Fluconazole: Uses and Administration
Fluconazole is a triazole antifungal used for superficial mucosal (oropharyngeal, oesophageal, or vaginal) candidiasis and for fungal skin infections. It is also given for systemic infections including systemic candidiasis, coccidioidomycosis, and cryptococcosis, and has been tried in blastomycosis, histoplasmosis, and sporotrichosis. The place of fluconazole in the treatment of fungal infections is discussed in the various sections under Choice of Antifungal.
Fluconazole is given by mouth or intravenous infusion in similar doses.
For intravenous infusion it is given as a solution containing 2 mg/mL at a rate of 5 to 10 mL/minute (300 to 600 mL/hour). In the USA, a maximum infusion rate of 100 mL/hour is recommended.
For superficial mucosal candidiasis (other than genital candidiasis), the usual dose of fluconazole in the UK is 50 mg daily by mouth, although 100 mg daily may be given if necessary.
Treatment usually continues for 7 to 14 days in oropharyngeal candidiasis (except in severely immunocompromised patients), for 14 days in atrophic oral candidiasis associated with dentures, and for 14 to 30 days in other mucosal candidal infections including oesophagitis. Higher doses are recommended in the USA where an initial dose of fluconazole 200 mg is followed by 100 mg daily and where the minimum treatment period is 14 days for oropharyngeal infection, or a minimum of 21 days and at least 14 days after resolution of symptoms for oesophageal infections doses of up to 400 mg daily may be used for oesophageal candidiasis if necessary.
Fluconazole 150 mg as a single oral dose may be used for genital candidiasis (vaginal candidiasis or candidal balanitis). Dermatophytosis, pityriasis versicolor, and Candida infections of the skin may be treated with fluconazole 50 mg daily by mouth for up to 6 weeks.
Systemic candidiasis, cryptococcal meningitis, and other cryptococcal infections may be treated with fluconazole orally or by intravenous infusion the initial dose is 400 mg followed by 200 to 400 mg daily. Duration of therapy is based on clinical and mycological response, but is usually at least 6 to 8 weeks in cryptococcal meningitis in the USA, treatment for 10 to 12 weeks after the CSF cultures become negative is recommended.
Fluconazole may also be used in daily doses of 100 to 200 mg orally or intravenously to prevent relapse after a primary course of antifungal treatment for acute cryptococcal meningitis in patients with AIDS. In immunocompromised patients at risk of fungal infections, fluconazole may be given prophylactically in a dose of 50 to 400 mg daily orally or by intravenous infusion, although long-term prophylaxis has been associated with the emergence of resistant organisms (see under Intermittent Doses, below). Doses for children over 4 weeks of age are 3 mg/kg daily for superficial infections (a loading dose of 6 mg/kg may be used on the first day if necessary), and 6 to 12 mg/kg daily for systemic infections. For prophylaxis in immunocompromised children, a dose of 3 to 12 mg/kg daily may be given. For infants under 2 weeks of age, all these doses should be given once every 72 hours for those aged between 2 and 4 weeks, the doses should be given every 48 hours.
A maximum dose of 400 mg daily should not be exceeded in children, or 12 mg/kg at appropriate intervals in infants. Dosage may need to be reduced in patients with renal impairment.
Fluconazole: Uses
Fluconazole is used in the treatment of oropharyngeal, esophageal, or vulvovaginal candidiasis and in the treatment of other serious systemic candidal infections (e.g., urinary tract infections,peritonitis, candidemia, disseminated candidiasis,meningitis, pneumonia). The drug also is used for the treatment of meningitis caused by Cryptococcus neoformans and for the treatment of blastomycosis, coccidioidomycosis, and histoplasmosis.
Fluconazole has been used for less severe infections such as superficial fungal infections, dermatophytoses, and onychomycosis. In addition, the drug is used for prevention of serious fungal infections (e.g., coccidioidomycosis, cryptococcosis, mucocutaneous candidiasis) in patients with human immunodeficiency virus (HIV) infection and for prevention of fungal infections in other immunocompromised individuals (e.g., cancer patients, bone marrow transplant patients).
Prior to initiation of fluconazole therapy, appropriate specimens for fungal culture and other relevant laboratory studies (e.g., serology, histopathology) should be obtained in order to isolate and identify the causative organism(s). Fluconazole therapy may be started pending results of these in vitro tests; however, once results are available, therapy should be adjusted accordingly. If fluconazole in vitro susceptibility tests are performed, results should be interpreted cautiously since currently available tests may not accurately reflect fluconazole’s in vivo activity.
Candidal Infections
Oropharyngeal and Esophageal Candidiasis
Oral or IV fluconazole is used in the treatment of oropharyngeal candidiasis in immunocompromised adults with acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex (ARC), malignancy, or other serious underlying disease and also is used orally or IV for the treatment of esophageal candidiasis in adults with AIDS, malignancy, or other serious underlying disease, including progressive systemic sclerosis.
Fluconazole appears to be at least as effective as and, in some cases, more effective than other antifungal agents used in the initial treatment of oropharyngeal and/or esophageal candidal infections and is considered a drug of choice for these infections.
Fluconazole has produced clinical resolution of signs and symptoms of the infection in 79-100% of patients with oropharyngeal candidiasis; however, microbiologic cures generally have been obtained in 44-87% of patients and the rate of relapse may be high, especially in neutropenic patients. In adults with esophageal candidiasis documented by endoscopy, fluconazole has produced clinical resolution of signs and symptoms of the infection in about 61-93% of patients. In one study in adults with esophageal candidiasis and progressive systemic sclerosis, fluconazole therapy produced mycologic cures in about 93% of patients within 2-4 weeks, but the relapse rate was almost 100% within 3 months after fluconazole therapy was discontinued.
HIV-infected patients with severe or recurrent episodes of oropharyngeal or esophageal candidiasis may benefit from long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent relapse.
Some clinicians consider topical therapy with oral clotrimazole or oral nystatin the treatment of choice for uncomplicated oropharyngeal candidiasis in HIV-infected individuals and recommend that systemic antifungal agents (e.g., oral fluconazole, oral itraconazole, oral ketoconazole) be reserved for the treatment of oropharyngeal candidiasis unresponsive to topical agents and for the treatment of severe oropharyngeal candidiasis with esophageal involvement. However, some clinicians prefer to use an oral azole antifungal agent for initial therapy of oropharyngeal candidiasis.
Oral fluconazole or itraconazole oral solution are at least as effective as topical therapy. In a study in HIV-infected adults with oropharyngeal candidiasis, the response rate and mycologic eradication rate after 14 days of therapy were 100 and 75%, respectively, in those who received oral fluconazole (100 mg once daily) and were 65 and 20%, respectively, in those who received topical clotrimazole (10-mg oral lozenge 5 times daily). In another study, 14 days of therapy with oral fluconazole (100 mg once daily as an oral suspension) was more effective than 14 days of therapy with topical nystatin (500,000 units as an oral suspension 4 times daily). The mycologic cure rate was 60% in the fluconazole group and 6% in the nystatin group and the rate of relapse at day 42 was 27 and 11%, respectively. The comparative efficacy of fluconazole and other antifungal agents after long-term follow-up needs further study.
