New Antifungal Antifungal Agents in Transplant and Cancer Patients. Georg Maschmeyer and Barbara Alexander Invasive fungal infections (IFI), in particular systemic candidiasis and invasive aspergillosis, have become increasingly important in immunocompromised patients during the past two decades. Invasive aspergillosis represents a predominant cause of death in patients with acute leukemia as well as in transplant recipients. Although amphotericin B deoxycholate (D-AmB) has been available for systemic antifungal treatment for more than 40 years, and despite its excellent in vitro antifungal activity, clinical outcome in patients with IFI has been disappointing. Reasons for the high failure rate in IFI patients treated with D-AmB are mainly the high incidence of severe infusion-associated adverse effects and the profound nephrotoxicity, hindering a full-dose D-AmB therapy over a sufficiently long period of time, and pharmacokinetic properties of D-AmB resulting in suboptimal drug concentrations in tissues affected by invasive aspergillosis. Lipid formulations of amphotericin B such as liposomal AmB, AmB lipid complex or AmB Colloidal Dispersion are significantly better tolerated and therefore less frequently discontinued, however, this does not translate into higher clinical success rates. The optimal dose of these agents has not yet been precisely defined, and the acquisition costs of these lipid formulations are considerably high. Itraconazole (ITR), a broad-spectrum triazole antifungal with good in-vitro activity against aspergillus spp., has been used mainly for oral antifungal prophylaxis and for maintenance treatment in patients with IFI who have responded to intravenous AmB and are going to be discharged for outpatient care. The recently introduced intravenous formulation of ITR has been shown to be as effective yet better tolerated than D-AmB in febrile neutropenic patients with fever refractory to antibiotics. Its efficacy for primary treatment of IFI has not yet been studied in a properly designed clinical trial. Due to its molecular size, it will not penetrate the blood-brain barrier, and it is important to know that the cyclodextrin carrier used for parenteral administration is not well dialyzed. Of three more recently developed broad-spectrum azoles, voriconazole, posaconazole and ravuconazole, voriconazole (VCZ) has been approved for clinical use in invasive aspergillosis and in invasive candidiasis due to fluconazole-resistant Candida spp. It has shown significantly superior response and survival rates when compared with D-AmB in patients with invasive aspergillosis. It effectively penetrates the blood-brain barrier and is therefore associated with a remarkable 25-30% success rate in patients with cerebral aspergillosis. Its clinical use, like that of other triazole antifungals, is limited by potential interactions with other drugs via the cytochrome p450 isoenzyme system. Apart from that, about 30% of patients treated with VCZ experience mostly transient visual disturbances, however, treatment discontinuation is required in a minority of these patients only. Caspofungin is the first licensed compound from a new class of antifungal agents, the echinocandins. It acts by inhibiting the glucan synthesis of the fungal cell wall and is not affected by any of the established mechanisms of resistance against polyene or azole antifungals. In a randomized comparison with D-AmB in patients with invasive candidiasis, it has shown at least equal clinical efficacy yet significantly better tolerability. In patients with invasive aspergillosis refractory to or intolerant of other antifungals, it has been shown to induce complete or partial response in about 45% of cases. Due to its excellent tolerability and very low potential for drug interactions, caspofungin provides a valuable new option for the treatment of IFI. Given the unique mode of action of the new echinocandins, a valid option for future antifungal treatment of IFI may be a combination of an echinocandin with a second-generation triazole or with an amphotericin B formulation.
Full conference title:
43rd Interscience Conference on Antimicrobial Agents
- ICAAC 43rd