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micro_db > Antifungals and Antivirals > Flashcards

Antifungals and Antivirals Flashcards

1
Q

does fungal infections are increasing or decreasing in prevalence

A

Fungal infections are increasing in prevalence, e.g. in patients with HIV infection & in patients being treated for malignancy (i.e., opportunistic infection)

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2
Q

how fungal infections present in immunosuppressed patients?

A

In immunosuppressed patients, infections may present insidiously or late, leading to a poor response to treatment

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3
Q

are fungi prokaryotes?

A

NO
Fungi = eukaryotes (i.e. have same cellular structure as host/human cells) versus bacteria = prokaryotes: greater challenges in developing non-toxic antifungal agents

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4
Q

what it is more difficult to develop human non-toxic antifungals

A

Fungi = eukaryotes (i.e. have the same cellular structure as host/human cells) versus bacteria = prokaryotes: greater challenges in developing non-toxic antifungal agents

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5
Q

does C. Albicans intrinsically resistant to azoles?

A

no, it acquires resistance

1) Candida krusei—–intrinsically resistant to fluconazole)
2) Candida albicans—-susceptible to fluconazole BUT can also acquire resistance to fluconazole
3) Candida Auris (emerging species)—-associated with infection outbreaks in hospitals – most resistant to fluconazole, with variable resistance to other antifungal classes
4) Aspergillus fumigatus—acquired azole resistance

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6
Q

what are the candida species that intrinsically resistant to azoles?

A 
Candida krusei-----intrinsically resistant to fluconazole)
Candida Auris (emerging species)----associated with infection outbreaks in hospitals – most resistant to fluconazole, with variable resistance to other antifungal classes
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7
Q

what is the mechanism of action of antifungals?

A

azoles and amphotericin B act on cell membrane:
act on sterols, including ergosterol, in the fungal cell membrane, causing increased permeability & leakage of cell constituents
e.g. polyenes such as amphotericin B inhibit ergosterol biosynthesis which causes leakage of cellular constituents

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8
Q

what antifungals act on cell wall?

A

interfere with synthesis of glucan in the cell wall

e.g. echinocandins

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9
Q

how do azoles work?

A

Inhibit fungal cytochrome P450, which decreases fungal synthesis of ergosterol from lanosterol

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10
Q

how do amphotericin B works?

A

Bind to ergosterol in the fungal cell membrane, which forms pores that disrupt electrolyte balance

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11
Q

how do echinocandins work?

A

Inhibit synthesis of β-glucan (a component of the fungal cell wall)

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12
Q

which antifungal interfere with DNA and RNA synthesis?

A

5-fluorocytosine

onverted to 5-fluorouracil by fungal cytosine deaminase, which then inhibits DNA and RNA synthesis

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13
Q

which antibiotic interferes with folate metabolism and used for PCP treatment?

A

. co-trimoxazole

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14
Q

what are the members of polyenes?

A

Amphotericin B & nystatin

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15
Q

how terbinafine works?

A

Inhibit fungal squalene epoxidase, which decreases ergosterol synthesis

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16
Q

how polyenes are administered?

A

Topical-nystatin mouthwash

systemic- amphotericin B lipid formulation (intravenous)

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17
Q

what are the signs of amphotericin toxicity?

A

–Toxicity can cause arrhythmias → cardiac arrest
–Nephrotoxicity
–Fever, chills
–Hypotension
–IV phlebitis (“amphoterrible”)
–Hypokalemia
–Hypomagnesemia
–Anemia
–Hearing loss
–Neuropathy
Lipid formulations have fewer side effects but more expensive, e.g. liposomal amphotericin B (Ambisome) or amphotericin B lipid complex

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18
Q

what are the routes of azole administration?

A

– topical: miconazole
– systemic (oral & parenteral)
– fluconazole, voriconazole, posaconazole, isavconazole

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19
Q

what is the spectrum of activity of azoles?

A

Fluconazole: Candida albicans (not C. krusei) but no activity against moulds
Voriconazole: all Candida & Aspergillus spp.
Posaconazole: Candida, Aspergillus & Mucorales spp.

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20
Q

do azoles work on C krusei?

A

no

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21
Q

what are the side effects of azoles?