Systemic anti-infective therapy is necessary for the treatment of esophageal candidiasis. Some clinicians state that a 14- to 21-day regimen of oral fluconazole (100 mg once daily) or itraconazole oral solution (200 mg once daily) is highly effective for the treatment of esophageal candidiasis, and oral ketoconazole is less effective. These clinicians suggest that itraconazole oral solution should be used in patients who fail to respond to oral fluconazole and that use of IV amphotericin B can be considered in patients with otherwise refractory disease. In a randomized, multicenter, double-blind study comparing oral fluconazole (initial dosage 100 mg daily increased to 200 mg daily if no symptomatic improvement occurred within 1-2 weeks) for up to 8 weeks with oral ketoconazole (initial dosage 200 mg daily increased to 400 mg daily if no symptomatic improvement occurred within 1-2 weeks) in AIDS patients with endoscopically confirmed esophageal candidiasis, endoscopic cure and resolution of esophageal symptoms occurred in 91 and 85% of patients receiving fluconazole, respectively, while endoscopic cure and resolution of symptoms occurred in 52 and 65% of patients receiving ketoconazole, respectively; results of another study in immunocompromised patients with esophageal candidiasis indicate that patients receiving fluconazole may require a shorter duration of initial therapy than those receiving ketoconazole.
Vulvovaginal Candidiasis
Oral fluconazole is used for the treatment of uncomplicated vulvovaginal candidiasis and for the treatment of complicated vulvovaginal candidiasis in nonpregnant women. Prior to initial use of antifungal therapy in a woman who has signs and symptoms of uncomplicated vulvovaginal candidiasis, the diagnosis should be confirmed either by demonstrating yeasts or pseudohyphae with direct microscopic examination of vaginal discharge (10% potassium hydroxide [KOH] wet mount or Gram stain) or by culture; identifying Candida by culture in the absence of symptoms is not an indication for antifungal treatment since approximately 10-20% of women harbor Candida or other yeasts in the vagina. In women with recurrent vulvovaginal candidiasis, vaginal cultures should be obtained to confirm the diagnosis and identify unusual Candida species (e.g., C. glabrata).
Uncomplicated Vulvovaginal Candidiasis
Oral fluconazole is effective for the treatment of uncomplicated vulvovaginal candidiasis when given as a single dose. A single 150-mg oral dose of fluconazole produces clinical cures (i.e., absence of vulvovaginal burning, itching, swelling, erythema, excoriation, dyspareunia, and/or ulceration and substantial decreases in vaginal discharge) 5-16 days after the dose in approximately 90-100% and mycologic cures in approximately 77-100% of nonpregnant women with uncomplicated vulvovaginal candidiasis. At 27-62 days after the single dose, clinical and mycologic cure rates are 61-90%, and the rate of relapse, reinfection, or recolonization is about 23%. Results of several studies in patients with uncomplicated vulvovaginal candidiasis suggest that a single 150-mg dose of oral fluconazole is as effective for this condition as multiple dose regimens of intravaginal clotrimazole,econazole, miconazole, or terconazole. In addition, the single-dose oral fluconazole regimen appears to be as effective for uncomplicated vulvovaginal candidiasis as oral itraconazole or oral ketoconazole.
In controlled studies in patients with vulvovaginal candidiasis, clinical and mycologic cure rates at 14 and 30-35 days were similar in patients receiving oral fluconazole (given as a single 150-mg dose) compared with patients receiving intravaginal clotrimazole (given as a 100-mg vaginal tablet once daily for 7 days) or miconazole (given as a 100-mg vaginal cream once daily for 7 days).At 14 days, the clinical cure rate was reported to be about 95-96% with fluconazole and 95-97% with intravaginal clotrimazole or miconazole and the mycologic cure rate was reported to be 77-80% with fluconazole and 72-82% with intravaginal clotrimazole or miconazole. At 30-35 days, the clinical cure rate was reported to be about 69-75% with fluconazole and 72-80% with intravaginal clotrimazole or miconazole and the mycologic cure rate was reported to be 61-63% with fluconazole and 57-63% with intravaginal clotrimazole or miconazole.
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 C. 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. Some clinicians suggest that a single oral dose of fluconazole may offer some advantage over conventional intravaginal therapy since it ensures compliance and may reduce or eliminate concurrent rectal infections that may serve as a source of reinfection. In weighing the potential risks and benefits of oral versus intravaginal therapy, the potential for toxicity (e.g., hepatotoxicity) and drug interactions associated with oral therapy should be considered. The incidence of adverse effects is higher in patients receiving single oral doses of fluconazole compared with those receiving intravaginal therapy; and this also should be weighed carefully.
Complicated and Recurrent Vulvovaginal Candidiasis
Oral fluconazole is used for the treatment of complicated vulvovaginal candidiasis, including recurrent and severe infections. Complicated vulvovaginal candidiasis is defined as infections that are recurrent or severe, caused by Candida other than C. albicans, or occurring in pregnant women or women with underlying disease such as uncontrolled diabetes, debilitation, or immunosuppression.
Optimum regimens for the treatment of recurrent vulvovaginal candidiasis (usually defined as 4 or more episodes of symptomatic vulvovaginal candidiasis 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). For the maintenance regimen, the CDC recommends 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.
The response rate to short-course antifungal regimens is lower in patients with severe vulvovaginal candidiasis (i.e., extensive vulvar erythema, edema, excoriation, and fissure formation) and either a 2-dose regimen of oral fluconazole (150 mg repeated 3 days later) or 7-14 days of an intravaginal azole antifungal is recommended for these infections. These more prolonged regimens may also be necessary for the treatment of vulvovaginal candidiasis in women with underlying debilitating medical conditions (e.g., those with uncontrolled diabetes or those receiving corticosteroid therapy). v 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.
Recurrent vulvovaginal candidiasis rarely 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 therapy with 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.
Candidemia and Other Candidal Infections
Fluconazole has been effective in the treatment of serious candidal urinary tract infections, peritonitis, and pneumonia. The drug also has been effective in the treatment of chronic mucocutaneous candidiasis, candidemia, chronic disseminated candidiasis (hepatosplenic candidiasis), candidal endocarditis, candidal meningitis, candidal osteomyelitis, and other severe systemic candidal infections. The drug has been effective in the treatment of some candidal infections that did not respond to therapy with amphotericin B. Fluconazole has been effective in the treatment of life-threatening candidal infections in organ transplant patients receiving immunosuppressive therapy. In some renal allograft recipients, fluconazole therapy effectively eliminated fungal infections without the need to discontinue or decrease dosage of immunosuppressive therapy.
