Systemic Antifungal Drugs / Antifungal Drugs

Front 1

What kind of patients are systemic fungal infections most common in?

Back 1

Impaired immune function:
1. AIDS
2. solid-organ transplants
3. cancer

Front 2

About 95% of the systemic fungal infections at UH are caused by?

Back 2

Candida spp or Aspergillus spp

Front 3

What infection has the highest (40%) mortality rate of any isolate from the blood?

Back 3

Candidemia

Front 4

What two species of Candida show resistance to Fluconazole and Itraconazole?

Back 4

Glabrata

Krusei

Front 5

What are the most common pathogens in Aspergillosis?

Back 5

A. fumigatus

A. flavus

Front 6

What are the most common sites of primary infection in invasive Aspergillosis?

Most common secondary site?

Back 6

Primary: Lungs & Sinuses

Secondary: CNS (mortality 95%)

Front 7

What other fungal species is Aspergillus hard to distinguish from?

Back 7

Fusarium spp.

Front 8

What is the mortality rate of invasive Aspergillus if untreated? If treated?

Back 8

Untreated = 100%

Treated = 50%

Front 9

What systemic antifungal drugs are Polyenes?

Back 9

Amphotericin B

Nystatin

Front 10

What systemic antifungal drugs are Azoles?

Back 10

1. Voriconazole
2. Itraconazole
3. Posaconazole
4. Fluconazole

Front 11

What systemic antifungal drugs are Echinocandins?

Back 11

1. Caspofungin
2. Anidulafungin
3. Micafungin

Front 12

What is the MOA of Amphotericin B?

Back 12

Binding to ergosterol in the fungal cell membrane creates porins

Porins increase cell permeability causing cell death

Front 13

What are the strengths of Amphotericin B?

Back 13

Extremely broad spectrum

*Gold standard for antifungal drugs

Front 14

What is does Amphotericin B treat in HIV patients?

Back 14

Cryptococcal meningitis

Front 15

What are the toxicities associated with Amphotericin B?

Back 15

Nephrotoxic
-dose dependent
-renal wasting of K+ and Mg++
-no permanent renal damage in pts. w/ normal renal func. before treatment

Fever & Chills due to release of IL-1, IL-6, TNF

Hypochromic, normocytic anemia w/ dec. hematocrit via decreased release of Erythropoietin

Front 16

How is renal damage due to Amphotericin B lessened?

Back 16

Giving 1L saline i.v. prior to treatment w/ Ampho B

Front 17

What are the advantages of lipid formulations of Amphotericin B?

(Ampho B enclosed in liposomes)

Back 17

Toxicity still occurs, but delayed

*disadvantages: still toxic and costs $$$$$

Front 18

What is the MOA of the Azoles?

Back 18

Inhibits CYP450 lanosterol 14a-methylase which prevents the formation of ergosterol

Front 19

What do the accumulated 14-alpha-methysterols do in the fungal cell?

Back 19

Inhibit the enzymatic of the ETC and cell growth is blocked

Front 20

Why shouldn't you treat w/ Azoles after treatment with Amphotericin B?

Back 20

Azoles take away the site of action of Amphotericin B

Front 21

Do Azoles kill fast or slow?

Back 21

Slow--static drugs which is OK as long as the patient has a patent immune system

Front 22

How does resistance to Azoles occur?

Back 22

Mutation of their binding site to the demethylase that makes -azoles unable to bind

Front 23

Do -azoles inhibit or induce CYP450?

Back 23

Inhibit

Front 24

What is the most commonly used systemic antifungal agent?

Back 24

Fluconazole

Front 25

What is the most commonly used systemic antifungal drug?

Back 25

Fluconazole

Front 26

What are the strengths of Fluconazole?

Back 26

1. Lacks major toxicity
2. Oral bioavailability is excellent
3. Extremely active against C. albicans

Front 27

What are the weaknesses of Fluconazole?

Back 27

1. Narrow spec. of activity
(only good against C. albicans & a few other species)
2. NOT cover C.krusei & 15-20% of C. galabrata isolates are resistant
3. NO Aspergillus activity

Front 28

What are the strengths of Itraconazole?

Back 28

Active against Aspergillus spp.

Front 29

What are the weaknesses of Itraconazole?

Back 29

1. Oral solution has limited F and it tastes like Kerosine

2. Drug-drug interactions via inhibition of human CYP450 is a big problem in pts. w/ allografts or cancer

Front 30

Is Amphotericin B superior to Voriconazole for the treatment of Aspergillus spp.?

Back 30

No

Front 31

What is the DOC for systemic infections caused by Aspergillus spp?

Back 31

Voriconazole b/c it is fungicidal for Aspergillus spp.

Front 32

What can Voriconazole also cover?

Back 32

Fusarium spp.
Scedosporium apiospermum
Candida Krusei (res. to Fluconazole)

Front 33

The patients must have ________ for Voriconazole to be effective in the treatment of infections caused by Fusarium spp.

Back 33

White Cells

Front 34

What is the F of Voriconazole?

Back 34

96% --change patient from i.v. to p.o. drug w/o a dose adjustment

Front 35

What are the weaknesses of Voriconazole?

Back 35

1. Hepatotoxic --> elevations of LFT's
2. Altered mental status
3. Visual disturbances
4. Nephrotoxic--vehicle for delivery accumulates in the plasma in pt w/ renal failure
5. Not effective against C. glabrata
6. Drug-Drug interactions
7. Need for therapeutic drug monitoring

Front 36

What is the spectrum of activity of Posaconazole?

