Ketoconazole: Uses
Oral ketoconazole is used in the treatment of blastomycosis, candidal infections (i.e., oropharyngeal and/or esophageal candidiasis, vulvovaginal candidiasis, candiduria, chronic mucocutaneous candidiasis),chromomycosis (chromoblastomycosis), coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis.
The drug also is used orally in the treatment of certain dermatophytoses and in the treatment of certain protozoal infections, including cutaneous or visceral leishmaniasis. In addition, ketoconazole has been used in the treatment of hypercalcemia in patients with sarcoidosis and the treatment of tuberculosis-associated hypercalcemia.
Based on ketoconazole’s endocrine effects, the drug has been used in the treatment of advanced prostatic carcinoma and various endocrine disorders. In the treatment of systemic or subcutaneous mycoses, oral ketoconazole is used principally in immunocompetent patients with mild to moderately severe infections caused by susceptible fungi.
The drug should not be used for initial therapy in severe, life-threatening infections. In addition, because CSF concentrations of ketoconazole are unpredictable following oral administration, the drug should not be used to treat CNS fungal infections, including candidal, coccidioidal, or cryptococcal meningitis. Because of the potential for treatment failure, relapse, and/or disease progression (e.g., from CNS dissemination), close follow-up during and following ketoconazole therapy is recommended.
Blastomycosis
Oral ketoconazole is used for the treatment of blastomycosis caused by Blastomyces dermatitidis. While IV amphotericin B or oral itraconazole generally are considered the drugs of choice for the treatment of blastomycosis, oral fluconazole or oral ketoconazole are alternatives for the treatment of mild to moderate disease. IV amphotericin B generally is the drug of choice for severe blastomycosis (including when the CNS is involved) and also is considered the drug of choice for all forms of the disease in immunocompromised individuals.
Ketoconazole usually has been effective when used in immunocompetent individuals with mild to moderate pulmonary or extrapulmonary blastomycosis, and the reported response rate with the drug is 70-100%. However, many clinicians consider oral itraconazole the drug of choice for the treatment of nonmeningeal, non-life-threatening blastomycosis and also recommend itraconazole for follow-up therapy in patients with more severe infections after an initial response has been obtained with IV amphotericin B. The fact that treatment failures have been reported when oral ketoconazole was used in the treatment of cutaneous or pulmonary blastomycosis in individuals who had asymptomatic or subclinical CNS involvement at the time of the initial diagnosis should be considered when selecting an antifungal agent for the treatment of blastomycosis.
Candidal Infections
Oral ketoconazole has been used for a variety of candidal infections, including candidiasis, candiduria, chronic mucocutaneous candidiasis, oropharyngeal or esophageal candidiasis, and vulvovaginal candidiasis. Mucocutaneous or noninvasive candidal infections such as oral thrush or oropharyngeal candidiasis usually can be adequately treated with topical antifungal therapy (e.g., clotrimazole oral lozenges, nystatin oral suspension, amphotericin B oral suspension) or oral antifungal agents (e.g., fluconazole, itraconazole, ketoconazole); however, topical therapy is usually is ineffective for the treatment of esophageal candidiasis and IV amphotericin B therapy may be required for the treatment of severe mucocutaneous candidiasis or infections caused by azole-resistant Candida.
Vulvovaginal Candidiasis
Oral ketoconazole has been effective for the treatment of uncomplicated vulvovaginal candidiasis in nonpregnant women, and limited data suggest that oral ketoconazole (200-400 mg daily for 3-6 days) may be as effective for vulvovaginal candidiasis as intravaginal therapy with clotrimazole, miconazole, or nystatin, ketoconazole.
Although oral ketoconazole is not considered a drug of choice for the treatment of uncomplicated vulvovaginal candidiasis, it is recommended as one of several alternatives for the maintenance treatment of recurrent vulvovaginal candidiasis. Because the effects of ketoconazole on the fetus are unknown, oral ketoconazole should not be used in the treatment of vulvovaginal candidiasis in pregnant women.
Uncomplicated Vulvovaginal Candidiasis
The US Centers for Disease Control and Prevention (CDC) and other clinicians recommend that uncomplicated vulvovaginal candidiasis (defined as vulvovaginal candidiasis that is mild to moderate, sporadic or infrequent, most likely caused by Candida albicans, or occurring in immunocompetent women) be treated with an intravaginal azole antifungal (e.g., butoconazole, clotrimazole, miconazole, terconazole, tioconazole) given in appropriate single-dose or short-course regimens or, alternatively, oral fluconazole given in a single-dose regimen.
