A limited but increasing number of antibiotics can be used to treat mycotic infections. Most have one or more limitations, such as profound side effects, a narrow antifungal spectrum, poor penetration of certain tissues, and the selection of resistant fungi. Finding suitable fungal targets is difficult because fungi, like humans, are eukaryotes. Many of the cellular and molecular processes are similar, and there is often extensive homology among the genes and proteins.

The classes of currently available drugs include the polyenes (amphotericin B and nystatin), which bind to ergosterol in the cell membrane; flucytosine, a pyrimidine analog; the azoles and other inhibitors of ergosterol synthesis, such as the allylamines; the echinocandins, which inhibit the synthesis of cell wall β-glucan; and griseofulvin, which interferes with microtubule assembly. Currently under investigation are inhibitors of cell wall synthesis, such as nikkomycin and pradimicin, and sordarin, which inhibits elongation factor 2.

In recent years, the number of antifungal drugs has increased, and additional compounds are currently under evaluation in clinical trials. Table 1 provides an abridged summary of the available drugs. Many of the newer chemo therapeutics are variations of the azole class of fungistatic drugs, such as the triazoles (voriconazole and posaconazole). These drugs and the newer compounds were designed to improve the antifungal efficacy and pharmacokinetics, as well as to reduce the adverse side effects.

Table 1. Comparison of Common Antifungal Drugs for the Treatment of Systemic Mycoses

Amphotericin B

 A. Description

T he major polyene antibiotic is amphotericin B, a metabolite of streptomyces. Amphotericin B is the most effective drug for severe systemic mycoses. It has a broad spectrum, and the development of resistance is rare. The mechanism of action of the polyenes involves the formation of complexes with ergosterol in fungal cell membranes, resulting in membrane damage and leakage. Amphotericin B has greater affinity for ergosterol than cholesterol, the predominant sterol in mammalian cell membranes. Packaging of amphotericin B in liposomes and lipoidal emulsions has shown superb efficacy and excellent results in clinical studies. These formulations are currently available and may replace the conventional preparation. The lipid preparations are less toxic and permit higher concentrations of amphotericin B to be used.

B. Mechanism of Action

Amphotericin B is given intravenously as micelles with sodium deoxycholate dissolved in a dextrose solution. Though the drug is widely distributed in tissues, it penetrates poorly to the cerebrospinal fluid. Amphotericin B firmly binds to ergosterol in the cell membrane. This interaction alters the membrane fluidity and perhaps produces pores in the membrane through which ions and small molecules are lost. Unlike most other antifungals, amphotericin B is cidal. Mammalian cells lack ergosterol and are relatively resistant to these actions. Amphotericin B binds weakly to the cholesterol in mammalian mem branes, and this interaction may explain its toxicity. At low levels, amphotericin B has an immunostimulatory effect.

 C. Indications

Amphotericin B has a broad spectrum with demonstrated efficacy against most of the major systemic mycoses, including coccidioidomycosis, blastomycosis, histoplasmosis, sporotrichosis, cryptococcosis, aspergillosis, mucormycosis, and candidiasis. The response to amphotericin B is influenced by the dose and rate of administration, the site of the mycotic infection, the immune status of the patient, and the inherent susceptibility of the pathogen. Penetration of the joints and the central nervous system is poor, and intrathecal or intra articular administration is recommended for some infections. Amphotericin B is used in combination with flucytosine to treat cryptococcosis. Some fungi, such as P boydii and A ter reus, do not respond well to treatment with amphotericin B.

 D. Side Effects

All patients have adverse reactions to amphotericin B, though these are greatly diminished with the new lipid preparations. Acute reactions that usually accompany the intravenous administration of amphotericin B include fever, chills, dyspnea, and hypotension. These effects can usually be alleviated by prior or concomitant administration of hydrocortisone or acetaminophen. Tolerance to the acute side effects develops during therapy.

 Chronic side effects are usually the result of nephrotoxicity. Azotemia almost always occurs with amphotericin B therapy, and serum creatinine and ion levels must be closely monitored. Hypokalemia, anemia, renal tubular acidosis, headache, nausea, and vomiting are also frequently observed. While some of the nephrotoxicity is reversible, permanent reduction in glomerular and renal tubular function does occur. This damage can be correlated with the total dose of amphotericin B given. Toxicity is greatly diminished with the lipid formulations of amphotericin B (ie, Abelcet, Amphotec, and AmBisome).

