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Investigation

Antibiotic Resistance

Research Lines

Content with Investigacion Virus del papiloma humano .

A) Effect of vaccination on the prevalence and distribution of Human Papillomavirus (HPV) genotypes. HPV vaccination was introduced in Spain in 2007-2008 for the prevention of cervical cancer and other cancers associated with these viral infections. The use of HPV vaccination is expected to lead to a decrease in vaccine genotypes in the population. However, it may also lead to an increase in other non-vaccine genotypes, similar to the change in vaccine serotypes observed in pneumococcal infections. This requires continuous surveillance of genotype frequency and data to monitor the efficacy of the HPV vaccination program.

B) Study of the distribution and dynamics of HPV infections in risk groups. There are some particularly vulnerable groups, some of them difficult to access (sex workers, transgender groups, etc.), in which HPV infections deserve special attention. The prevalence of HPV infection is especially high in people living with HIV and/or among men who have sex with men. Knowledge of the distribution and dynamics of infections is especially interesting in these groups, as they may help to improve current algorithms for the prevention of anogenital cancer.

C) Study of infection by HPV genotypes and their relationship with progression to neoplastic processes. The oncogenic capacity of some HPV genotypes and their involvement in the production of anogenital cancer is well known. In addition, there are other oncological processes, such as non-melanoma skin cancer, in which HPV could be implicated. Thus, members of the gamma-24 HPV species have recently been associated with skin cancer. It is to be hoped that the appearance of new genotypes and the performance of more extensive studies may lead to the identification of new associations between HPV and neoplastic processes.

D) Study of co-infections by different HPV genotypes. The presence of co-infections of different HPV genotypes is a very frequent finding, both in skin samples and in different mucous membranes. The great genetic diversity of HPV limits the ability of classical molecular methods to perform a comprehensive detection and study of the genotypes present. However, the use of massive sequencing makes it possible to eliminate some of these biases and to obtain more detailed information on the existing HPV populations, as well as to analyze interactions between the different genotypes.

E) Description of new HPV genotypes/variants. Currently at the International HPV Reference Center (Karolinska Institute, Sweden) more than 220 HPV genotypes are described, distributed in 5 different genera. However, improved molecular detection techniques, as well as the use of massive sequencing, are allowing this number to increase rapidly. The study of new genotypes and variants is essential for the validation and quality control of available diagnostic methods. Similarly, their characterization and the study of possible associations of HPV with pathologies other than those already known is a field of great interest for research.

Research projects

Content with Investigacion Virus del papiloma humano .

Título: Impact of vaccination against Human Papillomavirus in Spain: Studye of the distribution of genotypes and its application in surveillance. Principal Investigator: Horacio Gil. Starting/End dates: 2024-2026. Funding Entity: Acción Estratégica de Salud Intramural (AESI) del Instituto de Salud Carlos III. Project Reference: PI23CIII/00006.

Título: Effect of feminizing therapy on immune response in transgender women. Principal Investigator: Victor Manuel Sánchez Merino. Collaborating Investigator: Horacio Gil. Starting/End dates:2025-2027. Funding Entity: Acción Estratégica de Salud Intramural (AESI) del Instituto de Salud Carlos III. Project Reference: PI24CIII/00031.

Publications

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PBMCs gene expression signature of advanced cirrhosis with high risk for clinically significant portal hypertension in HIV/HCV coinfected patients

Salguero, Sergio; Brochado-Kith, Oscar; Verdices, Ana Virseda; et al; Jiménez-Sousa María A (‡, AC); Resino, Salvador (‡, AC). (12/12). 2023. PBMCs gene expression signature of advanced cirrhosis with high risk for clinically significant portal hypertension in HIV/HCV coinfected patients: A cross-control study. Biomedicine & pharmacotherapy. 159, pp.114220. ISSN 1950-6007.

Relative telomere length impact on mortality of COVID-19: Sex differences.Journal of medical virology.

Virseda-Berdices, Ana; Concostrina-Martinez, Leyre; Martinez-Gonzalez, Oscar; et al; Fernandez-Rodriguez, Amanda (‡), Jiménez-Sousa María A (‡). (14/14). 2023. Relative telomere length impact on mortality of COVID-19: Sex differences.Journal of medical virology. 95-1, pp.e28368. ISSN 1096-9071.

Plasma miRNA profile at COVID-19 onset predicts severity status and mortality.