Back 36

All fungi covered by Voriconazole + Zygomycetes

Front 37

What is the route of administration of Posaconazole?

Back 37

p.o.

*GI absorption is erratic

Front 38

What drug class is the gold standard for the treatment of Candidemia?

Back 38

Echinocandins

Front 39

What is the MOA of Echinocandins?

Back 39

Inhibit the synthesis of 1,3-beta-D-glucan

*side effects are less than -azoles
*key component of the fungal cell WALL in Candida & Aspergillus

Front 40

What is Caspofungin used for?

Back 40

1. Salvage therapy in patients w/ invasive aspergillosis who have not responded to amphotericin B as well as for invasive candidiasis/candidemia

2. Rapidly cidal against Candida spp. resistant to azoles

Front 41

What are the weaknesses of Echinocandins?

Back 41

1. Cost
2. No oral formulations available
3. Limited spectrum
(covers Candida spp., Aspergillus spp., & Pneumocystis spp.)

Front 42

What is the MOA of Flucytosine?

Back 42

5-FC --> 5-FU
5-FU --> 5-FUMP
5-FUMP --> 5-FdUMP
5-FdUMP inhib. Thymidylate Syn.
Lack of Thymidine inhibits DNA Syn.

Front 43

Why is Flucytosine not toxic to human cells?

Back 43

We don't convert 5-FC to 5-FU

Front 44

Why is 5-FC not used as a single agent?

Back 44

Resistance emerges rapidly

Front 45

What are the strengths of 5-FC?

Back 45

1. Administered p.o.
2. Rapid absorption & extensive distribution, including penetration into the CSF
3. Eliminated renally
4. Antifungal activity is syergistic w/ Azoles and Amphotericin B

Front 46

What are the weaknesses of 5-FC?

Back 46

Narrow spectrum:
-Cryptococcus neoformans
-some Candida spp.

Bone marrow suppression causing leukopenia & thrombocytopenia

Must be dosed QID (4X/day)

Rapid emergence of fungal resistance

Front 47

What is 5-FC given with to treat cryptococcal meningitis?

Back 47

Amphotericin B

Front 48

What is the MOA of both Amphotericin B and Nystatin?

Back 48

Bind to ergosterol in the cell membrane to form pores which allow ions & macromolecules to leak out of the cell; cell death ensues

Front 49

What fungi do the azoles cover?

Back 49

Candida albicans
Microsporum
Epidermophyton
Trichophyton
Pityrosporum orbiculare

Front 50

What is the MOA and route of administration of griseofulvin?

Back 50

Inhibits fungal mitosis by binding to polymerized microtubules & prevents the formation of the cytoplasmic microtubules needed for growth of the hyphae

p.o

Front 51

What is the therapeutic use of Griseofulvin?

Back 51

Covers all tineas

Front 52

What drugs have taken the place of Griseofulvin in the therapy of fungal infections?

Back 52

1. Terbinafine
2. Fluconazole

Front 53

What is the MOA of Terbinafine?
(Lamisil --brand name)

Back 53

Prevents ergosterol synthesis by inhibiting the enzyme squalene epoxidase

*accumulation of squalene kills the fungal cell*

Front 54

Where does Terbinafine accumulate?

Back 54

Skin
Nails
Fat Cells

Front 55

What Pregnancy Category should a drug be in order for a prego to take it w/o harm to the fetus?

Back 55

B

Front 56

What is the MOA of Tolnaftate?

What does it cover?

What is the route of administration?

Back 56

Unknown

Microsporum, Epidermophyton, Trichophyton, P. orbiculare

Topical

Front 57

Who develops oropharyngeal or esophageal Candida infections?

Back 57

Neonates & Children

90% of all HIV patients

Asthmatic patients using an inhaled steroid
(pts. should rinse mouth/throat after use; use of spacers dec. likelihood of Candida infections)

Front 58

What drug should be used to treat oropharyngeal thrush?

Back 58

Clotrimazole oral troches

*put in mouth and suck on it

Front 59

What is the route of administration of Terbinafine?

Back 59

p.o tablets & granules

Front 60

Candida colonize the genital tract of __________ of healthy women

Colonization is most common in:

Back 60

20-50%

1. women taking antibiotics
2. pregnancy
3. women w/ diabetes mellitus

Front 61

_______ of all healthy women will have at least one episode of Candidal vulvovaginitis?

Back 61

70-75%

Front 62

What are the signs and symptoms of CVV?

Back 62

Vaginal discharge
Pruritus
Discomfort/Pain during intercourse
White discharge & erythema

Front 63

What is the treatment for CVV?

Back 63

Three-day topical:
-Clotrimazole (200 mg suppository)
-Miconazole (200 mg suppository)

One-day topical:
-Clotrimazole (500 mg vaginal tab.)

Systemic therapy:
-Fluconazole (150 mg tab. p.o. 1 X)
(takes 48 h for symp. to improve)

Front 64

Trichophyton spp. invades the hair shaft and follicle and causes?

Back 64

Ringworm of scalp and hair
(tinea capitis)

Front 65

What is the treatment for tinea capitis?

Back 65

Griseofulvin - txt book DOC
(treat w/ 10 mg/kg/d p.o. 6 weeks)

Terbinafine or Fluconazole for 2 wks
(real world choices)

Topical tx w/ -azole in very young pts.

Front 66

What is the DOC for Onychomycosis?

Back 66

Terbinafine

*treat w/ 250 mg/d during the same week each month for 3 cons. mths.
*cure rate 80 + %

Front 67

What is the treatment for athlete's foot or jock itch?

Back 67

1. Topical terbinafine or tolnaftate
2. -azole is effective