These regimens generally have been associated with clinical and mycologic cure rates of 80-90% in otherwise healthy, nonpregnant women with uncomplicated infections. Although a 5-day regimen of oral ketoconazole has been used in the treatment of uncomplicated vulvovaginal candidiasis, the single-dose fluconazole regimen is the only oral regimen included in current CDC recommendations for the treatment of uncomplicated infections. The potential for toxicity (e.g., hepatotoxicity) and drug interactions associated with oral ketoconazole therapy should be considered.
Complicated and Recurrent Vulvovaginal Candidiasis
Oral ketoconazole has been used for chronic maintenance to prevent relapse of vulvovaginal candidiasis in a limited number of women with a history of recurrent infections. Optimum regimens for the treatment of recurrent vulvovaginal candidiasis (usually defined as 4 or more symptomatic episodes each year) have not been established.
Although each individual episode caused by C. albicans may respond to usual single-dose oral fluconazole or short-course intravaginal antifungal therapy, a longer duration of initial therapy may be necessary to achieve mycologic remission and chronic maintenance therapy may be necessary to prevent relapse.
The CDC and other clinicians recommend use of an initial intensive regimen consisting of 7-14 days of an intravaginal azole antifungal or a 2-dose regimen of oral fluconazole (150 mg repeated 3 days later) followed by a maintenance antifungal regimen (given for 6 months). Maintenance regimens recommended by the CDC include intravaginal clotrimazole (500 mg once weekly), oral ketoconazole (100 mg once daily), oral fluconazole (100-150 mg once weekly), or oral itraconazole (400 mg once monthly or 100 mg once daily).
These maintenance regimens can be effective in reducing recurrent infections; however, 30-40% of women will have recurrent disease once maintenance therapy is discontinued. Vaginal cultures should be obtained from patients with recurrent infections to confirm the diagnosis and identify the causative organism.
These infections may be caused by resistant strains of C. albicans or, more commonly, by other Candida with reduced susceptibility to azole antifungal agents (e.g., C. glabrata). It has been suggested that repeated treatment of recurrent vulvovaginal candidiasis with intravaginal azole antifungal agents and widespread and/or injudicious use of these agents for self-medication of vulvovaginal candidiasis may favor the selection of Candida that are resistant to azole antifungal agents.
Optimum therapy for the treatment of vulvovaginal candidiasis caused by Candida with reduced susceptibility to azole antifungal agents has not been determined to date. For the treatment of vulvovaginal candidiasis caused by Candida other than C. albicans, the CDC recommends 7-14 days of an antifungal agent other than fluconazole; if recurrence occurs, intravaginal boric acid (600-mg capsule once daily for 2 weeks) is recommended. Referral to a specialist is advised. Vulvovaginal candidiasis may occur more frequently and may be more severe in women with human immunodeficiency virus (HIV) infection than in women without HIV infection and these infections have been recognized as an early manifestation of acquired immunodeficiency syndrome (AIDS) in women.
While optimum therapy for recurrent vulvovaginal candidiasis in HIV-infected women has not been established, there is no evidence to date that these women have a lower response rate to the intravaginal or oral antifungal regimens usually recommended for the treatment of vulvovaginal candidiasis. Therefore, the CDC and other clinicians recommend that treatment of vulvovaginal candidiasis in HIV-infected women should be the same as that in women without HIV infection.
Chromomycosis
Oral ketoconazole has been used for the treatment of chromomycosis (chromoblastomycosis) caused by Phialophora spp. A response to ketoconazole has been obtained in some patients with mild to moderate infections, but not in those with more extensive disease. While optimum regimens for the treatment of chromomycosis have not been identified, other antifungal agents (e.g., flucytosine alone or in conjunction with amphotericin B, itraconazole) generally are preferred.
Coccidioidomycosis
Oral ketoconazole is used for the treatment of mild to moderate coccidioidomycosis caused by Coccidioides immitis. While acute, uncomplicated pulmonary coccidioidomycosis may be self-limiting and resolve spontaneously without specific antifungal therapy, severe pulmonary infections or disseminated coccidioidomycosis involving the skin, bone, meninges, and joints should be treated with aggressive antifungal agent therapy. The drugs of choice for the treatment of coccidioidomycosis are IV amphotericin B or oral fluconazole; oral itraconazole or oral ketoconazole are considered alternative agents. IV amphotericin B generally is the preferred agent for the initial treatment of severe or rapidly progressing coccidioidomycosis, especially in immunocompromised patients including those with HIV infection.
Histoplasmosis
Oral ketoconazole is used for the treatment of histoplasmosis caused by Histoplasma capsulatum. The drugs of choice for the treatment of histoplasmosis are IV amphotericin B or oral itraconazole; oral ketoconazole or oral fluconazole are considered alternative agents. IV amphotericin B generally is the preferred antifungal agent for the initial treatment of severe, life-threatening histoplasmosis, especially in immunocompromised patients such as those with HIV infection. When an oral agent is indicated in the treatment of histoplasmosis (e.g., for treatment of mild to moderate infections or as follow-up therapy in the treatment of severe infections in patients with HIV infection after a response has been obtained with amphotericin B), itraconazole may be the preferred agent.
