PHARM Pulmonary Infections - Fungal (Staudinger)

Question 1

MOA of amphotericin B?

Answer 1

Complexes with ergosterol to disrupt fungal cell membrane

–> not selective, also binds mammalian cholesterol

Question 2

Which 3 major classes of fungi can be treated with amphotericin B and list the 7 organisms in these classes?

Answer 2

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

Question 3

What is the mechanism of resistance to amphotericin B?

Answer 3

Alteration to ergosterol

Question 4

What is the route of administration for amphotericin B?

Answer 4

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.

Question 5

What are the most common immediate and long term AE’s associated with amphotericin B?

Answer 5

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.

Question 6

What is the MOA of the `azoles?

Answer 6

Binding and inhibition of fungal CYP450 enzymes –> ↓ ergosterol synthesis

Question 7

What is the mechanism of resistance to the ‘azoles?

Answer 7

Upregulation of fungal CYP450 enzymes

Question 8

What are 2 AE’s associated with the -azoles?

Answer 8

• Minor GI issues***
• Abnormalities in liver enzymes

*Relatively non-toxic

Question 9

Which -azole used for fungal infections has poor CSF penetration and which has good CSF penetration?

Answer 9

Poor penetration –> itraconazole

Good penetration –> fluconazole

Question 10

Which routes of administration exist for itraconazole?

Answer 10

Oral 55% bioavailability

and IV 99% bioavailability

Question 11

List the fungi which can be treated with itraconazole?

Answer 11

Aspergillus spp. (largely replaced by voriconazole)-

Dimorphic fungi: Histoplasma, Blastomyces, and Sporothrix

Dematiaceous Alternaria, Bipolaris, Curvularia

Question 12

Contraindications for fluconazole?

Answer 12

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

(

Question 13

How is fluconazole metabolized?

Answer 13

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

Question 14

What is the azole of choice for cryptococcal meningitis?

Answer 14

fluconazole

Question 15

Fluconazole is most commonly used for the treatment of what?

Answer 15

Mucocutaneous candidiasis

• UTI/peritnoitis
• Vaginal candidiasis
• Oropharyngeal and esophageal candidiasis

Maybe used as a prophylactic in pts with bone marrow transplant

Question 16

Via which routes can voriconazole be given?

Answer 16

IV and oral

Question 17

Voriconazole is an inhibitor of what?

Answer 17

Mammalian CYP3A4

just like the rest of the azole fam

Question 18

Which -azoles have both oral and IV formulations?

Answer 18

• itraconazole (3A4)
• fluconazole (3A4)
• voriconazole (2C19)

Question 19

What is a common AE of voriconazole?

Answer 19

Visual disturbances

Question 20

Voriconazole has a similar spectrum to what other -azole?

Answer 20

itraconazole

• Invasivie aspergillosis
• deep tissue candida
• esophageal candidiasis

… and some other L. Y. crap that I have never seen before

Question 21

What is the treatment of choice for invasive aspergillosis and some enviornmental molds?

Answer 21

voriconazole

Question 22

Which -azole can be given for Candida infections, including fluconazole-resistant specices such as Candida krusei and the dimorphic fungi?

Answer 22

voriconazole

Question 23

What is the MOA of echinocandins and list the 3 main drugs in this class?

Answer 23

Inhibit glucan synthase

caspofungin, micafungin, and anidulafungin

Question 24

Echinocandins (caspofungin, micafungin, anidulafungin) have activity against which 2 organisms?

Answer 24

• Candida
• Aspergillus

Question 25

Echinocandins are currently licensed for use in what situations?

Answer 25

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

Question 26

What is the mechanism to resistance of Echinocandins?

Answer 26

Point mutations in glucan synthase

Question 27

How are echinocandins administered?

Answer 27

Only IV formulation

(the only IV antifungal group effective against Candida)

Question 28

For which organism and specific situation is the use caspofungin indicated?

Answer 28

Invasive aspergillosis

Only as salvage therapy in pt’s that don’t respond to amphotericin B

Question 29

Risk associated with micafungin

Answer 29

Hepatocellular tumors and altered hepatocytes after 3+ months use

Only banned in Europe, no black box in the US

Question 30

Which anti-fungal is given for esophageal candidiasis and invasive candidiasis, includig candidemia?

Answer 30

anidulafungin

Question 31

Which echinocandins has the longest half-life of 24-48 hours?

Answer 31

anidulafungin

Question 32

What is the MOA of flucytosine?

Answer 32

Converted to FdUMP and FUTP, which inhibit DNA and RNA synthesis, respectively

Question 33

What are 3 AE’s of flucytosine?

Answer 33

• Anemia
• Leukopenia
• Thrombocytopenia

Question 34

Which 2 organisms can be treated with flucytosine?

Answer 34

Cryptococcus neoformans

Some Candida spp.