aminocandin and Aspergillosis

The frequency and spectrum of fungal infections have been increasing steadily over the last several decades. The reason for this increase may be explained by the increase in the number of immunocompromised patients due to malignancies, AIDS, invasive surgical procedures and transplantation. In parallel with this increase, several therapeutic options have become available but problems such as intrinsic or acquired antifungal resistance have led researchers to develop new antifungal drugs with expanded effectiveness. Reduced toxicity, enhancement of bioavailability and counteraction of resistance are features desired by clinicians. The aim of this article is to summarize the studies involving isavuconazole, ravuconazole, albaconazole, aminocandin and some other investigational antifungal agents. Most data on the clinical use of ravuconazole, isavuconazole and albaconazole are mainly available as meeting abstracts or limited to animal studies or Phase I/II studies in humans. These new antifungal agents in development offer extended half-lives, possibly reduced drug interaction profiles and good tolerance. In addition to activity against Candida and Aspergillus spp., they have a broad spectrum of activity including activity against resistant and emerging pathogens. The real possibilities of these agents will only be fully understood after adequate randomized clinical trials.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis, Invasive; Child; Clinical Trials as Topic; Half-Life; Humans; Lipopeptides; Nitriles; Pyridines; Quinazolines; Thiazoles; Triazoles

Aminocandin (IP960; HMR3270; NXL201) is a new echinocandin with broad-spectrum in vitro activity against Aspergillus and Candida spp. We compared the activity of aminocandin with that of amphotericin B (AmB), itraconazole (ITC) and caspofungin (CAS) in murine models of disseminated aspergillosis against three strains of A. fumigatus, two of which were fully susceptible (AF293 and A1163) and one was resistant to ITC (AF91). Mice were rendered temporarily neutropenic or persistently neutropenic with cyclophosphamide and were infected intravenously 3 days later. Temporarily neutropenic mice were treated with either intraperitoneal (i.p.) AmB (5mg/kg/dose), oral (p.o.) ITC (25mg/kg/dose), intravenous (i.v.) aminocandin (0.25-10mg/kg/dose), i.p. aminocandin (1mg/kg/dose) or solvent control for 9 days. Mice were euthanised 11 days post infection and the kidneys and liver were removed for quantitative culture. Following infection with AF293, only aminocandin 5mg/kg i.v. yielded 100% survival. Aminocandin 1mg/kg i.v., AmB 5mg/kg i.p. or ITC 25mg/kg p.o. were equivalent (P>0.05). Aminocandin 5mg/kg was superior to aminocandin 0.25mg/kg (P<0.0001) as well as all controls (P<0.0001) in reducing mortality. Following infection with AF91, only aminocandin at 5mg/kg and 1mg/kg i.v. yielded 100% survival, which was superior to ITC, aminocandin 0.25mg/kg and controls (all P<0.0001). In the persistently neutropenic model with A1163, aminocandin, CAS and micafungin (2-10mg/kg) were all effective at prolonging survival, with some impact on reducing culture burdens, even with alternate-day dosing (4mg/kg). The only fungicidal regimen was aminocandin 5mg/kg, which sterilised 40% and 50% of mice following infection with AF293 and AF91, respectively. Aminocandin at doses of > or =1mg/kg is highly effective in reducing mortality and organ burden in disseminated infection caused by ITC-susceptible and -resistant A. fumigatus.

Topics: Administration, Oral; Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Caspofungin; Colony Count, Microbial; Disease Models, Animal; Echinocandins; Injections, Intraperitoneal; Injections, Intravenous; Itraconazole; Kidney; Lipopeptides; Liver; Male; Micafungin; Mice; Survival Analysis; Treatment Outcome