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Uses and Administration of Itraconazole 100 mg (Sporanox)

Therapeutic use of Itraconazole 100 mg Capsules (Sporanox)

Itraconazole can be used to treat various superficial fungal infections, including the dermatophytoses, pityriasis versicolor, and mucosal and cutaneous forms of candidosis. It is also effective in patients with subcutaneous infections, such as chromoblastomycosis, sporotrichosis and certain forms of phaeohyphomycosis. It has become the drug of choice for non-life-threatening forms of blastomycosis and histoplasmosis, and is a useful alternative to amphotericin B for invasive aspergillosis. Maintenance treatment with itraconazole has helped to prevent relapse in patients with AIDS with histoplasmosis or cryptococcosis, and prophylactic treatment with this drug has helped to prevent aspergillosis and candidosis in neutropenic patients. However, it has not been adequately evaluated as an oral treatment for deep-seated forms of candidosis.

Mode of administration of Itraconazole 100 mg Capsules (Sporanox)

Vaginal candidosis can be treated with two 200-mg oral doses of itraconazole taken 6-8 h apart. In non-compromised individuals, oropharyngeal candidosis can be treated with 100 mg/day for 2 weeks, but neutropenic patients and those with AIDS often require 200-400 mg/day because of impaired oral absorption. Administering the oral solution formulation (200-400 mg/day for 1-2 weeks) often results in improved absorption.

The recommended dosage for patients with cutaneous dermatophytoses is 100 mg/day, but the duration of treatment depends on the site of infection. Tinea corporis or tinea cruris should be treated for 2 weeks, but tinea pedis and tinea manuum require treatment for 4 weeks. Pulsed treatment (in which a week of treatment is alternated with 3 weeks without treatment) has given good results in nail infections. Two pulses of itraconazole (400 mg/day) are recommended for fingernail infections, but toenails require three or more pulses of treatment. Itraconazole is also available for continuous treatment of nail infection and a dosage of 200 mg/day for 3 months is recommended.

The recommended dosage for patients with pityriasis versicolor is 200 mg/day for 1 week.

Itraconazole, at dosages from 200 to 400 mg/day, is usually effective in patients with subcutaneous or deep fungal infection. Some clinicians have used loading doses of 600 mg/day at the start of treatment in patients with life-threatening infections. Impaired absorption in neutropenic patients and those with AIDS will lead to low blood levels and higher dosages, or substitution of the oral solution formulation, may be required to ensure adequate serum concentrations. Absorption of itraconazole is reduced if it is given together with compounds that reduce gastric acid secretion: these drugs should be administered at least 2h after the intake of itraconazole. Dosages above 200 mg/day should be given as two divided doses.

Long-term maintenance treatment with itraconazole to prevent relapse in patients with AIDS with histoplasmosis or cryptococcosis should be administered at a dosage of 200 mg/day. To prevent fungal infection in neutropenic patients, the dose should be 400 mg/day and this should be commenced about 5-7 days before the anticipated onset of neutropenia.

Pharmacokinetics of Itraconazole

Absorption of itraconazole from the gastrointestinal tract is incomplete (about 55%), but is improved if the drug is given with food. Oral administration of a single 100-mg capsule will produce peak serum concentrations of between 0.1 and 0.2mg/l about 2-4 h later. Higher concentrations are obtained after repeated dosing, but there is marked variation between individuals. As with ketoconazole, there is a disproportionate increase in blood levels with increasing dosage. Serum concentrations are markedly reduced when gastric acid production is impaired.

Much higher blood concentrations (up to 1.0-1.5 mg/1) have been attained in patients with AIDS and neutropenic individuals following administration of a 5 mg/kg dose of the oral solution formulation of itraconazole for 1-2 weeks. This formulation is better absorbed if given without food.

