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Antifungal agents

ANTIFUNGAL AGENTS

Objectives:
To learn the general classes of fungal infections To learn the subclassification of antifungal drugs To know the mechanism of action and basic uses for antifungal drugs Fungal infections (mycoses), though not as frequent as bacterial or viral infections, have nonetheless been increasing in incidence in the human population over the last 15 years or so, largely as a consequence of increased numbers of cancer and immunocompromised patients, who are at greater risk owing to weakened immune systems and the chronic nature of the diseases. In addition, a number of fungal infections can be difficult to treat (oft referred to as ‘stubborn’), even when the offending organism is identified and appropriate therapy is applied. On the other hand, like bacteria, fungi have unique characteristics, distinct from their mammalian hosts, allowing for selective targeting of therapeutic drugs. Fungi are, however, much more complex organisms in comparison to bacteria, are in fact eukaryotic and often grow fairly slowly. Consequently, only a few drugs are aimed at interfering with cell division and have limited use. Most antifungal drugs are targeted to the cell membrane. Major fungal infections The number of different kinds of fungi out there is vast, and, of course, some of them are pleasant to eat. Only a small subset is capable of infecting humans. The following is a very general breakdown of types of fungal infections that occur based on site of infection: Cutaneous = skin, hair and nails
‘Athlete’s foot’, Ringworm, and Tinea cruris Mucocutaneous = moist skin and mucous membranes,
such as GI, perianal and vulvovaginal areas Pulmonary/Systemic
Aspergillus, cryptococcal meningitis, pulmonary histoplasmosis; also, systemic candidiasis Systemic fungal infections are more serious as they are usually more difficult to diagnose, are chronic in nature, and, in some cases, can become life-threatening. They occur more frequently in individuals with compromised immune systems (AIDS patients; transplant patients; cancer patients). Prophylactic treatment is sometimes indicated in AIDS patients and bone marrow transplant patients, but risk of developing resistance is high. Life-threatening infections require the use of more potent but much more toxic antifungals. Superficial fungal infections are almost always caused by dermatophytes or yeasts. In some
instances, they can be rather tenacious, requiring very long treatments, sometimes with both oral
and topical drugs.
Drug Classes
Note that the antifungals are classified by structure or mechanism, not by site of action, as some
of them may be used, for example, either topically or systemically depending on the infection.
1. (Macrolides)
Mechanism of action: binds to sterols present in the plasma membrane more selective for ergosterol = major fungal sterol broadest spectrum of any antifungal
given slowly IV as liposome suspension, or used topically given orally for GI fungi, but as such is really acting ‘topically’ drug of choice for life-threatening systemic infections
Invasive Aspergillus (30% survival); used with itraconazole Cryptococcal meningitis; used with flucytosine (alternative: fluconazole) some limited use for cutaneous (dermatophytic) infections Adverse effects: fairly toxic [some binding to mammalian membranes; effects reduced via use of liposome delivery] - fever and chills; vomiting; muscle spasms; modest hypotension (nearly 100% but treatable; small test dose usually given to assess reactions) - renal impairment (near 80%)
Mechanism of action: same as for Amphotericin B Uses: much too toxic for systemic (parental) use
→ used only topically
local (dermal), oropharyngeal, GI and vaginal candidiasis only [other than its nasty, bitter taste, adverse effects are uncommon]
2. (Antimetabolite)
Mechanism of action: selectively converted by fungi to active metabolites Absorption: well absorbed; used orally (only) Uses: only in combination with
→ amphotericin B for cryptococcal meningitis → itraconazole for blastomycoses [high incidence of resistance as well as toxicity reduced via use in drug combinations] Adverse effects: (narrow therapeutic window) → results from fluorouracil = major metabolite - bone marrow toxicity

