© paradigm publishing, inc.1 chapter 5 therapy for fungal and viral infections

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Chapter 5

Therapy for Fungal and Viral Infections

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Chapter 5 Topics

• Fungi and Fungal Diseases

• Viruses and Viral Infections

• HIV-AIDS and Antiretroviral Agents

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Learning Objectives

• Understand the differences between fungi and viruses and why the drugs to treat them must have very different mechanisms of action.

• Differentiate antifungals, antivirals, and antiretrovirals by their indications, therapeutic effects, side effects, dosages, and administration.

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Learning Objectives

• Use antifungal, antiviral, and antiretroviral terminology correctly in written and oral communication.

• Identify drugs used for HIV and understand their synergism.

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Fungi and Fungal Diseases

Fungi • Single-cell

organisms

• Mushrooms, yeasts, and molds

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Characteristics of Fungi

• Eukaryotic (defined nucleus): fungus, animal cell, and green plant cell

• Prokaryotic (no defined nucleus): bacteria• Fungi differ from green plants

– Lack chlorophyll– Reproduce by spores

• Fungi differ from animal cells– Have rigid cell wall unlike that of bacteria

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Discussion

In what ways are human cells similar to fungi cells? How are they different?

Human cell membranes contain cholesterol, and cell membranes of fungi contain ergosterol.

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Fungal Diseases

• Systemic fungal diseases most likely to occur in immunosuppressed by disease or drug therapy (corticosteroids or antineoplastics)

• Fungi can cause skin and nail infections

• Women on antibiotics often need antifungal for vaginal yeast infection

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Fungal Organisms and Resulting Infections

Organism Disease

Aspergillus Aspergillosis

Blastomyces Blastomycosis

*Candida (yeast) *Candidiasis

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Fungal Organisms and Resulting Infections

Organism Disease

Coccidioides Coccidioidomycosis

Cryptococcus Cryptococcosis

Histoplasma Histoplasmosis

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Drug ListAntifungals

– *amphotericin B (Abelcet (ABLC), AmBisome, Amphocin, Amphotec, Fungizone) IV, topical

– *clotrimazole (Mycelex) lozenge (for oral infection) topical, vaginal

– flucytosine (Ancobon)

– *griseofulvin (Fulvicin P/G, Gris-PEG)

capsule, tablet, oral suspension

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Drug ListAntifungals

– *ketoconazole (Nizoral) tablet, cream,shampoo

– *nystatin (Mycostatin) oral liq, tab, topical, vaginal

– *terbinafine (Lamisil) tablet, cream

– *terconazole (Terazol)

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Drug ListAntifungalsEchinocandin (IV)

– anidulafungin (Eraxis)

– caspofungin (Cancidas)

– micafungin (Mycamine)

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Drug ListAntifungalsTriazole

– *fluconazole (Diflucan) IV, oral liq, tab

– *itraconazole (Sporanox) caps, IV, oral liq

– posaconazole (Noxafil) oral liq

– voriconazole (VFEND) IV, oral liq, tab

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How Antifungals Work

• Prevent synthesis of ergosterol, building block for fungal cell membranes

• Human cell membranes– Use cholesterol– Affected minimally by antifungals

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How Antifungals Work

• Inhibit fungal cytochrome P-450– Different from human P-450– Have little effect on human cells

• Result: destroys fungi

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How Antifungals Are Dispensed

• Three forms – Topical agents

– IV agents

– Systemic agents

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Side Effects of Antifungals

• Reports of serious side effects, even for topical agents

• Pay close attention to dosing regimen to avoid overdosing

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amphotericin B (Fungizone)

• Used for blood-born, life-threatening fungal infections

• Blood levels of drug monitored and vitals checked during infusion

• Infused slowly. Not piggybacked, not mixed with normal saline

• Side effects: fever, chills, shaking, headache, anemia, renal toxicity

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Dispensing Issues of amphotericin B

• IV requires prophylaxis with aspirin, antihistamine, or acetaminophen

• **Technician—if no accompanying orders, contact pharmacist or prescriber

Warning!

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clotrimazole (Mycelex)

• Effective against oral candidiasis– Yeastlike fungi causing infection in the

mouth

• Troche (small lozenge)

Figure 3-16 Types of fungi and a fungal infection of the tongue. (Photo Source: Courtesy of Jason L. Smith, MD.)