Both IV amphotericin B and IV or oral fluconazole are considered drugs of choice for systemic invasive candidiasis; however, optimal antifungal regimens for these infections have been difficult to identify and there are drawbacks associated with each agent. While fluconazole may be better tolerated and easier to administer than IV amphotericin B, fluconazole-resistant strains of C. albicans are being isolated with increasing frequency from patients who have received prior fluconazole therapy (especially in HIV-infected patients) and some candidal infections (e.g., candidemia) are increasingly caused by candidal strains that are intrinsically resistant to fluconazole (e.g., C. krusei) or likely to be fluconazole resistant (e.g., C. glabrata). The choice of antifungal agent for the initial treatment of invasive candidal infections should take into consideration local and/or institutional epidemiologic data regarding prevalence of the various candidal strains and their patterns of resistance, the colonization status of the patient, severity and duration of neutropenia or immunosuppression, and history relating to prior fluconazole use. If the infecting organism is known or likely to be C. krusei, most clinicians recommend use of IV amphotericin B; however, fluconazole is preferred if the infection is caused by C. lusitaniae.
Because candidemia is associated with substantial morbidity and risk of long-term sequelae, antifungal agent therapy generally is recommended for all patients with candidemia (regardless of whether they are neutropenic or nonneutropenic) in addition to removal and/or exchange of any intravascular catheters. It has been suggested that oral fluconazole may be preferred over IV amphotericin B for the treatment of candidemia in nonneutropenic patients (both stable and unstable patients) unless there is evidence that the infection is caused by fluconazole-resistant strains or the patient previously received fluconazole. IV amphotericin B generally is preferred for the treatment of severe candidemia in patients who have infections caused by strains that may be fluconazole-resistant (e.g., C. krusei, C. glabrata), patients who have recently received fluconazole, and immunocompromised patients such as those with HIV infection. In a controlled study in patients with candidemia who were immunocompetent and had normal neutrophil counts, the response to conventional IV amphotericin B therapy (0.-0. mg/kg daily for 7 days, then 3 times weekly for an additional 10 days) or fluconazole therapy (400 mg daily given IV for 7 days, then orally for an additional 11 days) was similar and both regimens appeared to be equally effective. The overall response rate to a regimen of conventional IV amphotericin B or oral fluconazole also was similar in a prospective, randomized study that included both nonneutropenic and neutropenic patients with documented or presumed invasive candidiasis. However, further study is needed to more fully evaluate the relative efficacy of amphotericin B and fluconazole in immunocompromised patients or patients with severe infections.
Oral fluconazole or IV amphotericin B are recommended when treatment of candiduria is indicated (e.g., symptomatic or neutropenic patients, low-birthweight infants, patients with renal allografts, patients who will undergo urologic manipulations); fluconazole may be preferred unless the infection is caused by C. krusei or C. glabrata. Bladder irrigation with conventional amphotericin B also has been used. In a randomized study in hospitalized, geriatric patients with funguria caused by C. albicans, C. tropicalis, or C. glabrata, 5 days of bladder irrigation with conventional amphotericin B (25 mg of amphotericin B in 500 mL of 5% dextrose injection infused through an indwelling bladder catheter at a rate of 42 mL/hour) or a 5-day course of oral fluconazole (200-mg loading dose on day 1 followed by 100 mg once daily for 4 additional days) eradicated the funguria in 83 or 66% of patients, respectively.
Fluconazole also is used prophylactically to reduce the incidence of candidiasis in bone marrow transplant recipients who are receiving chemotherapy or radiation therapy. The drug also has been used for primary prophylaxis against fungal infections, including candidiasis, in a limited number of patients considered at high risk for developing such infections (e.g., cancer patients who are neutropenic, colonized with Candida, and/or are receiving corticosteroids, and certain AIDS patients).
Fluconazole has been used with good results in several patients with endophthalmitis caused by Candida, but treatment failures have been reported and the role of the drug in the treatment of this infection remains to be elucidated. Studies in rabbits indicate that fluconazole is distributed into the eye and that the drug inhibits growth of C. albicans in rabbit choroid-retina tissue and vitreous body when IV therapy is initiated within 24 hours postinoculation; the drug did not effectively inhibit growth of the organism when IV therapy was initiated 7 days postinoculation when the infection was well established.
Cryptococcal Infections
Oral or IV fluconazole is used in immunocompetent or immunocompromised adults for the treatment of meningitis caused by C. neoformans. The drug has been effective for the initial (primary) treatment of acute cryptococcal meningitis in both HIV-infected and HIV-negative adults and has produced clinical resolution of signs and symptoms of the infection in approximately 34-75% of these patients. Although amphotericin B (with or without concomitant flucytosine) has been considered the initial treatment of choice for cryptococcal meningitis, fluconazole is an alternative for these infections in patients whose disease is not severe since it generally is well tolerated and is distributed into CSF in high concentrations. While experience in children is limited, fluconazole also may be considered as an alternative to amphotericin B therapy in this age group.
Fluconazole has been effective in the treatment of acute cryptococcal meningitis in some patients who failed to respond to amphotericin B therapy. However, there is some evidence that fluconazole may be less effective than amphotericin B during early therapy of acute cryptococcal meningitis in patients with AIDS and may produce slower sterilization of CSF. In a randomized, multicenter study comparing amphotericin B (mean dosage of 0.4-0.5 mg/kg daily for 10 weeks with or without concomitant flucytosine) with oral fluconazole (400 mg in the first day and 200-400 mg thereafter for 10 weeks) in AIDS patients with cryptococcal meningitis, therapy was effective in 40% of patients receiving amphotericin B and in 34% of those receiving fluconazole. Although overall mortality between patients receiving amphotericin B and patients receiving fluconazole was similar (14% in patients receiving amphotericin B versus 18% in patients receiving fluconazole), mortality was higher during the first 2 weeks of therapy in patients receiving fluconazole (15% versus 8% in those receiving amphotericin B). CSF cultures were positive for an average of about 42 or 64 days in patients receiving amphotericin B or fluconazole, respectively. In another study comparing amphotericin B (0.7 mg/kg daily for 1 week, followed by this dose 3 times weekly for 9 weeks combined with flucytosine 150 mg/kg daily) with oral fluconazole (400 mg daily for 10 weeks) in a limited number of AIDS patients with cryptococcal meningitis, initial therapy was effective in all patients receiving amphotericin B but in only 43% of patients receiving fluconazole; CSF cultures were positive for an average of about 16 and 41 days in patients receiving these respective therapies. While patient groups in this study were similar with respect to severity of cryptococcal infection, the helper/inducer (CD4+, T4+) T-cell count was lower in the fluconazole group, confounding interpretation.
