Invasive Fungal Infections

what is yeast

a single celled form that reproduces by budding

examples of yeast

candida, cryptococcus, saccharomyces, trichosporon

what is mold

a multicellular hyphae

examples of mold

septate fungi (aspergillus, fusarium), penicillium, Rhizopus, zygomycetae (Mucor)

what are dimorphic fungi

grows as yeast in vivo or in vitro at 37 Celsius and grows as mold at 25 degrees Celsius

dimorphic fungi can be reulgated by factors such as:

temperature, CO2 concentration, pH

examples of dimorphic fungi

histoplasmosis, blastomycosis, coccidioidomycosis, sporotrichosis

why is there an increase in occurrence of severe funcal infections

immunocompromised hosts, potent broad-spectrum antibiotics, indwelling IV catheters

what is the most common cause of invasive fungal infections in humans

candida (a budding yeast)

which candida species is the most clinically significant

C. albicans

what occurs that allows candida to become pathogenic?

interruption of normal defense mechanism - intact integument is crucial in prevention of mucocutaneous of hematogenous candidiasis

what are the three predisposing factors to candida infections

chemotherapy, exposure to immunosuppressive agents, and neutropenia

clinical manifestations of candida

cutaneous syndrome of mucous membrane infections (diaper rash, thrush, esophagitis, vaginitis) - can cause candidemia and deep organ involvement with disseminated candida (respiratory, cardiac, endocarditis, urinary tract, arthritis, osteomyelitis, peritoneum, liver, spleen, gallbladder, intravascular, CNS)

what type of mold is aspergillus?

ubiquitous

which aspergillus species is the most common pathogenic?

A. fumigatus

what pathogen is an important cause of life-threatening infections in immunocompromised patients

aspergillus

pathogenesis of aspergillus

acquired by inhalation of airborne conidia (asexual spores) small enough to reach alveoli or paranasal sinuses

clinical manifestations of invasive aspergillus

pulmonary aspergillosis, sinus aspergillosis, CNS

clinical manifestations of allergic aspergillus

aspergillus sinusitis and allergic bronchopulmonary aspergillosis

T/F: invasive apergillus has a very poor prognosis rate and causes ~1.8 million deaths per year

true

risk factors for invasive aspergillosis

immunocompromised, chronic lung disease, and neutropenia

site of action for azoles and polyenes

cell membrane (ergosterol inhibitors/binders)

site of action for echinocandins

cell wall

site of action for pyrimidine analogues

intracellular

which drugs are polyenes?

amphotericin B and nystatin

which drugs are echinocandins?

anidulafungin, caspofungin, micafungin

which drugs are pyrimidine analogues

flucytosine

dosing of nystatin

400,000-600,000 units QID x 7-14 days

formulation of nystatin

oral suspension - not used systemically due to severe toxicity

ADRs of nystatin

N/V/D

dosing of AmB-deoxucholate (AmBd)

0.5-0.7 mg/kg/day

dosing of lipid formualtion-AmB (LFAmB)

3-5 mg/kg/day

which form of amphotericin B is perferred?

lipid formulation - reduces risk of nephrotoxicity but more expensive

what should be done for patients recieing Ambd formulation due to risk of infusion reactions

premedication is recommedned 30-60 minutes prior

ADRs of amphotericin B

nephrotoxicity, infusion related toxicities, electrolyte abnormalities

formulations of fluconazole

IV/PO

formulations of itraconazole

PO

formulations of voriconazole

IV/PO

formulations of posaconazole

PO

formulations of isavconazole

IV/PO

dosing for fluconazole

800 mg load and 400 mg daily

dosing for itraconazole

200 mg TID x 3 days then BID//daily

dosing of voriconazole

IV: 6 mg/kg x 2 doses then 3-4 mg/kg Q12H

PO: 400 mg BID then 200 mg BID

dosing of posaconazole

200 mg QID or 200 mg BID

dosing of isavuconazole

200 mg Q8H x 2 days, then 200 mg daily

clinical pearls for fluconazole

~90% bioavailability, and excellent CSF penetration

clinical pearls for itraconazole

mucosal disease after failing fluconazole, poor CSF penetration, capsules have increased absoprtion with food, and oral solutions should be taken on an empty stomach

