PHARM Pulmonary Infections - Fungal (Staudinger) Flashcards
MOA of amphotericin B?
Complexes with ergosterol to disrupt fungal cell membrane
–> not selective, also binds mammalian cholesterol
Which 3 major classes of fungi can be treated with amphotericin B and list the 7 organisms in these classes?
Opportunistic Yeasts: Candida spp. + *Cryptococcus neoformans*
Pathogenic opportunistic molds: Aspergillus fumigatus or flavus + agents of Mucormycetes (Mucor spp. or Rhizopus spp.)
Endemic (systemic) mycoses: Histoplasma capsulatum + Blastomyces dermatitidis + Coccidioides immitis
What is the mechanism of resistance to amphotericin B?
Alteration to ergosterol
What is the route of administration for amphotericin B?
IV
Shit drug with a narrow therapeutic window and a number of serious side effects, and VERY BAD RENAL toxicity –> Reserved for the severly ill, for life-threatening invasive fungal infections, where the pt cannot tolerate any other antifungal meds.
Obvi, needs close monitroing.
What are the most common immediate and long term AE’s associated with amphotericin B?
Immediate: fever, chills, muscle spasms/rigors, vomiting, HA, and hypotension. Also, CNS, and GI
–> May require phenothiazine !!!
Long term: renal toxicity, weight loss, hypotension, normochronic and normocytic anemia, hypomagnesemia, hypokalemia, etc.
What is the MOA of the `azoles?
Binding and inhibition of fungal CYP450 enzymes –> ↓ ergosterol synthesis
What is the mechanism of resistance to the ‘azoles?
Upregulation of fungal CYP450 enzymes
What are 2 AE’s associated with the -azoles?
- Minor GI issues***
- Abnormalities in liver enzymes
*Relatively non-toxic
Which -azole used for fungal infections has poor CSF penetration and which has good CSF penetration?
Poor penetration –> itraconazole
Good penetration –> fluconazole
Which routes of administration exist for itraconazole?
Oral 55% bioavailability
and IV 99% bioavailability
List the fungi which can be treated with itraconazole?
Aspergillus spp. (largely replaced by voriconazole)-
Dimorphic fungi: Histoplasma, Blastomyces, and Sporothrix
Dematiaceous Alternaria, Bipolaris, Curvularia
Contraindications for fluconazole?
Any drug that prolongs QT and also metabolized by 3A4
e.g. amioderone
fluconazole causes QT prolongation on its own via the inhibition fo Rectifier Potassium Channel –> combo increases the risk of torsades
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How is fluconazole metabolized?
Both a substrate and inhibitor of CYP3A4
***Avoid terfenadine (antihistamine)
Increases serium concentrations of CBB, immunosupressants, chemo drugs, benzos, TCA, SSRIs, and macrolides –> toxicity and d/d interactions
What is the azole of choice for cryptococcal meningitis?
fluconazole
Fluconazole is most commonly used for the treatment of what?
Mucocutaneous candidiasis
- UTI/peritnoitis
- Vaginal candidiasis
- Oropharyngeal and esophageal candidiasis
Maybe used as a prophylactic in pts with bone marrow transplant
Via which routes can voriconazole be given?
IV and oral
Voriconazole is an inhibitor of what?
Mammalian CYP3A4
just like the rest of the azole fam
Which -azoles have both oral and IV formulations?
- itraconazole (3A4)
- fluconazole (3A4)
- voriconazole (2C19)
What is a common AE of voriconazole?
Visual disturbances
Voriconazole has a similar spectrum to what other -azole?
itraconazole
- Invasivie aspergillosis
- deep tissue candida
- esophageal candidiasis
… and some other L. Y. crap that I have never seen before
What is the treatment of choice for invasive aspergillosis and some enviornmental molds?
voriconazole
Which -azole can be given for Candida infections, including fluconazole-resistant specices such as Candida krusei and the dimorphic fungi?
voriconazole
What is the MOA of echinocandins and list the 3 main drugs in this class?
Inhibit glucan synthase
caspofungin, micafungin, and anidulafungin
Echinocandins (caspofungin, micafungin, anidulafungin) have activity against which 2 organisms?
- Candida
- Aspergillus
Echinocandins are currently licensed for use in what situations?
Disseminated and mucocutaneous candidal infections in adult and pediatric pts 3yo +
- intraabdominal abscesses
- periotnitis
- plural space infections
Empirical antifungal therapy during febril neutropenia (replaced Amphotericin B)
Invasive aspergillosis in pts with tx refractory infections or sensitivity to other drugs
What is the mechanism to resistance of Echinocandins?
Point mutations in glucan synthase
How are echinocandins administered?
Only IV formulation
(the only IV antifungal group effective against Candida)
For which organism and specific situation is the use caspofungin indicated?
Invasive aspergillosis
Only as salvage therapy in pt’s that don’t respond to amphotericin B
Risk associated with micafungin
Hepatocellular tumors and altered hepatocytes after 3+ months use
Only banned in Europe, no black box in the US
Which anti-fungal is given for esophageal candidiasis and invasive candidiasis, includig candidemia?
anidulafungin
Which echinocandins has the longest half-life of 24-48 hours?
anidulafungin
What is the MOA of flucytosine?
Converted to FdUMP and FUTP, which inhibit DNA and RNA synthesis, respectively
What are 3 AE’s of flucytosine?
- Anemia
- Leukopenia
- Thrombocytopenia
Which 2 organisms can be treated with flucytosine?
Cryptococcus neoformans
Some Candida spp.
