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Las enfermedades neurodegenerativas consisten en un deterioro progresivo del sistema nervioso tanto central como periférico. Este deterioro produce la pérdida de la capacidad cognitiva y/o motora de una forma crónica e incurable. Aunque la detección de estas enfermedades y su diagnóstico es posible, aún no se conoce un tratamiento eficaz para revertir el daño o curar al paciente; tan solo existen tratamientos que enlentecen la evolución de estas. Por otro lado, algunos de estos trastornos presentan una prevalencia bastante elevada, como la enfermedad de Alzheimer, que además se sitúa entre las 10 primeras causas de muerte según la Organización Mundial de la Salud, ocupando el tercer lugar en Europa. A raíz de esta problemática, surgen investigaciones sobre nuevas terapias y fármacos para el tratamiento de enfermedades neurodegenerativas, así como el empleo de nuevas estrategias para el diagnóstico temprano y la prevención de estas patologías. En las últimas décadas, la melatonina, hormona secretada por la glándula pineal, ha ganado peso en el ámbito de la salud cerebral. La cuestión más importante es si las propiedades y los beneficios de la melatonina son suficientes como para prevenir y/o curar las enfermedades neurodegenerativas. Según los últimos estudios, un déficit de esta hormona podría estar relacionado con el origen de estas patologías, por ello, se podría utilizar como un biomarcador temprano. La terapia con melatonina está siendo muy prometedora en la prevención de estas enfermedades e incluso está mostrando que podría tener la capacidad de prolongar la vida de los pacientes en alguna de ellas.

Human adenovirus (HAdV) can produce disseminated disease with high mortality in pediatric allogenic hematopoietic stem cell transplant (allo-HSCT) recipients. In adult recipients, prospective studies addressing the incidence of HAdV infection and disease are lacking. The aim of this study was to characterize the kinetics of HAdV replication, the specific T-cell immune response, and the clinical impact of HAdV infection in adult allo- HSCT recipients. We found a high incidence of HAdV viremia, which was controlled by the T-cell immune response and without association with disseminated HAdV disease. Therefore, these data argue against the pre-emptive therapy for HAdV infection in adult allo- HSCT recipients.

Elderly people confined to chronic care facilities face an increased risk of acquiring infections by multidrug-resistant organisms (MDROs). This review presents the current knowledge of the prevalence and risk factors for colonization by MDROs in long-term care facilities (LTCF), thereby providing a useful reference to establish objectives for implementing successful antimicrobial stewardship programs (ASPs). We searched in PubMed and Scopus for studies examining the prevalence of MDROs and/or risk factors for the acquisition of MDROs in LTCF. One hundred and thirty-four studies published from 1987 to 2020 were included. The prevalence of MDROs in LTCF varies between the different continents, where Asia reported the highest prevalence of extended-spectrum ß-lactamase (ESBL) Enterobacterales (71.6%), carbapenem resistant (CR) Enterobacterales (6.9%) and methicillin-resistant Staphylococcus aureus (MRSA) (25.6%) and North America the highest prevalence to MDR Pseudomonas aeruginosa (5.4%), MDR Acinetobacter baumannii (15.0%), vancomycin-resistant Enterococcus spp. (VRE) (4.0%), and Clostridioides difficile (26.1%). Furthermore, MDRO prevalence has experienced changes over time, with increases in MDR P. aeruginosa and extended spectrum ß-lactamase producing Enterobacterales observed starting in 2015 and decreases of CR Enterobacterales, MDR A. baumannii, VRE, MRSA and C. difficile. Several risk factors have been found, such as male sex, chronic wounds, the use of medical devices, and previous antibiotic use. The last of these aspects represents one of the most important modifiable factors for reducing colonization with MDROs through implementing ASPs in LTCF.

[Objectives] The genus Enterobacter is a common cause of nosocomial infections. Historically, the most frequent Enterobacter species were those of Enterobacter cloacae complex and Enterobacter aerogenes. In 2019, E. aerogenes was re-classified as Klebsiella aerogenes owing to its higher genotypic similarity with the genus Klebsiella. Our objective was to characterise and compare the clinical profiles of bacteraemia caused by E. cloacae and K. aerogenes., [Methods] This 3-year multicentre, prospective cohort study enrolled consecutive patients with bacteraemia by E. cloacae or K. aerogenes. Baseline characteristics, bacteraemia features (source, severity, treatment), antibiotic susceptibility, resistance mechanisms and mortality were analysed. bacteraemia had received more antibiotics., [Results] The study included 285 patients with bacteraemia [196 (68.8%) E. cloacae and 89 (31.2%) K. aerogenes]. The groups showed no differences in age, sex, previous use of invasive devices, place of acquisition, sources or severity at onset. The Charlson score was higher among patients with E. cloacae bacteraemia [2 (1–4) vs. 1 (0.5–3); P = 0.018], and previous antibiotic therapy was more common in patients with K. aerogenes bacteraemia (57.3% vs. 41.3%; P = 0.01). Mortality was 19.4% for E. cloacae and 20.2% for K. aerogenes (P = 0.869). Antibiotic susceptibility was similar for both species, and the incidence of multidrug resistance or ESBL production was low (6% and 5.3%, respectively), with no differences between species., [Conclusion] Bacteraemias caused by E. cloacae and K. aerogenes share similar patient profiles, presentation and prognosis. Patients with E. cloacae bacteraemia had more co-morbidities and those with K. aerogenes bacteraemia had received more antibiotics.

