Abstract Objectives Eumycetoma is currently treated with a combination of itraconazole therapy and surgery, with limited success. Recently, olorofim, the lead candidate of the orotomides, a novel class of antifungal agents, entered a Phase II trial for the treatment of invasive fungal infections. Here we determined the activity of olorofim against Madurella mycetomatis, the main causative agent of eumycetoma. Methods Activity of olorofim against M.
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Abstract Objectives Eumycetoma is currently treated with a combination of itraconazole therapy and surgery, with limited success. Recently, olorofim, the lead candidate of the orotomides, a novel class of antifungal agents, entered a Phase II trial for the treatment of invasive fungal infections.
Here we determined the activity of olorofim against Madurella mycetomatis, the main causative agent of eumycetoma. Methods Activity of olorofim against M. We also investigated the in vitro interaction between olorofim and itraconazole against M. Results M. Olorofim demonstrated excellent potency against M. In vitro interaction studies demonstrated that olorofim and itraconazole work indifferently when combined.
Conclusions We demonstrated olorofim has potent in vitro activity against M. Introduction The poverty-associated disease mycetoma, which was added to the Neglected Tropical Disease List in by WHO, remains a major health problem in endemic areas.
In severe cases, amputation of the affected part may be the only remaining treatment option. Thus there is a dire need for another antifungal agent that is active against M. Given the potency and activity of olorofim, here we aim to evaluate its in vitro activity against M. Materials and methods In silico modelling The M. Mitochondrial targeting sequences of M. Isolates A total of 21 M. Among the isolates used, 14 isolates originated from Sudan, there was 1 isolate each from Algeria, Mali, India, Chad and the Netherlands and there were 2 isolates with unknown origin.
After incubation, the mycelia within were washed once with RPMI culture medium. In vitro susceptibility testing Susceptibility testing was carried out according to the previously described and validated method developed for susceptibility testing using a standardized hyphal inoculum. Efficacy of olorofim was compared with that of itraconazole. Olorofim was dissolved in DMSO and tested at a range of 0. Itraconazole was also dissolved in DMSO and tested at a range of 0.
The assay was carried out in round-bottom microtitre plates Greiner Bio-one, The Netherlands. For each fungal isolate, a drug-free and a negative control were included. MICs of olorofim and itraconazole were determined. All experiments were performed in triplicate. Olorofim and itraconazole interaction A chequerboard microdilution assay was used to evaluate the in vitro activity between olorofim and itraconazole.
Olorofim was evaluated using a concentration ranging from 0. The interaction between olorofim and itraconazole was analysed based on the FIC index and the interaction ratio IR.
Genus: Madurella Description and Natural Habitats Madurella is a dematiaceous phaeoid, or dark-walled filamentous fungus found in soil, particularly in tropical and subtropical areas of Africa, India, and South America. Madurella is pathogenic for humans and causes infections. Species The genus Madurella has two species; Madurella mycetomatis and Madurella grisea. See the summary of synonyms for the Madurella spp. Pathogenicity and Clinical Significance Madurella spp. Strains belonging to this genus are isolated specifically from cases with black-grain eumycetoma. The fungus enters the human body via trauma and the progression of mycetoma is very slow which may take several years.
History[ edit ] Madurella mycetomatis underwent many name changes. In , Brumpt described the first recorded case of mycosis caused by M. In , Brumpt corrected its genus to Madurella, in turn changing its name to Madurella mycetomi. This error was eventually[ when? Roughly a dozen other species of uncertain validity have been described as genus Madurella based on in vivo similarities and cultural sterility. Although similar, there were important physiological and morphological differences between the two well defined species, leading scientists to doubt their phylogeny. The development of ribosomal sequencing and other molecular techniques, led to the discovery that M.