Fernandez-Pato, Asier; Virseda-Berdices, Ana; Resino, Salvador; et al; Jiménez-Sousa María A (‡, AC); Fernandez-Rodriguez, Amanda (‡). (20/20). 2022. Plasma miRNA profile at COVID-19 onset predicts severity status and mortality. EMERGING MICROBES & INFECTIONS. 11(1):676-688. doi: 10.1080/22221751.2022.2038021.

Blood microbiome is associated with changes in portal hypertension after successful direct-acting antiviral therapy in patients with HCV-related cirrhosis.The Journal of antimicrobial chemotherapy.

Virseda-Berdices, Ana; Brochado-Kith, Oscar; Diez, Cristina; et al; Jimenez-Sousa, Maria Angeles. (16/16). 2021. Blood microbiome is associated with changes in portal hypertension after successful direct-acting antiviral therapy in patients with HCV-related cirrhosis.The Journal of antimicrobial chemotherapy. 77(3):719-726. doi: 10.1093/jac/dkab444. ISSN 1460-2091.

Chronic pulmonary aspergillosis update: A year in review. Med Mycol. 2019 Apr 1

Barac A, Kosmidis C, Alastruey-Izquierdo A, Salzer HJF; CPAnet. Chronic pulmonary aspergillosis update: A year in review. Med Mycol. 2019 Apr 1;57(Supplement_2):S104-S109. doi: 10.1093/mmy/myy070. PMID: 30816975.

PUBMED DOI

Laursen CB, Davidsen JR, Van Acker L, Salzer HJF, Seidel D, Cornely OA, Hoenigl M, Alastruey-Izquierdo A, Hennequin C, Godet C, Barac A, Flick H, Munteanu O, Van Braeckel E. CPAnet Registry-An International Chronic Pulmonary Aspergillosis Registry. J Fungi (Basel). 2020 Jun

Laursen CB, Davidsen JR, Van Acker L, Salzer HJF, Seidel D, Cornely OA, Hoenigl M, Alastruey-Izquierdo A, Hennequin C, Godet C, Barac A, Flick H, Munteanu O, Van Braeckel E. CPAnet Registry-An International Chronic Pulmonary Aspergillosis Registry. J Fungi (Basel). 2020 Jun 29;6(3):E96. doi: 10.3390/jof6030096. PMID: 32610566.

PUBMED DOI

Project from GEMICOMED (SEIMC) and REIPI. Molecular identification and susceptibility testing of molds isolated in a Prospective Surveillance of Triazole Resistance in Spain (FILPOP2 study). Antimicrob Agents Chemother. 2018 Jun

Alastruey-Izquierdo A*, Alcazar-Fuoli L, Rivero-Menéndez O, Ayats J, Castro C, García-Rodríguez J, Goterris-Bonet L, Ibáñez-Martínez E, Linares-Sicilia MJ, Martin-Gomez MT, Martín-Mazuelos E, Pelaez T, Peman J, Rezusta A, Rojo S, Tejero R, Vicente Anza D, Viñuelas J, Zapico MS, Cuenca-Estrella M; members of the FILPOP2 Project from GEMICOMED (SEIMC) and REIPI. Molecular identification and susceptibility testing of molds isolated in a Prospective Surveillance of Triazole Resistance in Spain (FILPOP2 study). Antimicrob Agents Chemother. 2018 Jun 25. doi: 10.1128/AAC.00358-18. PMID: 29941643.

PUBMED DOI

In vitro activity of APX001A against rare moulds using EUCAST and CLSI methodologies. J Antimicrob Chemother. 2019 May 1

Rivero-Menendez O, Cuenca-Estrella M, Alastruey-Izquierdo A.* In vitro activity of APX001A against rare moulds using EUCAST and CLSI methodologies. J Antimicrob Chemother. 2019 May 1;74(5):1295-1299. doi: 10.1093/jac/dkz022. PMID: 30753499.

PUBMED DOI

List of staff

Additional Information

Our general objective is to provide early knowledge about any emerging antibiotic resistance mechanism in our country. This contribution of knowledge is based on transversal objectives that we consider key, such as 1) the ability to adapt research to emerging resistance problems, 2) the promotion of cooperative and multidisciplinary research studies working in networks with different Spanish and foreign centers, 3) the transfer of research results in an agile way to the clinical practice of the national health system, and 4) the promotion of the interrelation of research with reference, advice, training and dissemination seeking the empowerment of all. 

