Observational cross-sectional case study of toxicities of antifungal drugs.

OBJECTIVES: In this study, we examined the toxicities, including poisoning and overdoses, with polyene, azole, flucytosine and echinocandin antifungals reported to the Swiss National Poison Centre. METHODS: An observational cross-sectional study on antifungals was performed based on reports between 1995 and 2016 to Tox Info Suisse. Patient demographic and clinical characteristics were summarised among all reported calls, stratified by age group. In secondary analyses, we evaluated cases with clinical follow-up information. RESULTS: In total, 149 cases were reported to the National Poison Centre during the study period, of which 49 (32.9%) were male and 91 (61.1%) were female, and 95 (63.8%) were adults and 54 (36.2%) were children (age ≤16 years). The most frequently reported drug class was azoles (136; 91.3%). In 31 cases (20.8%) reported by treating physicians, further clinical follow-up information was available. Nearly one-half of these patients were asymptomatic (15/31; 48.4%). In 11 patients (35.5%) among those with symptoms, the symptoms of toxicity were categorised with a strong causality to the respective antifungal. Clinical findings caused by triazoles were effects in the gastrointestinal tract, hallucinations and predelirium state. Clinical findings caused by polyenes were mostly minor symptoms with infusion-related effects or hypokalaemia. The severity was categorised as minor in 6 (54.5%) of 11 cases and as moderate in 5 cases (45.5%). CONCLUSION: Despite high administered doses, no severe or fatal cases occurred within the study period. Although various toxicities can occur with antifungal administration and overdoses, they showed a favourable safety profile.

Photochemical internalization (PCI)-mediated activation of CD8 T cells involves antigen uptake and CCR7-mediated transport by migratory dendritic cells to draining lymph nodes.

Antigen cross-presentation to cytotoxic CD8+ T cells is crucial for the induction of anti-tumor and anti-viral immune responses. Recently, co-encapsulation of photosensitizers and antigens into microspheres and subsequent photochemical internalization (PCI) of antigens in antigen presenting cells has emerged as a promising new strategy for inducing antigen-specific CD8+ T cell responses in vitro and in vivo. However, the exact cellular mechanisms have hardly been investigated in vivo, i.e., which cell types take up antigen-loaded microspheres at the site of injection, or in which secondary lymphoid organ does T cell priming occur? We used spray-dried poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with ovalbumin and the photosensitizer tetraphenyl chlorine disulfonate (TPCS2a) to investigate these processes in vivo. Intravital microscopy and flow cytometric analysis of the murine ear skin revealed that dendritic cells (DCs) take up PLGA microspheres in peripheral tissues. Illumination then caused photoactivation of TPCS2a and induced local tissue inflammation that enhanced CCR7-dependent migration of microsphere-containing DCs to tissue-draining lymph nodes (LNs), i.e., the site of CD8+ T cell priming. The results contribute to a better understanding of the functional mechanism of PCI-mediated vaccination and highlight the importance of an active transport of vaccine microspheres by antigen presenting cells to draining LNs.