Like most other azole antifungals, the protein binding of itraconazole is high, exceeding 99% in human serum. As a result, concentrations of the drug in body fluids such as CSF are minimal. In contrast, drug concentrations in tissues, such as lung, liver and bone, are two to three times higher than in serum. High concentrations of itraconazole are also found in the stratum corneum as a result of drug secretion in sebum. Itraconazole has been found to persist in the skin for 2-4 weeks after the end of a 4-week course of treatment. It persists in toenails for up to 6 months after the end of a 3-month course of treatment, but levels in the fingernails decline about 3 months after the end of treatment.

Less than 0.03% of an administered dose of itraconazole is excreted unchanged in the urine, but up to 18% is eliminated in faeces as unchanged drug.

Itraconazole: Uses

IV itraconazole and oral itraconazole capsules are used in immunocompromised and immunocompetent patients for the treatment of systemic fungal infections, including blastomycosis (pulmonary and extrapulmonary), histoplasmosis (including chronic cavitary pulmonary disease and disseminated, nonmeningeal disease), and aspergillosis (pulmonary and extrapulmonary in patients who do not respond to or cannot tolerate amphotericin B).

Itraconazole oral solution (but not itraconazole capsules) is used for the treatment of oropharyngeal and esophageal candidiasis. Itraconazole (given IV initially followed by itraconazole oral solution) is used for empiric antifungal therapy in febrile neutropenic patients. Oral itraconazole capsules are used in immunocompetent individuals for the treatment of tinea unguium (onychomycosis) of the toenail and/or fingernail caused by dermatophytes.

Itraconazole Uses

Itraconazole also is used orally for prevention of serious fungal infections (e.g., coccidioidomycosis, cryptococcosis, histoplasmosis, mucocutaneous candidiasis) in patients with human immunodeficiency virus (HIV) infection. Prior to initiation of IV itraconazole or oral itraconazole capsules for the treatment of systemic fungal infections, appropriate specimens for fungal culture and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained in order to isolate and identify the causative organism(s). Itraconazole therapy may be started pending results of these in vitro tests; however, once results are available, therapy should be adjusted accordingly. Prior to initiation of oral itraconazole capsules for the treatment of onychomycosis, appropriate nail specimens for microbiological studies (e.g., potassium hydroxide [KOH] preparation, fungal culture, nail biopsy) should be obtained to confirm the diagnosis.

Aspergillosis

Itraconazole is used in the treatment of pulmonary and extrapulmonary aspergillosis in patients who are intolerant of or who are refractory to IV amphotericin B. IV amphotericin B generally is considered the treatment of choice for invasive aspergillosis, especially for life-threatening and severe infections, and itraconazole is an alternative agent. In a limited number of patients with invasive aspergillosis who did not respond to or could not tolerate IV amphotericin B, oral itraconazole capsules (200-400 mg daily given for a median duration of therapy of 3-4 months) has been effective as second-line therapy.

Use of itraconazole for initial antifungal therapy in patients with pulmonary and extrapulmonary aspergillosis is being evaluated. In an open, multicenter study in adults with active invasive pulmonary aspergillosis (61% had received antifungal prophylaxis and some had received prior empiric antifungal therapy prior to study entry), itraconazole was given in a regimen that included IV itraconazole therapy initially (200 mg twice daily for 2 days then 200 mg once daily for 12 days) followed by oral itraconazole capsules (200 mg twice daily) for 12 weeks.

Itraconazole Uses

At the end of itraconazole therapy, 39% had a complete or partial clinical response (intent-to-treat analysis) and the median time to response was 55 days. In a multicenter open study in patients with invasive aspergillosis who received oral itraconazole capsules (200 mg 3 times daily for 4 days, followed by 200 mg twice daily for at least 4 months; some patients received drug therapy for more than 12 months), therapy was effective in about 39% of patients.

