antifungal agents

see also:

• fungi
• tinea fungal infections
• antibiotics

• 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.

• 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

• 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

• 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

• 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.

• selectively inhibit glucan synthase which is required for fungal cell wall synthesis

• 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

• inhibit fungi by blocking biosynthesis of fungal lipids, esp. ergosterol in cell membranes via inhibiting a P450-dependent enzyme
• avoid in pregnancy

• 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

• 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:

• 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