Chapter 34: Antifungal and Antiviral Agents

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1

What are the nine major fungal diseases?

  1. aspergillosis (Aspergillus fumigatus)
  2. blastomycosis (Blastomyces dermatitidis)
  3. candidiasis (Candida albicans)
  4. coccidioidomycosis (Coccidioides immitis)
  5. cryptococcosis (Cryptococcus neoformans)
  6. histoplasmosis (Histoplasma capsulatum)
  7. mucormycosis (Mucor and Rhizopus)
  8. sporotrichosis (Sporothrix schenckii)
  9. dermatophyte (skin) infections caused by Epidermophyton, Trichophyton, and Microsporum
2

What are the eight categories of anti fungal drugs?

  1. polyenes (nystatin)
  2. azoles (itraconazole)
  3. echinocandins (caspofungin)
  4. allylamines (terbinafine)
  5. pyrimidine (flucytosine)
  6. oxaborole (tavaborole)
  7. thiocarbamate (tolnaftate)
  8. miscellaneous (ciclopirox)
3

What fungus is most commonly observed in oral lesions?

Candida albicans

4

What are the two subcategories of fungal infections?

  1. opportunistic mycoses
  2. endemic mycoses
5

Which type of fungal infections occur in debilitated and immunocompromised patients?

opportunistic mycoses

6

What are four common opportunistic mycoses?

  1. candidiasis (Candida albicans)
  2. aspergillosis (Aspergillus fumigatus)
  3. cryptococcosis (Cryptococcus neoformans)
  4. mucormycosis (Mucor and Rhizopus)
7

Which type of fungal infections are caused by various pathogens distributed unevenly throughout the world?

endemic mycoses

8

What are four common endemic mycoses?

  1. blastomycosis (Blastomyces dermatitidis)
  2. histoplasmosis (Histoplasma capsulatum)
  3. coccidioidomycosis (Coccidioides immitis)
  4. sporotrichosis (Sporothrix schenckii)
9

What are two polyene antifungal drugs?

card image
  1. amphotericin B
  2. nystatin
10

What is the mechanism of action of polyene antifungal drugs such as amphotericin B and nystatin?

card image

They bind to ergosterol in fungal cell membranes, forming channels that cause leakage of ions.

11

What is the spectrum of activity of amphotericin B? (5)

It has a broad spectrum of antifungal activity:

  1. Candida
  2. Histoplasma capsulatum
  3. Cryptococcus neoformans
  4. Blastomyces dermatitidis
  5. Coccidioides immitis
12

What is the route of administration of amphotericin B for systemic infections?

slow intravenous infusion

13

What is the route of administration of amphotericin B for superficial Candida infections?

topical cream

14

What are the adverse effects of amphotericin B? (12)

The only adverse effects of topical amphotericin B are local irritation and mild gastrointestinal disturbances.

As an intravenous agent, however, amphotericin B is the most toxic antifungal in current use:

  1. hypotension
  2. delirium
  3. fever
  4. nausea
  5. vomiting
  6. headache
  7. thrombophlebitis
  8. hypochromic, normocytic anemia
  9. allergic reactions (including anaphylaxis)
  10. nephrotoxicity
15

What can be induced by amphotericin B which can increase digitalis toxicity?

hypokalemia

16

What is the spectrum of nystatin? (5)

It is slightly narrower than that of amphotericin B:

  1. Candida
  2. Histoplasma
  3. Cryptococcus
  4. Blastomyces
  5. dermatophytes
17

What is nystatin the drug of choice for?

oral candidiasis

18

How is nystatin administered?

As a 100,000 U/mL solution, 4-6 mL swished for 5 minutes before swallowing.

19

What are the adverse effects of nystatin? (3)

Only mild gastrointestinal disturbances:

  1. nausea
  2. vomiting
  3. diarrhea

The major complaint is its bitter, foul taste.