Paracoccidioidomycosis
Oral ketoconazole is used for the treatment of paracoccidioidomycosis (South American blastomycosis) caused by Paracoccidioides brasiliensis. While IV amphotericin B generally is preferred for the initial treatment of severe paracoccidioidomycosis, oral azole antifungal agents (e.g., ketoconazole, itraconazole) can be used in patients with less severe infections.
Dermatophytoses
Ketoconazole has been effective when used orally in the treatment of certain dermatophytoses (i.e., tinea capitis, tinea corporis, tinea cruris, tinea pedis, tinea manuum, tinea unguium) caused by Epidermophyton, Microsporum, or Trichophyton. Tinea corporis and tinea cruris generally can be effectively treated using a topical antifungal agent; however, an oral antifungal regimen may be necessary if the disease is extensive, dermatophyte folliculitis is present, the infection is chronic or does not respond to topical therapy, or the patient is immunocompromised or has coexisting disease.Tinea capitis and tinea barbae generally are treated using an oral antifungal regimen.
While topical antifungals usually are effective for the treatment of uncomplicated tinea manuum and tinea pedis, an oral antifungal regimen usually is necessary for the treatment of hyperkeratotic areas of the palms and soles, for the treatment of chronic moccasin-type (dry-type) tinea pedis, and for the treatment of tinea unguium (onychomycosis).
Dermatophytic infections of glabrous skin respond to oral ketoconazole at a more rapid rate than do infections of palmar-plantar skin; dermatophytic infections of nails respond at the slowest rate.
Pityriasis (Tinea) Versicolor
Oral ketoconazole has been effective when used in the treatment of pityriasis (tinea) versicolor, a superficial infection caused by Malassezia furfur (Pityrosporum orbiculare or P. ovale). Pityriasis (tinea) versicolor generally can be treated topically with an imidazole-derivative azole antifungal (e.g., clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole), an allylamine antifungal (e.g., terbinafine), ciclopirox olamine, or certain other topical therapies (e.g., selenium sulfide 2.5%). However, an oral antifungal (e.g., itraconazole, ketoconazole) may be indicated, with or without a topical agent, in patients who have extensive or severe infections or who fail to respond to or have frequent relapses with topical therapy.
Other Fungal Infections
Ketoconazole has been effective in some patients for the treatment of eumycetoma caused by Madurella mycetomatis. Although ketoconazole has been investigated for the treatment of aspergillosis, cryptococcosis, mucormycosis, and sporotrichosis, the drug generally has been ineffective and is not indicated for the treatment of these infections.
Prevention of Fungal Infections
HIV-Infected Individuals
Although ketoconazole has been used for prophylaxis against initial or recurrent mucocutaneous candidiasis in individuals with human immunodeficiency virus (HIV) infection, the drug is not included in the current guidelines of the Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA). The USPHS/IDSA currently states that primary prophylaxis to prevent first episodes of mucocutaneous candidiasis in HIV-infected adults, adolescents, infants, or children is not recommended because acute mucocutaneous candidiasis generally is treatable and rarely life-threatening and because of concerns about the potential for development of resistant Candida, possibility of drug interactions, and cost of antifungal prophylaxis.
However, chronic suppressive or maintenance therapy (secondary prophylaxis) may be indicated in HIV-infected individuals with a documented history of frequent or severe episodes of mucocutaneous candidiasis. If suppressive or maintenance therapy against mucocutaneous candidiasis is indicated in HIV-infected adults, adolescents, infants, or children with frequent or severe recurrences of oropharyngeal, esophageal, or vaginal candidiasis, the USPHS/IDSA recommends oral fluconazole as the drug of choice and itraconazole oral solution as an alternative.
Transplant Patients and Patients with Cancer
Oral ketoconazole has been used prophylactically in an attempt to reduce the incidence of fungal infections in cancer patients during periods of iatrogenic neutropenia but is not considered a good choice for antifungal prophylaxis.
Results of a limited number of studies in neutropenic cancer patients suggest that oral ketoconazole is more effective than placebo and at least as effective as oral nystatin in preventing fungal colonization and/or infection; however, some evidence indicates that oral ketoconazole may predispose these patients to colonization with ketoconazole-resistant fungi.
Use of primary antifungal prophylaxis in cancer patients undergoing myelosuppressive therapy or patients undergoing bone marrow transplantation (BMT) or solid organ transplantation remains controversial, particularly since such prophylaxis may predispose the patient to colonization with resistant fungi and/or result in the emergence of highly resistant organisms.
