Infectious Disease III: Antifungals and Antivirals

Question 1

What is the MOA and spectrum of amphotericin B? What are some side-effects and what fluid is it compatible with?

Answer 1

MOA - amphotericin B binds to ergosterol, altering cell membrane permeability and causing cell death

Spectrum:
- Yeasts: most candida spp. and cryptococcus neoformans
- Molds: aspergillis spp. and zygomycetes
- Dimorphic fungi: histo, basto, and coccidioides

Side-effects:
- infusion related: fever, chills, headache, malaise, rigors
- decreased potassium and magnesium
- nephrotoxicity

Only compatible in D5W
Lipid formulations must be filtered during preparation

Question 2

What are the differences in formulations of amphotericin B? Which formulation requires premedication and what is used as premedication?

Answer 2

Conventional amphotericin B deoxycholate has many toxicities. The amphotericin B lipid formulation (AmBisome) is associated with fewer toxicities (decreased infusion reactions, decreased nephrotoxicity).

The conventional amphotericin B requires premedication 30-60 minutes prior to the infusion:
- acetaminophen or NSAID
- diphenhydramine and/or hydrocortisone
- give NS boluses to decrease the risk of nephrotoxicity
- +/- meperidine to decrease the duration of severe rigors

Question 3

What is the MOA of flucytosine? When is it used? What is 1 side effect?

Answer 3

MOA - penetrates fungal cells and is converted to fluorouracil, which competes with uracil and interferes w/ fungal RNA and protein synthesis

Due to development of resistance, flucytosine should not be used alone. It is used in combination with amphotericin B for the treatment of invasive cryptococcal (meningitis) pr Candida infections.

Side effect: myelosuppression

Question 4

What is the MOA of the azole antifungals?
What are the 3 class effects?
Which azole:
- requires a renal dose adjustment
- has the worst hepatotoxicity
- can cause HF
- causes visual changes and phototoxicity
- has a different tablet vs. suspension dose and must be taken with food?

What is the IV:PO ratio for all azoles?
Which azoles have the SBECD vehicle?

Answer 4

MOA - decrease ergosterol synthesis and cell membrane formation

Class effects:
- increase LFTs
- QT prolongation (except isavuconazonium)
- many drug interactions (CYP450 inhibition)

• fluconazole requires a renal dose adjustment
• ketoconazole has severe hepatotoxicity that has led to liver transplant
• itraconazole can cause HF
• voriconazole may cause visual changes and phototoxicity
• posaconazole has a different tablet vs. suspension dose and must be taken with food

IV:PO ratio is 1:1 for all azoles

Drugs with sulfobutyl ether beta-cyclodextrin (SBECD) vehicle: voriconazole and posaconazle

Question 5

What fungi does fluconazole have activity against? What dosage forms are available? Can fluconazole penetrate the CNS?

Answer 5

Activity against: most candida spp., including C. albicans, C. parapsilosis, and C. tropicalis.
- Limited against: C. glabrata (resistance), C. krusei (fluconazole-resistant)

Dosage forms: PO and IV

Yes, fluconazole can penetrate the CNS. It can be used to treat fungal meningitis.

Question 6

What are the primary uses for itraconazole? What are its boxed warnings?

Answer 6

Primarily used for dimorphic fungi (blasto and histo) and nail bed infections (onychomycosis).

Boxed warnings:
- can worsen for casue HF
- can cause increased plasma concentrations of certain drugs that can lead to QT prolongation and ventricular tachyarrhythmias

Question 7

What is the brand name of the OTC ketoconazole? What are ketoconazole’s boxed warnings?

Answer 7

Nizoral A-D shampoo (OTC ketoconazole)

Boxed warnings
- hepatotoxicity which has led to liver transplantation and/or death
- QT prolongation
- only use oral tabs if other antifungal therapy is unavailable or not tolerated

Question 8

What is the brand name for voriconazole? What is vori primary used for? What is pertinent once CrCl < 50mL/min? What are 4 warnings and 3 side effects? Does it penetrate the CNS?