More specifically, our main scientific objectives are the characterization of the molecular bases of antibiotic resistance in pathogenic bacteria, the study of the molecular epidemiology and population structure of resistant bacteria, the characterization of the mobile genetic elements that carry resistance genes, and the development of diagnostic techniques and therapeutic alternatives against bacteria with extensive resistance to antibiotics. In this sense, research into the dissemination pathways of Enterobacteriaceae, Acinetobacter baumannii and carbapenemase-producing Pseudomonas aeruginosa (as a paradigm of extensive resistance and pan-resistance) is one of our current priority objectives.

Our general objective is to provide early knowledge about any emerging antibiotic resistance mechanism in our country. This contribution of knowledge is based on transversal objectives that we consider key, such as 1) the ability to adapt research to emerging resistance problems, 2) the promotion of cooperative and multidisciplinary research studies working in networks with different Spanish and foreign centers, 3) the transfer of research results in an agile way to the clinical practice of the national health system, and 4) the promotion of the interrelation of research with reference, advice, training and dissemination seeking the empowerment of all. 

More specifically, our main scientific objectives are the characterization of the molecular bases of antibiotic resistance in pathogenic bacteria, the study of the molecular epidemiology and population structure of resistant bacteria, the characterization of the mobile genetic elements that carry resistance genes, and the development of diagnostic techniques and therapeutic alternatives against bacteria with extensive resistance to antibiotics. In this sense, research into the dissemination pathways of Enterobacteriaceae, Acinetobacter baumannii and carbapenemase-producing Pseudomonas aeruginosa (as a paradigm of extensive resistance and pan-resistance) is one of our current priority objectives.

The current director of CNM is Dr. José Miguel Rubio Muñoz.

Dr. José Miguel Rubio has a degree in Biological Sciences from the Universidad Autónoma de Madrid (1986) and a PhD in Biological Sciences from the same university (1992). He carried out his doctoral thesis at the Department of Genetics of the Universidad Autónoma de Madrid, as Associate Professor (1988-1989), and at the School of Biology of the University of East Anglia in Norwich, UK, as Senior Research Assistant (1989-1992).

During his postdoctoral period he obtained a grant from the European Commission within the Human Capital and Mobility Program to be carried out at the University of “La Sapienza” in Rome, Italy and the Institute of Molecular Biology and Biotechnology in Crete, Greece (1993-1994). Subsequently, he made a further stay funded by the WHO and the university itself at the Department of Entomology, Wageningen University, The Netherlands (1994-1996).

Since 1997 he has been a member of the Instituto de Salud Carlos III (ISCIII), where he joined the Department of Parasitology of the National Center of Microbiology, as an EU-INCO postdoctoral fellow and later with a grant from the Autonomous Community of Madrid (CAM). She was part of the founding group of the National Center for Tropical Medicine (2003-2006) and of the 24/7 Alerts and Emergencies Unit (2006-2018) and is currently Head of the Malaria and Emerging Parasitosis Unit of the National Microbiology Center and is part, as research staff, of the Center for Biomedical Research Network on Infectious Diseases (CIBERINFEC/ISCIII).

During his scientific career he has been Visiting Scientist at the Leonidas e Marie Dean Center (FIOCRUZ-AMAZONAS, Manaus, Brazil) and is an External Consultant of the Parasitology Departments of Cairo University (Egypt) and the Medical Research Center (MRC) of Kuala Lumpur (Malaysia).  He also belongs or has belonged to different national and international committees:  Member of the expert group for malaria control of the European Centre for Disease Control (ECDC) since 2011; Expert-Evaluator for health programs of the European Commission since 2004; Spanish Representative (commissioned by ISCIII and MSC) in the Technical Scientific Committee of the TDR (WHO) 2007-2008; Spanish Deputy Focal Point for microbiology at the European Centre for Disease Control (ECDC) from 2012 to 2020; and, member of the Research Ethics Committee of ISCIII until 2019.

In this period he has published more than 100 articles in international indexed journals, 10 book chapters and has been co-editor of two books in the area of malaria, tropical medicine and neglected diseases. He has participated in 58 competitively funded research projects, 20 of them international, having been the principal investigator in 8 national and 11 international projects as PI of the project or WP leader. In addition, he has led five agreements with companies. Currently he has been awarded four sexenios of research, being presented this year 2025 to the fifth. In the teaching field, he participates in different postgraduate programs in the areas of microbiology and parasitology, having directed seven doctoral theses and more than 20 Master's or Degree final projects, both nationally and internationally. ​​​​​

El laboratorio de Referencia e Investigación en Resistencia a Antibióticos ofrece una amplia cartera de servicios al Sistema Nacional de Salud, las cuales pueden solicitarse en cnm-laboratorios.isciii.es. Jefe del Laboratorio: Jesús Oteo Iglesias (Punto focal Nacional de Resistencia antibiótica).

