precursor cells
Picornaviruses
Main features
Main features: icosahedral capsid, nonenveloped, linear (+)ssRNA
Acid STABLE → fecal-oral transmission → replicate in intestinal tract
Picornaviruses
Replication
Replicate exclusively in cell CYTOPLASM - NO replication proteins in virus particles (only protein shell + ssRNA)
Contain protease that cleaves one large polypeptide into multiple functional viral proteins
Picornaviruses include what 5 viruses
Poliovirus
Echovirus
Rhinovirus (NOT fecal oral, is fomit-hand or aerosol)
Coxsackie virus
Hepatitis A virus
Immune response to picornavirus includes what two mechanisms?
what defines host serotypes?
- IgA and IgG
- Maternal antibodies
Epitopes on capsid proteins recognized by antibodies that neutralize infectivity DEFINE HOST SEROTYPES
Picornavirus: Pathogenesis of infection:
Primary infection at mucosal surfaces → Viremia to infect target organs
Neutralizing IgM and IgG antibodies in the blood will block viremia
Neutralizing IgG antibodies block disease but will NOT block infection
IgA antibodies necessary at mucosal surfaces to block infection
Poliovirus
causes what 4 possible diseases
1) Paralytic poliomyelitis
2) Non-paralytic poliomyelitis (aseptic meningitis)
3) Abortive poliomyelitis (sore throat, malaise) - minor URI
4) MOST individuals asymptomatic → can circulate unnoticed
Paralytic poliomyelitis
Poliovirus destroys motor neurons in anterior horn → LMN disease (decreased DTRs, respiratory insufficiency)
Poliovirus: Replication
poliovirus ingested → replicates in lymphatics of GI tract (e.g. Peyer patches) → viremia → enter CNS, cross BBB → aseptic meningitis or paralytic poliomyelitis
Poliovirus:
Killed vaccine
SALK - only one used in USA because NO RISK for developing actual disease
Disadvantage: only IgG immunity, limited mucosal immunity
Poliovirus:
Live (attenuated) vaccine
Live (attenuated) vaccine = SABIN
Taken orally, induces IgA (local) immunity
Virus shed in feces, providing group immunity with person-to-person contact
Used in developing countries
Can get vaccine associated paralytic poliomyelitis
**Do not want to give to anyone with B cell dysfunction
Echoviruses:
2 diseases
aseptic meningitis and URI’s
Coxsackie A:
6 diseases
Aseptic meningitis
Paralysis
URI’s
Herpangina (mouth blisters)
Acute hemorrhagic conjunctivitis
Hand-foot-and-mouth disease
Coxsackie B: 7 diseases
Aseptic meningitis Paralysis URI’s Myocarditis (dilated cardiomyopathy) Pericarditis Bornholm disease Hepatitis
Hepatitis A:
transmission and disease
Transmission: fecal-oral
Disease: acute viral hepatitis