clinical pearls for voriconazole

step down therapy for C.krusei/glabrata, 90% bioavilability without regard to food intake, PO requires dosage reduction for hepatic impairment, excellent CSF penetration

clinical pearls for posaconazole

fatty foods increase the bioavailability of suspension, saturable kinetics

clinical pearls for isavuconazole

98% bioavailability, causes QTc shortening not prolongation

examples of new azole drugs for dermatological infections

albaconazole and efinaconazole

new azole drug for invasive infections, candida and aspergillus sp.

ravuconazole

DDI with fluconazole

inhibitor: CYP2C19, CYP2C9, CYP3A4

substrate: CYP3A4

DDI with itraconazole

inhibitor: CYP2C9, CYP3A4

substrate: CYP3A4

DDI for posaconazole

inhibitor: CYP3A4

DDI for voriconazole

inhibitor: CYP2C19, CYP2C9, CYP3A4

substrate: CYP2C19, CYP2C9, CYP3A4

DDI for isavuconazole

inhibitor: CYP3A4

substrate: CYP3A4

triazole ADRs

QTc prolongation, elevation of liver enzymes, alopecia

which triazole can cause concentration-dependent visual disturbances, hallucinations, and nightmares with

voriconazole

which triazole does not cause Qtc prolongation

isavuconazole

which triazole can cause elevation of liver enzymes more with high oral doses?

voriconazole

which triazole is associated with alopeica at prolonged/high doses?

fluconazole

how are echinocandins available?

IV

dosing of caspofungin

70 mg load then 50 mg daily

dosing of anidulafungin

200 mg load then 100 mg daily

dosing of micafungin

100 mg daily

clinical pearls for caspofungin

dosage reduction recommended for moderate-severe hepatic dysfunction

clinical pearls of anidulafungin and micafungin

no dosafge adjustments required

echinocandin properties

few ADRs (may see increase in LFT0, similar pharmacologic properties, administered IV only, do not require renal dose adjustments, large MW compared to azoles, do not penetrate bone or CNS very well

dosing for flucytosine

25 mg/kg/dose PO QID

pearls of flucytosine

should not be used alone, active form is a chemotherapeutic agent

ADRs for flucytosine

dose-related myelosuppression, acute hepatic and renal injury, hypokalemia

which candida is instrinsically resistant to fluconazole

C. Krusei

why is C. auris concerning

resistant to triazoles and amphotericin B

what is the portion of yeast called that acts as roots and tries to ‘wiggle’ in between cells

Hypha

what value is neutropenia

< 500

T/F: allergic aspergillus is not typically treated

true

which patient population experiences higher rates of invasive aspergillosis?

those with COPD

what is the name of the airborne particle inhaled from aspergillus

conidia

why do COPD patients get aspergillosis more than other groups?

lack of pulmonary defenses allows the conidia to germinate and ‘wiggle’ into the cells of the alveoli/lungs

best order of antibiotic classes to treat aspergillus

azoles > amphotericin B > random combos of drugs…

which medications should only be used as salvage therapy to treat aspergillus

echinocandins

MOA of polyenes

binds ergosterol and makes cell more permeable so the fungal insides/contents flood out and cause cell death

when is nystatin used

for oral candidiasis or local yeast infections

which drug is extremely toxic to cells

amphotericin B

which electrolyte abnormalities can be caused by amphotericin B

hypokalemia and hypomagnesemia

which triazole is best for invasive aspergillosis

voriconazole

benefits of new azoles (albaconazole, efinaconazole, ravuconazole)

broader spectrum, oral bioavailable, less DDIs

what are the two things to know for azoles?

QTc prolongation and lots of DDIs

which drug is fantastic for candida infections but not aspergillus

echinocandins

benefits of echinocandins

low DDIs, once daily dosing, low resistant rate

which drug is good for CNS infections

flucytosine

is aspergillus a mold or yeast?

mold

is candida a mold or yeast

yeast