Blastomycosis

Itraconazole is used in the treatment of pulmonary and extrapulmonary blastomycosis caused by Blastomyces dermatitidis. While both oral itraconazole capsules and IV amphotericin B are considered drugs of choice for the treatment of blastomycosis, amphotericin B is preferred for the treatment of severe infections, especially those involving the CNS. IV amphotericin B also generally is preferred for the initial treatment of presumptive blastomycosis in immunocompromised patients, including HIV-infected individuals.Many clinicians consider oral itraconazole the drug of choice for the treatment of nonmeningeal, non-life-threatening blastomycosis, including mild to moderate disseminated infections without CNS involvement, and also recommend the drug 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 an oral antifungal agent (e.g., ketoconazole) was used in the treatment of cutaneous or pulmonary blastomycosis in patients who had asymptomatic or subclinical CNS involvement at the time of the initial diagnosis should be considered when selecting an antifungal agent for patients with blastomycosis. Some clinicians state that azole antifungal agents should not be used for primary treatment of patients with CNS blastomycosis.

Histoplasmosis

Itraconazole is used in the treatment of histoplasmosis, including chronic cavitary pulmonary disease and disseminated nonmeningeal disease. Both IV amphotericin B and oral itraconazole capsules are considered drugs of choice for the treatment of histoplasmosis. However, IV amphotericin B generally is preferred for the initial treatment of severe, life-threatening histoplasmosis, especially in immunocompromised patients such as those with HIV infection.

Oral itraconazole generally is used in the initial treatment of mild to moderate infections (e.g., in patients who do not require hospitalization) or as follow-up therapy in the treatment of severe infections after a response has been obtained with amphotericin B. Itraconazole has been used for the treatment of disseminated histoplasmosis in patients with HIV infection.

The manufacturer states that data from a limited number of patients indicate that the response rate of histoplasmosis to itraconazole therapy in HIV-infected individuals is similar to that in patients not infected with this virus. However, the clinical course of histoplasmosis in HIV-infected individuals generally is more severe and usually requires long-term maintenance therapy to prevent relapse. Studies to further establish the safety and efficacy of the drug in the treatment of this infection in HIV-infected individuals, including investigation of optimum dosage and duration of maintenance therapy, are ongoing. Oral itraconazole is considered the drug of choice for primary prophylaxis and for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of histoplasmosis in HIV-infected individuals. (See Uses: Prevention of Fungal Infections in HIV-infected Individuals.)

Oropharyngeal and Esophageal Candidiasis

Itraconazole oral solution is used for the treatment of oropharyngeal and esophageal candidiasis. Because topical effects and drug exposure may be greater with the oral solution than with itraconazole capsules, only itraconazole oral solution should be used for the treatment of oropharyngeal and esophageal candidiasis. In 2 controlled studies in patients with oropharyngeal candidiasis (92% were HIV-infected), a clinical response (defined as cured or improved) was attained in 71-84% of patients receiving itraconazole oral solution. There is some evidence that itraconazole oral solution is at least as effective as oral fluconazole tablets and may be more effective than oral clotrimazole lozenges for the treatment of oropharyngeal candidiasis.

Itraconazole oral solution has been effective for the treatment of oropharyngeal candidiasis in some patients, including some HIV-infected individuals, who failed to respond to oral fluconazole. In a double-blind, randomized study in immunocompromised patients with esophageal candidiasis (93% were HIV-infected), a clinical response (defined as cured or improved) was attained in 94% of those who received itraconazole oral solution and 91% of those who received fluconazole tablets.

The median time to response was similar in both groups (27 or 28 days). Follow-up of a group of patients who had a clinical response to the drug indicated that 18% of those who had received itraconazole and 27% of those who had received fluconazole had relapse of esophageal candidiasis within 30 days after treatment was discontinued. Oral itraconazole is used as an alternative agent for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of mucocutaneous candidiasis (esophageal, oropharyngeal, vaginal) in HIV-infected individuals.

Sporotrichosis

Itraconazole is used in the treatment of sporotrichosis. While oral itraconazole may be effective in patients with mild to moderate pulmonary or disseminated sporotrichosis, IV amphotericin B is the drug of choice for the initial treatment of severe, life-threatening infections and whenever there is CNS involvement. Oral itraconazole generally is considered the drug of choice for the treatment of cutaneous, lymphocutaneous, or mild pulmonary or osteoarticular sporotrichosis and for follow-up therapy in more severe infections after a response has been obtained with IV amphotericin B.