Many clinicians recommend that treatment of cryptococcal meningitis in HIV-infected patients be initiated with a regimen of IV amphotericin B (with flucytosine) given for at least 2 weeks (or until the patients’s condition is stabilized) followed by a regimen of oral fluconazole or oral itraconazole administered for at least an additional 8-10 weeks or longer. Pending further accumulation of data and experience, some clinicians state that initial (primary) therapy with IV amphotericin B (with or without flucytosine) followed by fluconazole maintenance therapy may be most prudent, at least in patients with more severe disease and those at high risk, and that primary fluconazole therapy probably should be reserved for patients failing to adequately respond to or intolerant of amphotericin B and those with less severe disease (e.g., absence of neurologic manifestations, low CSF cryptococcal antigen titers).
The relative efficacy of initial therapy with conventional IV amphotericin B (0. mg/kg daily) given with flucytosine (100 mg/kg daily) or placebo for 2 weeks followed by oral fluconazole (800 mg daily for 2 days, then 400 mg daily for 8 weeks) or oral itraconazole (600 mg daily for 3 days, then 400 mg daily for 8 weeks) has been evaluated in a double-blind multicenter trial in patients with AIDS-associated cryptococcal meningitis. At 2 weeks, CSF cultures were negative in 60% of those who received amphotericin B with flucytosine compared with 51% of those who received amphotericin B alone. The clinical response to oral fluconazole or oral itraconazole for follow-up therapy was similar, but the rate of CSF sterilization at 10 weeks was higher in those who received fluconazole (72%) compared with those who received itraconazole (60%).
A regimen of oral fluconazole (400 mg daily for pulmonary infections or 400-800 mg daily for CNS infections) and oral flucytosine (100-150 mg/kg daily) has been used as an alternative regimen for the treatment of pulmonary or CNS cryptococcal infections in a limited number of patients. Although fluconazole used in conjunction with flucytosine may be effective for the treatment of mild to moderate pulmonary cryptococcal infections, this regimen has been ineffective in some patients with cryptococcal meningitis and is not recommended for initial treatment of such infections. In addition, when used for the treatment of cryptococcal meningitis in HIV-infected individuals, a regimen of fluconazole and flucytosine has been associated with a high incidence of adverse effects resulting in discontinuance of flucytosine in 28% of patients.
The mortality rate in AIDS patients during the first episode of cryptococcal meningitis has been about 25-58% despite amphotericin B therapy. In patients with AIDS who respond to initial antifungal therapy, the rate of relapse of cryptococcal infection is 35-65%, and chronic maintenance or suppressive antifungal therapy generally is considered necessary after initial treatment of the infection unless immune recovery has occurred as a result of potent antiretroviral therapy.
Oral fluconazole has been effective when used for long-term maintenance therapy for prevention of relapse of cryptococcal meningitis in patients with AIDS. (See Uses: Prevention of Fungal Infections in HIV-infected Individuals.) Results of a multicenter study comparing safety and efficacy of oral fluconazole (200 mg once daily) with those of IV amphotericin B (1 mg/kg once weekly) for prevention of relapse of the disease in AIDS patients who have negative cryptococcal cultures after initial adequate amphotericin B therapy indicate that the fluconazole regimen is more effective (in terms of preventing relapse of culture-positive meningitis) and better tolerated than the amphotericin B regimen for maintenance therapy in these patients. In a multicenter study comparing oral fluconazole maintenance (100-200 mg daily) with placebo in such patients, the overall calculated cumulative risk of cryptococcal recurrence at any site after 1 year of fluconazole maintenance was 5% versus 100% for placebo.
The efficacy of fluconazole maintenance in preventing cryptococcal relapse in patients with persistent prostatic infection following primary antifungal therapy appears to be lower than that in patients overall, but such reduced efficacy may be overcome at least partially by increased dosage of the drug. In a limited number of adults with AIDS who had persistent urinary cryptococcosis (including prostate infections) following adequate primary amphotericin B therapy (with or without flucytosine) for cryptococcal meningitis, oral fluconazole maintenance therapy resulted in mycologic cures in most patients, while relapse of cryptococcuria (with prostatic massage) and/or systemic infection occurred in the remaining patients during fluconazole maintenance.
Response (sustained suppression of prostatic massage-induced cryptococcuria and absence of evidence of systemic or CNS relapse) in such patients appears to be dose dependent, generally requiring oral fluconazole dosages of 200-600 mg daily, and requires several weeks to months of fluconazole maintenance to become manifest (in one study, the probability of response was estimated to be 36% after 4 weeks and 59% after 27 weeks of maintenance). Relatively large dosages (e.g., 600 mg or more daily) may effectively sterilize multiple large prostatic abscesses in some patients. However, factors that may be predictive of response, and optimum antifungal therapy in such patients remain to be more fully elucidated. In addition, because of the risk of relapse, some clinicians caution that the possibility of a prostatic focus of infection should be adequately excluded in any male patient if low-dose fluconazole maintenance is contemplated.
Oral fluconazole has been effective in a limited number of patients for the treatment of cutaneous or subcutaneous cryptococcosis. The drug also has been effective for the treatment of cryptococcal pneumonia in a limited number of patients, although surgical removal of the focus of infection was necessary in some patients; however, the possibility that cryptococcal pneumonia may be a manifestation of disseminated infection should be considered.
Coccidioidomycosis
Oral fluconazole has been used with some success in the treatment of coccidioidomycosis caused by Coccidioides immitis (e.g., meningitis, pulmonary infections, disseminated infections including soft tissue or bone and joint). In adults with coccidioidal meningitis, fluconazole has produced clinical and/or laboratory evidence of improvement when used alone or in conjunction with amphotericin B therapy. Oral fluconazole has been used for the treatment of coccidioidal meningitis in both HIV-infected and HIV-negative individuals. Because fluconazole generally is well tolerated and exhibits favorable pharmacokinetics (e.g., is distributed into CSF in high concentrations following oral or IV administration), the drug is considered a less toxic alternative to amphotericin B for the treatment of coccidioidal meningitis and other persistent coccidioidal infections, especially since long-term antifungal therapy usually is necessary for these infections. Fluconazole is considered a drug of choice for the treatment of coccidioidomycosis; however, IV amphotericin B generally is preferred for the initial treatment of severe coccidioidomycosis, especially in immunocompromised patients including HIV-infected individuals. Further study is needed to evaluate efficacy and establish optimum dosage of oral fluconazole for the treatment of coccidioidomycosis and to determine whether the drug substantially reduces morbidity and mortality. Some data indicate that the response rate may be improved when higher fluconazole dosages (i.e., 400 mg daily or higher) are used, and it has been suggested that the use of relatively low dosages (e.g., 50-100 mg daily) may contribute to the risk of infection recurrence.
Blastomycosis
Oral fluconazole has been used in the treatment of North American blastomycosis caused by Blastomyces dermatitidis. While oral itraconazole or IV amphotericin B are considered drugs of choice for the treatment of blastomycosis, oral fluconazole or oral ketoconazole are considered alternative agents. IV amphotericin B generally is preferred for the treatment of severe infections, especially those involving the CNS, and for the initial treatment of presumptive blastomycosis in immunocompromised patients, including HIV-infected individuals.