20

What are the two azole groups of antifungal drugs?

card image
  1. imidazoles
  2. triazoles
21

What is the spectrum of activity of the azole antifungal drugs? (6)

They have a broad spectrum of antifungal activity:

  1. dermatophytes
  2. Candida
  3. Histoplasma
  4. Blastomyces
  5. Aspergillus
  6. Sporothrix
22

What is the mechanism of action of the azole antifungal drugs?

card image

The azole ring binds to the fungal cytochrome P450 enzyme lanosterol 14-α-demethylase, thereby inhibiting the conversion of lanosterol to ergosterol.

23

Why do triazoles have lower toxicity and fewer drug–drug interactions than imidazoles?

Because they are more selective for the fungal cytochrome P450 enzymes.

24

What is the prototypical azole antifungal drug?

ketoconazole

25

Why isn't ketoconazole commonly used for systemic purposes today?

Because of several adverse effects due to inhibition of sex hormone synthesis and drug metabolism.

26

What water-insoluble triazole antifungal shows a broad spectrum of antifungal activity?

itraconazole

27

What is systemic itraconazole used to treat?

severe candidiasis

28

What are the adverse effects of itraconazole? (4)

  1. hypokalemia
  2. liver dysfunction
  3. heart failure (rare)
  4. some drug–drug interactions
29

What water-insoluble fluorine-substituted bistriazole has effective antifungal activity in immunocompetent and immunocompromised patients?

fluconazole

30

What unique property of fluconazole allows it to treat certain infections that other antifungals can't?

Its ability to penetrate the blood–brain barrier makes it valuable for cases of fungal meningitis.

31

What is fluconazole used to treat? (3)

  1. cryptococcal meningitis
  2. oropharyngeal candidiasis
  3. esophageal candidiasis
32

What are the adverse effects of fluconazole? (4)

  1. hypokalemia
  2. liver dysfunction
  3. QT elongation
  4. some drug–drug interactions
33

What triazole is used orally for systemic fungal infections, especially Aspergillus and Candida?

voriconazole

34

What is voriconazole the drug of choice for?

aspergillosis

35

What are the adverse effects of voriconazole? (4)

  1. erythematous rash
  2. visual disturbances
  3. hepatotoxicity
  4. headache
36

Which triazole is similar to itraconazole, but with activity against Mucorales (e.g. Mucor and Rhizopus)?

posaconazole

37

What is posaconazole used to treat?

oropharyngeal candidiasis

38

What are the adverse effects of posaconazole? (5)

  1. fatigue
  2. nausea
  3. diarrhea
  4. hepatic toxicity
  5. QT elongation
39

What water-soluble triazole is used for the treatment of severe systemic infections?

isavuconazole

40

What is isavuconazole used to treat? (3)

It was developed for life-threatening diseases.

  1. invasive aspergillosis
  2. invasive mucormycosis

It is also used to treat esophageal candidiasis.

41

What are two topical azoles of special interest in the treatment of oral candidiasis?

  1. miconazole
  2. clotrimazole
42

Which topical imidazole antifungal drug is used for various mucosal and cutaneous infections?

clotrimazole

43

How is clotrimazole administered?

As a 10 mg oral troche dissolved in the mouth.

44

What are the adverse effects of clotrimazole? (4)

Adverse effects are unlikely, but may include:

  1. oral burning
  2. altered taste
  3. xerostomia
  4. minor gastrointestinal upset
45

Which topical imidazole antifungal drug is useful against cutaneous candidiasis and vulvovaginitis?

miconazole

46

How is miconazole administered?

As a 50 mg tablet, placed on the gingiva of the canine fossa above tooth #8 and #9.

47

What is one adverse effect of miconazole that differs from those of clotrimazole?

The adverse oral effects are similar to clotrimazole, with the additional possibility of gingival irritation.

48

Which triazole is used for the treatment of onychomycosis and other superficial fungal infections?

efinaconazole

49

What is onychomycosis?

Infection of the nail bed; toenails most common.

