Antifungal drugs

Question 1

Amphotericin B, a polyenes used to treat systemic antifungal infections, what makes it so good and what makes it so bad?

Answer 1

good: broadest spectrum
bad: significant adverse side effects
(there are newer liposomal formulations associated with increased efficacy and decreased toxicity)

Question 2

How is amphotericin given, what is its mechanism of action?

Answer 2

IV

1. binds to ergosterol in fungal membrane
2. forms pore in the membrane thereby increasing membrane permeability
3. efflux of essential molecules
4. fungal death
   - binds only weakly to cholesterol

Question 3

What is amphotericin B not active against?

Answer 3

1. Candida Lusitaniae

2. Pseudallescheria boydii (scedosporium apiospermum)

Question 4

When is amphotericin used?

Answer 4

initial induction therapy (usually 4 weeks) to reduce fungal burden, then replaced by newer less toxic AZOLE drugs for consolidation therapy and prevention of relapse

Question 5

What is the ONLY antifungal agent that is approved in pregnant/ breast feeding women?

Answer 5

Amphotericin

Question 6

What is amphotericin the treatment of choice for?

Answer 6

Zygomycosis/mucormycosis

Question 7

What are the adverse infusion related effects for amphotericin a drug with a low therapeutic index ?

Answer 7

1. infusion related
   - fever, chills, muscle spasms, vomiting, headache and hypotension
   a. slow rate/decrease dose
   b. preemptive meds like antipyretic,antihistamine, corticosteroids

Question 8

What are the cumulative toxicities of amphotericin B?

Answer 8

1. nephrotoxicity
   a. reversible-decreased renal perfusion via vasoconstriction
   - reduce by using saline drip (Na loading)
   b. non reversible
   - renal tubular injury(prolonged administration)
   - tubular acidosis and severe K+ and Mg2+ wasting
   - more common in presence of diuretics or other nephrotoxic meds eg. aminoglycosides/cyclosporine
2. hepatotoxicity (occasional)
3. anemia
   - reversible suppression of erythrocyte production due to decreased EPO

Question 9

What are the bad parts of flucytosine and the good part?

Answer 9

bad:

1. narrow spectrum of activity
2. use is restricted by high incidence of resistance
   - mutations in cytosine permease, cytosine deaminase, uracil phosphoribosyl transferase or increase in cytosine synthesis

good:
good penetration into the CSF
-used for cryptococcal meningitis

Question 10

Is flucytosine used alone?

Answer 10

no typically in combination with other antifungal drugs

• especially ampho B and an azole
• ampho enhances flucytosine permeability

Question 11

How is flucytosine eliminated?

Answer 11

renally-dosage adjustment required in presence of renal insufficiency

Question 12

What is the mechanism of action of flucytosine?

Answer 12

1. taken up via cytosine permease
2. fungal specific cytosine deaminase –>5 fluorouracil
3. inhibits both DNA(thymidylate synthase) and RNA synthesis

Question 13

What does flucytosine+amphotericin B treat?

Answer 13

cryptococcosis and candidiasis

-cryptococcal meningitis (good CSF penetration of flucytosine and ampho b enhances fungal uptake of flucytosine)

Question 14

What does flucytosine + itraconazole treat?

Answer 14

chromoblastomycosis

Question 15

What are the adverse effects of flucytosine?

Answer 15

1. endogenous gut microflora express cytosine deaminase –>5 fluorouracil (antimetabolite)–>toxicity

• GI: nausea, vomiting diarrhea
• Bone marrow toxicity: anemia, leukopenia, thrombocytopenia

Tetratogenic

Question 16

What is the prototype imidazole?

Answer 16

ketoconazole

Question 17

What is the order of spectrum of activity for the triazoles?

Answer 17

Fluconazole

Question 18

What is the mechanism of action of azoles?