A

1) Hepatotoxicity
- Inhibits cytochrome P-450 → ↑ concentration of many drugs metabolized by P-450 (e.g., warfarin, simvastatin, cyclosporine, theophylline, etc.)
2) Gastrointestinal upset
3) Gynecomastia
4) QT prolongation → torsade de pointes
5) Hypokalemia
6) Additionally in ketoconazole
- -Adrenal cortex insufficiency
- -Topical use: local burning, reaction, and/or pruritus
7) Additionally in voriconazole
- -Dose-dependent, reversible visual disorders
- -Photosensitivity

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22
Q

echinocandins can be administered orally. True/False

A

Fale

intravenous only

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23
Q

echinocandins work on?

A

Candida spp., Aspergillus spp.

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24
Q

what are the side effects of echinocandins?

A
  • -flushing
  • -Hypotension
  • -Hepatotoxicity
  • -Gastrointestinal upset
  • -Phlebitis/pain at injection site
  • -Fever, shivering
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25
Q

what are the uses of terbinafine?

A

– For the treatment of tinea (ringworm) and fungal nail infection (onychomycosis)
– Oral or topical
– Mechanism of action-interferes with ergosterol synthesis
– Accumulates in keratin- good for treating dermatophyte infections
– Few interactions (monitor LFTs on oral therapy)
o Generally well- tolerated

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26
Q

why terbinafine is good for dermatophyte infections?

A

Accumulates in keratin

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27
Q

what are the agents of choice in superficial fungal infections?

A

1) Superficial infections—topical antifungals for 1 - 4 weeks
2) Extensive skin or nail infection—oral antifungals for 2 - 10 weeks
3) Onychomycosis (nail infection) – duration is until the nail grows out, terbinafine: 6-12 weeks, itraconazole for 1 week every month for 3 months
4) Candidiasis (thrush): topical azoles/polyenes +/- oral agents

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28
Q

what are the treatment options for systemic or opportunistic mycoses?

A
  • Amphotericin B for unknown or unidentified invasive fungal infection
  • Caspofungin for invasive infection due to Candida spp, pending susceptibility data, were available - empiric treatment
  • Fluconazole for invasive infection caused by Candida albicans& other susceptible strains
  • Voriconazole for invasive aspergillosis
  • Amphotericin B & flucytosine for cryptococcal meningitis
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29
Q

ampho B and flucytosine are used for?

A

cryptococcal meningitis

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30
Q

how P. jiroveci (carinii) infection is treated?

A
  • Trimethoprim-sulfamethoxazole (co-trimoxazole) is the drug of choice, high dose IV
  • Dapsone or clindamycin may be used
  • Adjunctive corticosteroids are indicated if there is severe hypoxia
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31
Q

what antifungals are used for prophylaxis of fungal diseases in patients with HIV?

A

• Anti-candida prophylaxis
- Fluconazole
• Following treatment of cryptococcosis
- long term fluconazole
• Anti-PCP
- e.g. PO co-trimoxazole nebulized pentamidine
N.B. Patients on HAART with viral suppression do not need long-term prophylaxis

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32
Q

what antifungals are used for prophylaxis of fungal diseases in hematology and oncology patients?

A
  • -Anti-candida prophylaxis: oral fluconazole
  • -Anti-aspergillus prophylaxis: oral posaconazole for at-risk patients (also protects against candida)
    e. g., AML, allogeneic HSCT, at-risk inpatients if proximity to demolition, construction, renovation work
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33
Q

what azole is used for aspergillus prophylaxis?

A

posaconazole

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34
Q

what are the challenges in developing antiviral agents?

A
  • Intracellular pathogens not extracellular
  • Latency, i.e. dormant for years (HSV, VZV, CMV, EBV)
  • Lack of culture systems for some viruses
  • Uncertainty regarding many viral genetic functions & pathogenic properties
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35
Q

what are the general mechanisms of action of antiviral agents?

A
  1. Direct inactivation of intact viruses (virucides)
  2. Augmentation or modification of host response to infection
  3. Inhibition of viral replication at the cellular level
36
Q

what are the virucides?