Since sporotrichosis in immunocompromised patients (e.g., HIV-infected individuals) is particularly aggressive and difficult to treat, IV amphotericin B probably is the drug of choice for initial therapy in these patients; however, treatment failures occur. Some clinicians recommend that HIV-infected individuals who have been treated for sporotrichosis receive oral itraconazole for lifelong suppressive or maintenance therapy to prevent relapse; such prophylaxis is not addressed in current US Public Health Service and Infectious Diseases Society of America (USPHS/IDSA) guidelines for the prevention of opportunistic infections in individuals infected with HIV.

Onychomycosis

Oral itraconazole capsules are used in immunocompetent individuals for the treatment of onychomycosis of the toenails (with or without fingernail involvement) and onychomycosis of the fingernails caused by dermatophytes (tinea unguium).

Prior to administration of itraconazole capsules for the treatment of onychomycosis, appropriate nail specimens should be obtained for microbiologic studies (e.g., potassium hydroxide [KOH] preparation, fungal culture, nail biopsy) to confirm the diagnosis. In double-blind, placebo-controlled studies in patients with onychomycosis of the toenails, oral itraconazole (200 mg as capsules given once daily for 12 consecutive weeks) resulted in a mycologic cure in 54% of patients; 35% were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% had mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity).

The mean time to overall success was approximately 10 months; however, 21% of those considered an overall success had relapse of onychomycosis. In a double-blind, placebo-controlled study in patients with onychomycosis of the fingernails, oral itraconazole given in a pulse-dosing regimen (200 mg as capsules twice daily for the first week, no itraconazole during weeks 2-4, and 200 mg as capsules twice daily during the fifth week) resulted in a mycologic cure in 61% of patients; 56% were considered an overall success and 47% had mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months; there were no relapses in those who were considered an overall success.

Paracoccidioidomycosis

Oral itraconazole capsules are used in the treatment of paracoccidioidomycosis (South American blastomycosis) caused by Paracoccidioides brasiliensis, and is considered a drug of choice for the treatment of this infection. While the most effective regimen for the treatment of paracoccidioidomycosis in HIV-infected individuals has not been identified, some clinicians suggest that these patients receive initial therapy with IV amphotericin B, and that a less toxic agent (e.g., oral itraconazole capsules, co-trimoxazole) can then be used for long-term suppressive therapy for prophylaxis against recurrence or relapse; such prophylaxis is not addressed in current guidelines recommended by the USPHS/IDSA for the prevention of opportunistic infections in individuals infected with HIV.

Coccidioidomycosis and Cryptococcosis

Although not considered a drug of first choice, oral itraconazole capsules are used as an alternative agent for the treatment of coccidioidomycosis or cryptococcosis. Itraconazole capsules also are used an alternative agent for primary prophylaxis of cryptococcosis or for suppressive or maintenance therapy to prevent recurrence or relapse of coccidioidomycosis or cryptococcosis in HIV-infected individuals.

Chromomycosis

Oral itraconazole capsules have been used with some success for the treatment of chromomycosis (chromoblastomycosis) caused by various dematiaceous fungi (e.g., Cladosporium, Exophiala, Fonsecaea, Phialophora).

Basidiobolomycosis

Oral itraconazole has been used in a limited number of patients for the treatment of GI basidiobolomycosis, a zygomycosis caused by Basidiobolus ranarum. B. ranarum has been isolated worldwide from decaying vegetation and soil and from the GI tracts of reptiles, amphibians, fish, and insectivorous bats (including in the US). Basidiobolomycosis most commonly occurs in tropical and subtropical regions such as eastern and western Africa and infection usually manifests as painless, subcutaneous nodules of the limbs, trunk, or buttocks secondary to traumatic inoculation.

