Antifungals Antivirals

• 1st Class: imidazoles
  • Not used for systemic infections anymore
    • miconazole
    • ketoconazole
• 2nd Class: triazoles
  • Used for systemic infections:
  • Good PO absorption, excellent toxicity profile.
    • Fluconazole  (penetrates BB barrier)
    • Itraconazole  (variable PO absorption - enhanced by food, bad with low stomach pH)  Does not penetrate BB barier.
      • Better for: Histoplasmosis, Coccidiomycosis, Blastomycosis, and sporotrichosis.
    • Posaconazole  (newest + broadest spectrum))
      • Better PO abtn with food (high fat).
    • Voriconazole (temp loss of sight, worst drug interactions!!)

• Thereby decreases ergosterol production.. intermediates accumulate.
• Decreased membrane enzyme activity.
• FUNGISTATIC!

Broad

• Aspergillus
• Candida (C. glabrata, C. krusei)

• Candida can develop resistance (more demethylase, and drug efflux)

• Oropharyngeal and vulvovaginal candidiasis
• IV fluconazole is equal efficacy to amphotericin B in uncomplicated candidemia.
  • However, if complicated (HIV, deep tissue Candida), use amphotericin B and caspofugin.
• Phrophylaxis in HIV and ICU not recommended.

• Oropharyngeal and vulvovaginal candidiasis
• IV fluconazole is equal efficacy to amphotericin B in uncomplicated candidemia.
  • However, if complicated (HIV, deep tissue Candida), use amphotericin B and caspofugin.
• Phrophylaxis in HIV and ICU not recommended.
• Itraconazole:
  • Uncomplicated histoplasmosis, coccidiomycosis, blastomycosis, and sporotrichosis.
  • Acute, chronic vaginal candidiasis, and HIV-assc oral/esophageal candidiasis.
• Voriconazole and Posaconazole - Aspergilus (superior to Amphotericin B)
• Posaconazole - activity against Zygomyces

• At higher doses inhibit human testosterone and coristone production.
  • Gynecomastia + loss of libido.
• Severe hepatitis.
• All toxicity better with 2nd class drugs (Ketoconazole is worst)
• Drug-Drug interactions!! (Cyp P450 metabolism)
  • Voriconazole is the worst!
  • The following lower azole levels:
    • Rifampin
    • Rifabutin
    • Long-acting barbiturates
    • Carbamazepine
    • Cisapride
  • Azole slows metabolism of: (need to lower dose of these agents)
    • Warfarin, Phenytoin, Tacrolimus, Cyclosporine, certain antihistamines, benzodiazepines, CCB, sulfonylureas, prednisolone, digoxins, statins, anti-HIV protease inhibitors.
  • Contraindicated:
    • Rifabutin and Voriconazole
    •  

Derived from echninocandin B

• Caspofungin
• Anidulafungin
• Micafungin

Aspergillus, Candida (even if resistant)

NOT active: Cryptococcus

• Candida can develop resistance (more demethylase, and drug efflux)

• Oropharyngeal and vulvovaginal candidiasis
• IV fluconazole is equal efficacy to amphotericin B in uncomplicated candidemia.
  • However, if complicated (HIV, deep tissue Candida), use amphotericin B and caspofugin.
• Phrophylaxis in HIV and ICU not recommended.

• Aspergillus (if cannot tolerate amphotericin B)
• Oral/esophageal candidiasis refractory to azoles and amphotericin B.

• Mild

Flucytosine

Aspergillus, Candida (even if resistant)

NOT active: Cryptococcus

• Never used alone
• Often used with Amphotericin B (need to monitor levels, AmpB lowers GFR increases 5-FC levels).

• Bone Marrow suppression: Neutropenia, Anemia, thrombocytopenia.
• Dose related side-effects.
• Efficacy not proven.

• Acyclovir
• Valacyclovir  (better PO absorption, less freq dosing)  --> Acyclovir (rapidly converts, resulting higher levels)
• Famciclovir  --> Penciclovir (converts)  
• Penciclovir

• Phosphorylated by viral thymidine kinase forming monophosphate compound.  
• Host cell kinases add two additional PO4's.  Triphosphate adds to replicating DNA.
• Acyclovir - acyclic side chain, causes premature DNA termination by DNA polimerase.
• Penciclovir --> Direct viral DNA polymerase inhibitor.
• Resistance: reduction in viral thymidine kinase.  (resistance to acyclovir = resistance to Ganciclovir
  • (same viral thymidine kinase)

• acyclovir PO - limited.  (15-20%)

• Renal: Excreted unchanged in urine  (Probenecid increases half-life)

Coverage/

Clinical Use

• DNA viruses
• Herpes Simplex Type I and II
  • Topical - minimal efficacy.
  • Acyclovir and Famcyclovir - used commonly for treatment and prevention.
    • IV acyclovir - used for herpes simplex encephalitis.
    • Varicella (need high doses)
    • Acyclovir IV:
      • Encephalitis
      • Ocular recurrent
      • Herpes Zoster in immunocompromised host.
      • EBV activity (not recommended)
      • CMV
    • Famcyclovir can decrease HepB and improve transaminases in chronic hepB
      • Synergistic if used with interferon.

• Minimal
• Rash? hematuria, headache, nausea.
• Neurotoxicity (1-4%) in IV acyclovir - lethargy, obtundation, hallucinations, coma.
  • Often have renal dysfunction and high acyclovir levels.
• Nephrotoxicity
  • If dehydrated: IV forms can develop crystalline nephropathy.

• Ganciclovir
• Valganciclovir

• Similar to acyclovir
• Thymidine kinase converts to monophosphate, human kinases convert ot triphosphate. 
• Ganciclovir triphosphate inhibits DNA polymerase, but does not terminate chain.
• Reaches 10X concentration inc ells than acyclovir.  Intracellular half-life 16-24hrs.
  • High concentrations --> better for CMV.

• Valganciclovir
  • Prodrug (better oral absorption)  Same as IV ganciclovir.

• acyclovir PO - limited.  (15-20%)

• Renal: Excreted unchanged in urine  (Probenecid increases half-life)

Coverage/

Clinical Use

• High intracellular concentrations --> better for CMV.
• Also active against herpes simplex, varicella, EBV.
• Good CSF penetration

• Requires thymidine kinase (if resistant to acyclovir, also resistant to ganciclovir)
• Good for CMV!!! (first line)
• CMV prophylaxis in transplant pts and AIDS with low CD4.

• Can incorporate into host DNA (bone marrow suppression:
  • Neutropenia  (need monitoring)
  • Thrombocytopenia  (need monitoring)
• CNS (headache, confusion, psychosis, coma) also common.