A

– Detergents, hence important of hand hygiene & ‘common cold’
– UV light inactivation, but there are issues of safety
– Cryotherapy, laser or podophyllin for treatment of warts, e.g. genital

37
Q

how augmentation/modification of host response defends against viruses

A

– These replace deficient host immune responses &/or enhance endogenous ones, i.e. immunomodulatory
– Immunoglobulin (high titer) after exposure e.g. varicella-zoster immunoglobulin (ZIG)
– Also, CMV e.g. transplant mismatch, rabies, e.g. animal bite, hepatitis B, e.g. needle stick
– Interferon, e.g. hepatitis

38
Q

what are the uses of agents that modify host immune response against viruses

A

Immunoglobulin (high titer) after exposure e.g. varicella-zoster immunoglobulin (ZIG)
– Also, CMV e.g. transplant mismatch, rabies, e.g. animal bite, hepatitis B, e.g. needle stick
– Interferon, e.g. hepatitis

39
Q

examples of agents that inhibit viral replication

A
  1. Aciclovir
  2. Valaciclovir
  3. Ganciclovir
  4. Valganciclovir
  5. Foscarnet (non nucleoside polymerase inhibitor)
  6. Cidofovir
  7. Anti-influenza agents (oseltamivir)
40
Q

what is the acyclovir?

A

– Active against HSV 1 & 2, VZV
– Analogue of guanosine; needs to be activated to achieve antiviral effect
– Initial phosphorylation step by viral thymidine kinase – activates drug
– Phosphorylated to triphosphate or active form within infected cell
– Incorporated into growing DNA chain
– Leads to chain termination
– Aciclovir triphosphate is also a direct inhibitor of viral DNA polymerase

41
Q

how does acyclovir work?

A
  • -Guanosine analog (nucleoside analog): initially HSV/VZV-coded thymidine kinase monophosphorylates the guanosine analog to an active intermediate, which is then phosphorylated by cellular kinases
  • -The phosphorylated drug is incorporated into the replicating viral DNA strand and inhibits the viral DNA polymerase → termination of viral DNA synthesis
  • -Selective action in infected cells only → minimal effect on host cells’ DNA replication
42
Q

why acyclovir works only on infected cells?

A

the drug is only activated in cells infected with HSV or VZV. In addition, the DNA polymerase in human cells has very little affinity for the active form of these drugs.

43
Q

what are the clinical uses of acyclovir?

A
  • Drug of choice for treatment of serious infections
  • HSV encephalitis
  • Neonatal HSV
  • Disseminated HSV
  • Disseminated varicella-zoster
  • Severe varicella pneumonia
  • Serious mucocutaneous, visceral or central nervous system disease due to herpes simplex or varicella-zoster
  • Recurrent genital HSV infection
  • Orolabial HSV infection
  • Herpes zoster
  • Prophylaxis of HSV infections in immunocompromised patients
44
Q

what are the side effects of acyclovir?

A

– crystal-induced acute kidney injury
Prevention: dosage adjustment, adequate hydration
–↑ Transaminases
–Gastrointestinal symptoms
–Thrombotic thrombocytopenic purpura
IV acyclovir can cause acute kidney injury because it precipitates into crystals at higher concentrations.

45
Q

what is the valacyclovir?

A
  • A prodrug, i.e. valyl ester of aciclovir
  • Rapidly absorbed from GIT
  • First pass intestinal & hepatic hydrolysis yields complete conversion to aciclovir
46
Q

what is the advantage of valacyclovir against acyclovir?

A

greater oral bioavailability

47
Q

what is the ganciclovir?

A

• First antiviral agent with activity against CMV
• Used primarily in patients with impaired cell mediated immunity
– AIDS
– Solid organ recipients & bone marrow transplants
• Derivative of aciclovir
• Analog of guanosine
• IV administration for HSV 1 & 2, VZV, CMV

48
Q

how does ganciclovir work?

A
  • -Guanosine analog (nucleoside analog): initially phosphorylated to 5’ monophosphate by the CMV-coded UL97 kinase → further phosphorylated to triphosphate by cellular kinases
  • -The phosphorylated drug is incorporated into the replicating viral DNA strand and inhibits the viral DNA polymerase → termination of viral DNA synthesis
  • -Lower selectivity than acyclovir and penciclovir → can affect host cell’s DNA replication
49
Q

what are the clinical uses of ganciclovir?

