Echinocandins

Echinocandins (i.e. caspofungin), semisynthetic lipo-peptides, inhibits the synthesis of (3-(l,3)-D-glucan, an... 

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. 

Zygomycetes are generally resistant to voriconazole and echinocandins and their presence should be suspected in any patient with progressive mold infection while receiving voriconazole and/or echinocandin therapy. 

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... 

Response to antifungal therapy in invasive candidiasis is often more rapid than for endemic fungal infections. Resolution of fever and sterilization of blood cultures are indications of response to antifungal therapy. Toxicity associated with antifungal therapy is similar in these patients as described earlier with the caveat that some toxicities maybe more pronounced in crit-ically-ill patients with invasive candidiasis. Nephrotoxicity and electrolyte disturbances, with amphotericin B in particular, are problematic and may not be avoidable even with lipid amphotericin B formulations. Fluconazole and echinocandins are generally safer options, and are generally well tolerated. Decisions to use one class of agents over the other is principally driven by concerns of non-albicans species, patient tolerability, or history of prior fluconazole exposure (risk factor for non-albicans species.). 

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... 

In patients who have failed initial therapy (i.e., salvage), liposomal amphotericin products, itraconazole, or the echinocandin caspofungin can be used. Itraconazole has a response rate of approximately 40%.100 Oral itraconazole exhibits erratic absorption the IV formulation is suspended in cyclodextrin, which is eliminated renally, and thus IV itraconazole should be avoided in patients with a creatinine clearance of less than 30 mL/minute (0.29 mL/s m2).103 Itraconazole also has negative inotropic cardiac effects and increases the serum concentrations of medications (e.g., cyclophosphamide, etopo-side, calcineurin inhibitors, and sirolimus). 

The echinocandins have a unique target for their antifungal activity—specifically, (5-1,3-glucan synthase, an enzyme that produces an important component of the fungal wall. Caspofungin is currently the only product of this class that is FDA approved it is indicated for treatment of IA refractory... 

There is an increasing amount of data regarding combination therapy with newly available triazoles, echinocandins, and polyenes in patients with fungal infections. Given the overall poor prognosis of IA in HCT recipients, many practitioners are treating patients with combination therapy known to be synergistic in vitro in order to maximize the chance of response. 

Synthesis of deuteriated and tritiated echinocandin B and anilinostearamide and the problem of HPLC isotope effects... 

During the reversed phase HPLC analysis of the tritiated echinocandin 77 it has been observed that the radioactivity of 77 has been detected prior to the UV absorbance of the... 

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. 

Candida albicans, C. tropicalis, C parapsilosis and resolution of signs and symptoms of infection Remove existing central venous catheters when feasible, plus Amphotericin B IV 0.6 mg/k day or Fluconazole IV/po 6 mg/kg/day or An echinocandin or Amphotericin B IV 0.7 mg/kg/day plus fluconazole IV/po 800 mg/day Patients intolerant or refractory to other therapf Amphotericin B lipid complex IV 5 m k day Liposomal amphotericin B IV 3-5 mg/kg/day Amphotericin B colloid dispersion IV 2-6 mg/k day (continued)... 

Echinocandin = caspofungin 70 mg loading dose, then 50 mg IV daily maintenance dose, or micafungin 100 mg daily, or anidulafungin 200 mg loading dose, then 100 mg daily maintenance dose. 

FR901379 - echinocandin-like lipopeptide with antifungal property... 

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