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griseofulvin (Fulvicin P/G, Gris-PEG)

• Used for fungal infections of hair, skin, nails

• Take with fatty meals

• Avoid sun• Side effects: dizziness, drowsiness,

passing headache

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nystatin (Mycostatin)

• Used for oral candidiasis

• Often used in liquid form, swish and swallow

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terbinafine (Lamisil)

• Kills fungus instead of inhibiting growth

• Oral form taken once daily– 6 weeks for fingernails – 12 weeks for toenails

• Topical form for ringworm

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Dispensing Issues of (Lamisil)

• Look-alike– Lamisil– Lomotil,– Lamictal

• Use dosing and indications to keep them straight

Warning!

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*foscarnet (Foscavir)

• *Used for cytomegalovirus (CMV) infections in immunocompromised

• IV infusion. Not rapid or bolus injection

• *Patient must be hydrated

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*fluconazole (Diflucan)

• *Oral form used for vaginal or oral candidiasis

• IV if cannot tolerate oral therapy• Side effects: headache, rash, GI

upset

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*itraconazole (Sporanox)

• *Fungal infections of nails

• Capsule taken twice a day with– Fatty meal, and – Cola to increase stomach acidity and

increase absorption

• *Drug is especially toxic to liver– Monitor for liver damage, jaundice

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*posaconazole (Noxafil)

• Prevents Candida and Aspergillus infections for immunocompromised

• *Broader spectrum of activity than other triazoles

• Oral suspension, shake well before administration

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voriconazole (VFEND)

• Alternative to amphotericin B• Can be started IV and switched to

oral dose• Can cause liver toxicity and blurred

vision

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Caspofungin (Cancidas)

• Inhibit synthesis of D-glucan, important cell wall component of fungus

• Only available in IV form for invasive aspergillosis if unresponsive to other therapies

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Terms to Remember

fungus

eukaryotic

prokaryotic

cholesterol

bacteria

aerobic

anaerobic

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Terms to Remember

nosocomial infection

Gram staining

ergosterol

permeability

troche

immunocompromised

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Viruses and Viral Infections

• *Virus – Minute infectious agent– Does not have all components of a cell– Replicate *within cell by using metabolic

process of *host cell– Can only replicate within a *living host

cell: animal, plant, or bacteria

Viruses

• Infectious particles that have core containing genetic material surrounded by protective protein coat called a capsid

Cannot grow, eat, or reproduce by

themselves; must enter another cell and use that cell for energy to grow and reproduce

• Do not respond to antibiotics; can stay dormant in body and become active later in life

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Virus and Bacterium

• A virus is much smaller than a bacterium.

• Image shows a virus infecting a bacterium.

Figure 3-15 A virus.

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Virus Characteristics

• Most viruses spread by– Direct contact– Ingestion of contaminated food and

water– Inhalation of airborne particles– Exposure to contaminated body

fluids/equipment

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Virus Characteristics

• Virion– An individual virus particle capable of

infecting a living cell– Consists of nucleic acid, DNA or RNA– Capsid (protein shell) surrounds and

protects nucleic acid

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Virus Characteristics

• Depending on virus, capsid is– Covered with a membrane called an

envelope – Not covered with an envelope

• Naked virus: a virus without an envelope

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Five Stages of Viral Infection(how viruses affect the body)

1. Virus attaches to a cell receptor.

2. Virus penetrates cell as cell membrane indents and closes around the virus.

3. Virus escapes into the cytoplasm of the cell.

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Five Stages of Viral Infection

4. Virus uncoats.• Sheds its covering• Releases DNA or RNA into cell nucleus

5. Virus converts nuclear activity in the cell to viral activity and reproduces new viral particles.

• *Uses energy of host cell to infect the cell and make more virus

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Blocking Viral Division

• All viruses have some characteristics different from uninfected cells

• These differences offer ways to block viral division– Normal cells not affected

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Viral Infections and Illnesses

• Common and significant illnesses– Influenza– Hepatitis, inflammation of the liver– HIV (human immunodeficiency virus)

• Chronic disease to be managed• Pharmacy team stay alert for drug

interactions

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Discussion

Provide an example of a common viral infection and the symptoms of this condition.

