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Fluconazole is a bis-triazole antifungal drug with novel pharmacokinetic properties (metabolic stability, relatively high water solubility) which contribute to its therapeutic activity. Clinical experience is limited to a relatively small number of mycoses and, as might be expected at this early stage of development, optimal dosage and duration of treatment for some serious mycoses is not yet established. Further study to evaluate higher dosages and to establish the efficacy of fluconazole relative to more established antifungal agents is required.
In patients with oropharyngeal or oesophageal candidiasis, fluconazole produces rapid relief and eradicates the yeast in 50 to 90% of patients. Relapse of oral infection is common in chronically immunocompromised patients regardless of the antifungal used, and adequate primary therapy plus long term prophylaxis appears necessary in patients with AIDS. A single oral dose of fluconazole was comparable to standard topical azole therapy in women with acute vaginal candidiasis.
Preliminary reports of success against deep-seated candidiasis are encouraging; moreover, experience in noncomparative clinical trials suggests that fluconazole 200 to 400mg once daily resolves infection in the majority of seriously ill patients. Clinical improvement has been reported in a few cases of pulmonary Aspergillus infection but the overall efficacy of conventional dosages of fluconazole in this mycosis has not been as impressive. Early experience in coccidioidosis, predominantly meningitis, suggests a beneficial clinical effect with oral fluconazole in this difficult to treat mycosis but relapse remains a problem.
Fluconazole is a promising treatment of cryptococcal meningitis. The rate of clinical resolution and eradication of Cryptococcus neoformans from cerebrospinal fluid has been similar between fluconazole and amphotericin B treatment groups in comparative trials. Comparative trials of maintenance therapy indicate a similar low rate of relapse among patients given oral fluconazole once daily and intravenous amphotericin B once weekly. However, these results are preliminary and further study is required.
Fluconazole has been well tolerated to date but wider clinical experience is needed, especially with regard to the rare occurrence of hepatotoxicity and exfoliative skin reactions.
The promising clinical response of patients with various forms of candidiasis or cryptococcosis — together with convenient administration regimens — recommends fluconazole as a useful addition to currently available systemic antifungal therapies, in particular for the treatment of mycoses in patients with AIDS.
Results of in vitro susceptibility tests do not accurately reflect the therapeutic efficacy of fluconazole. Relatively good activity against yeasts has been shown in specialised media (tissue culture agar and synthetic amino acid medium-fungal) but the MICs obtained in conventional media are generally many times greater for fluconazole than for ketoconazole. In contrast, fluconazole is the more potent azole in animal models of fungal infection. Studies in vivo have shown fluconazole to improve the survival of animals challenged with lethal inocula of Candida, Cryptococcus, Aspergillus, Blastomyces, Coccidioides, and Histoplasma. Fluconazole 40 to 120 mg/kg/day reduced the fungal burden of animals with systemic mycoses and lower dosages (25 to 10 mg/kg/day) cured 50 to 100% of animals with vaginal candidiasis or dermatophytoses.
The antifungal activity of azole derivatives relates to their inhibition of membrane sterol synthesis by fungal cytochrome P450 enzymes. While ketoconazole also inhibits mammalian cytochrome P450 enzymes, supratherapeutic concentrations of fluconazole have a minimal effect on mammalian enzymes and, thus, fluconazole appears to be free of adverse effects on steroid hormone production.
Fluconazole is very well absorbed after oral administration even in the presence of food, or antacid or H2-receptor antagonist pretreatment, and its bioavailability exceeds 90%. The peak plasma concentrations achieved after single oral doses of fluconazole 100mg and 400mg are 1.9 mg/L and 6.7 mg/L, respectively, in healthy volunteers. Continued oral administration of fluconazole for 6 to 10 days leads to an increase in peak plasma concentration of 2.5 times that achieved after a single dose.
Fluconazole is widely distributed and its apparent volume of distribution (0.8 L/kg) approximates that of total body water. Concentrations in cerebrospinal fluid, saliva, sputum and vaginal fluid approximate those attained in the plasma. In contrast to other azole antifungals which are highly bound, fluconazole is only 11% protein bound.
The primary route of elimination is via renal excretion with up to 80% of the drug recovered in urine unchanged. The elimination half-life is approximately 30 hours and is prolonged in patients with decreased renal function, necessitating dosage modification. Fluconazole is removed by haemo- and peritoneal dialysis.
The majority of clinical experience with fluconazole has been in patients with candidiasis or cryptococcosis. Fluconazole 50 to 100mg daily produced rapid resolution of the signs and symptoms of oropharyngeal candidiasis associated with AIDS or the treatment of malignancy. 88 to 100% of patients were clinically cured and cultures became negative in 50 to 90% of patients. Comparisons of fluconazole 50 to 100 mg/day with ketoconazole 200 to 400 mg/day and clotrimazole troches 50 mg/day found a similar rate of clinical remission and mycological eradication between these azole antifungals. Relapse was common in patients with AIDS regardless of the success of acute therapy. Whether this reflects regrowth of sequestered Candida or new infection is not clear but antifungal maintenance therapy has been advocated for these patients. In patients with chronic atrophic oral candidiasis, lesions outside the denture-bearing mucosa responded well but palatal lesions tended to relapse. Soaking the dentures nightly in chlorhexidine 0.2% solution significantly reduced the rate of recolonisation. In large multicentre studies of acute vaginal candidiasis, fluconazole 150mg as a single oral dose resolved the signs and symptoms of infection in ⩾ 80% of women evaluated 1 to 2 months post-treatment and was comparable to the efficacy of clotrimazole or econazole intravaginally for 3 and 6 days, respectively, and ketoconazole orally for 5 days.