Flucytosine

 A. Description

Flucytosine (5-fluorocytosine) is a fluorinated derivative of cytosine. It is an oral antifungal compound used primarily in conjunction with amphotericin B to treat cryptococcosis or candidiasis. It is effective also against many dematiaceous fungal infections. It penetrates well into all tissues, including cerebrospinal fluid.

B. Mechanism of Action

Flucytosine is actively transported into fungal cells by a permease. It is converted by the fungal enzyme cytosine deaminase to 5-fluorouracil and incorporated into 5-fluo rodexoyuridylic acid monophosphate, which interferes with the activity of thymidylate synthetase and DNA synthesis. Mammalian cells lack cytosine deaminase and are therefore protected from the toxic effects of fluorouracil. Unfortunately, resistant mutants emerge rapidly, limiting the utility of flucytosine.

 C. Indications

Flucytosine is used mainly in conjunction with amphotericin B for treatment of cryptococcosis and candidiasis. In vitro, it acts synergistically with amphotericin B against these organisms, and clinical trials suggest a beneficial effect of the combination, particularly in cryptococcal meningitis. The combination has also been shown to delay or limit the emergence of flucytosine-resistant mutants. By itself, flucytosine is effective against chromoblastomycosis and other dematiaceous fungal infections.

D. Side Effects

While flucytosine itself probably has little toxicity for mammalian cells and is relatively well tolerated, its conversion to fluorouracil results in a highly toxic compound that is probably responsible for the major side effects. Prolonged administration of flucytosine results in bone marrow sup pression, hair loss, and abnormal liver function. The con version of flucytosine to fluorouracil by enteric bacteria may cause colitis. Patients with AIDS may be more susceptible to bone marrow suppression by flucytosine, and serum levels should be closely monitored.

Azoles

A. Description

The antifungal imidazoles (eg, ketoconazole) and the tri azoles (fluconazole, voriconazole, and itraconazole) are oral drugs used to treat a wide range of systemic and localized fungal infections (Figure 1). The indications for their use are still being evaluated, but they have already sup planted amphotericin B in many less severe mycoses because they can be administered orally and are less toxic. Other imidazoles—miconazole and clotrimazole—are used topi cally and are discussed below.

Fig1. Structures of antifungal azoles. (Reproduced with permission from Katzung BG [editor]: Basic and Clinical Pharmacology, 11th ed. McGraw-Hill, 2009. © The McGraw-Hill Companies, Inc.)

B. Mechanism of Action

 The azoles interfere with the synthesis of ergosterol. They block the cytochrome P450-dependent 14α-demethylation of lanosterol, which is a precursor of ergosterol in fungi and cholesterol in mammalian cells. However, the fungal cytochrome P450s are approximately 100–1000 times more sensitive to the azoles than mammalian systems. The various azoles are designed to improve their efficacy, availability, and pharmacokinetics and reduce their side effects. These are fungistatic drugs.

 C. Indications

 The indications for the use of antifungal azoles will broaden as the results of long-term studies—as well as new azoles—become available. Accepted indications for the use of antifungal azoles are listed below.

Ketoconazole is useful in the treatment of chronic muco cutaneous candidiasis, dermatophytosis, and nonmeningeal blastomycosis, coccidioidomycosis, paracoccidioidomycosis, and histoplasmosis. Of the various azoles, fluconazole offers the best penetration of the central nervous system. It is used as maintenance therapy for cryptococcal and coccidioidal meningitis. Oropharyngeal candidiasis in AIDS patients and candidemia in immunocompetent patients can also be treated with fluconazole. Itraconazole is now the agent of first choice for histoplasmosis and blastomycosis as well as for certain cases of coccidioidomycosis, paracoccidioidomycosis, and aspergillosis. It has also been shown to be effective in the treatment of chromomycosis and onychomycosis due to dermatophytes and other molds. Voriconazole, which can be given orally or intravenously, exhibits a broad spectrum of activity against many molds and yeasts, especially aspergillosis, fusariosis, pseudallescheriasis, and other less common systemic pathogens. The newest triazole is posaconazole (Figure 2- A, which has a wide spectrum and demonstrated efficacy against fluconazole-resistant Candida species, asper gillosis, mucormycosis, and other opportunistic invasive molds. It is also well tolerated.