GI infections are extremely rare and possibly the result of ingestion of contaminated soil (especially near rivers or lakes) or fruits or vegetables contaminated with soil or feces from infected reptiles or amphibians. From April 1994 through May 1999, 7 cases of GI basidiobolomycosis were identified in Arizona. Most cases of GI basidiobolomycosis have been successfully treated with oral itraconazole (400 mg daily given for 3-19 months) after partial surgical resection of the GI tract; however, it is unclear whether a clinical response would have been obtained if itraconazole had been used alone without surgical intervention. Although ketoconazole also has been reported to be effective in at least one patient, amphotericin B has been ineffective for the treatment of GI basidiobolomycosis in several patients.

Empiric Therapy in Febrile Neutropenic Patients

Itraconazole (given IV initially followed by itraconazole oral solution) is used for empiric therapy of presumed fungal infections in febrile neutropenic patients. Safety and efficacy of itraconazole for this indication has been evaluated in an open, randomized study in febrile neutropenic adults with hematologic malignancies; patients received either itraconazole (200 mg IV twice daily for 2 days, then 200 mg IV once daily from days 3-14 followed by itraconazole oral solution 200 mg twice daily to complete up to 28 days of therapy) or conventional IV amphotericin B (0.7-1 mg/kg daily for up to 28 days). The therapeutic success rate (defined as patient survival with resolution of fever and neutropenia within 28 days of therapy, absence of emergent fungal infections, use of study drug without premature discontinuance because of toxicity or lack of efficacy, and therapy for 3 or more days) was 47% for itraconazole and 38% for amphotericin B (intent-to-treat analysis). Although the overall response rate was higher in those receiving itraconazole, more patients receiving itraconazole discontinued the drug because of persistent fever or changed antifungal therapy because of fever and more patients receiving amphotericin B discontinued the drug because of intolerance.

Prevention of Fungal Infections in HIV-infected Individuals

Oral itraconazole is used in selected patients with HIV infection for primary prophylaxis against cryptococcosis or histoplasmosis and for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of coccidioidomycosis, cryptococcosis, histoplasmosis, or mucocutaneous candidiasis.

The Prevention of Opportunistic Infections Working Group of the USPHS/IDSA has established guidelines for the prevention of opportunistic infections, including fungal infections, in HIV-infected individuals that include recommendations concerning prevention of exposure to opportunistic pathogens, prevention of first disease episodes, and prevention of disease recurrence. The USPHS/IDSA states that primary prophylaxis to prevent first episodes of mucocutaneous candidiasis in HIV-infected adults, adolescents, infants, and children is not recommended.

While routine primary prophylaxis to prevent first episodes of coccidioidomycosis, cryptococcosis, or histoplasmosis in HIV-infected adults, adolescents, infants, and children is not recommended, the USPHS/IDSA states that primary prophylaxis against cryptococcosis or histoplasmosis may be considered in certain selected individuals. The USPHS/IDSA recommends that HIV-infected adults, adolescents, infants, and children who have completed initial therapy for documented coccidioidomycosis, cryptococcosis, or histoplasmosis receive long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of these fungal infections.

In addition, the USPHS/IDSA states that HIV-infected individuals who have frequent or severe recurrences of mucocutaneous candidiasis may benefit from long-term suppressive or maintenance therapy (secondary prophylaxis). Because of concerns regarding use of oral azole antifungal agents during pregnancy, itraconazole should not be used for primary prophylaxis or for chronic suppressive or maintenance therapy in women who are pregnant. If a woman becomes pregnant while receiving itraconazole for prophylaxis and elects to continue the pregnancy, the drug should be discontinued.

Effective contraceptive measures are recommended for all HIV-infected women receiving an oral azole antifungal agent for suppressive therapy. Conventional IV amphotericin B may be the preferred agent if long-term suppressive or maintenance therapy against coccidioidomycosis, cryptococcosis, or histoplasmosis is indicated in an HIV-infected pregnant woman, especially during the first trimester.