There is some evidence that oral itraconazole may be more effective than oral fluconazole or oral ketoconazole for the treatment of blastomycosis and many clinicians consider itraconazole the preferred azole antifungal agent for the treatment of nonmeningeal, non-life-threatening blastomycosis 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.
Histoplasmosis
Oral fluconazole has been used with some success for the treatment of histoplasmosis caused by Histoplasma capsulatum. While IV amphotericin B or oral itraconazole are considered drugs of choice for the treatment of histoplasmosis, oral fluconazole or oral ketoconazole are considered alternative agents. Oral fluconazole (400-800 mg daily) has been effective when used in a limited number of HIV-infected patients with mild or moderately severe disseminated 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. In addition, oral itraconazole generally is the preferred azole antifungal agent for the treatment of mild to moderate histoplasmosis or as follow-up therapy in the treatment of severe infections after a response has been obtained with amphotericin B.
Sporotrichosis
Fluconazole is used as an alternative agent for the treatment of sporotrichosis. IV amphotericin B usually is considered the drug of choice for the initial treatment of severe, life-threatening infections and whenever there is CNS involvement and oral itraconazole 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. Fluconazole is considered second-line therapy for the treatment of cutaneous, lymphocutaneous, or osteoarticular sporotrichosis and, because it may be less effective than itraconazole, should be used be used only if the patient cannot tolerate itraconazole. Some clinicians state that fluconazole has not been shown to be effective and should not be used for the treatment of pulmonary sporotrichosis.
Aspergillosis
Fluconazole has been used orally, IV, or by intracavitary infusion in a few adults for the treatment of pneumonia or other respiratory tract infections caused by Aspergillus fumigatus, A. niger, or A. terreus. In one study, fluconazole had a clinical efficacy rate of 23-53% in Aspergillus infections and a mycologic cure rate of about 50% for A. fumigatus infections. Fluconazole has produced variable results in the treatment of infections caused by Aspergillus, and IV amphotericin B generally is considered the drug of choice and itraconazole usually is the preferred alternative for the treatment of aspergillosis.
Dermatophytoses
Oral fluconazole has been effective when used in the treatment of certain dermatophytoses (e.g., tinea capitis, tinea corporis, tinea cruris,tinea pedis) caused by Epidermophyton, Microsporum, or Trichophyton. Oral fluconazole also has been effective when used for the treatment of pityriasis (tinea) versicolor and for the treatment of onychomycosis.
Oral fluconazole (3-6 mg/kg daily for 2-6 weeks) has been effective for the treatment of tinea capitis in children 1.5-16 years of age, and has resulted in a clinical and mycologic cure in about 88-90% of patients. For the treatment of tinea corporis, tinea cruris, or tinea pedis in adults, oral fluconazole has been effective when given in a once-weekly regimen (150 mg once weekly for 2-6 weeks), and there is evidence that this once-weekly regimen is as effective as a once-daily regimen of the drug (50 mg once daily) for the treatment of these infections. Results of a randomized study indicate that the eradication rate at the end of treatment in patients with tinea corporis or tinea cruris is 82-88% in those receiving the once-weekly regimen or 94-100% in those receiving the once-daily regimen; at 1-month follow-up, the overall eradication rates were 91-100 or 91-94%, respectively. Although the optimum dosage regimen of oral fluconazole for the treatment of onychomycosis has not been identified, a once-weekly oral fluconazole regimen (150-450 mg once weekly for 3-12 months) has been effective for the treatment of onychomycosis of the toenail in a limited number of adults. However, additional study is needed and there is some evidence that fluconazole may be less effective than oral itraconazole or oral terbinafine for the treatment of onychomycosis.
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).
Prevention of Fungal Infections in HIV-infected Individuals
Fluconazole has been used in HIV-infected individuals for primary prophylaxis against serious fungal infections (e.g., cryptococcosis) and for long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of certain fungal infections (e.g., coccidioidomycosis, cryptococcosis, mucocutaneous candidiasis).
The Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (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 (oropharyngeal, esophageal, vaginal) may benefit from long-term suppressive or maintenance therapy.
Because of concerns regarding use of oral azole antifungal agent during pregnancy, fluconazole 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 fluconazole prophylaxis and elects to continue the pregnancy, prophylaxis 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
Coccidioidomycosis
The USPHS/IDSA states that routine primary prophylaxis against coccidioidomycosis in HIV-infected patients living in coccidioidomycosis-endemic areas is not recommended. Some clinicians suggest that primary prophylaxis should be considered for HIV-infected individuals who have positive CF serologic results without active disease, but that it is unclear whether primary prophylaxis would be useful for HIV-infected individuals living in areas endemic for coccidioidomycosis. Active coccidioidomycosis has developed in HIV-infected individuals who were receiving azole therapy for other conditions. Routine skin testing with coccidioidin in HIV-infected individuals who live in areas endemic for coccidioidomycosis is not predictive of disease and generally is not recommended. Within an endemic area, a positive serologic test might indicate an increased risk for active infection; however, routine serologic testing does not appear useful and is not recommended.
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 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, and concerns regarding the possibility of drug interactions, potential for development of resistance, and cost. 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 primary 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 itraconazole (given as oral 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 CD4+ 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 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).
The agent of first choice for primary prophylaxis against histoplasmosis in HIV-infected adults, adolescents, or pediatric patients is oral itraconazole (given as capsules); the USPHS/IDSA makes no recommendation regarding an alternative to itraconazole. There is some evidence that oral fluconazole may be ineffective for preventing first episodes of histoplasmosis.
Mucocutaneous Candidiasis
The USPHS/IDSA states that primary prophylaxis to prevent first episodes of mucocutaneous candidiasis (esophageal, oropharyngeal, vaginal) 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.
Prevention of Recurrence
Coccidioidomycosis
The USPHS/IDSA recommends that HIV-infected individuals who have completed initial therapy for documented coccidioidomycosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse. The USPHS/IDSA recommends oral fluconazole as the drug of choice and IV amphotericin B and oral itraconazole (given as capsules) as alternatives. Long-term suppressive therapy for prophylaxis against recurrence or relapse of coccidioidomycosis in HIV-infected adults, adolescents, infants, and children generally is continued for life. Although HIV-infected individuals may be at low risk for recurrence of systemic fungal infections if their CD4+ T-cell count increases to greater than 100/mm3 while receiving potent combination antiretroviral therapy, the USPHS/IDSA states that data are insufficient to date to warrant a recommendation regarding discontinuance of prophylaxis against coccidioidomycosis in these individuals.
