• encapsulated spores
• found in soil, bird droppings
• common infection- AIDS patients

1. inhalation
2. phagocytosis by macrophages where organisms can multiply
3. infection of reticuloendothelial system including lymphatics

skin

cornea

systemic

superficial skin

superficial infections of GI and GU tract

• oft tissue infection
• pneumonia
• meningits
• UTI
• septacemia

May be chronic but indolent or invasive, life threatening

• chronic treatment with antibact. and antifungal drugs in those with chronic immunocompromise (ex: AIDS)
• discourage px use

• decrease synthesis of ergosterol by inhibiting fungal cyc P450
  • selective because show less inh. of human CYP450

• broad spec
  • candida
  • blastomycosis
  • histoplamsosis
  • dermatophytes
  • cryptococcus
  • Pseudallescheria boydi (R to amphotericin B)

• indication
  • cryptococcal meningitis
  • candidemia
  • mucucutaneous candidiasis
  • px in high risk neutropenic patients and HIV/AIDS patients with recurrent oral or esophageal condidiasis, but resistance more common

• rash (Steven Johsnon)
• inhibitor of CYP29, so increase serum conc. of phenytoin and warfarin

• indications
  • dimorphic fungi histoplasma, blastomyces, sporothrix
  • effective against dermatophytes
• PK
  • poor CNS penetration
  • oral admin only via capsules or solution
  • absorption of capsules reduced by proton pump inhibitors and H2 antagonists
  • reduce bioavail when co admin with rifamycins

• potent inhibitor of CYP3A4
  • CI: statins, midazolam, triazolam
• CHF
  • CI: ventricular dysfunction

• px in immunocomp. patients
  • only azole active against Zygomycetes
  • aspergillus as well

Must take orraly with a full meal for proper absorption

• PK
  • oral and IV admin
• adverse effects- visual disturbances common (30%) like bluring and changes in color vision or brightness during first 30 minutes of dose, and reversible
• indications
  • invasive aspergillus (better outcomes and less toxicity than amphoterin B)
  • infections of candida
  • infections of dimorphic fungi

• amphipathich polyene
• binds to ergosterol
• forming artificial membrane pores
• allow leakage of intracellular ions and macromolecules out of fungal cell membrane

Adverse effects caused by its binding to cholesterol in cells of host

• first azole not used IV due to high level of human CYP 450 inh.
• indications
  • topically- chronic mucocutaneous candidiasis
  • orally- dermatophytes
• adverse effects
  • pruritus
  • hepatitis risk (CI: h/o hepatitis)

• mechanism- inhibit syn. of beta(1-3)glucan to disrupt the fungal cell wall
• pharmacokinetics
  • water soluble
  • well tolerated, but CI:cyclosporin (elevated liver enzymes)
  • IV administration
• indications
  • invasive aspergillus in patients not responsive to amphotericin B or voriconazole
  • candidemia
• adverse effects- liver toxicity

• indications- very broad spectrum for serious life threatening systemic mycotic infections
  • intrathecal for fungal meningitis (can't penetrate BBB) 
  • usually start with it than switch long term to azole if patient immunocomp. and requires long term therapy
• PK
  • must use IV (poor GI absorption) for treatment of systemic mycoses
  • excreted slowly, so can accum. causing toxicity
  • approved formulations: amphotericin B deoxycholate (conventional) and lipid formulations
• mechanism of adverse effects
  • unwanted binding to cholesterol of cells of host

• toxicity limits its use (esp. long term), so we cannot exceed cummulative dose of 2 g's
• adverse reactions
  • immediate infusion reaction
    • chills
    • fever
    • muscle spasms
    • headache
    • vomiting
    • hypotension
  • long term: renal damage
    • starts with reversible decreased perfusion
    • then ends with irreversible tubular injury
• reduce by slow IV drip infusion
  • sodium loading to reduce renal damage
  • load with antipyretics, antihistamines

• amphotericin B prefered to azolles and caspofungin

• advantages
  • decrease renal toxicity
  • less severe immediate infusion reactions with two of the approved formulation
• disadvantages
  • third lipid formulation has more severe immediate infusion reaction
  • hepatotoxicity risk greater
  • more expensive

• PK
  • too toxic to be given parenterally (similar to amphotericin B)
  • available as creams, ointments, suppositories for application on skin and mucous membranes
• indications- local candidal infections including thrush and vaginal candida

• terbinafine
• nystatin
• some OTC azoles like clotrimazole and miconazole

• mechanism of action
  • keratophilic like griseofulvin, but also has direct fungicidal properties
  • inhibits fungal enzyme, leading to increase in intracellular levels of squalene to toxic levels
• PK- oral administration (time of admin. depends on infection)
• indication- dermatophytoses, esp. onychomycosis (fingernail and toenail infections)
• adverse effects- well tolerated with no drug interactions, but some GI upset and headache

• PK
  • insoluble, so admin. orally in microcrystalline form
  • tx must persist for 2-6 wks or until old infection is gone
• mechanism
  • interferes with MT assembly, so no mitosis can occur
  • deposited in newly growing keratin of skin and nails
  • while there it prevents fungal infection of new growth
• adverse effects
  • allergic syndrome similar to serum sickeness
  • hepatitis
  • GI disturbances
• drug interactions
  • warfarin
  • phenobarbital

itraconazole

terbinafine

• mechanism
  • taken up by a membrane permease in fungal cells and converted to potent antimetabolite 5- fluorouracil
  • 5 flurouracil inhibits thymidylate synthase
  • humans dont do this reaction
• indications- narrow spec never used alone
  • w/ amphotericin B, it treats systemic Cryptococcus neoformans
  • w/ itraconazole for chromoblastomycosis
• PK- oral formulation, excreted unchanged\
• adverse effects- serious toxicity eps. w/ cases of renal insufficiency and sometimes AIDS patients
  • anemia
  • leukopenia
  • thrombocytopenia