Assoc. Prof. Ivan Lambeve-mail: itlambev@mail.bg

Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and Toxicology

Antifungal drugs(Abstract)

Human fungal infections have increased dramaticallyin recent years, owing mainly to advances in surgery,cancer treatment, and critical care accompanied by increases in the use of broad-spectrum antimicrobialsand the HIV epidemic. These changes have resultedin increased numbers of patients at risk for fungalinfections.

Fungal infections are usually more difficult to treatthan bacterial infections, because fungal organisms growslowly and because fungal infections often occur in tissu-es that are poorly penetrated by antimicrobial agents(e.g., devitalized or avascular tissues). Therapy of fungalinfections usually requires prolonged treatment.

Superficial fungal infections involve cutaneous sur-faces, such as the skin, nails, and hair, and mucousmem-brane surfaces, such as the oropharynx and vagina.

Deepseated or disseminated fungal infections causedby dimorphic fungi, the yeasts Cryptococcus neoformans,and various Candida spp. respond to a limited number ofsystemic agents: amphotericin B desoxycholate (a poly-ene), amphotericin B liposomal preparations, flucyto-sine (a pyrimidine antimetabolite), the newer azoles, in-cluding ketoconazole, fluconazole, itraconazole andvoriconazole, and capsofungin (an echinocandin).

1. Polyene antibiotics

Amphotericin B and Nystatin bind tothe fungal cell membrane component ergosterol, lead-ing to increased fungal cell membrane permeability andthe loss of intracellular constituents. Amphotericin hasa lesser affinity for the mammalian cell membrane com-ponent cholesterol, but this interaction does account formost adverse toxic effects associated with this drug.Amphotericin B has activity against Candida spp., Cryptococcus neoformans, Blastomyces dermatitidis,Histoplasma capsulatum, Sporothrix schenckii,Coccidioides immitis, Paracoccidioides braziliensis,Aspergillus spp., Penicillium marneffei etc.

Amphotericin uses i.v. for treatment of Candida esopha-gitis, rapidly progressive mucormycosis or invasive aspergillosis. Intrathecal infusion of amphotericin B isuseful in patients with meningitis caused by Coccidioides.Intravenous administration of amphotericin B is the treatment of choice for mucormycosis and is used forinitial treatment of cryptococcal meningitis, severe orrapidly progressing histoplasmosis, blastomycosis, and coccidioidomycosis. Intraocular injection following pars plana vitrectomy has been used successfully for fungal endophthalmitis.

The major acute reaction to i.v. amphotericin B is fever and chills. Tachypnea and respiratory stridoror modest hypotension also may occur, but truebronchospasm or anaphylaxis is rare. Patients withpreexisting cardiac or pulmonary disease may tolerate the metabolic demands of the reaction poorly and develop hypoxia or hypotension. Although the reaction ends spontaneously in 30 to 45 minutes, pethidine may shorten it. Pretreatment with oral paracetamol or use of i.v.hydrocortisone hemisuccinate, at the start of the infusion decreases reactions. Infants, children, andpatients receiving therapeutic doses of glucocorticoidsare less prone to reactions. Azotemia occurs in 80% ofpatients who receive Amphotericin in deep mycoses.

Sevral lipid formulations of amphotericin B – colloidal dispersion and liposomal amphotericin B, have beendeveloped in an attempt to reduce the toxicity profileof this drug and to increase its efficacy. Formulatingamphotericin with lipids alters drug distribution, withlower levels of drug in the kidneys, reducing the incidence of nephrotoxicity. The lipid formulations appear to be equivalent to conventional amphotericinB both in the treatment of documented fungal infections and in the empirical treatment of the febrile neutropenic patient. While less toxic, thelipid formulations are significantly more expensivethan conventional amphotericin B.

Nystatin is a polyene antifungal drug with a ring structure and a mechanism of action similar to that of amphotericin B. Too toxic for systemic use, nystatin is limited to the topical treatment of superficial infections caused by C. albicans. Infections commonlytreated by this drug include oral candidiasis(thrush), mild esophageal candidiasis, and vaginitis.

