Antivirals and Antifungals

• Fungi are eukaryotes with a cellular structure similar to human cells, posing challenges in developing antifungal agents that are not toxic to human cells
• Antifungal mechanisms of action target specific fungal structures/processes to be effective but specific, acting on cell membrane, cell wall, interfering with DNA/RNA synthesis, and folate metabolism
• Polyenes like Amphotericin B & Nystatin disrupt ergosterol in the cell membrane, increasing cell permeability, with broad activity against yeasts & moulds like Aspergillus and Mucorales
• Azoles like Fluconazole, Voriconazole, Posaconazole, and Isavuconazole affect the cell membrane, inhibiting ergosterol biosynthesis, with Fluconazole having activity against C. albicans but not moulds
• Echinocandins like Caspofungin and Anidulafungin interfere with glucan synthesis in the cell wall, often used as first-line for systemic Candida infections
• Terbinafine disrupts ergosterol biosynthesis, used for treating Tinea and fungal nail infections, with topical or oral routes
• Flucytosine inhibits DNA/RNA synthesis, mostly effective against yeasts like Cryptococcus and Candida, with variable resistance among Candida species
• Choice of antifungal agent depends on the type of infection, with different durations and agents for superficial mycoses, onychomycosis, candidiasis, and systemic mycoses
• Antifungal prophylaxis is recommended for specific patient groups like HIV+ individuals, transplant recipients, and those with certain conditions
• Antiviral agents face challenges due to intracellular vs extracellular pathogens, latency, lack of culture systems for some viruses, and uncertainty regarding viral genetic functions and pathogenic properties
• Transplant-related viral infections include Herpes viruses
• New & emerging viral threats include COVID-19, Ebola, and Avian influenza
• Antiviral Mechanisms of action 1:

  • Virucides directly inactivate intact viruses
  • Methods include detergents for hand hygiene with the common cold & influenza, UV light inactivation, and cryotherapy, laser, or podophyllin for treating warts and genital warts
• Antiviral Mechanisms of action 2:

  • Augmentation / Modification of Host Response replaces deficient host immune responses & enhances endogenous ones
  • Includes the use of immunomodulatory immunoglobulin (high titre) after exposure to viruses like Varicella zoster, CMV, Rabies, Hep B, and Interferon for Hepatitis
• Antiviral Mechanisms of action 3:

  • Inhibition of viral replication using drugs like Aciclovir, Valaciclovir, Ganciclovir, Valganiciclovir, Foscarnet, and Cidofovir, which is an anti-influenza agent
• Aciclovir Mechanism of action:

  • Analogue of guanosine that needs to be activated to achieve antiviral effect
  • Initial phosphorylation step by viral thymidine kinase activates the drug
  • Phosphorylated to triphosphate (active form) within infected cell, leading to chain termination
  • Also a direct inhibitor of viral DNA polymerase
• Aciclovir clinical uses:

  • Active against HSV-1 & 2, VZV
  • Drug of choice for serious infections like HSV encephalitis, Neonatal HSV, Disseminated HSV, Disseminated VZV, Severe varicella pneumonia
  • Routes: IV or PO
  • Limited toxicity as active form is only present in virally infected cells, but nephrotoxicity can occur
• Variations of Aciclovir:

  • Valaciclovir is a pro-drug, rapidly absorbed from the GIT
  • Ganciclovir is a derivative of aciclovir, the 1st antiviral agent with activity vs CMV, administered IV for HSV 1 & 2, VZV, and CMV
• Foscarnet Mechanism of action:

  • Pyrophosphate analogue that forms complexes with DNA polymerases inhibiting further DNA synthesis
  • Administered IV due to poor PO bioavailability
  • Used for Ganciclovir-resistant CMV, CMV retinitis, Aciclovir-resistant mucocutaneous HSV or VZV
• Cidofovir Mechanism of action:

  • Triphosphate active form, a competitive inhibitor of viral DNA polymerase
  • Broad spectrum anti-herpesvirus activity, developed primarily as an anti-CMV agent
  • Used for resistant CMV, HSV, CMV retinitis, and adenovirus infection in stem cell transplant recipients
• Anti-influenza agents:

  • Oseltamivir (Tamiflu) is a Neuraminidase (NA) inhibitor specific for influenza A & B NA
  • Clinical uses include reducing duration & severity of symptoms when given within 48 hours of symptom onset
• ANTI-SARS-Cov-2 agents:

  • Paxlovid (Nirmatrelvir/Ritonavir) PO x 5 days, recommended for those at risk of severe COVID-19
  • Remdesivir IV x 3 days for unvaccinated individuals at risk of progression to severe COVID-19