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 crurisMucocutaneous = 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: onlyin 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
Worksheet 1 MAS367 Sample Sizes, Allocation, Bias and Randomization 1. The Beck depression inventory score is often used as the outcome measure in trialsthat assess treatments for depression. It has standard deviation 8 (no units). Supposethat in a trial comparing two treatments there is interest in detecting a difference of 3.5between the mean Beck depression inventory scores in the two gro