The flu (influenza) with symptoms of malaise, myalgia (muscle pain), headache, chills, and fever

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Classification of Viral Infections

Viral infections classified in two ways– Viral duration and severity– Viral infection

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Viral Duration and Severity

• Acute: quickly resolves, no latent infection. Common cold, flu

• Chronic: protracted course with long periods of remission interspersed with reappearance. Herpes virus infection

• Slow: progressive course, ends in death. HIV (AIDS)

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Viral Infection

• Local: affects tissues of a single system, such as the respiratory tract, eye, or skin

• Generalized: has spread or is spreading to other tissues by way of bloodstream or tissues of the CNS

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Viral Latency

• Virus lies dormant, then under certain conditions, reproduces and behaves like an infective agent (usually from a stress that taxes the immune system)

• *Latency problem with herpes virus and HIV

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Virus and Cell Interaction

• A virus can damage host cell by– Altering the cell– Incorporating into genetic material of

host cell– Dividing when host cell divides– Killing host cell

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Virus and Cell Interaction

• Most viruses have several antigens on their surface

• Antigens stimulate host to produce immunoglobulins– An antibody that may prevent an organism

from attaching to a cell receptor or may destroy organism

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Interferon

• Some virus-infected cells respond by producing interferon– Substance that protects neighboring

uninfected cells from viral infection– Inhibits viral RNA synthesis– Host specific

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Vaccination

• Introduces a vaccine into the body to produce immunity to actual agent

• Exposes patient to a virus component or a similar strain that does not produce infection

• When vaccinated patient encounters actual virus, infection cannot develop

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Discussion

Who should receive an influenza vaccine?

High-risk patients such as healthcare workers, nursing home residents, public safety workers, individuals over 65 years old, and immunocompromised patients.

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Antivirals

• Body can produce interferons

• But, some viruses cause normal cells to transform into cancer cells

• Antivirals prevent virus cell replication without interfering with host cell’s normal function– Difficult to develop

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Drug ListAntiviralsSystemic Agents

– acyclovir (Zovirax)

– amantadine (Symmetrel)

– cidofovir (Vistide)

– famciclovir (Famvir)

– foscarnet (Foscavir)

– ganciclovir (Cytovene)

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Drug ListAntiviralsSystemic Agents

– oseltamivir (Tamiflu)

– ribavirin (Copegus, Rebetol, Virazole)

– rimantadine (Flumadine)

– valacyclovir (Valtrex)

– valganciclovir (Valcyte)

– zanamivir (Relenza)

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Drug ListAntiviralsOcular Agent

– ganciclovir (Vitrasert)

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Therapeutic Uses of Antivirals

• Cytomegalovirus (CMV) retinitis• Herpes simplex• Herpes simplex keratitis• Herpes zoster (shingles)• Influenza prophylaxis• Varicella (chicken pox)• Hepatitis B

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Side Effects of Antivirals

• Range from mild to severe– Mild: headache– Severe: renal disorders

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amantadine (Symmetrel)

• Inhibits uncoating which prevents absorption of viral particles into host cell

• Used for influenza A prophylaxis or treatment

• Also used for Parkinson disease• Rare side effects

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Dispensing Issues of amantadine (Symmetrel)

• Amatadine, rimantadine, and ranitidine can be easily confused

• Use dosing and indications to keep them straight

Warning!

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acyclovir (Zovirax)

• Used for– Genital herpes– Acute herpes zoster (shingles)– Varicella (chicken pox) – Herpes encephalitis (in IV form)

• Range of short- and long-term side effects

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famciclovir (Famvir)

• Used for– Acute herpes zoster (shingles)– Herpes simplex in immunocompromised– Genital herpes

• Dosed less frequently than acyclovir

• Prodrug

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ganciclovir (Cytovene)

• Used for cytomegalovirus (CMV) in immunocompromised

• When mixing, technicians must use chemotherapy agent precautions and label correctly

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Dispensing Issues of Cytovene

• Can be confused– Cytovene with dosages of 250 mg and

500 mg– Cytosar (chemotherapy agent) with

dose of 10 mg

Warning!

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Dispensing Issues of ganciclovir and foscarnet

• Patients given ganciclovir (Cytovene) or foscarnet (Foscavir) IV must be well hydrated

• Usually “standing orders” for hydration when prescribed

• If not, contact pharmacist or prescriber

Warning!