Cryptococcosis
The USPHS/IDSA recommends that HIV-infected individuals who have completed initial therapy for documented cryptococcosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse, unless immune recovery has occurred as a result of potent combination antiretroviral therapy. The USPHS/IDSA recommend oral fluconazole as the drug of choice and IV amphotericin B and 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 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 combination 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 therapy in individuals meeting these criteria. The USPHS/IDSA notes that recurrences could occur in individuals discontinuing suppressive therapy and states that suppressive therapy should be restarted if the CD4+ T-cell count decreases to less than 100-200/mm3. The safety of discontinuing suppressive therapy in HIV-infected infants and children has not been studied, and children should receive lifelong suppressive therapy after an episode of cryptococcosis.
Histoplasmosis
For long-term suppressive therapy in HIV-infected patients with documented histoplasmosis that has been adequately treated, the USPHS/IDSA states that oral itraconazole (given as capsules) is the drug of choice and IV amphotericin B is an alternative.
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 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 prophylaxis against recurrent oropharyngeal or vulvovaginal candidiasis in HIV-infected patients for the same reasons they do not recommend routine primary prophylaxis against candidiasis, the USPHS/IDSA states that suppressive therapy may be considered for HIV-infected individuals who have frequent or severe recurrences of these candidal 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 therapy as prophylaxis 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 (given as the oral solution) as an alternative.
Long-term suppressive therapy for prophylaxis against recurrence or relapse of fungal infections in HIV-infected patients generally is continued for life. In some HIV-infected patients who had been receiving oral fluconazole for prevention of recurrence of oropharyngeal candidiasis for a median duration of 18 months (range: 4-98 months) and were receiving potent combination antiretroviral agent therapy (about 50% had plasma HIV-1 RNA levels lower than the limits of detection), discontinuance of oral fluconazole suppressive therapy resulted in a recurrence of oropharyngeal candidiasis in only 10% of patients within 6-11 months. Although HIV-infected patients receiving suppressive antifungal prophylaxis may be at low risk for recurrence of fungal infections 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.
Prevention of Fungal Infections in Transplant Patients and Patients with Cancer
Fluconazole is used prophylactically to reduce the incidence of candidiasis in patients undergoing bone marrow transplantation (BMT) who are receiving chemotherapy or radiation therapy.The drug also has been used for prophylaxis of fungal infections in patients undergoing liver transplantation and in cancer patients considered at risk for neutropenia and fungal infections. There is some evidence that fluconazole prophylaxis in transplant and cancer patients can reduce the frequency of oropharyngeal and/or systemic candidiasis during the period prior to neutrophil recovery. In addition, fluconazole prophylaxis may reduce the need for empiric antifungal agent therapy in such patients. Efficacy of oral fluconazole (400 mg once daily) for prophylaxis against fungal infections in neutropenic patients has been evaluated in a randomized, placebo-controlled study involving 274 cancer patients 18-80 years of age receiving cytotoxic chemotherapy or conditioning therapy for BMT. While the percentage of patients not requiring empiric therapy with IV amphotericin B therapy was similar in both groups (57% of those receiving fluconazole and 50% of those receiving placebo required no such therapy), complete success without fungal colonization was achieved in 37% of those receiving fluconazole and 20% of those receiving placebo. In addition, there was a lower incidence of superficial fungal infections in those receiving fluconazole (7%) than in those receiving placebo (18%), and only 3% of those receiving fluconazole developed definite invasive fungal infections compared with 17% of those receiving placebo. While fluconazole prophylaxis did not affect the overall mortality rate, intent-to-treat analysis indicates that the number of deaths attributable to definite invasive fungal infection was lower in the fluconazole group (1 of 15) than in the placebo group (6 of 15).
Use of primary antifungal prophylaxis in cancer patients undergoing myelosuppressive therapy or patients undergoing 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. Retrospective studies have shown an increased risk of colonization with Candida krusei in BMT recipients and in neutropenic patients who received fluconazole prophylaxis; in one study, about 41% of patients receiving fluconazole had colonization with C. krusei compared with 17% of those not receiving fluconazole. Therefore, most clinicians generally discourage primary prophylactic antifungal therapy, except in certain carefully selected high-risk patients in whom potential benefits are expected to justify possible risks. Many experts, however, state that controlled, randomized studies should continue to evaluate the use of fluconazole for prevention of fungal infections in cancer patients and in BMT recipients.
Administration
HIGH DOSES
Doses higher than those recommended by licensed product information for fluconazole have been tried in patients with life-threatening infections caused by Candida spp., Cryptococcus neoformans, and Coccidioides immitis.
Dose finding studies have found daily doses of 800 to 1000 mg of fluconazole to be effective and well tolerated. In a study of 11 HIV-infected patients who received fluconazole 800 to 1000 mg daily intravenously for 3 weeks then orally until the CSF culture became negative, 6 patients had responded at 10 weeks and another 2 improved clinically. Daily doses of up to 800 mg have been used in blastomycosis and coccidioidomycosis, and doses of 10 mg/kg daily have been tried in disseminated candidiasis.
INTERMITTENT DOSES
Concern has been expressed about the increasingly widespread use of fluconazole and, in particular, about the impact of continuous fluconazole therapy in immunocompromised patients on the development of resistance (see under Antimicrobial Action, above). Nevertheless, fluconazole remains popular for primary and secondary prophylaxis. Some investigators have suggested the use of intermittent doses’ although this could further increase the risk of infections with resistant organisms. Once-weekly treatment with fluconazole has been tried in onychomycosis and tinea capitis.
Administration in renal impairment
Patients with renal impairment may require dosage reduction. Normal loading or initial doses of fluconazole should be given on the first day of treatment and subsequent doses should be adjusted according to creatinine clearance (CC):
- CC more than 50 mL/minute: 100% of the standard recommended dose
- CC less than 50 mL/minute and not receiving dialysis: 50% of the standard recommended dose
- patients on regular haemodialysis: 100% of the standard recommended dose after each dialysis session No dosage adjustment is needed in patients with renal impairment given single-dose therapy.
Leishmaniasis
Fluconazole has been tried in the treatment of cutaneous leishmaniasis caused by Leishmania major. In a randomised, double-blind, placebo-controlled study, 80 patients received a six-week course of oral fluconazole 200 mg daily, of whom 63 had complete healing of lesions after 3 months, compared with 22 of 65 patients who received placebo. However, others have reported a response rate not significantly different from placebo.
Preparations
International Brand Drug Names
The information about drugs around the world. Many drugs are marketed under different names in different countries.
Fluconazole: Dosage and Administration
Administration
Fluconazole is administered orally or by IV infusion. Since absorption of fluconazole from the GI tract is rapid and almost complete, IV therapy with the drug generally is reserved for patients who do not tolerate or are unable to take the drug orally.
Oral Administration
Fluconazole may be given orally without regard to meals. Fluconazole powder for oral suspension should be reconstituted at the time of dispensing by adding 24 mL of distilled or purified water to the container labeled as containing 0.35 or 1.4 g of the drug to provide a suspension containing 50 or 200 mg/5 mL, respectively. The bottle should be shaken vigorously to suspend the powder; in addition, the suspension should be shaken well just prior to administration.
