Efficacy and Safety of Nirmatrelvir/Ritonavir, Molnupiravir, and Remdesivir in a Real-World Cohort of Outpatients with COVID-19 at High Risk of Progression: The PISA Outpatient Clinic Experience.

INTRODUCTION: Different antivirals are available for the treatment of outpatients with COVID-19. Our aim was to describe a real-world experience of outpatient management of COVID-19 subjects at high risk of progression. METHODS: This prospective observational study conducted in the University Hospital of Pisa (January 2022-July 2022) included consecutive COVID-19 outpatients with at least one risk factor for disease progression. Patients received nirmatrelvir/ritonavir, molnupiravir, or 3-day remdesivir, according to the Italian Medicines Agency (AIFA) indications. All patients were followed up until 30 days from the first positive nasopharyngeal swab. The primary endpoint was a composite of death or hospitalization. Secondary endpoints were occurrence of adverse events and a negative test within 10 days from the first positive test. Multivariable analysis was performed to identify factors associated with death or hospitalization. RESULTS: Overall, 562 outpatients were included: 114 (20.3%) received molnupiravir, 252 (44.8%) nirmatrelvir/ritonavir, and 196 (34.9%) 3-day remdesivir. The composite endpoint occurred in 2.5% of patients and was more frequent in patients treated with remdesivir (5.1%) compared with molnupiravir (1.8%) or nirmatrelvir/ritonavir (0.8%, ANOVA among groups p = 0.012). On multivariable Cox regression analysis, presence of ≥ 3 comorbidities, hematological disease, gastrointestinal symptoms, and each-day increment from symptoms onset were factors associated with death or hospitalization, while antiviral treatment was not a predictor. Adverse events occurred more frequently in the nirmatrelvir/ritonavir group (49.2%). Nirmatrelvir/ritonavir compared with remdesivir was associated with a higher probability of having a negative test within 10 days from the first positive one. CONCLUSION: Death or hospitalization did not differ among high-risk COVID-19 outpatients treated with currently available antivirals. Safety and time to a negative test differed among the three drugs.

Impact of infectious diseases consultation as a part of an antifungal stewardship programme on candidemia outcome in an Italian tertiary-care, University hospital.

Candidemia is a major cause of in-hospital mortality. Antifungal stewardship programme (AFSP) providing infectious diseases consultation (IDC) might improve the outcome. We evaluate the impact on candidemia mortality of IDC as part of AFSP restricting the use of all antifungals with exception of fluconazole. We retrospectively reviewed the charts of patients with documented candidemia in our hospital during the period 2012-2014 evaluating the impact of several variables on 30-days in-hospital mortality. We reviewed data on 276 patients with documented candidemia: 200 (72%) were treated without IDC and 76 (28%) with IDC. In the group without IDC, 52 patients (26%) received no antifungal therapy. Antifungals used for treating candidemia were (no IDC/IDC): azoles (74%/42%); echinocandins (0%/46%); liposomal and lipidic complex amphotericin B (0%/12%). The 30-day in-hospital mortality was respectively (no IDC/IDC) 37% vs. 20% (p = 0.011). The multivariate analysis confirmed IDC as independent factor protecting from death (OR 0.511, 95% CI 0.251-0.994; p = 0.046), together with fungemia due to non-albicans Candida (OR 0.565, 95% CI 0.327-0.977; p = 0.042). Age >65 years was associated with a higher risk of death (OR 1.989, 95% CI 1.055-3.895; p = 0.038). The additional cost for the use of echinocandins driven by IDC in the study period was €207,000. IDC, as a part of a restrictive front-end antimicrobial stewardship programme (ASP), providing a timely right choice of antifungal therapy, increases the cost of antifungal drugs but might be a contributing protective factor from mortality due to candidemia. Efforts to increase the number of IDC in patients with candidemia seems to be warranted.

Gelatin nanoparticles produced by a simple W/O emulsion as delivery system for methotrexate.

Biodegradable hydrophilic gelatin nanoparticles, containing different initial amounts of methotrexate (MTX), were prepared using a simple solvent evaporation technique based on a single water-in-oil emulsion and stabilized by the use of glutaraldehyde as cross-linking agent. The effects of several parameters on particle size, drug encapsulation efficiency and drug release were investigated. Size and shape of the nanoparticles were examined by scanning electron microscopy. The release of MTX was monitored in vitro and the mechanism of release was studied. Particles with a mean diameter of 100-200 nm were produced, which were able to release MTX following a diffusion-controlled mechanism of release. It was observed that the initial amount of MTX used for sample loading did not have any effect on the pattern of release, while it affected the amount of drug entrapped into the nanoparticles and also both the release rate and the total amount of drug released.