The microbiology of sepsis is more than the application of new technologies in diagnosis

Sepsis; New technologies; DiagnosisSèpsia; Noves tecnologies; DiagnòsticSepsis; Nuevas tecnologías; DiagnósticoAdequate and rapid microbiological diagnosis of sepsis is essential for correct treatment, having a direct impact on patient prognosis. Clinical Microbiology Services must adapt fast circuits that allow prioritizing and individualizing the diagnosis of these patients. The measures adopted should not be based solely on the incorporation of new technologies but, to a large extent, on ensuring accurately collection and processing of samples, avoiding unnecessary losses of time in processing and ensuring that the information derived from this process adequately reaches the prescribing physician

Promover la RSE en el público interno, caso Los Grobo Agropecuaria

La presente tesis de producción propone el desarrollo de un Proceso Integral de Planificación de comunicación interna enmarcado en el Programa de Voluntariado Corporativo CampoSocial, llevado adelante por la Fundación Emprendimientos Rurales Los Grabo y Los Grabo Agropecuaria. En primer lugar, realizamos una auditoría comunicacional en profundidad sobre las herramientas utilizadas para el desarrollo del voluntariado y los actores comprometidos. El resultado de dicha intervención expuso las fortalezas y debilidades comunicacionales del programa que fueron plasmadas en un primer producto comunicacional: un Resumen Ejecutivo. Los cambios contextúales y nuestra intervención en el campo de acción determinaron un nuevo escenario. Desde la Fundación se nos consultó y pidió asesoramiento para arribar a posibles soluciones, por lo que en base a una realidad dinámica definimos los lineamientos de la planificación y elaboramos un plan con herramientas comunicacionales adaptables a la misma. El trabajo consta del presente documento donde desarrollamos una auditoría comunicacional en profundidad y una posterior planificación. Además, como material gráfico adicional presentamos el Resumen Ejecutivo.Facultad de Periodismo y Comunicación Socia

Tiempo para la toma de decisiones en sepsis

Código de sepsis; Gestión de la sepsis; Indicadores de calidadCodi de sèpsia; Gestió de la sèpsia; Indicadors de qualitatSepsis Code; Sepsis management; Quality indicatorsIntroduction. This study aimed to identify the common barriers leading to delayed initial management, microbiological diagnosis, and appropriate empirical antimicrobial treatment in sepsis. Patients and methods. A cross-sectional study was performed by the application of a population-based survey. Four different surveys were designed, targeting the healthcare personnel located in main hospital areas [emergency department (SEMES); infectious diseases and clinical microbiology-microbiological diagnosis (SEIMC-M); intensive care and infectious diseases, (SEMICYUC-GTEIS); and infectious diseases and clinical microbiology-clinical diagnosis, (SEIMC-C)]. Results. A total of 700 valid surveys were collected from June to November 2019: 380 (54.3%) of SEMES, 127 (18.1%) of SEIMC-M, 97 (13.9%) de SEMICYUC-GTEIS and 96 (13.7%) of SEIMC-C, in 270 hospitals of all levels of care. The qSOFA score was used as a screening tool. The most used biomarker was procalcitonin (n=92, 39.8%). The sepsis code was implemented in 157 of 235 participating centers (66.2%), particularly in tertiary level hospitals. The mean frequency of contaminated blood cultures was 8.9% (8.7). In 85 (78.7%) centers, positive results of blood cultures were available within the first 72 hours and were communicated to the treating physician effectively by phone or e-mail in 76 (81.7%) cases. The main reason for escalating treatment was clinical deterioration, and the reason for de-escalating antimicrobials was significantly different between the specialties. Quality indicators were not frequently monitored among the different participating centers. Conclusion. There are significant barriers that hinder adequate management processes in sepsis in Spanish hospitals.Introducción. Este estudio tuvo como objetivo identificar las barreras comunes que conducen al retraso en el manejo inicial, el diagnóstico microbiológico y el tratamiento antimicrobiano empírico adecuado en la sepsis. Pacientes y métodos. Se realizó un estudio transversal mediante la aplicación de una encuesta de base poblacional. Se diseñaron cuatro encuestas diferentes, dirigidas al personal de salud ubicado en las principales áreas hospitalarias [urgencias (SEMES); enfermedades infecciosas y microbiología clínica-diagnóstico microbiológico (SEIMC-M); cuidados intensivos y enfermedades infecciosas (SEMICYUC-GTEIS); y enfermedades infecciosas y microbiología clínica-diagnóstico clínico, (SEIMC-C)]. Resultados. Se recogieron un total de 700 encuestas válidas de junio a noviembre de 2019: 380 (54,3%) de SEMES, 127 (18,1%) de SEIMC-M, 97 (13,9%) de SEMICYUC-GTEIS y 96 (13,7%) de la SEIMC-C, en 270 hospitales de todos los niveles de atención. El qSOFA se utilizó principalmente como herramienta de detección. El biomarcador más utilizado fue la procalcitonina (n=92, 39,8%). El código sepsis estaba implementado en 157 de 235 centros participantes (66,2%), particularmente en hospitales de tercer nivel. La frecuencia media de hemocultivos contaminados fue del 8,9% (8,7). En 85 (78,7%) de los centros, los resultados de los hemocultivos positivos estuvieron disponibles en las primeras 72 horas y se comunicaron al médico responsable del paciente por teléfono o correo electrónico en 76 casos (81,7%). El motivo principal de la escalada del tratamiento fue el deterioro clínico y el motivo de la desescalada de los antimicrobianos fue significativamente diferente entre las especialidades. Los indicadores de calidad no se monitorizaban con frecuencia en los diferentes centros. Conclusión. Existen importantes barreras que dificultan los procesos de manejo adecuado de la sepsis en los hospitales españoles.This research has received an unrestricted grant Beckton, Dickinson and Company (BD), S.A