Primary Prophylaxis

Safety and efficacy of oral itraconazole for primary prophylaxis of serious fungal infections in HIV-infected individuals has been evaluated in a prospective, randomized, placebo-controlled study in 149 patients with advanced HIV infection. There was failure of prophylaxis in 19% of those receiving oral itraconazole (200 mg once daily) and 29% of those receiving placebo. Prophylaxis failures related to invasive fungal infections (histoplasmosis, cryptococcosis, aspergillosis) were more frequent in those receiving placebo than in those receiving itraconazole; however, the incidence of prophylaxis failure due to recurrent or refractory mucosal candidiasis was similar in both groups. While itraconazole prophylaxis significantly delayed the time to onset of histoplasmosis and cryptococcosis, a survival benefit was not demonstrated in those receiving the drug.

Cryptococcosis

The USPHS/IDSA states that, although routine primary prophylaxis against cryptococcosis is not recommended, primary prophylaxis may be considered in HIV-infected adults and adolescents with CD4+ T-cell counts less than 50/mm3 and in infants and children with severe immunosuppression (as defined by age-adjusted criteria). Routine prophylaxis is not recommended because of the relative infrequency of cryptococcal disease, lack of evidence of survival benefit associated with prophylaxis, as well as other concerns (e.g., possibility of drug interactions, potential for development of resistance, cost considerations).

The need for primary prophylaxis or suppressive therapy against other fungal infections (e.g., coccidioidomycosis, histoplasmosis, mucocutaneous candidiasis) should be considered while making the decision concerning prophylaxis against cryptococcosis. Routine testing of asymptomatic individuals for serum cryptococcal antigen is not recommended because of the low probability that results will affect clinical decisions. HIV-infected individuals cannot completely avoid exposure to Cryptococcus neoformans; there is no evidence that exposure to pigeon droppings is associated with an increased risk for cryptococcosis. Oral fluconazole is the agent of choice for primary prophylaxis against cryptococcosis in HIV-infected adults, adolescents, infants, and children and oral itraconazole (given as capsules) is considered an alternative.

Histoplasmosis

The USPHS/IDSA states that primary prophylaxis against histoplasmosis may be considered in HIV-infected adults or adolescents with absolute helper/inducer (CD4+, T4+) T-cell counts less than 100/mm3 who are at especially high risk of exposure to Histoplasma capsulatum because of occupational exposure or who live in a community with a hyperendemic rate of histoplasmosis (at least 10 cases/100 patient years) and also may be considered for HIV-infected infants or children with severe immunosuppression (as defined by age-adjusted criteria) who live in areas endemic for histoplasmosis.

When a decision is being made regarding whether to use primary prophylaxis against histoplasmosis in these HIV-infected individuals, clinicians should consider the local incidence of histoplasmosis, possibility of drug interactions, toxicity, development of resistance, cost, and the need for prophylaxis against other fungal infections (e.g., candidiasis, cryptococcosis).

Routine skin testing with histoplasmin or serologic testing for histoplasmosis antibody or antigen in HIV-infected individuals who live in areas endemic for histoplasmosis is not predictive of disease and is not recommended. Although HIV-infected individuals living in or visiting histoplasmosis-endemic areas cannot completely avoid exposure to H. capsulatum, those with CD4+ T-cell counts less than 200/mm3 should avoid activities known to be associated with increased risk (e.g., creating dust while working with surface soil; cleaning chicken coops that are heavily contaminated with droppings; disturbing soil beneath bird-roosting sites; cleaning, remodeling, or demolishing old buildings; exploring caves). Oral itraconazole (given as capsules) is the agent of choice for primary prophylaxis against histoplasmosis in HIV-infected adults, adolescents, or pediatric patients; the USPHS/IDSA makes no recommendation regarding an alternative to itraconazole.

Prevention of Recurrence

Coccidioidomycosis

For long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse in HIV-infected adults, adolescents, infants, and children with documented coccidioidomycosis that has been adequately treated, the USPHS/IDSA recommends oral fluconazole as the drug of choice and IV amphotericin B or oral itraconazole (given as capsules) as alternatives. Long-term suppressive or maintenance therapy for prophylaxis against recurrence or relapse of coccidioidomycosis in HIV-infected individuals generally is continued for life. Although HIV-infected individuals receiving suppressive antifungal prophylaxis against coccidioidomycosis may be at low risk for recurrence of this fungal infection if their CD4+ T-cell count increases to greater than 100/mm3 while receiving potent combination antiretroviral agent therapy, the USPHS/IDSA states that data are insufficient to date to warrant a recommendation regarding discontinuance of prophylaxis in these individuals.