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oseltamivir (Tamiflu)

• Prevents influenza A and B

• Initiate within 48 hours of symptom onset

• Food improves tolerance

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ribavirin (Virazole)

• Inhalant antiviral, maximum absorption with aerosol generator via an endotracheal tube

• For viral infections and children with RSV• Side effects: fatigue, headache, insomnia,

nausea, anorexia

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rimantadine (Flumadine)

• Used for influenza prophylaxis or treatment

• Fewer side effects than amantadine (Symmetrel)

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valacyclovir (Valtrex)

• For herpes zoster in immunocompetent adults and genital herpes

• Take within 48 hours of onset of zoster rash with water

• Shortens postherpetic neuralgia duration

• Side effects: nausea, vomiting, diarrhea, constipation

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zanamivir (Relenza)

• Used for influenza A and B

• Take within 48 hours of onset of symptoms

• 2 inhalations daily, 12 hour intervals, for 5 days

• If using bronchodilator, use immediately prior to administration of zanamivir

• Sometimes prophylactic

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ganciclovir (Vitrasert)

• Ophthalmic antiviral

• Available in oral and IV form

• Pregnant women should not handle this drug

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Terms to Remember

virusvirioncapsidenvelopenaked virusfluhepatitishuman immunodeficiency virus (HIV)

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Terms to Remember

acute viral infection

chronic viral infection

slow viral infection

local viral infection

generalized viral infection

latency

immunoglobulin

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Terms to Remember

interferon

vaccination

antiviral

prodrug

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HIV-AIDS and Antiretrovirals

• HIV is a retrovirus– Copies its RNA genetic information into

the host’s DNA– Uses reverse transcriptase, a retroviral

enzyme

• Antiretroviral drugs limit progression of HIV retrovirus

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Seven Classes of Antiretroviral Drugs

• Nucleoside reverse transcriptase inhibitors (NRTIs)

• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

• Nucleotide reverse transcriptase inhibitors (NtRTIs)

• Protease inhibitors (PIs)

• Fusion inhibitors

• Chemokine receptors

• Integrase inhibitors

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Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• Mimic a DNA building block to inhibit the actions of the enzyme nucleoside reverse transcriptase

• Prevents replication of HIV

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Drug List

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

– abacavir (Ziagen)

– didanosine (Videx)

– emtricitabine (Emtriva)

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Drug List

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

– lamivudine (Epivir)

– stavudine (Zerit)

– zidovudine, AZT (Retrovir)

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Side Effects of NRTIs

• GI distress is common– Nausea, diarrhea, abdominal pain– Usually improves within first 2 weeks of

therapy

• More permanent side effects include degeneration of the liver

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Dispensing of NRTIs

• Taken with or without food

• Generally do not interfere with other drugs

• Administered in two or three doses per day

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lamivudine (Epivir)

• Used for HIV and chronic hepatitis B

• Must be taken exactly as prescribed

• Fewest side effects of any of the NRTIs

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zidovudine, AZT (Retrovir)

• One of the first drugs for HIV treatment

• Can be combined with all NRTIs– Exception: stavudine

• Used in combination with lamivudine (with or without PI) for needlestick or sexual exposure

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Dispensing Issues of zidovudine, AZT (Retrovir)

• Do not use the abbreviation AZT for zidovudine

• Use of abbreviation can lead to medical errors

Warning!

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Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Inhibit action of HIV reverse transcriptase

• Prevent formation of DNA copy of viral RNA

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Drug List

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

– delavirdine (Rescriptor)– efavirenz (Sustiva)– nevirapine (Viramune)

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efavirenz (Sustiva)

• Dosed once a day, prefer bedtime• Avoid high-fat meals• Side effects

– Dizziness, headache– Vivid dreams, nightmares, hallucinations

• Typically 1 to 3 hours after administration• Usually subside after 2 to 4 weeks on drug

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nevirapine (Viramune)

• Lower dose first 2 weeks, then increased to therapeutic level to avoid rash

• Antibiotic rifampin interferes with this drug

• Decreases serum concentration of PIs

• Must monitor liver functions

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Nucleotide Reverse Transcriptase Inhibitor (NtRTIs)

• Mimic a DNA building block to stop formation of DNA copy

• Less toxicity than NRTIs

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Drug List

Nucleotide Reverse Transcriptase Inhibitor (NtRTIs)

