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ANTIFUNGAL CHEMOTHERAPY

ANTIFUNGAL CHEMOTHERAPY

Classes of Antifungal Drugs
Specific Drugs
 
Amphotericin B
 
Flucytosine
 
Ketoconazole
 
Fluconazole
 
Itraconazole
 
Clotrimazole
 
Griseofulvin
 
Miscellaneous Agents
Bibliography

Fungi are an important cause of human infection. Some, such as Histoplasma capsulatum and Coccidioides immitis, are indigenous to selected geographic areas and are unlikely to be contracted by persons who do not live or travel there. Others, including Candida species and Cryptococcus neoformans, are more universally distributed and are seen primarily in patients with selected forms of immunosuppression or exposure to broad-spectrum antibiotics. Patients with HIV/AIDS are especially predisposed to infection by these fungi, with various clinical presentations. Numerous antifungal agents have been approved, and Table 78-1 provides typical dosages for many of them. However, data on efficacy, safety, and dosing, as well as on the necessary length of treatment, are much less well established than for most antibacterial agents. Reports of carefully controlled, prospective, and blinded studies are few, and problems regarding the use of most of the antifungals are complicated further by a lack of standards for susceptibility testing and blood level determinations.

Table 78-1. Dosages of commonly employed antifungal agents

Classes of Antifungal Drugs
Antifungal agents can be grouped into several classes. The polyenes, which include amphotericin B, nystatin, and candicidin, are characterized by the presence of a hydrophilic region and four to seven double bonds. None is absorbed well after oral administration, and all are considered to be relatively toxic when parenterally administered. Additionally, all are poorly soluble in aqueous solvents. The mechanism of action, probably through binding to fungal ergosterol (a component of the fungal cell wall), allows for the formation of channels within the fungal cell membrane, with a resultant loss of vital elements. Lack of binding characterizes the occasionally resistant organism, such as Candida lusitaniae.
The azoles (imidazoles and triazoles) include miconazole, terconazole, fluconazole ketoconazole, and econazole. Imidazoles differ from triazoles by having two (rather than three) nitrogen atoms in the five-member azole ring. The triazole configuration increases tissue penetration, prolongs half-life, and enhances efficacy while decreasing toxicity. Unlike polyenes, which are active primarily against systemic mycoses, azoles are also effective against dermatophytes. The mechanism of action is through inhibition of intracellular cytochrome P-450, which is required for demethylation of the ergosterol precursor lanosterol and is generally fungistatic.
Specific Drugs
Amphotericin B
Amphotericin B is the standard treatment for disseminated fungal infections, against which all other agents and combinations are judged. It is active against virtually all pathogenic fungi, although occasional resistance and tolerance are encountered. Pharmacokinetically, the drug is poorly absorbed after oral administration, and it must be given intravenously for systemic infections. Its lack of absorption has made amphotericin B a useful component for bowel decontamination or treatment of candidal overgrowth syndromes in selected clinical situations. After parenteral administration, less than 5% is recovered in urine, and only 40% can be found in serum and other fluids. The remainder is presumably absorbed by cell membranes and is then slowly released during prolonged periods. The drug can be detected for more than 8 weeks after commonly employed dosages. Blood levels of amphotericin B are typically below 2 µg/mL, an amount barely greater than the minimum inhibitory concentrations required for many of the fungi treated with this compound. The drug penetrates poorly into body fluids other than serum, and cerebrospinal fluid levels have been demonstrated to be only about 2% to 3% of simultaneous serum levels. Nevertheless, occasional cures of central nervous system infections, such as cryptococcal meningitis, have been effected with this drug.
The solubility of amphotericin B is poor, and it is marketed with deoxycholate to ensure colloidal dispersion. It must be reconstituted with sterile water and then added to 5% dextrose in water (5% D/W) in an amount sufficient to provide a final concentration of 0.1 mg/mL. This formulation cannot be mixed with other solutions, and other compounds should not be admixed. It is no longer necessary to cover the bottle with a paper bag during administration. A 22-mm filter causes partial retention of the agent and should be avoided.