50

Which imidazole is used for the treatment of tinea infections?

luliconazole

51

What are tinea infections?

Fungal infections of the skin, including:

  1. tinea pedis (Athlete's foot)
  2. tinea cruris (Jock itch)
  3. tinea corporis (ringworm)
52

What are the three echinocandin antifungal drugs?

card image
  1. caspofungin
  2. micafungin
  3. anidulafungin
53

What is the mechanism of action of echinocandin antifungal drugs?

card image

They noncompetitively inhibit of synthesis of 1,3-β-D-glucan components of fungal cell walls by inhibiting 1,3-β-d-glucan synthase.

54

What types of patients receive echinocandin antifungal drugs as prophylaxis?

hematopoietic stem cell transplant (HSCT) recipients

55

Why would echinocandin antifungals be used in combination therapy with azole antifungals?

Because of their different mechanisms of action, these antifungal agents has synergistic effects.

56

What is caspofungin used to treat? (2)

  1. candidal infections
  2. aspergillosis
57

What are the adverse effects of caspofungin? (5)

The common adverse effects resemble histamine-mediated symptoms.

  1. rash
  2. facial swelling
  3. pruritus
  4. hepatic toxicity
  5. hypokalemia
58

What is micafungin used to treat? (2)

  1. esophageal candidiasis
  2. aspergillosis
59

What is anidulafungin used to treat? (4)

  1. esophageal candidiasis
  2. candidemia
  3. invasive candidiasis
  4. aspergillus
60

What synthetic fluoridated cytosine analogue is orally effective in the treatment of systemic fungal infections?

card image

flucytosine

61

What is the spectrum of activity of flucytosine? (4)

It has a limited antifungal spectrum:

  1. Candida
  2. Cryptococcus
  3. Cladosporium
  4. Phialophora
62

What is the mechanism of action of flucytosine?

It is converted to 5-fluorouracil in fungal cells, which is metabolized to 5-fluorodeoxyuridine monophosphate, a competitive inhibitor of thymidylate synthetase, an enzyme needed for DNA synthesis.

63

What is flucytosine used to treat?

  1. systemic candidiasis
  2. cryptococcosis
64

What is a frequent challenge to treatment of fungal infections with flucytosine?

fungal resistance

65

Why is flucytosine normally used in combination with amphotericin B?

It appears to increase fungal uptake of flucytosine and to result in synergistic effects against certain diseases.

66

What is a unique property of the distribution of flucytosine?

It attains a concentration in cerebrospinal fluid approximately 65% to 90% that of the plasma.

67

What are the adverse effects of flucytosine?

The major toxicity is depression of bone marrow.

  1. anemia
  2. leukopenia
  3. thrombocytopenia
  4. hepatomegaly
  5. nausea
  6. vomiting
  7. diarrhea
  8. severe enterocolitis (rare)
68

What are the two allylamine antifungal drugs?

  1. naftifine
  2. terbinafine
69

What is the mechanism of action of the allylamine antifungal drugs?

They inhibit squalene epoxidase, important in the synthesis of ergosterol.

70

What benzylamine drug has the same mechanism of action as the allylamines?

butenafine

71

What oxaborole antifungal drug is used topically to treat onychomycosis?

tavaborole

72

What is the mechanism of action of tavaborole?

It inhibits aminoacyl-transfer ribonucleic acid (tRNA) synthetase, which is essential in fungal protein synthesis.

73

What thiocarbamate antifungal drug is commonly used as a topical antifungal agent against mild to moderate superficial dermatophyte fungal infection?

tolnaftate

74

What broad-spectrum hydroxypyrimidine derivative antifungal drug is used for dermal infections?

ciclopirox

75

What is the most common type of oral fungal infection?

candidiasis

76

What is the usual length of treatment for oral candidiasis regardless of which drug is used?

2 weeks

77

What are the three topical antifugals of choice to treat oral candidiasis?

