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antifungals

antifungal agents

introduction

  • oral antifungals other than nystatin generally have potentially serious adverse effects and important drug interactions.
    • reserve these antifungals for:
      • widespread or chronic, mycologically confirmed superficial fungal infection not responding to repeated topical Rx
      • tinea in hair bearing areas (groin or scalp ringworm) or on palms of hand or soles of feet
      • tinea previously treated with corticosteroids
      • onychogryphosis due to confirmed fungal infection
  • tinea capitis:
    • highly contagious & mainly effects children
    • start oral antifungals (griseofulvin in children) after cultures taken but without waiting culture results if clinical suspicion is high
    • whilst topical Rx may be used as adjunctive Rx to limit spread, they are unlikely to be effective in curing it.
  • onychogryphosis:
    • oral terbinafine is Rx of choice if more than mild distal infection (see below)
  • mild uncomplicated fungal skin infections:
    • generally reasonable to start topical antifungal Rx empirically without sampling for micro/culture, although samples should be taken when Dx is in doubt, the infection is severe or widespread, and when considering oral Rx.
    • individual topical azoles provide similar cure rates
    • topical terbinafine once daily for 7 days is as effective as topical azoles for 4weeks, and more effective when terbinafine Rx is longer (4-6 wks).
    • avoid concurrent topical corticosteroids unless there is severe inflammation
    • topical azole Rx should be continued for two weeks after symptoms and signs of infection resolve.

systemic non-azole antifungals:

amphotericin B:
  • produced by Streptomyces nodosus
  • 1st purified in 1956
  • an amphoteric polyene macrolide which is almost insoluble in water and unstable at 37degC
  • acts by binding to ergosterol in the fungal cell membrane presumably creating pores
  • as it also binds to cholesterol in animal cell mebranes, this may account for some of its toxicity
  • inhibits most fungi that are pathogens in man as is also useful in Rx Naegleria meningoencephalitis
  • poorly absorbed from GIT thus IV or intrathecal use only for systemic use, although oral use may be used for lumenal GIT disease
  • clinical usage:
    • fungal meningoencephalitis:
      • intrathecal injection 0.5mg 3x a week for up to 10wks or longer
    • systemic candidiasis:
      • usually used in conjunction with flucytosine which reduces resistance to flucytosine whilst allowing lower doses of amphotericin
    • corneal ulcers:
      • 1mg/ml solution topically every 30min
  • adverse effects:
    • chills, fever, vomiting, headache
      • Rx by aspirin, phenothiazines, antihistamines, corticosteroids, or stopping injections for several days
    • impaired renal and hepatic function
    • anaemia
    • hypotension, hypokalaemia, neurologic symptoms
      • NB. liposomal delivery appears to be less nephrotoxic & neurotoxic
flucytosine:
  • 5-fluorocytosine is a oral antifungal
  • inhibits fungal cells that convert flucytosine to fluorouracil with resultant inhibition of thymidylate synthetase & thus DNA synthesis
  • resistant mutants emerge readily, thus generally used in combination with amphotericin B
  • clinical use:
    • oral 150mg/kg/d (less if renal failure)
  • adverse effects:
    • prolonged high serum levels may cause:
    • bone marrow depression, alopecia, abnormal liver function
griseofulvin:
  • isolated from Penicillium griseofulvum in 1939
  • mainly inhibits the dermatophytes
  • poorly soluble in water, thus available as microsize particles or ultrmicrosize which is absorbed twice as well
  • topical use has little effect
  • the only TGA approved oral antifungal Rx for children with tinea capitis (2008)
  • clinical use:
    • dermatophytoses (esp. Tricophyton rubrum which responds poorly to other Rx):
      • hair or skin only involved: 3-6wks course
      • fingernails: 3-6 months
      • toenails: may require longer than 6 months
  • adverse effects:
    • drug interactions include warfarin
    • allergic reactions consisting of fever, skin rashes, leukopenia & serum-sickness reactions
terbinafine:
  • oral antifungal
  • reports of hepatic failure, Stevens-Johnson syndrome & blood dyscrasias prompted TGA to recommend use only after topical Rx failed and for the shortest possible time and with regular monitoring.
  • the Rx of choice for onychomycosis (dermatophyte nail infections)
    • meta-analysis of 36 studies found higher cure rates with terbinafine (76%) than for pulsed itraconazole (63%), continuous itraconazole (59%), griseofulvin (60%) or fluconazole (48%) - ref: Br J Dermatol 2004; 150:537-44;
    • listed on PBS as authority item for proximal or extensive onychomycosis (>80% of nail), caused by dermatophyte proven by microscopy or culture when topical Rx has failed.
    • NB. topical antifungals have a very limited role here as only suitable for mild superficial, early infection of the distal part of the nail, and even then have a low cure rate and may require 12 months Rx or longer.
    • for onychomycosis, consider pulsed itraconazole (2-3 courses) if unable to tolerate terbinafine or if cause is candida
  • Cochrane review found terbinafine was more effective than griseofulvin in curing athlete's foot (tinea pedis).
    • small trials found no significant difference between terbinafine or the azoles.

echinocandin antifungals

  • selectively inhibit glucan synthase which is required for fungal cell wall synthesis
micafungin
  • once daily slow iv infusion 100mg/d in adults and 1-2mg/kg in children for 15 days gives comparable results to amphotericin B or fluconazole for Rx of invasive candidiasis
  • terminal half-life 10-17hrs
  • minimal hepatic metabolism
  • mainly excreted in the faeces
  • premature infants clear it 2-6x faster than adults
  • 10% develop haematological adverse reactions
anidulafungin
caspofungin

antifungal azoles:

general overview:
  • inhibit fungi by blocking biosynthesis of fungal lipids, esp. ergosterol in cell membranes via inhibiting a P450-dependent enzyme
  • avoid in pregnancy
topical or IV only:
  • clotrimazole:
    • 1% cream for dermatophytoses & vaginal candidiasis
    • too toxic for systemic use
  • miconazole:
    • 2% cream for dermatophytoses & vaginal candidiasis
    • IV 30mg/kg/d for systemic disease
oral systemic:
  • ketoconazole:
    • 200-400mg once a day:
    • oral or vaginal candidiasis 1-2wks but 4-10months if immunodeficient
    • dermatophytosis 3-8wks
    • poor levels in CNS though
    • adverse effects:
      • nausea, vomiting, elevated AST
      • very rarely progressive hepatotoxicity at high doses
      • inhibits P450 thus drug interactions esp. antihistamines causing torsades de pointes
  • fluconazole:
    • more readily absorbed than ketoconazole & penetrates CNS better
    • half-life 30hrs & greatly prolonged in renal impairment
    • dose:
      • 100-200mg once a day
    • adverse effects:
      • as for ketoconazole
  • itraconazole:

nystatin:

  • polyene macrolide which acts by binding to ergosterol on cell mebrane
  • only active if in direct contact with candida, not active significantly against other fungi
  • safe in pregnancy
  • clinical use:
    • topical to mucosal or skin surfaces
    • orally to clear GIT source of candida
  • adverse effects:
    • contact dermatitis - thus avoid use on skin/vulva when Rx vaginal candidiasis
antifungals.txt · Last modified: 2014/04/02 00:01 (external edit)