In Vitro Antifungal Activity of Isavuconazole against Madurella mycetomatis

Abstract

dCurrently, therapy of black-grain mycetoma caused by Madurella mycetomatis consists of extensive debridement of the infected tissue combined with prolonged antifungal therapy with ketoconazole or itraconazole. In the present study, the in vitro activity of the new triazole isavuconazole toward M. mycetomatis was evaluated. Isavuconazole appeared to have high activity against M. mycetomatis, with MICs ranging from <0.016 to 0.125 g/ml. Due to its favorable pharmacokinetics, isavuconazole could be a promising antifungal agent in the treatment of mycetoma. Madurella mycetomatis is the most common causative agent of eumycetoma. This chronic, granulomatous infection is often found in the lower extremities, but it has been reported in other parts of the body as well (4). The infection starts as a small subcutaneous nodule, which gradually progresses into chronic inflammatory lesions with multiple sinuses that excrete a purulent and seropurulent discharge containing black grains. To date, treatment of eumycetoma in areas where eumycetoma is endemic consists of a combination of extensive mutilating surgery or amputation of the infected tissue or limb and prolonged antifungal therapy with ketoconazole or itraconazole (1). However, eumycetoma is associated with high recurrence rates, even after amputation of the affected limb. For M. mycetomatis, the susceptibility to antifungal agents belonging to the classes of polyenes, azoles, allylamines, and echinocandins has been determined (3,18, 20 Khartoum, Sudan, in 1999 and 2000) in duplicate. The strains were identified previously by morphology, PCRrestriction fragment length polymorphism (RFLP), and internal transcribed spacer (ITS) sequencing (2, 19). MICs were determined by using the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) assay (3). In brief, M. mycetomatis colonies were inoculated in RPMI 1640 medium containing 0.35 g/liter L-glutamine and 1.98 mM 4-morpholinepropanesulfonic acid, sonicated (5 s at 28-m maximum power, Beun de Ronde, The Netherlands), and incubated for 7 days at 37°C. The mycelia were harvested by another sonication step and 5-min centrifugation at 2,628 ϫ g. The pellet was washed and resuspended in sterile saline, and the fungal suspension was adjusted to 70% transmission at 660 nm (Novaspec II; Pharmacia Biotech). The drug concentrations tested ranged from 0.016 g/ml to 16 g/ml isavuconazole. As comparator agents, ketoconazole and itraconazole were tested at the same concentrations. XTT was administered to facilitate endpoint reading. MICs were determined spectrophotometrically and defined as the lowest concentration of antifungal agent where at least an 80% growth reduction was measured. Candida parapsilosis (ATCC 22019) was included in the study as a quality control strain.In concordance with previously published data, M. mycetomatis was strongly inhibited by low concentrations of ketoconazole and itraconazole (18), the antifungal agents currently used to treat mycetoma in the areas where my...

Madurella mycetomatis Is Highly Susceptible to Ravuconazole

“…These MICs were not only considerably lower than those found for ketoconazole and itraconazole in the present study, but they were also lower than those reported for voriconazole (0.016–1 µg/ml), posaconazole (0.03–0.125 µg/ml), and isavuconazole (0.016–0.125 µg/ml) [4], [5], [6]. Only a few reports are available regarding the susceptibility of other eumycetoma causative agents towards ravuconazole.…”

“…The infection by M. mycetomatis is characterized by the presence of black grains in tissue [3]. Previous reports showed that this fungus was most susceptible to the azole class of antifungal agents [4], [5], [6]. Ketoconazole and itraconazole are the most frequently used drugs for the treatment of mycetoma.…”

Eumycetoma on the Foot Caused by Madurella mycetomatis: Amputation After Significant Worsening During Pregnancy

“…Surgery is indicated for the treatment of local and disseminated lesions with or without bone involvement, as it reduces the number of lesions and the duration of drug treatment. Amputation is indicated for cases with massive bone destruction, massive disease that does not respond to prolonged medical treatment and for patients who experience severe drug side-effects (2,15). The use of orthopaedic aids as soon as possible after amputation is essential for achieving a high quality of life.…”

Eumycetoma and actinomycetoma – an update on causative agents, epidemiology, pathogenesis, diagnostics and therapy

“…A recently published study investigated the in vitro activity of the new triazole antifungal isavuconazole against Madurella mycetomatis . Isavuconazole revealed high in vitro activity against Madurella mycetomatis .…”