A
  • Prophylaxis & pre-emptive treatment for those most at risk of CMV disease in transplant recipients
  • Pneumonia
  • GI disease (e.g. colitis)
  • Encephalitis
  • Retinitis
50
Q

what are the side effects of ganciclovir?

A

1) Hematological abnormalities
- -Pancytopenia (additive effect when administered with NRTIs)
2) Nephrotoxicity
3) Gastrointestinal symptoms
4) CNS
- -Headache
- -Confusion
- -Paresthesias

51
Q

what is the advantage of valganciclovir against ganciclovir

A

A prodrug of ganciclovir with better oral bioavailability used to treat cytomegalovirus (CMV) infections.

52
Q

what is the foscarnet?

A

A viral DNA/RNA polymerase and HIV reverse transcriptase inhibitor used to treat acyclovir-resistant HSV infections and as a second-line treatment for CMV retinitis in patients who are immunocompromised.
• Pyrophosphate analog
• Does not require phosphorylation
• Forms complexes with DNA polymerases inhibiting further DNA synthesis
• In vitro activity against many herpes family viruses

53
Q

does foscarnet require phosphorylation to be active?

A

no

54
Q

what are the main uses of foscarnet?

A

Ganciclovir-resistant CMV retinitis

Acyclovir-resistant HSV

55
Q

what are the side effects of foscarnet?

A

–Nephrotoxicity
–Gastrointestinal symptoms
–CNS
Headache
Confusion
Paresthesias
Seizures due to electrolyte abnormalities (e.g., hypocalcemia)
–Hematological abnormalities
Leukopenia
Neutropenia

56
Q

how foscarnet works?

A

Viral DNA/RNA polymerase inhibitor and HIV reverse transcriptase inhibitor: direct inhibition of viral DNA polymerases by binding to the pyrophosphate binding site of enzyme

57
Q

what is the cidofovir?

A
  • Developed primarily as anti-CMV agent
  • Mechanism of action via two phosphorylation steps required to reach active triphosphate form, cellular enzymes, competitive inhibitor of viral DNA polymerase & triphosphate exhibits greater affinity for viral DNA polymerase
  • Broad spectrum anti-herpesvirus activity
58
Q

does cidofovir require initial phosphorylation?

A

As it is a monophosphate analog, cidofovir does not require initial phosphorylation. Cellular kinases within an infected cell phosphorylate the molecule to cidofovir diphosphate, which is incorporated into the genomic DNA of the virus.

59
Q

what are the clinical uses of cidofovir?

A
  • For CMV, especially CMV retinitis
  • Ganciclovir & foscarnet resistant strains of CMV
  • Aciclovir resistant HSV strains
  • Adenovirus infection in allogenic stem cell transplant patient
60
Q

what CMV infections especially are treated with cidofovir

A

CMV retinitis

61
Q

what are the side effects of cidofovir

A

Dose dependent nephrotoxicity & neutropenia

Nephrotoxicity is reduced with administration of probenecid and IV fluids

62
Q

what is the oseltamivir?

A
  • Neuraminidase inhibitor
  • Specific for influenza A & B neuraminidase
  • Oral formulation, Well-tolerated
  • Resistance emerged in 2007-08, not yet a widespread clinical problem but increasing
  • Give within 48 hrs of onset symptoms to patients at risk of severe influenza infection
  • Reduces duration & severity of symptoms
  • Can also be given as prophylaxis to ‘at-risk’ patients exposed to influenza (e.g., outbreak)
63
Q

what is the MOA of oseltamivir?

A

These agents inhibit viral budding and prevent dissemination of the virus into the bloodstream by inhibiting the neuraminidase (required for viral exit of the cell) found in the influenza virus.

64
Q

at what time period of symptom onset oseltamivir should be administered?

A

In influenza A and B, the rapid administration of neuraminidase inhibitors within 1–2 days of symptom onset is vital to reduce the duration of illness and alleviate symptoms.

65
Q

what is the route of administration of zanamivir?

A

Orally inhaled agent via inhaler and also available in IV formulation

66
Q

what are the contraindications of zanamivir?

A

in COPD patients (bronchospasm) & children <7 years of age

67
Q

what are the side effects of oseltamivir?