3. (Cytoskeleton Agent)
Mechanism of action: proposed to inhibit microtubules blocks fungal mitosis, therefore is fungistatic
Absorption: poor - very insoluble orally administered in a microcrystalline form Uses: systemic uses for dermatophytosis (eg. skin and, esp. nail infections, though for the latter terbinafine is preferred), extended treatments [after or sometimes with treatment with triazoles]
[also highly effective against Athlete’s foot and ringworm] - allergic syndrome (like serum sickness: fatigue. - rare) - drug interaction with warfarin or phenobarbital

4. (Imidazoles)

Mechanism of action: inhibit fungal ergosterol biosynthesis selectively inhibit fungal cytochrome P450 enzymes (original oral ‘azole’, not as selective as newer azoles, ie. significant inhibition of mammalian P450 enzymes) Absorption: low - improved with food and low gastric pH used orally, but has very slow onset; poor CSF and urinary tract penetration (largely supplanted by more expensive itraconazole or fluconazole) Adverse effects: (narrow therapeutic window) highly dose-dependent - endocrine: interferes with adrenal and gonadal steroid synthesis* - hepatotoxicity (rare but can prove fatal) - drug interactions →*action on human cytochrome P450 (eg. ↑ warfarin; ↑ cyclosporine; and vice versa) → decreased absorption of ketoconazole when administered with rifampin, H2 antagonists or antacids Absorption: extremely poor - both used topically: creams and, in the case of clotrimazole, oral troches (=lozenges) Uses: wide-spread, over-the-counter use as topical antifungals
dermatophytic infections (eg. tineas corporis) oropharyngeal thrush (candidiasis; alternatives to nystatin)
5. (Triazoles)
Mechanism of action: inhibit fungal ergosterol biosynthesis Absorption: OK, low bioavailability (no CSF penetration) Uses: most potent of the azoles for systemic infections
drug of choice for persistent dermatophytic infections
effective against all types of Aspergillus infection
preferred agent for endemic mycoses (eg. Histoplasma) - drug interactions (esp. non-sedating antihistamines) (no effect on steroid biosynthesis; variable effect on mammalian P450 system, less than with ketoconazole but still of potential concern) Absorption: good; used orally and IV (excellent CSF penetration)
agent of choice for cryptococcal meningitis (unless life-threatening: use AmpB)
prophylactically for bone marrow transplants and AIDS patients Adverse effects: (widest therapeutic window) few and mild concern for all azoles: newly observed emergence of resistant strains in AIDS [resistance to azoles is otherwise fairly rare] Voriconazole (most recently approved (2002) azole, derived from Absorption: good; used orally and IV (good CSF penetration, however*) agent of choice for invasive Aspergillus
active against Candida (even those resistant to fluconazole), Cryptococcus and endemic mycoses, but ineffective against mucormycosis (soil saprophytes) Adverse effects: sporadic visual disturbances* (~30%); hepatotoxicity (2-3%) (Allylamines)
Mechanism of action: inhibits fungal squalene metabolism increased levels of squalene are toxic to fungi; also reduces ergosterol Uses: effective for most cutaneous mycoses either topically (eg. tinea corporis
and tinea cruris) or, in the case of terbinafine, orally for nail infections (90% cure
rate, without side effects)
7. (Echinocandin)
Caspofungin (most recently approved antifungal – Jan 2001) Mechanism of action: inhibits beta (1,3)-D-glucan synthesis, blocking cell wall Absorption: poor; highly protein; administered IV Uses: active against a number of fungi, but particularly effective against invasive candidiasis and aspergillosis (promising new alternative to
amphotericin) via once daily IV administration; no activity against cryptococcus Adverse effects: fever, nausea, vomiting, flushing; some irritation at inj site; wall synthesis via IV: invasive candidiasis & Cell Wall:
-Caspofungin inhibits
beta (1,3)-D-glucan synthesis
Cell Membrane:
-polyenes bind ergosterol
-imidazoles and triazoles inhibit
ergosterol synthesis
-allylamines inhibit squalene
oxidase (
 squalene=toxic)
Nucleus:
-griseofulvin inhibits mitosis
-flucytosine inhibits DNA &
RNA synthesis

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