Anti-Sporothrix activity of ibuprofen combined with antifungal

Abstract

The in vitro activity of ibuprofen, a nonsteroidal anti-inflammatory drug, was evaluated against Sporothrix brasiliensis and S. schenckii, either alone or in combination with amphotericin B, itraconazole, or terbinafine. The inhibitory activity of ibuprofen as a single agent was determined according to minimum inhibitory concentration (MIC) values, while the effect of ibuprofen combined with amphotericin B, itraconazole, or terbinafine was estimated by microdilution checkerboard methodology. The ultrastructural alterations of S. schenckii after exposure to the combination of ibuprofen and amphotericin B were evaluated by scanning electron microscopy (SEM) and flow cytometry analysis. As a single agent, ibuprofen inhibited Sporothrix growth with a MIC median of 256 μg/mL, while the MIC medians of ibuprofen in combination with antifungals were 16 μg/mL and 128 μg/mL. The MIC values of amphotericin B, itraconazole, and terbinafine were reduced when isolates were co-incubated with ibuprofen, mainly the polyene. The major alteration after treatment with the ibuprofen/amphotericin B combination was the increase in the presence of filamentous forms and high membrane damage with loss of plasma membrane integrity. In summary, we demonstrated that ibuprofen increases the in vitro activity of antifungals, mainly amphotericin B, against S. brasiliensis and S. schenckii. Future in vivo studies exploring combination therapy with ibuprofen and antifungals in animal models are needed to confirm its efficacy.

Keywords: Amphotericin B; Ibuprofen; Sporothrix brasiliensis; Sporothrix schenckii.

Fig. 1

Sporothrix schenckii alterations after exposure to the combination of ibuprofen and amphotericin B evaluated by scanning electron microscopy. The untreated culture exhibits yeasts with elongated shape, budding yeasts, and hyphae (a), while cultures treated with 128 μg/mL ibuprofen (b) or 0.001 μg/mL amphotericin B (c) show conidia with altered structure and amorphous cells (arrows). A chlamydospore-like structure was observed after exposure to the ibuprofen/amphotericin B combination (arrow in d), and filamentous forms were the most frequent after this treatment (e). Bars: 10 μm