Amphotericin B is administered in doses of 0.5 to 0.7 mg/kg per day. Doses of 1.0 to 1.5 mg/kg per day have been employed for disseminated aspergillosis and meningeal fungal infections. Larger doses are associated with enhanced toxicity without increased efficacy. Normally, a test dose of 1 mg in 50 to 200 mL of 5% D/W is given over 1 to 2 hours to prevent possible anaphylaxis. If the agent is tolerated, the dose is increased to up to 0.5 mg/kg per day, usually administered in 500 mL of 5% D/W over 4 to 6 hours. In most cases, the maximum daily dose is 50 mg. Generally, dose escalation is at a rate of 0.1 to 0.3 mg/kg per day, although this can be increased for severe disease. Generally, dosage modification for renal dysfunction is not needed. Although anecdotal reports of successful infusions lasting fewer than 4 to 6 hours have been published, occasionally severe adverse reactions, including cardiac arrest, have occurred with more rapid administration. Alternatively, the drug may be administered on alternate days with double the usual daily dose. This is especially useful for outpatients. The length of treatment depends on the disease. Under many circumstances, it may be necessary to render therapy for several months. Amphotericin B may be utilized in selected cases of mucosal disease and has been employed widely for patients with HIV/AIDS-related stomatitis and esophagitis. Dosage in these situations is generally 0.3 to 0.5 mg/kg, with total doses as low as 200 to 300 mg. Although most cases of this disease are now treated with oral antifungals, selected cases may still require this form of management. In unusual circumstances, amphotericin B can be administered by alternative routes. As an example, selected cases of C. immitis meningitis may benefit from intrathecal therapy. Intraarticular regimens of less than 15 mg per dose have been employed for selected fungal arthritides.
Adverse reactions to amphotericin B are common and may be severe. This compound is considered to be a rather toxic agent and should be administered by persons comfortable with its use. Chills, fever, and hypotension may be encountered, especially early in therapy. Such problems usually subside as medication is continued. Concurrent administration of hydrocortisone within the bottle may be beneficial. Premedication with 1 g of acetaminophen or salicylic acid, 30 to 45 minutes before infusion of amphotericin, is also useful. Nephrotoxicity is the most significant side effect of this agent and occurs in up to 80% of cases. Elevations of serum creatinine to 2 to 3 mg/dL are routinely noted and may necessitate intermittent discontinuation of the drug. There is often evidence of tubular disease, and proximal renal tubular acidosis may be observed. Renal vasoconstriction and abnormalities of glomerular filtration may also be important. Maintenance of adequate fluid and sodium loading may prove protective. Significant decreases in serum potassium may also be observed with amphotericin B. Profound hypokalemia may occur when amphotericin B is given with other drugs that may also cause this effect.
Anemia is routinely observed and is thought to be secondary to either bone marrow suppression or inhibition of erythropoietin production. Thrombocytopenia or neutropenia rarely occurs, and aplastic anemia has not been reported. Adult respiratory distress syndrome has been reported when amphotericin B is used with granulocyte transfusion. The etiology may be related to lysis of aggregates of transfused granulocytes that are trapped in the pulmonary parenchyma.
An oral suspension of amphotericin B (100 mg/mL) has recently become available, with use primarily targeted at HIV/AIDS patients. The recommended dose is 1 to 5 mL (100 to 500 mg) four times daily for a minimum of 2 weeks.
Several forms of liposomal amphotericin B have recently been approved by the FDA and appear to be associated with decreased nephrotoxicity and an increased capacity for dosing to at least 5 mg/kg. Table 78-2 summarizes comparative data. No one is distinctly better than the others, but any one may be the therapy of choice for invasive infections with Aspergillus species; use for other fungal infections is uncertain. All have the capacity to cause acute severe reactions, similar to those seen with amphotericin B, and should be administered with a test dose and dose escalation. Fortunately, many of the patients who receive the liposomal preparations will already have had experience of amphotericin B and are less likely to have acute adverse reactions. The liposomal preparations have also been recommended for use in patients with nephrotoxicity from amphotericin B. Expense precludes their routine use, and it is uncertain whether they are beneficial for most fungal infections.

