Echinocandins Amphotericin

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... 

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.). 

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). 

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)... 

Caspofungin is the first of a new class termed the echinocandins. It was approved in the US and in Europe in 2001. It shows activity against infections with Aspergillus and Candida, and works by inhibiting p(, 3)-D-Glucan of the fungal cell wall. Compared to amphotericin B, caspofungin seems to have a relatively low incidence of side-effects. 

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). 

Caspofungin, the first approved drug from a new class of antifungals, the echinocandins, has been demonstrated in three clinical trials to produce comparable clinical response to fluconazole and amphotericin B for esophageal candidiasis. The incidence of adverse events of caspo-... 

Pneumocandins and echinocandins compose a new class of cyclic lipopeptide antifungal compounds [38]. Echinocandin B, 9, inhibits 1,3-P-D-glucan synthase in C. albicans, a critical enzyme in the production of cell well components. Two semi-synthetic derivatives have entered clinical trials. Merck s L-724,872 has been well tolerated in phase I clinical studies and is currently in phase II trials in patients with HIV and candidiasis. However, it is not absorbed orally and must be delivered intravenously. Lilly s LY303366 is also currently in clinical trials with people with HIV and candidiasis. These compounds appear to have fungicidal activity yet are not as toxic as Amphotericin B [21,29, 30]. 

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