– tenofovir (Viread)

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Protease Inhibitors (PIs)

• Inhibit protease enzyme, which cleaves certain HIV protein precursors needed to replicate virus

• Result: production of immature, noninfectious virions

• Combined with other antiretroviral drugs

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Drug List

Protease Inhibitors (PIs)– amprenavir (Agenerase)– atazanavir (Reyataz)– darunavir (Prezista)– fosamprenavir (Lexiva)

– indinavir (Crixivan)

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Drug List

Protease Inhibitors (PIs)– nelfinavir (Viracept)

– ritonavir (Norvir)

– saquinavir (Fortovase, Invirase)

– tipranavir (Aptivus)

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indinavir (Crixivan)

• Do not take with– St. John’s wort– Grapefruit juice– With food, especially high-fat

• 48 ounces/day of water (kidney stones)• Package with a desiccant• Patient to store in original container

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nelfinavir (Viracept)

• Can cause diarrhea– Loperamide and calcium carbonate can

help control

• Take with food

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ritonavir (Norvir)

• Increases serum concentrations and decreases dosage frequency of other PIs

• Given at a low dose

• Take with food

• Many side effects

• Store in refrigerator

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tipranavir (Aptivus)

• May have some advantages over other PIs– More adaptable structure to protease binding

sites

– Delivery system improves dissolution and bioavailability of drug

• Given with ritonavir (Norvir) as boost

• Black Box warning

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Discussion

How do fusion inhibitors represent an advance in the treatment of HIV?

Prevents AIDS virus from entering the cell

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Fusion Inhibitors and Chemokine Coreceptors

• Prevent HIV from entering immune cells

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Drug List

Fusion Inhibitors– enfuvirtide (Fuzeon)

Chemokine Coreceptor– maraviroc (Selzentry)

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maraviroc (Selzentry)

• First drug approved for R5 Virus

• Given with other antiretrovirals

• Taken without regard to food

• Side effect: cough

• Patient must be monitored closely for infection

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Integrase Inhibitor

• Drug blocks enzyme integrase

• Integrase inserts DNA produced by reverse transcriptase into patient’s DNA

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Drug List

Integrase Inhibitor– raltegravir (Isentress)

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raltegravir (Isentress)

• Blocks action of enzyme integrase

• Used only in combination with other HIV drugs

• Reduces amount of HIV in blood

• Increases white blood cell count which helps fight infection

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Responding to HIV Exposure

• Centers for Disease Control (CDC) guidelines for healthcare workers exposed to HIV– Post-exposure prophylaxis (PEP)– Begin within two hours– Can decrease risk of infection by 80%

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Combining Antiretrovirals

• Standard care for AIDS treatment is to combine three or more drugs

• Regimens complex and difficult to follow

• Problem with compliance

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Combining Antiretrovirals

Regimen Type Recommendation

standard therapy NNRTI: efavirenz + lamivudine + (zidovudine or tenofovir or stavudine)

PI: lopinavir-ritonavir + lamivudine + (zidovudine or stavudine)

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Combining Antiretrovirals

Regimen Type Recommendation

alternative therapy 3-NRTI: abacavir + lamivudine + (zidovudine or stavudine)

post-exposure prophylaxis (PEP)

zidovudine + lamivudine + (indinavir or nelfinavir)

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Dispensing Issues of Antiretrovirals

• Avoid these antiretroviral drug combinations– didanosine with stavudine and

zalcitabine– zidovudine with stavudine

Warning!

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Combining Antiretrovirals

• Increasing number of manufacturers combining antiretrovirals into 1 tablet

• Decreases pill load

• Improves compliance– Partial compliance can lead to drug

resistance

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Discussion

What is one of the biggest problems when treating HIV?

Noncompliance with drug regimen due to problematic side effects and complex dosing.

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Terms to Remember

*retrovirus

reverse transcriptase

*antiretroviral

nucleoside reverse transcriptase inhibitor (*NRTI)

non-nucleoside reverse transcriptase inhibitor (*NNRTI)

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Terms to Remember

nucleotide reverse transcriptase inhibitor (*NtRTI)

*protease inhibitor (PI)

fusion inhibitor

chemokine coreceptor

integrase inhibitor

*post-exposure prophylaxis (PEP)