Table 78-2. Liposomal amphotericin B preparations

Flucytosine
Flucytosine is a fluorinated pyrimidine related to fluorouracil; it is useful for selected candidal and cryptococcal infections. Its mechanism of action is incompletely understood but is probably related to its conversion to fluorouracil within the fungal cell. It is well absorbed from the gastrointestinal tract and penetrates into most tissues. Most of the compound is excreted in active form in the urine, with levels averaging 200 to 500 µm/mL. Peak serum values are only 70 to 80 mg/mL. Renal insufficiency (as may be seen with concurrent use of amphotericin B) may result in potentially toxic levels of flucytosine unless the dosage is regulated. The usual dosage of this drug is 150 mg/kg per day in four divided doses. The compound is supplied in either 250-mg or 500-mg tablets.
Flucytosine is relatively safe and usually well tolerated. Bone marrow depression may occur in the presence of renal dysfunction. The cause of this depression is not completely known but appears to be related to the metabolism of the parent compound to 5-fluorouracil. Suppression rarely occurs when blood levels of flucytosine are below 100 mg/mL. The presence of renal impairment necessitates dosage reduction. One method is to give a dose (37.5 mg/kg) at varying intervals depending on creatinine clearance (e.g., every 6 hours at more than 40 mL/min, every 12 hours at 20 to 40 mL/min, and every 24 hours at 10 to 20 mL/min). No nomogram is satisfactory for the anuric patient; however, blood levels can be measured by high-pressure liquid or gas chromatography. Flucytosine is cleared by hemodialysis or peritoneal dialysis, and a single dose of 37.5 mg/kg is recommended after each treatment. Bone marrow depression develops in about 5% of patients who receive this drug, typically anemia or neutropenia. Nausea, diarrhea, and vomiting are occasionally seen but are infrequently severe and rarely necessitate discontinuation of therapy.
The use of flucytosine as monotherapy is indicated only in selected patients with candiduria, in whom rapid achievement of high levels may preclude emergence of resistance. It is most frequently employed in combination with amphotericin B for serious cryptococcal infections. For cryptococcal meningitis in the HIV-negative patient, use of the two agents reduces the dose of amphotericin B (from 0.6 to 0.3 mg/kg) and the duration of therapy (from 10 to 6 weeks). In the presence of HIV infection, cryptococcal meningitis is not curable, and the addition of flucytosine may intensify anemia and other adverse reactions. However, some authorities recommend its use for the first 2 weeks of treatment. In a recent study of flucytosine plus fluconazole (vs. fluconazole alone) in AIDS patients with cryptococcal meningitis, survivorship was enhanced at 2 months (32% vs. 12%) and headache was decreased at 1 month in those who received the combination. Other data suggest that the combination may also be useful for the therapy of serious candidal infections. Flucytosine is not effective against infections caused by species of Aspergillus or Mucor.
Ketoconazole
Ketoconazole is an oral preparation active in vitro against Candida, Coccidioides, Blastomyces, Histoplasma, and most dermatophytes. The usual daily dose is 200 to 400 mg. Ketoconazole is extensively metabolized, and the dosage need not be altered in renal failure. Levels in the cerebrospinal fluid and urine are low, and the drug should not be considered for use in infections at these sites. Orally administered ketoconazole requires gastric acid for absorption, and this product must be given with food. In achlorhydric patients, administration with 8 oz of orange juice, cola, or ginger ale will improve absorption.
Ketoconazole has been successfully used to treat candidal infections involving mucous membranes, including esophagitis. It is inferior to fluconazole for esophageal candidiasis in AIDS patients, but its early use may prove initially less expensive. Outcomes in the treatment of thrush in patients with HIV infection are similar for the two agents. Ketoconazole has also been reported useful in the management of coccidioidomycosis, histoplasmosis, cryptococcal infection (nonmeningeal), sporotrichosis, and blastomycosis. Chronic relapsing forms of coccidioidomycosis and paracoccidioidomycosis appear to be stabilized with low doses of this agent given for up to 1 year. One study has documented the efficacy and limited toxicity of high doses (up to 1,200 mg/d) in the management of fungal infections of the central nervous system.