D. Side Effects

 The adverse effects of the azoles are primarily related to their ability to inhibit mammalian cytochrome P450 enzymes. Ketoconazole is the most toxic, and therapeutic doses may inhibit the synthesis of testosterone and cortisol, which may cause a variety of reversible effects such as gynecomastia, decreased libido, impotence, menstrual irregularity, and occasionally adrenal insufficiency. Fluconazole and itraconazole at recommended therapeutic doses do not cause significant impairment of mammalian steroidogenesis. All the antifungal azoles can cause both asymptomatic elevations in liver function tests and rare cases of hepatitis. Voriconazole causes reversible visual impairment in about 30% of patients.

Since antifungal azoles interact with P450 enzymes that are also responsible for drug metabolism, some important drug interactions can occur. Increased antifungal azole concentrations can be seen when isoniazid, phenytoin, or rifampin is used. Antifungal azole therapy can also lead to higher than expected serum levels of cyclosporine, phenytoin, oral hypoglycemics, anticoagulants, digoxin, and prob ably many others. Serum monitoring of both drugs may be necessary to achieve a proper therapeutic range.

Echinocandins

 The echinocandins are a new class of antifungal agents that perturb the synthesis of the pervasive cell wall polysaccharide β-glucan by inhibiting 1,3-β-glucan synthase and disrupting cell wall integrity. The first licensed drug, caspofungin, has shown efficacy against invasive aspergillosis and systemic candidiasis due to a wide range of Candida species (see Figure 2-B). T his intravenous agent may be especially indicated for refractory aspergillosis. Caspofungin is well tolerated.

Similar to caspofungin, two newly approved echinocandins, micafungin and anidulafungin, also inhibit the synthesis of β-glucan and have a similar spectrum of activity against species of Candida and Aspergillus, as well as several other molds. Micafungin (see Figure 2-C) and anidulafungin were recently licensed for the treatment of esophageal candidiasis and for the antifungal prophylaxis of hematopoietic stem cell transplant patients. Both seem to have better pharmacokinetics and in vivo stability than caspofungin. Clinical studies suggest that they will be useful in the treatment of mucosal and systemic candidiasis, refractory invasive aspergillosis, and in combination with amphotericin B or some of the newer triazoles.

Griseofulvin

Griseofulvin is an orally administered antibiotic derived from a species of penicillium. It is used to treat dermatophytoses and must be given for long periods. Griseofulvin is poorly absorbed and concentrated in the stratum corneum, where it inhibits hyphal growth. It has no effect on other fungi.

After oral administration, griseofulvin is distributed throughout the body but accumulates in the keratinized tis sues. Within the fungus, griseofulvin interacts with micro tubules and disrupts mitotic spindle function, resulting in inhibition of growth. Only actively growing hyphae are affected. Griseofulvin is clinically useful for the treatment of dermatophyte infections of the skin, hair, and nails. Oral therapy for weeks to months is usually required. Griseofulvin is generally well tolerated. The most common side effect is headache, which usually resolves without discontinuation of the drug. Less frequently observed side effects are gastrointestinal disturbances, drowsiness, and hepatotoxicity.

Terbinafine

 Terbinafine is an allylamine drug; it blocks ergosterol syn thesis by inhibiting squalene epoxidase (see Figure 2-D). Terbinafine is given orally to treat dermatophyte infections. It has proved quite effective in treating nail infections as well as other dermatophytoses. Side effects are not common but include gastrointestinal distress, headaches, skin reactions, and loss of sense of taste. For the long-term treatment of tinea unguium, terbinafine—as well as itraconazole and fluconazole—may be given intermittently, using a pulse treatment protocol.

Fig2. Newer antifungal drugs. A: Posaconazole. B: Caspofungin. C: Micafungin. D: Terbinafine.