In vitro activities of new and conventional antifungal agents against clinical Scedosporium isolates

The susceptibilities of 13 clinical isolates of Scedosporium apiospermum and 55 clinical isolates of S. prolificans to new and conventional drugs belonging to three different classes of antifungal agents, the azoles (miconazole, itraconazole, voriconazole, UR-9825, posaconazole), the polyenes (amphotericin B, nystatin and liposomal nystatin), and allylamines (terbinafine), were studied by use of proposed standard M38-P of NCCLS. Low growth-inhibitory antifungal activities were found in vitro for most of the drugs tested against S. prolificans isolates, with the MICs at which 90% of isolates are inhibited (MIC90s) being >8 μg/ml; the MIC90s of voriconazole and UR-9825, however, were 4 μg/ml. S. apiospermum isolates were more susceptible in vitro, with the highest activity exhibited by voriconazole (MIC90s, 0.5 μg/ml), followed by miconazole (MIC90s, 1 μg/ml), UR-9825 and posaconazole (MIC90s, 2 μg/ml), and itraconazole (MIC90s, 4 μg/ml). The MICs of terbinafine, amphotericin B, and the two formulations of nystatin (for which no statistically significant differences in antifungal activities were found for the two species) for S. apiospermum isolates were high. Cross-resistance was observed among all the azoles except posaconazole and among all the polyenes except the lipid formulation. A distribution analysis was performed with the MICs of each drug and for each species. Bimodal and skewed MIC distributions were obtained, and cutoffs indicating the borders of different MIC subpopulations of the distributions were determined on the basis of the normal plot technique. These cutoffs were in many cases reproducible between 48 and 72 h.

Scedosporium is a ubiquitous filamentous fungus with a worldwide distribution (30). The genus includes two medically important species, Scedosporium apiospermum (which is also known by its teleomorphic name Pseudallescheria boydii) and S. prolificans (which is also known as S. inflatum). S. apiospermum has been recovered from soil, sewage, polluted water (34), and animal and bird manure, while S. prolificans has been isolated from soil, cats, horses, and birds (38). These two species can easily be differentiated from each other macroscopically because of the more rapid growth of S. prolificans on potato-dextrose agar and microscopically because S. prolificans forms annellides with swollen bases (32).

These species cause infections in both immunocompetent and immunosuppressed individuals. S. prolificans can cause asymptomatic colonization of the external ear or the respiratory tract; localized infections of the joints, nail, eye, and sphenoid sinus (21); and disseminated infections in immunocompromised patients (10) with hematological malignancies (20, 31) or in organ transplant recipients (4). Similarly, S. apiospermum colonizes the tracheobronchial tree and causes mycetoma, invasive pulmonary infection (26), and disseminated infections of the central nervous system (11, 13, 14, 17).

The fungal spores infect an individual via the respiratory tract, ulcerative lesions in the gastrointestinal tract, surgical wounds, and inoculation from trauma (4). After the spores reach the target organ, they produce hyphae that may eventually sporulate in tissue, enter the bloodstream, and disseminate to other organs, particularly the kidneys, lungs, and brains (4). Most of the disseminated infections are fatal, despite antifungal treatment. If patients recover their granulocytes, they may survive.

The therapeutic approach for patients with S. apiospermum or S. prolificans infections involves complete surgical resection of the lesion with or without antifungal therapy, whose role is uncertain (12, 37). Infections caused by S. apiospermum have been treated with amphotericin B (35), miconazole, ketoconazole (38), itraconazole (29), and voriconazole (11), with variable clinical responses. S. prolificans is resistant in vitro to many antifungals, with the MICs of most of drugs tested being greater than 16 g/ml (8).

Given the demand for more aggressive antifungal therapy for the management of infections caused by Scedosporium species and the in vitro resistance of Scedosporium species to the common antifungal agents, new, more active antifungal drugs are required. Therefore, the susceptibilities of 13 clinical isolates of S. apiospermum and 55 clinical isolates of S. prolificans to new drugs (voriconazole, UR-9825, terbinafine, posaconazole, and liposomal nystatin) were determined and compared with the activities of conventional antifungal agents (miconazole, itraconazole, amphotericin B, and nystatin) (3, 9, 18). Cross-resistance between the drugs was studied, and a distribution analysis was performed in order to establish cutoffs in the in vitro susceptibilities on the basis of the frequency distributions of the MICs.