IV Administration
IV infusions of fluconazole should be administered once daily at a rate not exceeding 200 mg/hour. Fluconazole injections for IV infusion should be inspected visually for discoloration and particulate matter prior to administration whenever solution and container permit. The injection for IV infusion should be discarded if the solution is cloudy or precipitated or if the seal is not intact. Viaflex® Plus containers of fluconazole should be checked for minute leaks by firmly squeezing the bag. The injection should be discarded if the container seal is not intact or leaks are found or if the solution is cloudy or contains a precipitate. Additives should not be introduced into the plastic injection container. The injection in plastic containers should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration from the secondary container is complete.
Dosage
Oral and IV dosage of fluconazole are identical. Dosage of the drug should be based on the type and severity of the infection, identity of the causative organism, and the patient’s renal function and response to therapy. Fluconazole therapy should be continued until clinical parameters and/or laboratory tests indicate that active fungal infection has subsided; an inadequate period of treatment may lead to recurrence of active infection. Chronic maintenance or suppressive therapy with fluconazole usually is necessary to prevent relapse in patients with acquired immunodeficiency syndrome (AIDS) and cryptococcal meningitis or recurrent oropharyngeal candidiasis.
Adult Dosage
Oropharyngeal and Esophageal Candidiasis
For the treatment of oropharyngeal or esophageal candidiasis, the usual adult dosage of fluconazole is 200 mg given as a single dose on the first day of therapy, followed by 100- or 200-mg doses given once daily. Dosages up to 400 mg given once daily may be used depending on the patient’s response. Although clinical evidence of oropharyngeal candidiasis generally resolves within several days following initiation of fluconazole therapy, the manufacturer and some clinicians recommend that the drug be continued for at least 2 weeks to decrease the likelihood of relapse.
However, other clinicians question the need for such prolonged therapy in patients with this infection. Patients with esophageal candidiasis should receive fluconazole therapy for a minimum of 3 weeks and for at least 2 weeks after symptoms have resolved. Optimum dosage for maintenance therapy in patients with oropharyngeal candidiasis has not been established. Oral dosages of 50-100 mg once daily generally have been used effectively for maintenance therapy in these patients; dosages up to 200 mg once daily occasionally have been used.
Vulvovaginal Candidiasis
For the treatment of uncomplicated vulvovaginal candidiasis in nonpregnant women, the usual dosage of oral fluconazole is a single (1 day only) 150-mg oral dose. For the treatment of recurrent vulvovaginal candidiasis in nonpregnant women, two 150-mg doses of oral fluconazole should be given 3 days apart to achieve mycologic remission and then a maintenance regimen of 100-150 mg once weekly should be given for 6 months to prevent recurrence. A 2-dose regimen of oral fluconazole (two 150-mg doses given 3 days apart) also is recommended for the treatment of severe vulvovaginal candidiasis in nonpregnant women.
Other Candidal Infections
For the treatment of systemic candidiasis, the usual adult dosage of fluconazole is 400 mg given as a single dose on the first day of therapy, followed by 200-mg doses given once daily. In a limited number of patients with candidal urinary tract infections and peritonitis, dosages of 50-200 mg daily have been used. Optimum dosage and duration of therapy in patients with candidemia, disseminated candidiasis, and pneumonia have not been established; however, a limited number of such patients have received fluconazole dosages up to 400 mg daily. Some clinicians have recommended that patients with invasive candidiasis should receive fluconazole in a dosage of 400-800 mg daily. Therapy should be continued for a minimum of 4 weeks and for at least 2 weeks after symptoms have resolved.
Cryptococcal Infections
For the treatment of cryptococcal meningitis, the usual adult dosage of fluconazole is 400 mg given as a single dose on the first day of therapy, followed by 200- to 400-mg doses given once daily. Some evidence suggests that the 400-mg dosage is more effective than lower dosages in the treatment of this infection. Higher dosage of fluconazole (i.e., 800-1000 mg daily) has been used in some patients with human immunodeficiency virus (HIV) infection for the treatment of cryptococcal meningitis. For initial therapy of cryptococcal meningitis, fluconazole usually is continued for 10-12 weeks after the CSF is sterile.
Coccidioidomycosis
For the treatment of coccidioidal meningitis in adults, fluconazole dosages of 200-800 mg once daily have been recommended. For the treatment of coccidioidal meningitis in patients with AIDS, fluconazole dosages of 400-800 mg daily are recommended.Concomitant intracisternal, intraventricular, or intrathecal amphotericin B therapy has been used in some patients.
Blastomycosis or Histoplasmosis
If fluconazole is used for the treatment of blastomycosis or histoplasmosis, a dosage of 400-800 mg daily is recommended.
Prevention of Fungal Infections in HIV-infected Individuals
For primary prophylaxis against cryptococcosis in adults or adolescents with HIV infection and absolute helper/inducer (CD4+, T4+) T-cell counts less than 50/mm3, the Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) recommends a dosage of oral fluconazole of 100-200 mg once daily.
While there is some evidence that oral fluconazole given in a dosage of 400 mg once weekly may be effective for primary prophylaxis against fungal infections in HIV-infected individuals, this regimen is not included in current USPHS/IDSA guidelines, and further study is needed to evaluate efficacy of regimens other than daily administration for primary prophylaxis.
For long-term suppressive or maintenance therapy (secondary prophylaxis) of coccidioidomycosis in HIV-infected adults or adolescents who have had documented, adequately treated infections, a fluconazole dosage of 400 mg once daily is recommended by the USPHS/IDSA. For suppressive or maintenance therapy to prevent recurrence or relapse of cryptococcosis in HIV-infected adults or adolescents who have had documented, adequately treated infections, the usual dosage of oral fluconazole is 200 mg once daily.
Some clinicians recommend that, for long-term suppressive therapy against cryptococcosis, oral fluconazole be given in a dosage of 400 mg daily for the first 4 weeks followed by 200 mg daily. If oral fluconazole is used for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of mucocutaneous candidiasis (oropharyngeal, vaginal, esophageal) in HIV-infected adults or adolescents who have had frequent or severe episodes of these candidal infections, the USPHS/IDSA recommends a dosage of 100-200 mg once daily.
While fluconazole has been given in a dosage of 200 mg once weekly for long-term suppressive therapy in HIV-infected women with a history of oropharyngeal or vaginal candidiasis, this regimen is not included in current USPHS/IDSA guidelines, and there are concerns that such a regimen would promote emergence of fluconazole-resistant strains of Candida. Long-term suppressive or maintenance therapy for prophylaxis against recurrence or relapse of fungal infections in HIV-infected patients generally is continued for life. However, the USPHS/IDSA states that it may be reasonable to discontinue suppressive or maintenance therapy of cryptococcosis in certain adults and adolescents who have immune recovery as the result of potent combination antiretroviral therapy.
