Lecture 2: Pharm of Pulmonary Infections - Fungal Flashcards
MOA of Amphotericin B?
Complexes with ergosterol to disrupt fungal cell membrane
Which 3 major classes of fungi can be treated with Amphotericin B and list the 7 organisms in these classes?
- Yeasts: Candida + Cryptococcus neoformans
- Organisms causing endemic mycoses: H. capsulatum + Blastomyces dermatitidis + Coccidioides immitis
- Pathogenic molds: Aspergillus fumigatus + agents of mucormycosis
What is the mechanism of resistance to Amphotericin B?
Alteration to ergosterol
What is the route of administration for Amphotericin B?
IV
What are the most common immediate and long term AE’s associated with Amphotericin B?
- Immediate = FEVER, chills, muscle spasms, vomiting, HA, and hypotension
- Long term = renal toxicity
What is the MOA of Flucytosine?
Converted to FdUMP and FUTP, which inhibit DNA and RNA synthesis, respectively
Which 2 organisms can be treated with Flucytosine?
- C. neoformans
- Some Candida spp.
What is the mechanism of resistance to Flucytosine?
Altered drug metabolism
How is Flucytosine administered?
Water-soluble oral form
What are 3 AE’s of Flucytosine?
- Anemia
- Leukopenia
- Thrombocytopenia
What is the MOA of the Azoles?
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 has a greater propensity to inhibit mammalian CYP450 enzymes?
Ketoconazole
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 and IV
List 6 fungi which can be treated with Itraconazole?
- Dimorphic fungi: Histoplasma, Blastomyces, and Sporothrix
- Aspergillus* spp. (largely replaced by voriconazole)
- Dermatophytoses and onychomycosis
In which form does Fluconazole have the highest bioavailability and via which routes can it be given?
- High oral bioavailability
- Can be given via IV as well
Which 3 -azoles have the highest absorption and are more often used for systemic coverage?
- Fluconazole
- Voriconazole
- Posaconazole
What is the azole of choice for cryptococcal meningitis?
Fluconazole
Fluconazole is most commonly used for the treatment of what?
Mucocutaneous candidiasis
Via which routes can Voriconazole be given?
IV and oral
Voriconazole is an inhibitor of what?
Mammalian CYP3A4
Which 3 -azoles have both oral and IV formulations?
- Itraconazole
- Fluconazole
- Voriconazole
What is a common AE of Voriconazole?
Visual disturbances
Voriconazole has a similar spectrum to what other -azole?
Itraconazole
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
How is Posaconazole administered?
Liquid oral preparation only
What is the only -azole with significant activity against the agents of mucormycosis?
Posaconazole
Posaconazole has activity against most species of ______ and _______.
Posaconazole has activity against most species of Candida and Aspergillus.
Posaconazole is currently licensed for use in what 3 situations?
- Salvage therapy in invasive aspergillosis
- Prophylaxis of fungal infections during induction chemotherapy for leukemia
- Allogenic bone marrow transplant pt’s w/ GVHD
What is the MOA of Echinocandins and list the 3 main drugs in this class?
- Inhibit glucan synthase
- Caspofungin, Micafungin, and Anidulafungin
Echinocandins have activity against which 2 organisms?
- Candida
- Aspergillus
Echinocandins are currently licensed for use in what 2 situations?
- Disseminated and mucocutaneous candidal infections
- Emperic antifungal therapy during febril neutropenia (replaced Amphotericin B)
What is the mechanism to resistance of Echinocandins?
Point mutations in glucan synthase
How are Echinocandins administered?
Only IV formulation
For which organism and specific situation is the use of the Echinocandin, Caspofungin indicated?
- Invasive aspergillosis
- Only as salvage therapy in pt’s that don’t respond to amphotericin B
The Echinocandin, Micafungin, has a specific spectrum of activity against which organisms and in which situation is it indicated?
- Mucocutaneous candidiasis
- Candidemia
- Prophylaxis of candidal infections in bone marrow transplant pt’s
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 black box warning for Flucytosine?
contraindicated or to be used with extreme caution in pts with:
renal impairment
pregnant/breast feeding
bone marrow depression
The current use of glucytosine is in combination with what?
For what condition?
Liposomal amphotericin B
Cryptococcal meningitis
What is the black box warning for Micafungin?
hepatocellular tumors
Voriconizole has greatest affinity for which CYP?
CYP2C19
What is the black box warning for itraconazole?
Waht is a common adverse effect associated with liver disease?
heart failure due to inotropic effects
can cause severe liver disease with intractable vomiting
What can be seen on EKG in patients who take Fluconazole (especially when taken with drugs metabolized by CYP3A4) ?
QT prolongation leading to Torsades
What is the black box warning for Amphotericin B?
Can lead to toxicity where?
used for treating life threatening fungal infections only
Nephrotoxicity because it has an affinity for cholesterol on human cels
An overdose of amphotericin B can cause what cardiac issue?
Cardiac arrest
