Itraconazole resistance

The goal of treating recurrent WC is control of the infection, rather than cure. First, any acute episodes are treated, followed by maintenance therapy. For the treatment of acute episodes, intravaginal or oral azoles can be utilized. Although acute episodes of recurrent WC will respond to azole therapy, some patients may require prolonged therapy in order to achieve remission. To achieve remission, a second dose of oral fluconazole 150 mg repeated 3 days after the first dose or 14 days of topical azole therapy can be used. The practitioner should consider that non-albicans infections are more common in recurrent WC therefore fluconazole and itraconazole resistance may make these agents less effective. 

There have been few controlled studies that assess the effectiveness of antifungals. Doubling of the fluconazole dosage to 400 or 800 mg/day may be effective in some patients with infection caused by Candida of intermediate resistance, although the response may be only transient. Fluconazole oral suspension may be beneficial in some patients because of increased salivary concentrations obtained when the suspension is taken with the swish-and-swaUow technique. Itraconazole oral suspension is effective in 55% to 70% of patients however, the benefit is short-lived if chronic suppressive therapy is not maintained, and there is a high likelihood of the development of itraconazole resistance. Amphotericin B oral suspension is limited primarily to use in azole-refractory patients It has broad spectrum... 

Twenty percent of HIV-infected patients develop fluconazole-resistant Candida albicans isolates after repeated exposure to fluconazole.33 To treat fluconazole-resistant oropharyngeal candidiasis, daily itraconazole for 2 to 4 weeks may be used. Oral itraconazole solution exhibits a mycological cure rate of 88% and a clinical cure rate of 97% in immunocompromised patients.34 Fluconazole-resistant esophageal candidiasis should be treated with intravenous amphotericin B or caspofungin. 

Disseminated histoplasmosis Acute (Infantile) Subacute Progressive histoplasmosis (immunocompetent patients and immunosuppressed patients without AIDS) 0.02-0.05 Disseminated histoplasmosis Untreated mortality 83% to 93% relapse 5% to 23% in non-AIDS patients therapy is recommended tor all patients Nonimmunosuppressedpatients Ketoconazole 400 mj day orally x 6-12 months or amphotericin B 35 mg/kg IV Immunosuppressed patients (non-AIDS) or endocarditis or CNS disease Amphotericin B >35 mg/kg x 3 months followed by fluconazole or itraconazole 200 mg orally twice daily x 12 months Life-threatening disease Amphotericin B 0.7-1 mg/kg/day IV for a total dosage of 35 mj kg over 2-4 months once the patient is afebrile, able to take oral medications, and no longer requires blood pressure or ventilatory support therapy can be changed to itraconazole 200 mg orally twice daily for 6-18 months Non-life-threatening disease Itraconazole 200-400 mg orally daily for 6-18 months fluconazole therapy 400-800 mg daily should be reserved for patients intolerant to itraconazole, and the development of resistance can lead to relapses... 

Cross-resistance - Fungal isolates exhibiting reduced susceptibility to fluconazole or itraconazole also may show reduced susceptibility to voriconazole, suggesting that cross-resistance can occur among these azoles. 

The spectrum of action of azole medications is broad, including many Candida species, C neofbrmans, the endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), the dermatophytes, and, in the case of itraconazole and voriconazole, even aspergillus infections. They are also useful in the treatment of intrinsically amphotericin-resistant organisms such as P boydii. 

Voriconazole is similar to itraconazole in its spectrum of action, having excellent activity against Candida sp (including fluconazole-resistant species such as C krusei) and the dimorphic fungi. Voriconazole is less toxic than amphotericin and is the treatment of choice for invasive aspergillosis. 

The spectrum of activity of flucytosine is restricted to Cryptococcus neoformans, some Candida species, and the dematiaceous molds that cause chromoblastomycosis. Flucytosine is not used as a single agent because of its demonstrated synergy with other agents and to avoid the development of secondary resistance. Clinical use at present is confined to combination therapy, either with amphotericin B for cryptococcal meningitis or with itraconazole for chromoblastomycosis. 

Management Prolonged and repeated systemic therapy with fluconazole, itraconazole or ketoconazole - always with the risk of development of resistance - is crucial, treatment of an underlying endocrine disorder has no effect on candidiasis. Genetic counseling is indicated. 

Flucytosine has been successfully used in combination with ketoconazole, fluconazole, and itraconazole. Flucytosine and ketoconazole were synergistic in about 40% of yeast isolates resistant to flucytosine alone. The synergistic action of flucytosine with the triazoles against Candida species was seen both in vitro and in vivo (3-6). 

The activity of itraconazole against black fungi can be augmented by combining it with flucytosine the combination has prevented the development of flucytosine resistance (89). 

Koks C, Meenhorst P, Bult A, and Beijnen J. Itraconazole Solution Summary of Pharmacokinetic Features and Review of Activity in the Treatment of Fluconazole-resistant Oral Candidosis in HIV-infected Persons. Pharmacol Res 2002 46 195-201. 

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