Echinocandins Azoles

Treatment of candidiasis is presented in Table 38-4. Amphotericin B may be switched to fluconazole (IV or oral) for completion of therapy. Azoles and deoxycholate amphotericin B are similarly effective however, fewer adverse effects are observed with azoles. Echinocandins are at least as effective as amphotericin B or fluconazole in nonneutropenic adult patients with candidemia. 

Two to three weeks of fluconazole or itraconazole solution are highly effective and demonstrate similar clinical response rates.32 Doses of 100 to 200 mg are effective in immunocompetent patients but doses up to 400 mg are recommended for immunocompromised patients. Due to variable absorption, ketoconazole and itraconazole capsules should be considered second-line therapy. In severe cases, oral azoles may prove ineffective, warranting the use of amphotericin B for 10 days. Although echinocandins and voriconazole are effective in treatment of esophageal candidiasis, experience remains limited. 

Preclinical studies suggest mold-active azoles plus echinocandins have enhanced activity against Aspergillus A. terreus should be considered resistant to amphotericin B Activity of amphotericin B and voriconazole is decreased versus Aspergillus species higher doses or combination therapy may be indicated in more refractory cases... 

Although more invasive, esophageal candidiasis does not typically evolve into a life-threatening infection. However, topical therapy is ineffective. Azoles (fluconazole, itraconazole solution, or voriconazole), echinocandins, or intravenous amphotericin B (in cases of unresponsive infections) are effective treatment options. Parenteral therapy should be used in patients who are unable to take oral medications.20... 

Select azole antifungals (e.g., itraconazole, voriconazole, and posaconazole) and the echinocandins are available for IA treatment. For initial therapy of IA, voriconazole had higher response and survival rates than c-AMB.102 An advantage of voriconazole is its 96% oral bioavailability, making use of this oral drug an attractive and less expensive alternative. The dose of voriconazole was 6 mg/kg IV every 12 hours for two doses, followed by 4 mg/kg IV every 12 hours for at least 7 days, at which time oral voriconazole 200 mg every 12 hours could be administered. Common toxicities reported with voriconazole include infusion-related, transient visual disturbances (i.e., blurred vision, altered color perception, photophobia, and visual hallucinations), skin reactions (i.e., rash, pruritus, and photosensitivity), elevations in hepatic transaminases and alkaline phosphatase, nausea, and headache.102 In addition, voriconazole increases the serum concentrations of medications cleared by cytochrome P-450 2C9, 2C19, and 3A4 (e.g., cyclophosphamide and calcineurin inhibitors) concomitant voriconazole-sirolimus should be avoided.103... 

J. Como, W. Dismukes (1994). Oral azole drugs as antifungal therapy. New Engl. J. Med. 330 263. D. W. Denning (2003). Echinocandin antifungal drugs. Lancet 362 1142-1151. 

Pharmacotherapy of fungal disease has been revolutionized by the introduction of the relatively nontoxic oral azole drugs and the echinocandins. Combination therapy is being reconsidered, and new formulations of old agents are becoming available. Unfortunately, the appearance of azole-resistant organisms, as well as the rise in the number of patients at risk for mycotic infections, has created new challenges... 

Very few drug interactions occur with the echinocandins, compared with the azoles. This is because echinocandins are not acted on by the major liver enzymes. 

Resistance to other antifungal agents such as amphotericin B has been observed less frequently in clinical fungal isolates however, the molecular basis of this resistance is not currently well understood. To solve the problems associated with antifungal resistance a number of novel azole drugs (e.g. voriconazole) and novel classes of drug (e.g echinocandins) have been developed (see Chapter 12). 

Echinocandins inhibit formation of j3(l,3)D-glucans in the cell wall < /Candida and caspofungin is approved for clinical use. Susceptible fungi include Candida and Aspergillus species. Resistance can be conferred in C. albicans by mutation in one of the genes that encodes /3f l,3)D-glucan synthase. Azole-resistant isolates of C. albicans remain susceptible to echinocandins. 

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