Dispone de dos programas de Vigilancia oficiales y gratuitos que engloban los ensayos ofertados ya sea como aislamientos individuales o mediante estudio de brotes. El Laboratorio utiliza asimismo técnicas de PCR en tiempo real para la detección de genes de resistencia, estas técnicas se han adaptado a un formato multiplex que permite detectar varios genes en la misma reacción. En los últimos años se han incluido metodologías basadas en la secuenciación de genomas completos para el análisis de bacterias multiresistentes (WGS).

Programa de vigilancia de Haemophilus influenzae. Responsables: María Pérez Vázquez (Punto focal Nacional de Haemophilus influenzae) y Belén Aracil. Laboratorio encargado de la identificación, estudio de sensibilidad y análisis genotípico de aislados de Haemophilus influenzae, centrándose esencialmente en la patología invasiva debida este patógeno. 

Programa de vigilancia de Resistencia a Antibióticos. Responsables: María Pérez Vázquez  y Belén Aracil (Punto focal Nacional de Resistencia antibiótica). Laboratorio encargado de la identificación, el estudio de sensibilidad antibiótica, y el diagnóstico fenotípico y genotípico de los diferentes mecanismos de resistencia a antibióticos fundamentalmente en enterobacterias y gram-negativos no fermentadores y Enterococcus spp.

Estudio de brotes. Responsables: Belén Aracil y María Pérez Vázquez. El programa incluye la caracterización de brotes nosocomiales y clones emergentes de alto riesgo mediante diferentes técnicas moleculares (tabla resumen). Éstas, nos permiten realizar estudios filogenéticos con el fin de obtener una información detallada acerca la relación entre los diferentes aislados y su trazabilidad. El objetivo final es generar datos que se transfieren a los hospitales como ayuda para la prevención o control de la propagación del brote.

Acreditación y Calidad. Responsable: Belén Aracil. El laboratorio Referencia e Investigación en Resistencia a Antibióticos ha sido de los primeros en el ISCIII en la utilización de técnicas acreditadas por la Entidad Nacional de Acreditaciones (ENAC). Este laboratorio consiguió la primera acreditación homologada de técnicas diagnósticas en 2012, programa que ha sido ampliado, de manera que en la actualidad más de la mitad de las técnicas ofrecidas al Sistema Nacional de Salud están debidamente acreditadas por ENAC.

Técnicos responsables de las técnicas realizadas en el Laboratorio: Noelia Lara Fuella y Verónica Bautista Sánchez.

En la siguiente imagen se resumen las técnicas ofrecidas al Sistema Nacional de Salud.

PROGRAMAS NOMBRE CARTERA SERVICIO PATÓGENO DETERMINACIÓN, DETECCIÓN, ANÁLISIS MÉTODOS

Programa de vigilancia de Haemophilus

Programa de vigilancia de resistencia a antibióticos.

Identificación bacteriana

Haemophilus sp.

Enterobacterias, gram-negativos no fermentadores, Enterococcus spp

Identificación bacteriana

Bioquímicos

MALDI TOF

Secuenciación de RNAr

Identificación capsular

Haemophilus influenzae

 

Identificación capsular fenotípica y genotípica

Aglutinación serológica en latex

PCR ind/multiplex

Determinación de Sensibilidad

Haemophilus sp.

Enterobacterias, gram-negativos no fermentadores, Enterococcus

 

Determinación de Sensibilidad

Microdilución                

Tiras epsilon               

Kirby Bauer

Métodos fenotípicos de detección de mecanismos de resistencia

Enterobacterias, gram-negativos no fermentadores,

 

Métodos fenotípicos de detección de mecanismos de resistencia

Discos y tabletas combinados con inhibidores                

Tiras combinadas     

Test de Hodge modificado

CabaNP                               

Inmunocromatografía CBP

Métodos genotípicos de detección de mecanismos de resistencia

Haemophilus sp.

Enterobacterias, gram-negativos no fermentadores, Enterococcus

 

ADN, PCR y secuenciación

PCR ind/multiplex

Análisis comparativo de las secuencias

Tipificación molecular/análisis filogenéticos

Haemophilus sp.

Enterobacterias, gram-negativos no fermentadores, Enterococcus

 

Corte enzimas de restricción, electroforesis

ADN, PCR y secuenciación

Preparación de librerías y secuenciación y análisis de genomas completos

 

PFGE

 

MLST

 

WGS