Oesophageal candidiasis responded well to treatment with fluconazole 50 or 100mg daily. Typically the drug eradicated Candida from the oesophagus of evaluable patients and produced rapid resolution of pain and dysphagia. However, mycological cure did not improve oesophageal symptoms in patients with progressive systemic sclerosis in whom oesophageal dysmotility and antireflux medication predisposed to colonisation but not to invasive candidiasis. Preliminary results of a double-blind comparative trial suggest that fluconazole 100 to 200 mg/day produces mycological eradication rates equal to those of ketoconazole 200 to 400 mg/day and a greater degree of endoscopically confirmed healing.
Symptomatic urinary tract infection responded well to fluconazole, generally 50mg daily, but urinary tract candidiasis is an ill-defined entity and controlled clinical studies are needed to evaluate the role of fluconazole in its management.
Fluconazole 50mg daily was comparable to ketoconazole 200mg daily in a double-blind multicentre study of patients with various dermatophyte infections. Very few data are available on the efficacy of fluconazole in mycoses confined to keratinised tissue, including hair and nails, although therapeutic drug concentrations have been measured in skin and nail tissue.
In noncomparative premarketing clinical trials fluconazole 50 to 400mg daily was used to treat a small number of patients with deep-seated candidiasis, and satisfactory clinical response and mycological eradication was achieved in approximately 85 and 76% of patients, respectively. Moreover, fluconazole was used successfully in many patients unresponsive to or intolerant of more established antifungal treatment. Fluconazole 100 to 300 mg/day proved useful in the few patients treated for pulmonary candidiasis or candidaemia associated with haematological malignancy, but there are insufficient data to generalise about the efficacy of fluconazole in neutropenic patients. Fluconazole 50mg daily was comparable to oral polyene prophylaxis in preventing the development of oropharyngeal candidiasis in patients at high risk of developing neutropenia but further study is needed to determine if fluconazole prophylaxis confers any protection against invasive fungal infection.
Use of fluconazole has been particularly promising in patients with AIDS-related cryptococcal meningitis in whom conventional therapy with amphotericin B and flucytosine, while effective, is difficult to administer and carries considerable risk of toxicity. Success in individual patients and in noncomparative studies has prompted comparative studies between fluconazole and amphotericin B in patients with active cryptococcal meningitis. Preliminary analysis of ongoing trials found that fluconazole 200 to 400 mg/day cured or improved approximately 60% of patients treated to date and this response was similar to the success rate recorded for amphotericin B in all but 1 participating centre.
Fluconazole (generally 100 or 200 mg/day) has also been evaluated as maintenance therapy in patients with AIDS who had negative cerebrospinal fluid cultures after primary treatment. The median follow-up period varied between 10 weeks and 11 months, during which 7 clinical relapses occurred in 59 patients. A comparison between daily oral fluconazole (200mg) and weekly intravenous amphotericin B (1 mg/kg) is continuing.
Conventional dosages of fluconazole have been less impressive in pulmonary Aspergillus infection although experience is limited to small Japanese trials. Clinical improvement was achieved with fluconazole 50 or 100mg daily alone or in addition to intrathecal antifungals in patients with coccidioidal meningitis; however, the problem of relapse with this mycosis remains.
Fluconazole has generally been well tolerated. In clinical trials utilising dosages between 50 and 400mg daily, the overall incidence of adverse reactions was approximately 16%, with nausea, headache, skin rash, abdominal pain, vomiting and diarrhoea being reported most commonly. Only 1.5% of patients discontinued treatment due to adverse reactions and 1.3% discontinued due to laboratory abnormalities — most frequently liver function test abnormalities. Rarely, patients with AIDS have developed exfoliative skin reactions during treatment, but the role of fluconazole in this reaction is uncertain. Hepatotoxicity has also been reported rarely in patients with serious underlying disease receiving fluconazole in addition to other potentially hepatotoxic agents. The causal association of these reactions with fluconazole is uncertain but, because of their potential seriousness, patients who develop liver function abnormalities or skin rash during treatment should be monitored closely.
Dosage and Administration
The daily dosage of fluconazole is the same by oral or intravenous routes. The recommended dosage in patients with oropharyngeal or oesophageal candidiasis is 200mg on the first day followed by 100mg once daily for a minimum of 2 weeks in oropharyngeal infection and 3 weeks plus at least 2 weeks after symptoms resolve in oesophageal infection. A single oral dose of 150mg is recommended in women with acute vaginal candidiasis.
For the treatment of serious candidiasis or cryptococcal meningitis, the recommended dosage is 400mg on the first day followed by 200mg once daily. The dosage should be increased to 400mg if clinically indicated. The minimum recommended treatment interval for patients with deep-seated candidiasis is 4 weeks. Patients with cryptococcal meningitis should receive active treatment for 10 to 12 weeks after cultures of cerebrospinal fluid become negative; thereafter fluconazole 200mg once daily is recommended for suppression of relapse in patients with AIDS.
A small number of children greater than 3 years of age have been safely treated with 3 to 6 mg/kg/day.
The following dosage modification is recommended in patients with impaired renal function: full dosage if creatinine clearance exceeds 0.8 ml/sec (50 ml/min), half recommended dosage if creatinine clearance is 0.35 to 0.8 ml/sec (21 to 50 ml/min), and one-quarter recommended dosage if creatinine clearance is 0.18 to 0.35 ml/sec (11 to 20 ml/min). The full recommended dose should be given after each session of regularly scheduled haemodialysis. No change is necessary for single-dose treatment.
KeywordsFluconazole Candidiasis Ketoconazole Azole Cryptococcosis
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