Answer 18

Azoles are fungistatic/fungicidal

1. Inhibit 14 alpha demethylase (CYP45) involved in biosynthesis of ergosterol from lanosterol
   - impairs membrane function
   - increases membrane permeability
   - decreases activity of membrane associated proteins

Question 19

What are the common adverse side effects of all azoles?

Answer 19

1. GI distress
2. Hepatotoxicity-requires hepatic enzyme monitoring
3. fetal abnormalities

Question 20

When should itraconazole and voriconazole never be given to a patient?

Answer 20

when the patient is taking statins due to increased risk of developing rhabdomyolysis

Question 21

What azoles have good CNS penetration?

Answer 21

fluconazole and voriconazole

Question 22

What azole needs real adjustment?

Answer 22

Fluconazole

Question 23

What limits ketoconazole use?

Answer 23

• oral ketoconazole requires acidic environment for absorption
• poor penetration into CSF and urine
• many adverse effects due to inhibition of CYP450 enzymes involved in adrenal and gonadal steroid synthesis
• ->decreased cortisol and decreased testosterone
• –>gynecomastia, libido, impotence, menstrual irregularities, hypotension and fatigue

-many drug interactions of CYP450 3A4

• rarely used now, largely replaced by itraconazole
• still used topically to treat dermatophyte infections

Question 24

What is the spectrum of activity fluconazole?

Answer 24

Narrowest spectrum of activity of all azole drugs but

• good oral bioavailability and EXCELLENT penetration into the CSF
• fewest drug interactions of all azoles

Question 25

Does fluconazole have many adverse effects?

Answer 25

no only minor effects: nausea, headache, skin rash and GI, and alopecia (reversible, long/high dose)

Question 26

How is fluconazole eliminated?

Answer 26

80% of drug eliminated unchanged in the urine | -useful in treatment of fungal BLADDER infections

Question 27

What does fluconazole used to treat?

Answer 27

1. Candida - mucocutaneous candids - poor activity toward C. glabrata and no activity against C. krusei 2. TREATMENT OF CHOICE for cryptococcal meningitis -used as consolidation/maintenance therapy with ampho b/flucytosine 3. good activity against coccidioides 4. variable activity against endemic dimorphic fungi - less active than itraconazole against histoplasmosis, balstoplsmisis, sporotrichosis - only used if itraconazole not well tolerated 5. dermatophytes

Question 28

What is fluconazole the therapy of choice for?

Answer 28

1. Cryptococcal meningitis | 2. coccidioidal meningitis

Question 29

What should itraconazole not be used for?

Answer 29

- meningitis | - bladder infections

Question 30

HOw is the spectrum of activity of itraconazole vs. fluconazole?

Answer 30

broader spectrum but more adverse effects and many potential drug interactions

Question 31

What are the clinical uses of itraconazole?

Answer 31

1. oral treatment of dermatophytes 2. oral treatment of onychomycosis 3. preferred agent for non-meningeal blastomyces/histoplasma/coccidioides 4. effective against candida - but more adverse effects than fluconazole 5. active against aspergillus - less effective than voriconazole

Question 32

What are the adverse effects of itraconazole?

Answer 32

Triad 1. Hypertension 2. Hypokalemia 3. Peripheral edema Can cause CHF in patients with ventricular dysfunction -not be used if history of ventricular dysfunction or CHF

Question 33

What is the spectrum of voriconazole?

Answer 33

newer extended spectrum azole -distributed into CSF (absorption inhibited by fatty meals, bioavailability is unpredictable and affected by genetic polymorphisms) - less toxic than ampho b but has unique side effects - non linear dosing - inhibitor of CYP2C19, 2c9, 3a4

Question 34

What is the spectrum of activity for voriconazole?

Answer 34

1. Excellent activity against candida - even C. Glabrata and C. krusei 2. good activity against dimorphic fungal infections - blastomycosis, histoplasmosis, sporothrix, coccidioidomycosis 3. effective against pseudoallerischerideri boydii/scedosporium 4. enhanced activity against aspergillus and fusarium - treatment choice for aspergillus

Question 35

What is voriconazole the drug of choice for?

