Antifungal Agents Part 2 Flashcards
What is the MOA of echinocandins?
glucan synthesis inhibitor leading to noncompetitive inhibition 1,3-beta-D-glucan, an integral polysaccharide component of fungal cell wall –> fungicidal
inability to maintain the osmotic integrity of the fungal cell wall
two genes, FKS1 and FKS2, encode for glucan synthase expression –> mutations confer cross resistance to all echinocandins - wipes out whole class if you have either gene, can’t use any
What is the spectrum of activity of echinocandins?
1st line: C. glabrata, C. krusei, C. lusitaniae, C. auris
C. albicans, C. tropicalis
may add micafungin to voriconazole in severe aspergillus infections
Caspofungin
poor oral bioavailability - administered by IV infusion
no dosage adjustment for renal insufficiency or mild hepatic impairment
What is the clinical use of caspofungin?
candidemia - 70mg loading dose on day 1, then 50mg q24h
esophageal candidiasis, fungal infections in febrile neutropenia, invasive aspergillosis in pts refractory to or intolerant other therapies
What are the drug interactions for caspofungin?
does not induce or inhibit CYP450 system
What are the adverse effects of caspofungin?
histamine-mediated symptoms - rash, facial swelling, pruritus, flushing
fever
phlebitis at infusion site
N/V, HA
Micafungin
not absorbed orally - give IV
no dosage adjustment for renal dysfunction
drug interactions - not metabolized via CYP450 pathways
What is the clinical use of micafungin?
candidemia - 100 mg daily
oropharyngeal and esophageal candidiasis
aspergillosis
prophylaxis of candida infections in HSCT
What are the adverse effects of micafungin?
hyperbilirubinemia, N/D, eosinophilia, rash, pruritis, urticarial
Anidulafungin
not absorbed orally - must be administered IV
not metabolized or renally eliminated –> undergoes slow chemical degradation
no dosage adjustments required for renal or hepatic dysfunction
What is the clinical use of anidulafungin?
candidemia and other candida infections
esophageal candidiasis
What are the adverse effects of anidulafungin?
histamine-mediated symptoms - rash, urticaria, flushing, pruritis, hypotension
diarrhea, increased LFTs, hypokalemia
Rezafungin
long-acting echinocandin
no adjustments in renal or hepatic dysfunction
approved for candidemia and invasive candidiasis
What are the adverse effects of rezafungin?
hypokalemia, diarrhea, fever
Ibrexafungerp
new antifungal!
similar to echinocandins, through structurally different
available orally; bioavailability dependent on gastric acid
better absorbed with food
does not penetrate CNS
What is the spectrum of activity of ibrexafungerp?
candida species, aspergillus species, pneumocystis
not active against mucor, fusarium, cryptococcus, histoplasmosis, blastomyces
What is the clininical use of ibrexafungerp?
vulvovaginal candidiasis, recurrent also
contraindicated in pregnancy!! - use effective contraception during and for 4 days after treatment
What are the adverse effects of ibrexafungerp?
N/V/D, abdominal pain, dizziness, does NOT cause QT prolongation
What is the DOC for C. albicans?
fluconazole?
What is the DOC for C. glabrata?
echinocandins
What is the DOC for C. parapsilosis?
fluconazole
What is the DOC of C. tropicalis?
fluconazole
What is the DOC of C. krusei?
echinocandins
What is the DOC of C. lusitaniae?
fluconazole, echinocandins
What is the DOC of C. auris?
echinocandins
What is the DOC of cryptococcus?
fluconazole, amphotericin, flucytosine
What is the DOC of blastomyces?
itraconazole
What is the DOC of histoplasma?
itraconazole
What is the DOC of coccidioides?
fluconazole
What is the DOC of aspergillus?
voriconazole
What is the DOC of mucor?
amphotericin
What is the oropharyngeal candidiasis?
infection of the oral mucosa with candida species
most common opportunistic infection in people living with HIV
What is esophageal candidiasis?
infection of the esophagus with candida species
Oropharyngeal and esophageal candidiasis primary line of host defenses against superficial candida infections is what?
cell-mediated immunity (mediated by CD4 Tcells)
prevalence of EC increased secondary to HIV and other severely immunocompromised pts
What are the local risk factors for oropharyngeal and esophageal candidiasis?
use of inhaled steroids and antibiotics; dentures; xerostomia due to drugs, chemo, HSCT, radiotherapy to head/neck; smoking; disruption of oral mucosa caused by chemo and radiotherapy, ulcers, endotracheal intubation, trauma, burns
What are the systemic factors for oropharyngeal and esophageal candidiasis?
drugs (cytotoxic agents, corticosteroids, immunosuppressants after organ transplantation, PPIs)
neonates or elderly; HIV infection/AIDS (depletion of CD4, HIV viral load); diabetes; malignancies; nutritional deficiencies
What are the clinical manifestations of oropharyngeal candidiasis?
cottage-cheese appearance, yellowihs-white soft plaques overlying areas of erythema on buccal mucosa, tongue, gums, throat
plaques easily removed
sx: painful mouth, burning tongue, metallic taste, dysphagia, odynophagia
What is the clinical presentation of esophageal candidiasis?
dysphagia, odynophagia, and retrosternal chest pain; fever; plaques can be hyperemic or edematous with ulceration
to diagnose: upper GI endoscopy with biopsy
What is the treatment for oropharyngeal candidiasis?
treat for 7-14 days
topical therapy for mild infection:
clotrimazole 10mg troche 5x/day
nystatin 100,000units/mL suspension, 5mL swish and swallow QID
miconazole 50mg mucoadhesive buccal tablet, apply to upper gum region daily x7-14 days
What is systemic treatment for oropharyngeal candidiasis?
fluconazole 100-200mg daily
What is treatment for fluconazole reffractory OPC?
treat for >/=14 days (up to 28 days)
itraconazole solution 200mg daily
What is the treatment for esophageal candidiasis?
treat for 14-21 days
systemic therapy always required!!
fluconazole 200-400mg PO/IV daily
itraconazole solution 200mg PO daily
What is the treatment for EC fluconazole refractory?
treat for 21-28 days
itraconazole solution 200mg PO daily
What is vulvovaginal candidiasis?
infection in women with or w/o sx who have positive vaginal cultures for candida species (C. albicans)
uncomplicated: sporadic infection that is susceptible to all forms of antifungal therapy regardless of treatment duration
complicated: recurrent VVC, severe disease, non-candida albicans infection, host factors (DM, immunosuppression, pregnancy)
What increases the risk of vulvovaginal candidiasis?
sexually active; oral-genital contact increases risk; contraceptive agents; antibiotic use!!; post-menopausal women taking HRT
no established association with diet, douching, or tight-fitting clothing
Vulvovaginal candidiasis - topical agents
uncomplicated VVC: cure rates 80-95% with topical or oral azoles, 70-90% with nystatin
topical preparations can decrease efficacy of latex condoms and diaphragms
What is the treatment for VVC? - OTC/topical
butoconazole 2% cream
clotrimazole
miconazole
tioconazole
What is the treatment for VVC? - prescription
prescription/topical: nystatin 100,000 units tab; terconazole cream or suppository
prescription/oral: fluconazole 150mg tab, 1 tab PO x 1 day!!
What is the treatment of complicated VVC?
immunocompromised or have DM
use same drugs, but extend duration of therapy to 10-14 days
pregnancy: topical agents safe, oral agents contraindicated
What is the treatment for recurrent VVC?
> 4 episodes within 12mo period - two stage treatment: topical/oral azole x10-14 days followed by fluconazole 150mg PO once weekly for 6mo
