Tamás Papp

In vitro antifungal activity of antipsychotic drugs and their combinations with conventional antifungals against Scedosporium and Pseudallescheria isolates.

In the present study, in vitro antifungal activities of five antipsychotic drugs (i.e., chlorpromazine hydrochloride, CPZ; trifluoperazine hydrochloride, TPZ; amantadine hydrochloride; R-(-)-deprenyl hydrochloride, and valproic acid sodium salt) and five conventional antifungal drugs (i.e., amphotericin B, AMB; caspofungin, CSP; itraconazole; terbinafine, TRB and voriconazole, VRC) were investigated in broth microdilution tests against four clinical and five environmental Scedosporium and Pseudallescheria isolates. When used alone, phenothiazines CPZ and TPZ exerted remarkable antifungal effects. Thus, their in vitro combinations with AMB, CSP, VRC, and TRB were also examined against the clinical isolates. In combination with antifungal agents, CPZ was able to act synergistically with AMB and TRB in cases of one and two isolates, respectively. In all other cases, indifferent interactions were revealed. Antagonism was not observed between the tested agents. These combinations may establish a more effective and less toxic therapy after further in vitro and in vivo studies for Scedosporium and Pseudallescheria infections.

In Vitro Antifungal Activity of Cysteine Derivatives and their Combinations with Antifungal Agents Against Clinically Relevant Scedosporium species

Background: Members of the genus Scedosporium are emerging human pathogens, causing a wide range of infections. Their treatment means a challenge for clinicians, mostly because of the low susceptibility of these causative agents to conventional antifungal drugs. New alternative therapeutic approaches are required for better clinical outcomes. Cysteine and its derivatives alone or in combinations with antifungal drugs might have improved antifungal effects against Scedosporium species. Methods: The in vitro antifungal effects of two cysteine forms and three of their derivatives (i.e., D-cysteine, L-cysteine, L-cysteine-methyl ester hydrochloride, N-isobutyryl-D-cysteine, and N-isobutyryl-L-cysteine) were determined using the CLSI M38-A2 broth microdilution method. The in vitro drug interactions between the most effective cysteine derivatives and some conventional antifungal drugs were also investigated using checkerboard assays in case of four clinical isolates. Results: L-cysteine-methyl ester hydrochloride proved to be the most effective among the investigated compounds. N-isobutyryl-L-cysteine exhibited antifungal activity against one Scedosporium aurantiacum strain only. D-cysteine, L-cysteine and N-isobutyryl-D-cysteine proved to be ineffective against Scedosporium spp. in the investigated concentration range. No significant differences were found in the susceptibilities between environmental and clinical isolates. L-cysteine-methyl ester hydrochloride could interact synergistically with amphotericin B, caspofungin, terbinafine and voriconazole. Antagonistic interactions were not observed between the investigated compounds. Conclusions: The present study provides an evidence for the in vitro antifungal activity of L-cysteinemethyl ester hydrochloride and the synergistic interactions between this cysteine derivative and conventional antifungal agents. Based on our results, L-cysteine-methyl ester hydrochloride in combination with antifungal drugs could be applicable in the treatment of human Scedosporium infections in the future. However, further studies are required to clarify the antifungal mechanism of L-cysteine-methyl ester hydrochloride and to investigate its activity in vivo.