A

gastrointestinal symptoms
Headache
Upper respiratory tract infections

68
Q

what are the nucelos(t)ide analogs used to treat HBV infection?

A

– High barrier to HBV resistance: Entecavir, tenofovir

– Low barrier to HBV resistance: Lamivudine, adefovir, telbivudine

69
Q

what is the tenofovir?

A

An analog of adenosine-5-monophosphate that functions as a nucleotide reverse transcriptase inhibitor (NtRI). Tenofovir is used to treat chronic hepatitis B infection in patients > 12 years of age and those with HIV-1 infection.

70
Q

how tenofovir works?

A

phosphorylated to triphosphate in hepatic cells (activation) → binds to viral DNA polymerase → causes premature termination of DNA transcription

71
Q

describe pegylated interferon-α and interferon-α

A

Antiviral and immunomodulatory effect via intercellular and intracellular mechanisms : inhibits viral protein synthesis, promotes the breakdown of viral RNA, and induces the increased expression of MHC class I molecules

72
Q

what are the side effects of pegylated interferon-α and interferon-α

A
  • -flu-like symptoms
  • -Bone marrow suppression
  • -Depressive mood
  • -Seizures
  • -Induction of autoantibodies
  • -Myopathy
  • -thyroiditis
  • -alopecia
  • -nephrotoxicity and hepatotoxicity?
73
Q

what are the uses of pegylated interferon-α and interferon-α

A
  • -Monotherapy in acute hepatitis C and chronic active hepatitis B
  • -As a combination treatment in chronic hepatitis C
74
Q

what are the contraindications of pegylated interferon-α and interferon-α

A
  • -Decompensated cirrhosis
  • -Psychiatric conditions
  • -Pregnancy
  • -Autoimmune conditions
  • -Leukopenia or thrombocytopenia
75
Q

how HBV treatment is monitored?

A

DNA PCR

76
Q

what are the interferons?

A
  • Alpha, beta & gamma interferon, Part of human cytokine response
  • Produced in response to wide variety of infectious & immune stimuli
  • Induce antiviral state within target cell – bind to cell surface receptors
  • Active against many viruses
  • Pegylated interferon alpha; more sustained viral suppression & convenient administration
77
Q

what are other uses of pegylated interferon-alfa?

A
  • -Kaposi sarcoma
  • -Adjuvant therapy for malignant melanoma
  • -Essential thrombocythemia
78
Q

antivirals against hepatitis C act on?

A

viral proteins, i.e. NS3, NS5A & NS5B

79
Q

what are the DAAs?

A

direct acting antivirals

  • -New agents that act directly on the hepatitis C virus at various points in the viral life cycle.
  • -NS3/4A protease inhibitors: inhibit NS3/4A (an HCV serine protease required for viral replication) (simeprevir)
  • -Non-nucleoside NS5A polymerase inhibitors: inhibition of the viral NS5A phosphoprotein → prevents HCV RNA replication (daclatasvir, ledipasvir)
80
Q

the response of HCV to treatment is influenced by?

A 
–	underlying liver damage
–	HIV co-infection
–	compliance
–	genotype (2 &amp; 3 more sensitive than 1)
–	viral load 
–	antiviral resistance
81
Q

which HCV genotypes are more susceptible to treatment?

A

2 an 3 more than 1

82
Q

what is the sustained virological response of HCV to treatment?

A

• Sustained virological response (SVR): Undetectable HCV RNA in serum at 12 or 24 weeks post-treatment

83
Q

what is the ribavirin?

A

Antiviral drug that is used to treat hepatitis C, RSV infection, and viral hemorrhagic fever (e.g., Lassa fever, Hantavirus infection). It is a nucleoside analog that can act on both RNA and DNA viruses. For hepatitis C, it is always used in combination with other medications such as simeprevir or PEG-interferon-α. Adverse effects include nausea, irritability, hemolytic anemia, and severe teratogenicity.

84
Q

how ribavirin works

A

Guanosine analog (nucleoside inhibitor): competitive inhibition of IMP dehydrogenase → prevents synthesis of guanine nucleosides

85
Q

what are the side effects of ribavirin?

A
  • -Hemolytic anemia
  • -Severely teratogenic
  • -Gastrointestinal symptoms

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