Cryptococcosis

For long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse in HIV-infected adults, adolescents, infants, and children with documented cryptococcosis that has been adequately treated, the USPHS/IDSA recommends oral fluconazole as the drug of choice and IV amphotericin B or oral itraconazole (given as capsules) as alternatives.

There is some evidence from a randomized, double-blind, controlled study in HIV-infected individuals with documented, adequately treated cryptococcal meningitis that oral fluconazole (200 mg once daily) is more effective than oral itraconazole (200 mg once daily) for suppressive therapy in these patients since the rate of culture-positive relapse of cryptococcosis was 4% in those receiving fluconazole compared with 23% in those receiving itraconazole.

Suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of cryptococcosis in HIV-infected individuals generally is continued for life, unless immune recovery has occurred as a result of potent antiretroviral therapy.

Limited data indicate that discontinuing suppressive or maintenance therapy in HIV-infected adults and adolescents who have successfully completed initial therapy for cryptococcosis, remain asymptomatic with respect to cryptococcosis, and have sustained (e.g., for 6 months or longer) increases in CD4+ T-cell counts to greater than 100-200/mm3 in response to potent antiretroviral therapy is associated with a low risk for recurrence of cryptococcosis.

Based on this data and more extensive cumulative data on safety of discontinuing long-term suppressive therapy for other opportunistic infections, the USPHS/IDSA states that it is reasonable to consider discontinuation of suppressive or maintenance therapy in individuals meeting these criteria. The USPHS/IDSA notes that recurrences could occur in individuals discontinuing therapy and states that suppressive or maintenance therapy should be restarted if the CD4+ T-cell count decreases to less than 100-200/mm3. The safety of discontinuing suppressive or maintenance therapy in HIV-infected infants and children has not been studied; children should receive lifelong suppressive therapy after an episode of cryptococcosis.

Histoplasmosis

For long-term suppressive or maintenance therapy to prevent recurrence or relapse in HIV-infected adults, adolescents, infants, and children with documented histoplasmosis that has been adequately treated, the USPHS/IDSA recommends oral itraconazole (given as capsules) as the drug of choice and IV amphotericin B as an alternative. Long-term suppressive or maintenance therapy against histoplasmosis in HIV-infected individuals generally is continued for life. Although patients receiving suppressive antifungal prophylaxis may be at low risk for recurrence of histoplasmosis if their CD4+ T-cell counts increase to greater than 100/mm3 while receiving potent combination antiretroviral agent therapy, the USPHS/IDSA states that data are insufficient to date to warrant a recommendation regarding discontinuance of prophylaxis in these individuals.

Mucocutaneous Candidiasis

The USPHS/IDSA states that use of long-term suppressive or maintenance therapy should be considered in adults and adolescents who have a history of documented esophageal candidiasis (especially those who have had multiple episodes), taking into consideration the potential for development of resistant strains of Candida. In addition, the USPHS/IDSA states that use of suppressive therapy also should be considered for infants and children who have severe, recurrent mucocutaneous candidiasis, especially those with esophageal candidiasis.

Although many experts do not recommend long-term suppressive therapy of recurrent oropharyngeal or vulvovaginal candidiasis for the same reasons they do not recommend primary prophylaxis against candidiasis, the USPHS/IDSA states that suppressive therapy against candidiasis may be considered in HIV-infected individuals who have frequent or severe recurrences of these infections.

However, several factors should be addressed when considering such therapy, including the impact of recurrences on the patient’s well-being and quality of life, the need for prophylaxis against other fungal infections, cost of prophylaxis, drug toxicities, drug interactions, and potential for development of drug resistance among Candida and other fungi. If long-term suppressive or maintenance therapy 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 (given as the oral solution) as an alternative.

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