2. Antifungal Azoles are synthetic drugswith broad-spectrum fungistatic activity. Azoles can bedivided into two groups: the older imidazole agents (clotrimazole, ketoconazol, miconazole) in whichthe five-member azole nucleus contains two nitrogensand the newer triazole compounds (fluconazole, itraconazole, and voriconazole), in which the azole nucleus contains three nitrogens.

All azoles exert antifungal activity by inhibitingcytochrome P450 enzymes responsible for the demethylation of lanosterol to ergosterol. Reduced fungal membrane ergosterol concen-trations result in damaged, leaky cell membranes. The toxicity of these drugs depends ontheir relative affinities for mammalian and fungalcytochrome P450 enzymes. The triazoles tend to have fewer side effects, better absorption, better drug distribution in body tissues, and fewer drug interactions.

Fluconazole does not require an acidic envi-ronment, as does ketoconazole, for GI absorption. About 80 to 90% of an orally administereddose is absorbed, yielding high serum drug levels. Thet1/2 of the drug is 27 to 37 h, permitting once-daily dosing in patients with normal renal function.Only 11% of circulating drug is bound to plasma pro-teins.The drug penetrates widely into most body tissues,including normal and inflamed meninges. Cerebrospinalfluid levels are 60 to 80% of serum levels, permitting ef-fective treatment for fungal meningitis. About 80% ofthe drug is excreted unchanged in the urine, and 10% is excreted unchanged in the feces. Dosage reductionsare required in the presence of renal insufficiency.

Fluconazole is very effective in the treatment of infec-tions with most Candida spp. Thrush in the end-stageAIDS patient, often refractory to nystatin, clotrimazole,and ketoconazole, can usually be suppressed with oralfluconazole. AIDS patients with esophageal candidiasisalso usually respond to fluconazole. A single 150-mgdose has been shown to be effective treatment for vagi-nal candidiasis. A 3-day course of oral fluconazole is ef-fective treatment for Candida urinary tract infectionand is more convenient than amphotericin B bladder ir-rigation. Stable nonneutropenic patients with candidemiacan be adequately treated with fluconazole.

Fluconazole may be an alternative to amphotericin Bin the initial treatment of mild cryptococcal meningitis.Coccidioidal meningitis, previously treated withboth intravenous and intrathecal amphotericin B, appears to respond at least as well to prolonged oral fluconazole therapy.

A significant decrease in mortality from deep-seatedmycoses was noted among bone marrow transplant re-cipients treated prophylactically with fluconazole.

Fluconazole taken prophylactically by end-stage AIDSpatients can reduce the incidence of cryptococcal meningitis, esophageal candidiasis, and superficial fungal infections.

Fluconazole is well tolerated. Nausea, vomiting, abdom-inal pain, diarrhea, and skin rash have been reported infewer than 3% of patients. Asymptomatic liver enzymeelevation has been described, and several cases of drug-associated hepatic necrosis have been reported. Alopecia has been reported as a common adverse eventin patients receiving prolonged high-dose therapy. Coad-ministration of enzyme inhibitor fluconazole withphenytoin results in increased serum phenytoin levels.

Itraconazole is lipophilic and water insoluble and requires a low gastric pH for absorption.Oral bioavailability is variable, only 50 to 60% whentaken with food and 20% or less when the drug is takenon an empty stomach. Itraconazole is highly proteinbound (99%) and is metabolized in the liver and ex-creted into the bile.Itraconazole is most useful in the long-term suppressivetreatment of disseminated histoplasmosis in AIDS andin the oral treatment of nonmeningeal blastomycosis.It is the drug of choice for all forms of sporotrichosisexcept meningitis. Itraconazole has replaced ketoconazole as the drug of choice in the treatmentof paracoccidioidomycosis and chromomycosis.

Ketoconazole (Nizoral®) can be absorbed orally, but it requires an acidic gastric environment.Ketoconazole remains useful in the treatment of cuta-neous and mucous membrane dermatophyte and yeastinfections, but it has been replaced by the newer tria-zoles in the treatment of most serious Candida infec-tions and disseminated mycoses. Ketoconazole is usu-ally effective in the treatment of thrush, but fluconazoleis superior to ketoconazole for refractory thrush.Widespread dermatophyte infections on skin surfacescan be treated easily with oral ketoconazole when theuse of topical antifungal agents would be impractical.Treatment of vulvovaginal candidiasis with topical imi-dazoles is less expensive.

