Antifungals Antivirals

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    Antifungals

    Amphotericin B

    • Long cycle polyene binds ergosterol in membrane, leaks K+ --> rapid fungal death.
    • FUNGICIDAL
    • Two forms:
      • Deoxycholate form (ABD)  (STANDARD)
      • Lipid preparations  (less toxic, same efficacy, but very high $$$)
        • Use if renal dysfunction (see below)
    • Toxicity:
      • Nephrotoxic
        • vasoconstriction of renal arterioles, decrease in GFR.
        • Impairs proximal and distal tubular reabsorption --> K+, Mg, HCO3 wasting.
        • Often reversible, except if long-term then:
          • Permanent nephron loss and damaged tubular basement membrane.
        • Hydrate before therapy to decrease risk.
      • Fever
        • Not allergic, no anaphylaxis.
        • Can pre-medicate with acetaminophen or 25-50mg of hydrocortisone.
      • Phlebitis
        • High incidence of phlebitis
        • Use central venous line.
    • Clearance:
      • Not affected by hepatic/renal dysfunction.
      • Degrated slowly, accummulates in machophages.  (Detect in serum 7w post-tx)
      • Poor CSF penetration.
    • Coverage:
      • Most effective for systemic fungal infections
    • Resistance:
      • Alters sterol structure - can only grow on mucusal surfaces or urine.
        • Candida lusitaniae (initially susceptible but then resistant)
        • Fusarium
        • Pseudalles-cheriba boydii

    Azoles

     

     

    Azoles
    Drugs Two classes:
    • 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!!)
    Mechanism: Inhibit Cytochrome P450-dependent demethylation system
    • Thereby decreases ergosterol production.. intermediates accumulate.
    • Decreased membrane enzyme activity.
    • FUNGISTATIC!
    Absorption Good PO, often better with food
    Clearance Hepatic
    Coverage

    Broad

    DO NOT cover:
    • Aspergillus
    • Candida (C. glabrata, C. krusei)
    Resistance
    • 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.
    Clinical Use
    • 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
    Toxicity
    • 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
        •  

     

    Echinocandins

     

    Echinocandins
    Drugs

    Derived from echninocandin B

    • Caspofungin
    • Anidulafungin
    • Micafungin
    Mechanism: Block cell wall polysaccharide
    Absorption Good PO, often better with food
    Clearance Hepatic
    Coverage

    Aspergillus, Candida (even if resistant)

     

    NOT active: Cryptococcus

    Resistance
    • 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.
    Clinical Use
    • Aspergillus (if cannot tolerate amphotericin B)
    • Oral/esophageal candidiasis refractory to azoles and amphotericin B.
    Toxicity
    • Mild
    Interactions Cyclosporin, Tacrolimus, Dilantin, Tegretol, etc..

     

    Flucytosine

    Flucytosine
    Drugs

    Flucytosine

    Mechanism: Deamination + phosphorylation --> 5-FU --> inhibits thymidylate synthetase (impairs DNA/RNA synthesis)
    Absorption Good PO
    Clearance  
    Coverage

    Aspergillus, Candida (even if resistant)

     

    NOT active: Cryptococcus

    12% of C. albicans and 3-5% of Cryptococcus neoformans demonstrate resistance.
    Clinical Use
    • Never used alone
    • Often used with Amphotericin B (need to monitor levels, AmpB lowers GFR increases 5-FC levels).
    Toxicity
    • Bone Marrow suppression: Neutropenia, Anemia, thrombocytopenia.
    • Dose related side-effects.
    • Efficacy not proven.
    Interactions  
    Notes:   

     

    Nystatin

    • Only Effective for Candida
    • Do not use on tinea or other dermatophyte infections

     

    Antivirals

     

    Acyclovir/Valacyclovir/Famciclovir

    Block DNA Transcription
    Drugs
    • Acyclovir
    • Valacyclovir  (better PO absorption, less freq dosing)  --> Acyclovir (rapidly converts, resulting higher levels)
    • Famciclovir  --> Penciclovir (converts)  
    • Penciclovir
    Mechanism:
    • 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)
    Absorption
    • acyclovir PO - limited.  (15-20%)
    Clearance
    • 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.
     
    Toxicity
    • 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

    Block DNA Transcription
    Drugs
    • Ganciclovir
    • Valganciclovir
    Mechanism:
    • 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.
    Absorption
    • acyclovir PO - limited.  (15-20%)
    Good CSF Penetration
    Clearance
    • 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.
    Toxicity

     

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