42. Antimicrobial Therapy: Antiviral and Antifungal Agents

Antiviral Agents (Oral)

Three medications used in the treatment of Herpes zoster infections are:

• acyclovir, valacyclovir, and famciclovir.

Viruses replicate by co-opting the host cell’s metabolic machinery.

Antiviral Treatment Overview: Herpes Virus

Herpes viruses are associated with a broad spectrum of diseases, cold sores, genital infections

Herpes zoster, also known as shingles, is caused by reactivation of varicella-zoster virus (VZV), the same virus that causes varicella (chickenpox).

Herpes simplex virus (HSV) comes in two forms: HSV-1 (oral herpes) and HSV-2 (genital herpes).

The drugs that are effective against Herpes viruses exert their actions during the acute phase of viral infections and are without effect during the latent phase.

Overview of Microbiology: Viruses

DNA (DNA virus) or RNA (RNA virus)

Contain the genetic information for their own replication but need to utilize the host’s machinery for reproduction.

Viral Pathogens include:

• Herpes Simplex Virus (HSV): HSV-1: oral and HSV-2: genital)

• Herpes Zoster Virus (HSV): shingles

• Varicella Zoster Virus (VZV): chicken pox

Enveloped DNA

Antiviral Agents: Acyclovir (Zovirax®)

Mechanism of Action

• Inhibits DNA synthesis and viral replication.

Indications(all four)

• Shingles (Herpes Zoster Virus or HZV)

• Chickenpox (Varicella Zoster Virus or VZV)

• Genital Herpes (Herpes Simplex Virus or HSV-2)

• Herpes Labialis or Cold sores (HSV-1)

Pharmacokinetics

• Poor bioavailability (need to take 5 times a day)

Adverse Effects

• CNS and GI < valacyclovir, famciclovir

Antiviral Agents: Valacyclovir (Valtrex®)

Mechanism of Action

• Inhibits DNA synthesis and viral replication.

• Valacyclovir is a prodrug; converted to acyclovir

• Indications (all four similar to acyclovir)

Pharmacokinetics

• Better bioavailability (need to take 3 times a day)

Adverse Effects

• both CNS and GI > Acyclovir

Antiviral Agents: Famciclovir

Mechanism of Action

• Inhibits DNA synthesis and viral replication.

• Famciclovir is a prodrug biotransformed to penciclovir.

Indications (missing chickenpox)

Pharmacokinetics

• Better bioavailability (need to take 3 times a day)

Adverse Effects

• both CNS and GI similar to valacyclovir, > acyclovir

Antifungal Treatment Overview

Fungi are yeasts or molds

All fungi are eukaryotic organisms

Immunocompromised hosts are at the greatest risk

Amphotericin B, the azoles, echinocandins are the primary drugs used in systemic infections.

Antifungal Agents: Drug Categories

Polyenes

• Amphotericin-B

Azoles

• Imidazole: Ketoconazole (CYP-450 inhibitor)

  • 2 nitrogens

• Triazole: Fluconazole, Itraconazole, Voriconazole, Posaconazole

  • 3 nitrogens

Eichinocandins

• Caspofungin

• Micafungin

Miscellaneous

• 5-Flucystosine

Inhibitors of Fungal Membrane Stability (Polyenes)

Amphotericin B

• Binds to ergosterol disrupting cell membrane

• Is a polyene antibiotic

• Used IV to treat serious disseminated yeast and fungal infections, particularly in immunocompromised patients.

• widest antifungal spectrum of any agent

Inhibitors of the Ergosterol Synthesis Pathway: Inhibitors of 14α- Sterol Demethylase, a microsomal cytochrome P450 enzyme

Azole Antifungal Agents

• are broad-spectrum disrupt the fungal cell membrane by inhibiting the synthesis of ergosterol, a CYP450 enzyme.

• imidazoles and triazoles.

• The azoles antifungals can inhibit cytochrome P450 enzymes.

• This class of drugs, particularly ketoconazole, is a significant inhibitor of hepatic CYP450 isozymes and susceptible to clinically significant drug interactions.

5-Flucystosine

blocks nucleic acid synthesis.