Side effects of ketoconazole are minor, although hepatitis may occur and should be considered in patients on long-term, high-dose therapy. At least one fatal case of hepatitis caused by this drug has been reported, in a patient who was receiving only 200 mg/d for 2 months. Additionally, it may depress synthesis of both testosterone and corticosteroids, which may result in oligospermia, gynecomastia, and abnormalities of menstruation. These side effects are associated more with high daily doses than with prolonged therapy and are reversible on discontinuation of the drug.
Drug interactions are an important consideration with the use of ketoconazole. Agents that should be given with caution at the same time as ketoconazole include (but are not limited to) histamine2 antagonists, rifampin, terfenadine, cisapride, didanosine, protease inhibitors, and cyclosporine.
Fluconazole
Fluconazole is available in both oral and IV formulations. In vitro activity occurs against species of Candida, C. neoformans, H. capsulatum, C. immitis, and Blastomyces species. Activity against Aspergillus and Mucor is limited. Unlike ketoconazole, it is well absorbed orally and is not affected by gastric acidity. It distributes well to tissues, and levels within inflamed meninges are 60% to 80% of those in serum. Clinically, fluconazole in doses of 100 mg daily has been successfully used for oropharyngeal and esophageal candidiasis. It is more effective than clotrimazole troches for the former and at least as effective as ketoconazole. A study employing a daily 100-mg dose of fluconazole in AIDS patients demonstrated its superiority (endoscopically and clinically) over ketoconazole (200 mg daily) for therapy of Candida esophagitis.
Oral fluconazole at a dosage of 200 mg/d is the agent of choice to maintain suppression of cryptococcal meningitis in AIDS patients after initial therapy with amphotericin B. If amphotericin B cannot be utilized for primary treatment, 400 mg of fluconazole per day for 8 weeks (followed by 200 mg/d for suppression) may be employed.
IV fluconazole is an important agent for the management of invasive candidal infections in seriously ill patients. Its ease of administration and excellent safety profile make it an appealing alternative to amphotericin B for disseminated candidal infections. At dosages of 400 to 800 mg/d, it appears to be as effective as amphotericin B for invasive candidiasis in critically ill patients who are not neutropenic. However, some species of Candida are inherently resistant to fluconazole, so epidemiologic information regarding individual hospitals is vital. A loading dose that is double the daily dose should be administered to reach steady state promptly. Amphotericin B remains the agent of choice for Candida endophthalmitis.
Fluconazole inhibits cytochrome P-450 hepatic enzymes. Drug interactions resulting in higher levels of warfarin (Coumadin), cyclosporine, and hydantoin, among others, have been observed. Life-threatening cardiac arrhthymias may result from the combined use of fluconazole with terfenadine or cisapride.
Itraconazole
Itraconazole, available as capsules or as an oral suspension, is a triazole with potent in vitro activity against Candida, Cryptococcus, Aspergillus, Mucor, and others. The oral solution has been approved for oral and esophageal candidiasis. The dosage is 100 to 200 mg/d; the solution should be vigorously swished for several seconds and swallowed. Strains of Candida resistant to fluconazole may remain sensitive to this agent. Adverse effects are generally minor, although a case of fatal hepatitis has been reported. Itraconazole capsules require gastric acid for absorption and should be taken with food. Acid beverages enhance absorption (see earlier section on ketoconazole). The oral solution (10 mg/mL, 150-mL bottle) has enhanced bioavailability in fasting situations. Generally, patients should not take oral solution and capsules simultaneously.
The recommended doses of itraconazole range from 100 mg/d (superficial infections) to 200 mg/d (deep-seated systemic infections). Doses of up to 400 mg daily can be employed for recalcitrant infections. The length of therapy ranges from 3 days (vaginal candidiasis) to many months.
Itraconazole appears well tolerated in patients with HIV infection and has been successfully employed both therapeutically and suppressively for cryptococcal meningitis. Similarly, it appears to be a well-tolerated and effective agent for histoplasmosis in patients with AIDS and may become the agent of choice for this disease.
Clotrimazole
Clotrimazole is a topical product useful in treating infections caused by both dermatophytes and Candida albicans. It is available as a 1% ointment, a topical solution, a lozenge, and 100- and 500-mg vaginal tablets. Because of its broad spectrum of activity, it is often employed when a specific organism has not been identified. A controlled clinical trial has demonstrated the effectiveness of clotrimazole lozenges given five times daily to treat chronic oral candidiasis; however, efficacy is less than that seen with fluconazole or ketoconazole.