  1. clotrimazole
  2. nystatin
  3. miconazole
78

What is the standard dosage of clotrimazole for treatment of oral candidiasis?

Allow one 10 mg oral troche to dissolve in the mouth, 5 times daily, for 14 days.

79

What is the standard dosage of nystatin for treatment of oral candidiasis?

Swish 4-6 mL (400,000-600,000 U) solution for at least 5 minutes before swallowing; repeat every 4 times daily for 14 days or until resolution.

80

What is the standard dosage of miconazole for treatment of oral candidiasis?

Place one 50 mg tablet per day on the gingiva of the canine fossa above tooth #8 and #9 for 14 days.

81

What are systemic antifungals indicated over topical antifunngals in the treatment of oral candidiasis?

For more extensive disease or difficult cases, such as immunocompromised patients with AIDS.

82

What are the four systemic antifugals of choice to treat extensive oral candidiasis?

  1. itraconazole
  2. fluconazole
  3. posaconazole
  4. caspofungin
83

What is the standard dosage of itraconazole for treatment of oral candidiasis?

Give 200 mg by mouth daily for 7-14 days.

84

What is the standard dosage of fluconazole for treatment of oral candidiasis?

Give 200 mg by mouth on day 1, then 100 mg by mouth once daily for 14 days.

85

What is the standard dosage of posaconazole for treatment of oral candidiasis?

Give 100 mg (2.5 mL) by mouth twice daily on day 1, then 100 mg (2.5 mL) by mouth once daily, for 13 days.

86

What is the standard dosage of caspofungin for treatment of oral candidiasis?

Give 50 mg intravenously once daily for 7-14 days, or longer if more severe.

87

What are the six groups of antiviral drugs based on the infections they treat?

  1. influenza virus
  2. ocular herpes
  3. systemic herpes
  4. respiratory syncytial virus
  5. hepatitis B
  6. hepatitis C
88

What type of virus is influenza?

RNA virus

89

What are the six steps in the life cycle of a RNA virus?

card image
  1. penetration of the cell through endocytosis
  2. uncoating of virion via M2-induced H+ influx
  3. release of the viral RNP
  4. replication of viral RNA
  5. translation of viral mRNA
  6. assembly and release of new virons
90

What is the mechanism of action of amantadine and rimantadine?

They inhibit viral M2 protein, thus preventing the H+ influxe required for uncoating of the virus.

91

What is the mechanism of action of oseltamivir, zanamivir, and peramivir?

They inhibit viral neuraminidase, thus blocking the release of progeny virus from the infected cells.

92

What are the two types of influenza vaccines?

  1. trivalent inactivated vaccine
  2. live-attenuated intranasal vaccine
93

How soon after administration of an influenza vaccine does protection develop, and how long does it last?

Antibodies reach a protective level approximately two weeks after immunization, and persist for 6 months.

94

What type of virus are herpesviruses?

DNA viruses

95

What are the six steps in the life cycle of a DNA virus?

card image
  1. penetration of the cell through endocytosis
  2. uncoating of virion
  3. release of the viral DNA
  4. incorporation of viral DNA into host DNA
  5. transcription of viral mRNA
  6. translation of viral mRNA
  7. assembly and release of new virons
96

What are the three major herpesviruses in humans?

  1. herpes simplex virus (HSV)
  2. varicella zoster virus (VZV)
  3. cytomegalovirus (CMV)
97

What is the mechanism of action of cyclovir, valacyclovir, and penciclovir?

They are activated by virus-encoded enzymes and inhibit DNA polymerase.

98

What virus commonly causes winter outbreaks of respiratory tract illness?

respiratory syncytial virus (RSV)

99

What are the five primary viruses that can affect the liver

hepatitis A, B, C, D, and E

100

Which two viruses are the most common causes of chronic hepatitis infections?

  1. hepatitis B (HBV)
  2. hepatitis C (HCV)
101

What are six antiviral drugs used to treat HBV infection?