Answer 35

Invasive aspergillus/fusarium

Question 36

What the side effects to voriconazole?

Answer 36

1. periostitis (bone pain-associated with long term therapy) - inflammation of the periosteum 2. transient vision changes-visual blurring - flashes of light - changes in color vision - -affects 30% of patients - -seen after first dose/diminishes with time 3. photosensitivity/rash-rarely Stevens Johnson syndrome associated with high concentrations >5.5 4. visual/auditory hallucinations 5. seizures

Question 37

Posaconazole is the newest azole what is its spectrum of azole family?

Answer 37

broadest spectrum -maybe poor penetration to CSF and urine

Question 38

What is posaconazole used for?

Answer 38

1. treatment of invasive fungal infections - candida and aspergillus 2. antifungal prophylaxis in neutropenia 3. salvage therapy for mucormycosis * *****only azole effective against zygomycosis/mucormycosis

Question 39

How do echinocandins work?

Answer 39

cidal -competitively inhibit B 9(1-3) D glucan synthase complex involved in biosynthesis of the principal building block of the fungal wall - impairs structural integrity of fungal wall - increases osmotic instability leading to cell wall death

Question 40

Does echinocandins penetrate the CSF do they inhibit CYP450?

Answer 40

no

Question 41

What is the spectrum of activity for echinocandins?

Answer 41

1. Candida (including glabrata and krusei) - fungicidal with minimal effects 2. aspergillus - used in salvage therapy for invasive aspergillosis that fail initial treatment with ampho b or voriconazole -NO Significant activity toward cryptococcus or dimorphic fungi

Question 42

What are systemic antifungal drugs for cutaneous infections?

Answer 42

griseofulvin and terbinafine

Question 43

What does grisoefulvin treat?

Answer 43

``` mycotic infections of skin, nail, and hair due to: dermatophytes -microsporum -epidermophyton -trichophyton ``` no activity against any other fungi

Question 44

What are the side effects of griseofulvin?

Answer 44

1. nervous system; headache, lethargy, vertigo and blurred vision 2. skin: urticaria, photosensitivity, rash and skin eruptions 3. hepatotoxicity (rare) 4. leukopenia, neutropenia and monocytosis (rare) 5. fetal abnormalities -inducer of CYP450

Question 45

What is the mechanism of action of griseofulvin? IS it static or cidal

Answer 45

static -binds to fungal microtubules preventing the formation of mitotic spindles inhibiting fungal mitosis -treatment needs to be continued until affected tissue is completely replaced by new tissue

Question 46

Terbinafine an oral antifungal agent deposits where? What is its activity and clinical use?

Answer 46

deposits in the skin, nail hair and fat - activity is limited to dermatophytes and candida albicans - cure rate is 90% effective-MORE effective than griseofulvin or itraconazole!

Question 47

What is the mechanism of action of terbinafine?

Answer 47

inhibition of fungal squalene epoxidase 1. increased squalene-->toxic products 2. impaired fungal membrane function

Question 48

What is nystatin? What is its MOA? What does it treat?

Answer 48

topical antifungal - similar to Amho B-binds to ergosterol and forms pores in the fungal membrane - -to toxic for IV administration - not significantly absorbed from sin, mucus membrane or GI tract * NOT active against dermatophytes - used in the treatment of oral candidiasis (swish and swallow)

Question 49

What are the topical azoles?

Answer 49

clotrimazole, miconazole, terconazole creams, lozenges, suppositories treat: 1. oral and vulvovaginal candidiasis 2. dermatophyte infections

Question 50

What are topical allylamines and benzylamines? WHat is the MOA?

Answer 50

1. Allylamines-terbinafine and naftifine 2. Benzylamines-butenafine act like terbinafine to inhibit squalene epoxidase - spectrum of activity limited to 1. candida albicans 2. dermatophytes -used in the treatment of tinea cruris, tinea corporis, and tinea pedis