Griseofulvin
Griseofulvin is an oral agent that is active only against dermatophytes. Therefore, an accurate diagnosis is necessary before treatment is begun. Griseofulvin is supplied as 125-mg, 250-mg, and 500-mg capsules or tablets, and peak blood levels of about 1 mg/mL are reached. The usual dosage for adults is 500 mg twice daily, and therapy should be continued for more than 4 weeks even if the infection clears before that time. For stubborn nail infections, therapy should be anticipated to last more than 3 months.
Side effects are minor and consist primarily of nausea, which may be noted in up to 15% of patients. Occasionally, neuritis and mild confusion can be noted. Hematologic and hepatic dysfunction occur rarely. Adverse drug interactions with warfarin can be seen.
Miscellaneous Agents
Terbinafine, a well-absorbed oral antifungal, is used in the United States primarily for the management of dermatophytes associated with onychomycosis. When administered at a dosage of 250 mg/d for fingernail or toenail onychomycosis (6 weeks or 12 weeks, respectively), it is at least as effective as griseofulvin.
Supersaturated potassium iodide is employed for the management of lymphocutaneous sporotrichosis. The drug is given orally, and treatment is initiated with a dose of 5 drops mixed in a liquid three times daily. The dose is increased by up to 4 drops per day to a maximum of 120 drops per day. If treatment is continued for several months, supersaturated potassium iodide is effective and may preclude the need for harsher regimens. Toxicity is manifested by gastrointestinal upset or increased lacrimation or salivation. An acneiform rash may be noted at any stage of therapy and is generally not considered a reason to discontinue treatment. (R.B.B.)
Bibliography
Anaissie EJ, et al. Fluconazole versus amphotericin B in the treatment of hematogenous candidiasis: a matched cohort study. Am J Med 1996;101:170–176.
Patients with cancer and hematogenous candidiasis were matched for underlying conditions. Forty-five patients received each agent. Rates of survival and clinical response were no different, but drug-related adverse reactions were significantly higher in those who received amphotericin B (67% vs. 9%). This investigation could not identify different candidal species as being associated with outcome. The authors conclude that fluconazole is a satisfactory alternative to amphotericin B for hematogenous candidiasis and is less toxic. Several other studies have reached the same conclusion. However, it must be remembered that certain azole-resistant Candida species do not respond to fluconazole, and this caveat must be a factor in the choice of antifungals for severe infections.
Bennett JE, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 1979;301:126–131.
Multicenter study of 50 patients with cryptococcal meningitis in the pre-AIDS era. Demonstrates that the addition of flucytosine to amphotericin B allows a reduction in the course of therapy from 10 to 6 weeks and a decrease in amphotericin B dosage from 0.6 to 0.3 mg/kg per day. Combination therapy resulted in greater cure rates, fewer relapses, and more rapid sterilization of cerebrospinal fluid.
Bozette SA, et al. A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in AIDS. N Engl J Med 1991;324:580–584.
In patients with AIDS, fluconazole was an effective suppressant of cryptococcal meningitis versus placebo (3% vs. 37% relapse) following initial successful therapy with amphotericin B. The dosage of fluconazole was 100 to 200 mg daily and was well tolerated.
Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. N Engl J Med 1994;330:263–273.
The authors provide an excellent review of the chemistry, mechanisms of action, pharmacology, drug interactions, and uses of the oral azole antifungals. The section on drug interactions is particularly useful. Although fluconazole and itraconazole have potential roles in the treatment of systemic candidiasis, their efficacy, particularly in neutropenic patients, requires further study.
Grant SM, Clissold SP. Fluconazole: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in superficial and systemic mycoses. Drugs 1990;39:877–916.
Excellent single-source reference on the properties of this antifungal agent. Deals primarily with the oral preparation and reviews published data concerning its clinical applications.
Kauffman CA. Role of azoles in antifungal therapy. Clin Infect Dis 1996;22(Suppl 2):S148–S153.