  1. lamivudine (3 TC)
  2. entecavir
  3. adefovir
  4. telbivudine
  5. clevudine
  6. tenofovir
102

What are six antiviral drugs used to treat HCV infection?

  1. interferons
  2. ribavirin,
  3. sofosbuvir
  4. telaprevir
  5. boceprevir
  6. simeprevir
103

What glycoproteins secreted by virus-infected cells promote the establishment of an antiviral state in uninfected cells?

interferons

104

What are the three major groups of interferons?

α, β, and γ

105

What are the two mechanisms of action of interferon in treatment of viral infections?

card image
  1. It stimulates synthesis of an oligonucleotide polymerase that synthesizes a series of oligonucleotides, which stimulate cellular endonucleases to cleave viral mRNA
  2. It stimulates synthesis of a protein kinase that phosphorylates and inactivates eukaryotic initiation factor, which stops protein synthesis.
106

What interferon is used in the treatment of HBV?

interferon α2a

107

What does "pegylation" of interferon α2a accomplish?

It adds polyethylene glycol (PEG) to interferon, which makes it last longer in the body.

108

What are the six major types of drugs used to treat HIV/AIDS?

  1. nucleoside reverse transcriptase inhibitors (NRTIs)
  2. non-nucleoside reverse transcriptase inhibitors (NNRTIs)
  3. protease inhibitors (PIs)
  4. integrase strand transfer inhibitors (INSTIs)
  5. entry inhibitors (CCR5 antagonist)
  6. fusion inhibitors.
109

What is the mechanism of action of the following antiviral drugs?

  1. abacavir
  2. didanosine
  3. emtricitabine
  4. stavudine
  5. tenofovir

There are NRTIs, which are nucleotide analogues that competitively inhibit reverse transcriptase.

110

What is the mechanism of action of the following antiviral drugs?

  1. delavirdine
  2. efavirenz
  3. etravirine
  4. nevirapine
  5. rilpivirine

There are NNRTIs, which work by noncompetitive inhibition of the reverse transcriptase enzyme.

111

What is the mechanism of action of the following antiviral drugs?

  1. amprenavir
  2. atazanavir
  3. darunavir
  4. lopinavir
  5. nelfinavir

They inhibit protease, the viral enzyme responsible for cleavage of proteins required for assembly of virions.

112

What is the mechanism of action of the following antiviral drugs?

  1. dolutegravir
  2. elvitegravir
  3. raltegravir

They block the action of integrase, a viral enzyme of the HIV type 1, which is involved in integrating viral DNA into the host chromosome.

113

What is the mechanism of action of the antiviral drug maraviroc?

It inhibits the CCR5 receptor on human cells, which blocks the HIV gp120 from associating with it, thus preventing enerty of HIV into the host cell.

114

What is the mechanism of action of the antiviral drug enfuvirtide?

It binds to a viral envelope gp120, which prevents fusion between the viral envelope with host plasma membrane, blocking HIV from entering the cell.

115

What is the combination of antiretroviral drugs used to treat HIV infections called?

highly active antiretroviral therapy (HAART)

116

What are four drug cominations used to treat HIV?

tenofovir (NRTI) + emtricitabine (NRTI) + one of the following:

  1. efavirenz (NNRTI)
  2. ritonavir-boosted atazanavir (PI)
  3. ritonavir-boosted darunavir (PI)
  4. raltegravir (ISTI)
117

What is the best antiviral drug to use as soon as HSV-associated viral lesions appear?

acyclovir

118

What is the is the drug of choice for the control of recurrent Herpes labialis?

penciclovir

119

What are two drugs usful in treating acyclovir-resitance HSV strains?

  1. ganciclovir
  2. foscarnet
120

What are three common co-viral infections in AIDS patients and their concomitant oral lesions?

  1. HPV (papillomas, condylomas)
  2. CMV (aphthae-like ulcerations)
  3. EBV (oral hairy leukoplakia)