Answer 8

voriconazole (Vfend, Vfend IV)

voriconazole is the primary treatment for Aspergillus

Once CrCl < 50mL/min, the IV vehicle SBECD accumulates, so PO voriconazole is preferred

Warnings
- hepatotoxicity
- visual disturbances (optic neuritis)
- phototoxicity
- QT prolongation

Side effects
- increased LFTs
- increase SCr
- CNS toxicity (hallucinations)

Yes, voriconazole penetrates the CNS and can be used to treat fungal meningitis

Question 9

What is posaconazole’s brand name? What is pertinent once the eGFR is < 50? What is 1 warning?

Answer 9

posaconazole (Noxafil)

Once eGFR < 50, the IV vehicle SBECD can accumulate, so oral treatment is preferred at this point

Warning
- QT prolongation

Question 10

What is a contraindication of isavuconazonium? Does it require a filter if IV?

Answer 10

Contraindicated in familial short QT syndrome, since it causes QT shortening, not prolongation

Yes, it requires a filter during IV administration (0.2-1.2 micron)

Question 11

Aside from inhibiting CYP3A4, which azoles inhibit CYP2C9? What drugs can decrease absorption of posaconazole? What is necessary to absorb itraconazole and ketoconazole?

Answer 11

Fluconazole and voriconazole inhibit CYP2C9, which can increase the effects of warfarin.

PPIs and cimetidine can decrease absorption of posaconazole suspension. They should be stopped during therapy.

Itraconazole and ketoconazole require and acidic gut to be absorbed, so separate antacids two hours before and two hours after doses.

Question 12

What is the MOA of echinocandins? What is the only dosage form that these drugs come in? What is 1 warning for this class? What are some benefits of this class (3)?

Answer 12

MOA - inhibit the synthesis of beta (1,3)-D-glucan, which is an essential part of the fungal cell wall.

Only available as injections

Warning
- histamine-mediated symptoms have occurred (rash, pruritis, facial swelling, flushing, hypotension)

Benefits
- do not require dose adjustment in renal impairment
- very few drug interactions
- usually once daily dosing (except rezafungin)

Question 13

What is the brand name for caspofungin and micafungin? Which echinocandin requires light-protection during administration?

Answer 13

caspofungin (Cancidas)
micafungin (Mycamine)

Micafungin requires light-protection during administration

Question 14

What is the preferred treatment for candida albicans oropharyngeal infection (thrush)?

Answer 14

mild disease: topical antifungals (clotrimazole, miconazole)

moderate-severe disease or HIV+: fluconazole

alternative: nystatin

Question 15

What is the preferred treatment for candida albicans esophageal infection?

Answer 15

fluconazole

alternative: echinocandin

Question 16

What is the preferred treatment for candida krusei and glabrata, and all candida bloodstream infections?

Answer 16

echinocandin

alternative: amphotericin B, high-dose fluconazole (if susceptible)

Question 17

What is the preferred treatment for aspergillus?

Answer 17

voriconazole

alternative: amphotericin B, isavuconazonium

Question 18

What is the preferred treatment of cryptococcus neoformans meningitis?

Answer 18

amphotericin B + flucytosine (5-FC)

alternative: high-dose fluconazole + flucytosine (5-FC)

Question 19

What is the preferred treatment for dermatophytes (nail bed infection)

Answer 19

terbinafine or itraconazole

alternative: fluconazole

Question 20

What is the MOA of neuraminidase inhibitors? When do these need to be started to be most effective?

Answer 20

MOA - reduce the amount of virus in the body by inhibiting the enzyme that enables the release of new viral particles from infected cells.
- oseltamivir, zanamivir, peramivir

Must be started within 48 hours of illness onset to be most effective. They decrease the duration of symptoms by ~1 day and decrease complications.

Question 21

What are the dosage forms of oseltamivir? What is the dosing for treatment and prophylaxis? What is 1 warning and 3 side effects? Can it be used in pregnancy?

