Oral delivery of brain-targeted miltefosine-loaded alginate nanoparticles functionalized with polysorbate 80 for the treatment of cryptococcal meningitis.

OBJECTIVES: To develop alginate nanoparticles functionalized with polysorbate 80 (P80) as miltefosine carriers for brain targeting in the oral treatment of cryptococcal meningitis. METHODS: Miltefosine-loaded alginate nanoparticles functionalized or not with P80 were produced by an emulsification/external gelation method and the physicochemical characteristics were determined. The haemolytic activity and cytotoxic and antifungal effects of nanoparticles were assessed in an in vitro model of the blood-brain barrier (BBB). A murine model of disseminated cryptococcosis was used for testing the efficacy of oral treatment with the nanoparticles. In addition, serum biomarkers were measured for toxicity evaluation and the nanoparticle biodistribution was analysed. RESULTS: P80-functionalized nanoparticles had a mean size of ∼300 nm, a polydispersity index of ∼0.4 and zeta potential around -50 mV, and they promoted a sustained drug release. Both nanoparticles were effective in decreasing the infection process across the BBB model and reduced drug cytotoxicity and haemolysis. In in vivo cryptococcosis, the oral treatment with two doses of P80 nanoparticles reduced the fungal burden in the brain and lungs, while the non-functionalized nanoparticles reduced fungal amount only in the lungs, and the free miltefosine was not effective. In addition, the P80-functionalization improved the nanoparticle distribution in several organs, especially in the brain. Finally, treatment with nanoparticles did not cause any toxicity in animals. CONCLUSIONS: These results support the potential use of P80-functionalized alginate nanoparticles as miltefosine carriers for non-toxic and effective alternative oral treatment, enabling BBB translocation and reduction of fungal infection in the brain.

Possible Trichosporon asahii urinary tract infection in a critically ill COVID-19 patient

Background:Trichosporon asahii, an emerging fungal pathogen, has been frequently associated with invasive infections in critically ill patients.Case report:A 74-year-old male patient diagnosed with COVID-19 was admitted to an Intensive Care Unit (ICU). During hospitalization, the patient displayed episodes of bacteremia by Staphylococcus haemolyticus and a possible urinary tract infection by T. asahii. While the bacterial infection was successfully treated using broad-spectrum antibiotics, the fungal infection in the urinary tract was unsuccessfully treated with anidulafungin and persisted until the patient died.Conclusions:With the evolving COVID-19 pandemic, invasive fungal infections have been increasingly reported, mainly after taking immunosuppressant drugs associated with long-term broad-spectrum antibiotic therapy. Although Candida and Aspergillus are still the most prevalent invasive fungi, T. asahii and other agents have emerged in critically ill patients. Therefore, a proper surveillance and diagnosing any fungal infection are paramount, particularly in COVID-19 immunocompromised populations. (AU)

Antecedentes:Trichosporon asahii, un hongo patógeno emergente, se ha asociado con frecuencia con infecciones invasivas en pacientes enfermos en estado crítico.Caso clínico:Un paciente de sexo masculino de 74 años de edad, con diagnóstico positivo para la COVID-19, ingresó en una unidad de cuidados intensivos. Durante la hospitalización el paciente presentó episodios de bacteriemia por Staphylococcus haemolyticus y una posible infección del tracto urinario por T. asahii. Mientras la infección bacteriana fue tratada exitosamente con antibióticos de amplio espectro, la infección micótica urinaria no remitió con anidulafungina y persistió hasta la muerte del paciente.Conclusiones:Con la pandemia de la COVID-19 se han notificado cada vez más casos de infecciones micóticas invasivas, principalmente después del uso de fármacos inmunosupresores, asociados con terapia de antibióticos de amplio espectro. Aunque Candida y Aspergillus siguen siendo los hongos invasores más prevalentes, T.asahii y otras especies han emergido en pacientes enfermos en estado crítico. Por lo tanto, la vigilancia y el diagnóstico de las infecciones micóticas es primordial, particularmente en poblaciones inmunodeficientes por la COVID-19. (AU)