Nausea, vomiting, and anorexia occur commonly withketoconazole, especially when high doses are pre-scribed. Epigastric distress can be reduced by taking ke-toconazole with food. Pruritis and/or allergic dermatitisoccurs in 10% of patients. Liver enzyme elevations dur-ing therapy are not unusual and are usually reversible.Severe ketoconazole-associated hepatitis is rare.At high doses, ketoconazole causes a clinically sig-nificant reduction in testosterone synthesis and blocksthe adrenal response to corticotropin. Gynecomastia,impotence, reduced sperm counts, and diminished li-bido can occur in men, and prolonged drug use can re-sult in irregular menses in women. These hormonal ef-fects have led to the use of ketoconazole as a potentialadjunctive treatment for prostatic carcinoma.

Clotrimazole is a broad-spectrum fungistatic imidazole drug used in the topical treatment of oral, skin, and vaginal infections with C. albicans. It isalso employed in the treatment of infections with cutaneous dermatophytes.Topical use results in therapeutic drug concentra-tions in the epidermis and mucous membranes; lessthan 10% of the drug is systemically absorbed. Although clotrimazole is generally well tolerated, local abdominal cramping, increased urination, and transient liver enzyme elevations have been reported.

3. Fuorinated pyrimidinesFlucytosine (5-flucytosine, 5-FC)is an analogue of cytosine that was originallysynthesized for possible use as an antineoplasticagent. 5-FC is converted to 5-fluorouracil inside the cell by the fungal enzyme cytosine deaminase. Activemetabolite 5-fluorouracil interfere with fungal DNAsynthesis by inhibiting thymidylate synthetase. Incor-poration of these metabolite into fungal RNA inhibitprotein synthesis.Flucytosine has significant antifungal activity againstC. albicans, other Candida spp., C. neoformans, andthe fungal organisms responsible for chromomycosis.

4. EchinocandinsCapsofungin is a semisynthetic lipopeptide. It inhibits the synthesis of beta-D-glucan, a cell wall component of filamentousfungi. Capsofungin is approved for the treatment of invasive aspergillosis in patients not responding to other antifungal agents, such as lipid formulations of amphotericin B, and itraconazole.

Adverse effects are mediated through histamine release: facial flushing, rash, fever, and pruritis. Nausea and vomiting have also been reported. Dosereductions are required in the presence of moderatehepatic insufficiency.

5. Allylamines – reversible noncompetitive inhibitorsof the fungal enzyme squalene monooxygenase, which converts squalene to lanosterol. With a decrease in lanosterol production, ergosterolproduction is also diminished, affecting fungal cellmembrane synthesis and function. These agents gener-ally exhibit fungicidal activity against dermatophytesand fungistatic activity against yeasts.Naftifine is available for topical use only in the treat-ment of cutaneous dermatophyte and Candida infections.Terbinafine (Lamisil®) is available for topical and systemic use (oral tablet) in the treatment of dermatophyte skin and nail infections.

6. PyridonesCiclopirox olamine is a pyridone derivativefor the treatment of cutaneous dermatophyteinfections, cutaneous C. albicans infections,and tinea versicolor caused by Malassezia furfur. It interferes with fungal growth by inhibiting macromolecule synthesis.

7. ThiocarbamatesTolnaftate is an antifungal agent effective in the topical treatment of dermatophyte infections and tinea.

8. Nonpolyene antibioticsGriseofulvin is an oral fungistatic agent usedin the long-term treatment of dermatophyte infectionscaused by Epidermophyton, Microsporum, and Trichophyton spp. Produced by the mold Penicilliumgriseofulvin, this antibiotic inhibits fungal growth bybinding to the microtubules responsible for mitotic spindle formation, leading to defective cell walldevelopment. The drug binds to keratin precursor cellsand newly synthesized keratin in the stratum corneumof the skin, hair, and nails, stopping the progression ofdermatophyte infection. In the treatment of ringworm of the beard, scalp, and other skin surfaces, 4 to 6 weeks of therapy is often required.