Answer 21

Oseltamivir (tamiflu)
- comes in capsules and suspension

Treatment, age > 12 yo: 75mg BID x5 days
Prophylaxis, age > 12 yo: 75mg QD x10 days

Warning: neuropsychiatric events (sudden confusion, delirium, hallucinations, unusual behavior or self-injury)

Side effect: headache, nausea, vomiting

Yes it can be used in pregnancy. It is the preferred neuraminidase inhibitor in pregnancy!

Question 22

What dosage form does zanamivir come in? What is 1 warning?

Answer 22

Zanamivir (Relenza Diskhaler) is an inhaler

Warning
- bronchospasm (do not use in asthma/COPD or with any breathing problems)

Question 23

What is the MOA of baloxavir marboxil? When should it be started? What is a benefit of it?

Answer 23

MOA - endonuclease inhibitor

Needs to be started w/in 48 hours of symptom onset

Benefit: single-dose regimen

Question 24

What are 3 antivirals for herpes simplex virus and varicella zoster virus? In what patients should we have caution in?

Answer 24

• acyclovir (Zovirax) - dosed based on IBW, including obese pts
• valacyclovir (Valtrex)
• famciclovir - prodrug of penciclovir

Caution in patients with renal impairment, the elderly, and/or those receiving nephrotoxic drugs

Question 25

What are 2 topical treatment options for herpes labialis & what is the dosing? What are 3 systemic drugs that can be used?

Answer 25

Docosanol (Abreva) - OTC; apply 5x daily at first sign of outbreak, continue until healed Acyclovir (Zovirax) - Rx; apply 5x daily for 4 days (can be used on genital sores) Systemic: - acyclovir - valacyclovir - famciclovir

Question 26

When must treatment of genital herpes be initiated? What are the 3 drugs that we can use?

Answer 26

Treatment must be initiated during the prodrome period or within 1 day of lesion onset. - acyclovir (sometimes up to 5x/day dosing) - valacyclovir - famciclovir

Question 27

How is HSV encephalitis treated?

Answer 27

IV acyclovir x14-21 days

Question 28

When is treatment of varicella zoster virus/herpes zoster most effective? How should pain be treated? What are the immunization recommendations to prevent shingles?

Answer 28

Treatment is most effected when started within 72 hours of onset of zoster rash. - acyclovir for 7 days - valacyclovir for 7 days - famciclovir for 7 days Pain: - topical medications (Lidoderm patch, lidocaine gel) - neuropathic pain meds (pregabalin, gabapentin, duloxetine, TCAs) - NSAIDs - opioids Immunizations: - shingles (Shingrix) recommended in adults ≥ 50 years who are immunocompetent and adults ≥ 19 years who are or will be immunosuppressed

Question 29

What are the treatments of choice for cytomegalovirus? What meds should be reserved for refractory cases? What medications can be used for secondary prophylaxis?

Answer 29

Treatments of choice for CMV: ganciclovir, valganciclovir Refractory: foscarnet, cidofovir Secondary ppx: letermovir (in pts receiving a kidney transplant if donor is CMV pos or bone marrow tx if recipient is CMV pos), ganciclovir and valganciclovir (in pts receiving SOT if donor is CMV pos)

Question 30

What is valganciclovir's brand name? What is a boxed warning for ganciclovir and valganciclovir? Can these be used in pregnancy?

Answer 30

valganciclovir (Valcyte) Boxed warning: myelosuppression NO these cannot be used in pregnancy. Females should use contraception during treatment and for 30 days after.

Question 31

What is 1 boxed warning for foscarnet?

Answer 31

Boxed warning - renal impairment

Question 32

How can Epstein-Barr Virus be spread?

Answer 32

(aka "mono") Transmitted through bodily fluids, primarily saliva, and can be spread by kissing There is no treatment for EBV. Symptoms usually resolve in 2-4 weeks.