A succicnt review of the subject that does not stress infections in HIV/AIDS. Seventy-two articles are cited, and problems related to the emergence of azole resistance are mentioned.
Laine L, et al. Fluconazole compared with ketoconazole for the treatment of Candida esophagitis in AIDS. Ann Intern Med 1992;117:655–660.
Randomized trial of two agents that demonstrates more rapid clinical and endoscopic improvement in patients treated with fluconazole (90% vs. 50%). Patients treated with ketoconazole often improved clinically but not endoscopically. Suggested reasons for differences in outcome include better absorption of fluconazole and enhanced in vitro activity against Candida species.
Larsen RA. Azoles and AIDS. J Infect Dis 1990;162:727–730.
This commentary continues to recommend amphotericin B as the primary therapy for cryptococcal meningitis in AIDS, but describes fluconazole as a satisfactory agent for suppression following successful initial therapy. The author points out the value of fluconazole and itraconazole in selected AIDS patients with histoplasmosis and significant candidal infections.
Mayanja-Kizza H, et al. Combination therapy with fluconazole and flucytosine for cryptococcal meningitis in Ugandan patients with AIDS. Clin Infect Dis 1998;26:1362–1366.
The authors performed a randomized trial on 58 AIDS patients with cryptococcal meningitis who received either fluconazole (200 mg/d orally for 2 months) or fluconazole plus flucytosine (150 mg/kg per day in three divided doses for the first 2 weeks). All patients then received 200 mg of fluconazole thrice weekly for an additional 4 months. The death rate within the study period was substantially decreased in patients who received the combination, and the severity of headache similarly decreased significantly in this group. There appeared not to be a correlation between clinical outcome and results of the in vitro susceptibility tests performed on 32 isolates. This combination of antifungals needs to be better studied, and the doses may need to be increased to obtain maximal benefits. The regimens were well tolerated.
The Medical Letter. Systemic fungal infections. Med Lett Drugs Ther 1996;38:9–12.
A concise overview of products available for the management of deep fungal infections. It contains no information on the lipsomal amphotericin B preparations. A chart of indications and doses is provided.
Pathak A, Pien FD, Carvalho L. Amphotericin B use in a community hospital, with special emphasis on side effects. Clin Infect Dis 1998;26:334–338.
A retrospective review of 102 patients who received amphotericin B deoxycholate during an approximate 3-year period was conducted. A major outcome was that the vast majority of patients tolerated the product well! Most could be treated without premedication. The major value of this investigation is to emphasize the relative safety of the cheapest and best-studied of the amphotericin B products. The liposomal preparations should be reserved for a very small subset of patients who require high doses, or in whom significant renal failure from amphotericin B clearly develops.
Singh RM, Perdue BE. Amphotericin B: a class review. Formulary 1998;33:424–447.
An excellent overview comparing the available formulations of amphotericin. Three lipsomal forms have been approved by the FDA. All are substantially more expensive than amphotericin B deoxycholate, and it remains uncertain how much better they are clinically. It is very difficult to detect important differences among the three liposomal forms. One of them should probably be used to treat invasive disease associated with Aspergillus infection. Although these forms are marketed as having advantages in patients with renal dysfunction associated with amphotericin B deoxycholate, the author has not found this problem to be significant when the original formulation is used carefully. All forms may be associated with acute toxicities and should be administered with a loading dose followed by dose escalation.
Walsh TJ, et al. Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases. Clin Infect Dis 1998;26:1383–1396.
Patients who clinically failed therapy with amphotericin B or who had renal failure (drug-induced or before treatment) or acute amphotericin B toxicity were enrolled to receive amphotericin B lipid complex. Most patients were infected with either Aspergillus or Candida. Approximately 60% demonstrated a clinical response, including 40% with Aspergillus. Renal function improved in those who entered the study with renal failure. The authors correctly conclude that amphotericin B lipid complex is indicated for selected conditions.

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One comment on “ANTIFUNGAL CHEMOTHERAPY

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