More echinocandins better therapies?

B. de Pauw

Author address: 

University Medical Center St Radboud, Nijmegen, The Netherlands

Abstract: 

During the past two decades, Candida has evolved into an key pathogen in the category of nosocomial infections. Neutropenic patients and recipients of organ transplants are at high risk followed by patients admitted to intensive care units and neonates. Multiple logistic regression analysis learned that repeated bowel surgery, longterm use of central venous catheters, Candida colonization, use of broadspectrum antibiotics, and hemodialysis constitute independent predisposing factors. In patients with hematologic malignancies the use of antifungal prophylaxis, particularly with absorbable drugs, was linked to a higher incidence of non-albicans candidemia. This change in the pattern has been attributed to the prophylactic use of fluconazole. The attributable mortality from candidemia ranges from about 40% in patients with uncomplicated candidemia to over 90% for those who suffer from an acute disseminated disease. In patients with malignancies aspergillosis has even superseded candidiasis as the most prominent invasive fungal infection. Reports on the overall incidence of acute aspergillosis are confusing. The figures vary between 0% and 25% depending on the study population. Amphotericin B has been the drug of choice for all invasive fungal infections in severely ill patients for more than 30 years. Clinical failure due to development of resistance is rare but the drug has a very narrow therapeutic index. Lipid formulations offer a much safer alternative but there are limits such as a compromised kidney function and increased cyclosporine levels in transplant recipients. The use of azoles is limited by their interactions with cytochrome P450 which prohibits their uncomplicated exploit in patients who require other drugs that depend on the same metabolic pathway. Echinocandins, of which caspofungin is the best studied representative, constitute a totally new class of antifungal agents. Whilst polyenes and azoles interact with ergosterol in the cell membrane, echinocandins inhibit noncompetitively the synthesis of 1,3-b-D-glucan. This 1,3-b-Dglucan is an essential component of chitin in the cell wall, a structure that human cells do not share. Interference with glucan synthesis ultimately leads to lysis of the fungal cell. This mechanism of action makes that cross-resistance with azoles and polyenes is not expected and holds promise for their use against resistant fungi both as single agents and in combinations. Candins exhibit fungicidal activity against Candida species, including fluconazole-resistant species, and showed activity against Aspergillus species with a notable lack of activity against Cryptococcus neoformans and Zygomycetes. The safety profile of caspofungin proved excellent. There is no evidence of histamine release related to the administration of caspofungin. The incidence of caspofungin-related clinical and laboratory adverse event was similar to fluconazole. Mild elevations in transaminases have been noted when caspofungin had been given concurrently with cyclosporin A. It appears feasible to co-administer caspofungin with drugs like mofetil, tacrolimus, itraconazole and amphotericin B without added toxicity.
2005

abstract No: 

S13.2

Full conference title: 

2nd Trends in Medical Mycology
    • TIMM 2nd (2010)