Prevention of Fungal Infections in Transplant Patients and Patients with Cancer
For the prevention of candidiasis in bone marrow transplant recipients, the recommended dosage of fluconazole is 400 mg once daily. In patients in whom severe granulocytopenia (neutrophil count less than 500/mm3) is anticipated, fluconazole therapy should be initiated several days before expected onset of neutropenia and should be continued for 7 days after the neutrophil count exceeds 1000/mm3.
Pediatric Dosage
The usual dosage of fluconazole in pediatric patients ranges from 3-12 mg/kg once daily; doses exceeding 600 mg daily are not recommended. The manufacturer states that a dosage of 3, 6, or 12 mg/kg daily in pediatric patients is equivalent to a dosage of 100, 200, or 400 mg daily, respectively, in adults. Some older children may have clearances similar to those of adults.
For the treatment of meningitis or septicemia caused by susceptible Candida, neonates and infants 3 months of age or younger have received fluconazole in a dosage of 5-6 mg/kg once daily given orally or by IV infusion over 1 hour. In some neonates and infants with septicemia, an initial loading dose of 10 mg/kg was administered followed by 5 mg/kg once daily. Based on data available to date regarding the pharmacokinetics of fluconazole in premature neonates, the manufacturer recommends that neonates 2 weeks of age or younger receive the same daily dose as older children but the dose should be administered once every 72 hours.
Oropharyngeal and Esophageal Candidiasis
For the treatment of oropharyngeal or esophageal candidiasis, the manufacturer recommends that pediatric patients receive 6 mg/kg of fluconazole on the first day followed by 3 mg/kg once daily. Dosage for esophageal candidiasis may be increased up to 12 mg/kg daily if necessary, based on the condition of the patient and the response to the drug. Treatment for oropharyngeal candidiasis should be continued for a minimum of 2 weeks to decrease the likelihood of relapse and treatment of esophageal candidiasis should be continued for a minimum of 3 weeks and for at least 2 weeks after symptoms have resolved.
Other Fungal Infections
Fluconazole has been given in a dosage of 6-12 mg/kg daily for the treatment of systemic candidal infections in pediatric patients. The manufacturer recommends that cryptococcal meningitis in pediatric patients be treated with an initial 12-mg/kg dose on the first day followed by 6 mg/kg once daily. Dosage may be increased to 12 mg/kg daily if necessary based on the condition of the patient and the response to the drug Fluconazole should be continued for 10-12 weeks after the CSF becomes culture negative.
Prevention of Fungal Infections in HIV-infected Individuals
For primary prophylaxis against cryptococcosis in HIV-infected infants and children with severe immunosuppression, the recommended dosage of oral fluconazole is 3-6 mg/kg once daily. If oral fluconazole is used for long-term suppressive or maintenance therapy to prevent recurrence or relapse of cryptococcosis or mucocutaneous candidiasis (oropharyngeal, esophageal) in HIV-infected infants and children, the recommended dosage is 3-6 mg/kg once daily. A dosage of 6 mg/kg once daily is recommended for prophylaxis against recurrence or relapse of coccidioidomycosis in these pediatric patients.
Dosage in Renal Impairment
In patients with impaired renal function, dosage of fluconazole must be modified in response to the degree of impairment and should be based on the patient’s measured or estimated creatinine clearance.
The patient’s creatinine clearance (Ccr) can be estimated by using the following formula: The manufacturer recommends that adults with impaired renal function receive an initial loading dose of 50-400 mg of fluconazole (based on the type of infection being treated), then patients with creatinine clearances exceeding 50 mL/minute should receive 100% of the usual daily dose and those with creatinine clearances of 50 mL/minute or less should receive 50% of the usual daily dose. Patients who are undergoing regular dialysis should receive 100% of the usual daily dose after each dialysis period.
These dosage recommendations are based on the pharmacokinetics of the drug following multiple doses; further dosage adjustments may be necessary depending on the condition of the patient. The manufacturer states that modification of the single oral dose of fluconazole for the treatment of vulvovaginal candidiasis is unnecessary in patients with impaired renal function.
The manufacturer states that the pharmacokinetics of fluconazole have not been studied in children with impaired renal function; recommendations for dosage reduction in such children should parallel those recommended for adults.
Therapeutic Use of Fluconazole 50, 100, 150, 200 mg Tablets (Diflucan)
Fluconazole can be used to treat mucosal and cutaneous forms of candidosis. It is also effective in various forms of dermatophytosis and pityriasis versicolor.
It is a promising drug for treatment of deep forms of candidosis in patients without neutropenia, but should not be used as first-line treatment in neutropenic patients unless there are particular reasons for favouring it against established management. Fluconazole has proved to be a useful prophylactic treatment against candidosis in neutropenic patients. However, it is ineffective in aspergillosis and mucormycosis.
Fluconazole is a useful drug in acute cryptococcal meningitis, but should not be used as first-line treatment in patients with AIDS unless there are particular reasons for withholding amphotericin B. However, it is more effective and better tolerated than amphotericin B as maintenance treatment to prevent relapse of cryptococcosis in patients with AIDS.
Fluconazole is now the drug of choice for patients with coccidioidal meningitis. However, it must be continued for life to prevent relapse.
Fluconazole 50, 100, 150, 200 mg Tablets (Diflucan): Mode of Administration
As absorption following oral administration is good, this is the preferred method of administration. If the patient cannot take the drug by mouth, the intravenous solution can be used. This should be infused at a rate of 5-10 ml/min.
Vaginal candidosis can be treated with a single 150-mg oral dose of fluconazole. Oropharyngeal candidosis should be treated with 50-200 mg/day for 1-2 weeks. Oesophageal and mucocutaneous forms of candidosis and lower urinary tract candidosis require 100-200 mg/day for 2-4 weeks.
The recommended dose for patients with cryptococcosis or deep forms of candidosis is 400 mg/day. However, some clinicians have used higher dosages in life-threatening infections. The duration of treatment will differ from patient to patient, depending upon the nature and extent of the infection and the underlying illness. At least 6-8 weeks is usually required for successful treatment of cryptococcosis in patients without AIDS. The recommended dose for children is 1-2 mg/kg for superficial forms of candidosis and 5 mg/kg for cryptococcosis or deep forms of candidosis.
Long-term maintenance treatment with fluconazole to prevent relapse in patients with AIDS with cryptococcosis should be administered at a dosage of 200 mg/day. To prevent candidosis in neutropenic patients, the dose should be 100-400 mg/day. Patients at high risk of developing a deep-seated infection should receive 400 mg/day and this should be commenced several days before the anticipated onset of neutropenia and continued for 1 week after the neutrophil count recovers to 1 x 109/1.
Patients with renal impairment should be given the normal dose for the first 48 h of treatment. Thereafter, in persons with a creatinine clearance of 21-40 ml/min, the dosage interval should be doubled to 48 h or the dose halved. Persons with a clearance of 10-20 ml/min require a 72-h interval between doses.
Patients receiving regular haemodialysis require the usual dose after each dialysis session.