Infection of long-term central venous catheters (CVCs) remains a challenge in the clinical management of cancer patients. We aimed to determine whether a lock solution with taurolidine-citrate-heparin would be more effective than placebo for preventing nontunneled CVC infection in high-risk neutropenic hematologic patients. We performed a prospective, multicenter, randomized (1:1), double-blind, parallel, superiority, placebo-controlled trial involving 150 hematological patients with neutropenia carrying nontunneled CVCs who were assigned to receive CVC lock solution with taurolidine-citrate-heparin or heparin alone. The primary endpoint was bacterial colonization of the CVC hubs. Secondary endpoints were the incidence of catheter-related bloodstream infection (CRBSI), CVC removal, adverse events related to the lock solution, and the 30-day case fatality rate. CVC lock solution with taurolidine-citrate-heparin was associated with less colonization of the CVC hubs than that with placebo, with no statistically significant differences: 4.1%, versus 10.1% (relative risk [RR] = 0.41, 95% confidence interval [CI] = 0.11 to 1.52), with a cumulative incidence of 4.17 (95% CI = 0.87 to 11.70) and 10.14 (95% CI = 4.18 to 19.79), respectively. There were no significant differences regarding the secondary endpoints. Only three episodes of CRBSI occurred during the study period. No adverse events related to the administration of the lock solution occurred. In this trial involving high-risk patients carrying nontunneled CVCs, the use of taurolidine-citrate-heparin did not show a benefit over the use of placebo. Nevertheless, the safety of this prevention strategy and the trend toward less hub colonization in the taurolidine-citrate-heparin group raise the interest in assessing its efficacy in centers with higher rates of CRBSI. (This study has been registered in ISRCTN under identifier ISRCTN47102251.)

[Objetives] The aim of this study was to identify CMV drug resistance mutations (DRM) in solid organ transplant (SOT) recipients with suspected resistance comparing next-generation sequencing (NGS) with Sanger sequencing and assessing risk factors and the clinical impact of resistance., [Methods] Using Sanger sequencing as the reference method, we prospectively assessed the ability of NGS to detect CMV DRM in the UL97 and UL54 genes in a nationwide observational study from September 2013 to August 2016., [Results] Among 44 patients recruited, 14 DRM were detected by Sanger in 12 patients (27%) and 20 DRM were detected by NGS, in 16 (36%). NGS confirmed all the DRM detected by Sanger. The additional six mutations detected by NGS were present in <20% of the sequenced population, being located in the UL97 gene and conferring high-level resistance to ganciclovir. The presence of DRM by NGS was associated with lung transplantation (p = 0.050), the administration of prophylaxis (p = 0.039), a higher mean time between transplantation and suspicion of resistance (p = 0.038) and longer antiviral treatment duration before suspicion (p = 0.024). However, the latter was the only factor independently associated with the presence of DRM by NGS in the multivariate analysis (OR 2.24, 95% CI 1.03 to 4.87)., [Conclusions] NGS showed a higher yield than Sanger sequencing for detecting CMV resistance mutations in SOT recipients. The presence of DRM detected by NGS was independently associated with longer antiviral treatment.

El objetivo principal de la presente tesis doctoral es definir acciones que nos permitan optimizar el tratamiento anticipado como estrategia preventiva de la infección por citomegalovirus utilizando los nuevos avances tecnológicos y del conocimiento, de los que ahora disponemos, que facilitan y mejoran el diagnóstico y la monitorización virológica e inmunológica de la infección. Para ello en primer lugar, se plantea como objetivo determinar un umbral estándar de replicación para el inicio del tratamiento anticipado según el riesgo del paciente de desarrollar infección por citomegalovirus. En segundo lugar, determinar las diferencias entre infección primaria y recurrente y, analizar el impacto de la adquisición de la respuesta inmune específica de células T frente a CMV y el uso de la profilaxis secundaria en la ocurrencia de infección recurrente en el paciente con serología negativa para litomegalovirus previa al trasplante. En tercer lugar, analizar el impacto clínico de la neutropenia relacionada con el tratamiento anticipado con valganciclovir, determinando los factores de riesgo que la producen y aquellos que pueden minimizarla. Apoyándonos sobre estos tres pilares, podremos individualizar el tratamiento anticipado, mejorar su manejo y su aplicabilidad clínica en el receptor de trasplante de órgano sólido infectado por citomegalovirus.