Therefore, many clinicians discourage primary prophylaxis with antifungal agents except in certain carefully selected high-risk patients in whom potential benefits are expected to justify possible risks (e.g., patients in institutions that have a high incidence of fungal infections or circumstances where the frequency of systemic candidal infections is high). When primary antifungal prophylaxis is warranted in cancer patients or BMT or solid organ transplant patients, use of oral fluconazole or, alternatively, IV amphotericin B is recommended.
Protozoal Infections
Acanthamoeba Infections
Oral ketoconazole has been used in conjunction with topical anti-infective agents (e.g., miconazole, neomycin, metronidazole, propamidine isethionate) in the treatment of Acanthamoeba keratitis. Optimum therapy for Acanthamoeba keratitis remains to be clearly established, but prolonged local and systemic therapy with multiple anti-infective agents and, often, surgical treatment (e.g., penetrating keratoplasty) are usually required. A regimen of oral ketoconazole, rifampin, and co-trimoxazole has been used successfully for the treatment of chronic Acanthamoeba meningitis in several immunocompetent children.
Leishmaniasis
Oral ketoconazole has been used for the treatment of cutaneous or mucocutaneous leishmaniasis caused by Leishmania major (oriental sore), L. mexicana, L. panamensis, L. braziliensis, or L. tropica. Cutaneous leishmaniasis may subside spontaneously; however, treatment generally is required if lesions are disabling or disfiguring or fail to heal within 6 months or when dissemination to mucosal leishmaniasis is likely (e.g., L. braziliensis infections).
While pentavalent antimony compounds such as sodium stibogluconate (not commercially available in the US) or meglumine antimonate (not commercially available in the US) generally are considered the treatment of choice for cutaneous or mucocutaneous leishmaniasis, some clinicians suggest that IV amphotericin B (conventional or liposomal formulations) also is a drug of choice for these infections; alternative agents include IV or IM pentamidine, oral azole antifungal agents (e.g., itraconazole, ketoconazole), or topical paromomycin (for cutaneous leishmaniasis when there is a low potential for mucosal spread).
Ketoconazole has been used in a limited number of patients for the treatment of antimony-resistant visceral leishmaniasis (kala-azar) caused by L.donovani; however, the drug appears to be less effective in these infections than in the treatment of cutaneous leishmaniasis.
Prostate Cancer
Because of ketoconazole’s ability to inhibit testicular and adrenal steroid synthesis, the drug has been used in the treatment of advanced prostatic carcinoma. Ketoconazole has been used as a first-line agent in a few patients, but usually is used as second-line hormonal therapy in patients with stage IV recurrent prostatic cancer. A limited number of patients with androgen-independent prostatic cancer have received ketoconazole in conjunction with doxorubicin. Ketoconazole has been used effectively as an adjunct in the acute management of disseminated intravascular coagulation (DIC) associated with prostatic carcinoma in a limited number of patients.
Hypercalcemia
Ketoconazole has been used with some success for the treatment of hypercalcemia in adults with sarcoidosis. By competitively inhibiting synthesis of 1,-dihydroxyvitamin D, ketoconazole may reduce elevated serum concentrations of the vitamin that apparently may contribute to sarcoidosis-associated hypercalcemia.
Ketoconazole has been shown to produce a dose-dependent decrease in serum 1,-dihydroxyvitamin D concentrations in healthy individuals and hypercalcemic patients with primary hyperparathyroidism.
However, while ketoconazole generally decreases serum concentrations of the vitamin, the drug has reduced serum calcium concentrations in some, but not all, patients with sarcoidosis-associated hypercalcemia. In addition, hypercalcemia and increased serum 1,-dihydroxyvitamin D concentrations may recur when ketoconazole dosage is decreased or the drug discontinued.
Although corticosteroids generally have been used for the treatment of sarcoidosis-associated hypercalcemia, ketoconazole may be an alternative. Ketoconazole also has been effective in a few adolescents for the treatment of tuberculosis-associated hypercalcemia.
Other Uses
Ketoconazole has been used effectively for the palliative treatment of Cushing’s syndrome (hypercortisolism), including adrenocortical hyperfunction associated with adrenal or pituitary adenoma or ectopic corticotropin-secreting tumors. Ketoconazole has been used in a limited number of geriatric patients 75 years or older for the treatment of corticotropin-dependent Cushing’s syndrome, and may provide an effective alternative in patients who cannot tolerate surgical treatment. Although further study is needed, ketoconazole has been used with some success in a limited number of patients for the treatment of dysfunctional hirsutism and in a limited number of boys for the treatment of precocious puberty.