RESUMEN
Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Depsipéptidos/uso terapéutico , Hospitalización/estadística & datos numéricos , Péptidos Cíclicos/uso terapéutico , SARS-CoV-2/efectos de los fármacos , Adulto , Anciano , COVID-19/virología , Línea Celular Tumoral , Depsipéptidos/efectos adversos , Depsipéptidos/farmacología , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Estimación de Kaplan-Meier , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Péptidos Cíclicos/efectos adversos , Péptidos Cíclicos/farmacología , SARS-CoV-2/fisiología , Resultado del Tratamiento , Carga Viral/efectos de los fármacosRESUMEN
We retrospectively investigated the impact of high vancomycin minimum inhibitory concentration (MIC > 2 µg/ml) on the outcome of 53 patients with bacteremia caused by methicillin-susceptible Staphylococcus aureus (MSSA). Vancomycin MIC was determined by broth microdilution according to CLSI methods. The primary outcome was 30-day all-cause mortality from the date of the first positive blood culture. The mortality rate was 22.6% (12 of 53 patients). High vancomycin MIC (odds ratio (OR) = 9.3; 95% confidence interval (95% CI) = 1.31-63.20; p = 0.027), Charlson comorbidity index ≥ 3 (OR = 10.3; 95% CI = 1.3-102.04; p = 0.03), advanced age (OR = 35.8; 95% CI = 2.3-659.2; p = 0.01), and severe sepsis (OR = 8.5; 95% CI = 1.2-61.4; p = 0.03) were associated with mortality.