Decrease of invasive pneumococcal disease (IPD) in adults after introduction of pneumococcal 13-valent conjugate vaccine in Spain

A prospective laboratory-based multicenter study that collected all adult invasive pneumococcal disease (IPD) episodes from 6 Spanish hospitals before (2008-2009) and after (2012-2013). The 13-valent pneumococcal conjugate vaccine (PCV13) licensure was conducted in order to analyze the impact of PCV13 introduction for children on adult IPD. A total of 1558 IPD episodes were detected. The incidence of IPD decreased significantly in the second period by-33.9% (95% CI,-40.3% to-26.8%). IPD due to PCV7 serotypes (-52.7%; 95% CI,-64.2% to-37.5%) and to PCV13 additional serotypes (-55.0% 95% CI, -62.0% to-46.7%) significantly decreased whereas IPD due to non-PCV13 serotypes remained stable (1.0% 95% CI,-12.9% to 17.2%). IPD due to all PCV13 additional serotypes significantly declined with the exception of serotype 3 (-11.3%; 95% CI-35.0% to 21.1%). IPD due to two non-PCV13 serotypes varied: serotype 6C that rose (301.6%; 95% CI, 92.7% to 733.3%, p<0.001), related to the expansion of ST386(6C), and serotype 8 that decreased (-34.9%, 95% CI,-57.1 to-1.2, p = 0.049), related to a decline of the ST63(8). The recombinant clone ST6521(11A) (variant of ST156(9V)) increased in frequency. The decrease of serotype 19A IPD was linked to a fall in those antibiotic susceptible clones. In the last period, rates of penicillin-and cefotaxime-resistance remained under 10% and 4%, respectively. Adult IPD decreased after the PCV13 introduction in Spain due to herd protection. The spread of multidrug resistant clones (ST386(6C), ST6521(11A)) related to non-PCV13 serotypes needs further surveillance

A systematic literature review and expert consensus on risk factors associated to infection progression in adult patients with respiratory tract or rectal colonisation by carbapenem-resistant Gram-negative bacteria

Multi-drug resistance; Risk factor; ColonizationResistencia a múltiples fármacos; Factor de riesgo; ColonizaciónResistència a múltiples fàrmacs; Factor de risc; ColonitzacióObjective. Risk factors (RFs) associated with infection progression in patients already colonised by carbapenem-resistant Gram-negative bacteria (CRGNB) have been addressed in few and disperse works. The aim of this study is to identify the relevant RFs associated to infection progression in patients with respiratory tract or rectal colonisation. Material and methods. A systematic literature review was developed to identify RFs associated with infection progression in patients with CRGNB respiratory tract or rectal colonisation. Identified RFs were then evaluated and discussed by the expert panel to identify those that are relevant according to the evidence and expert’s experience. Results. A total of 8 articles were included for the CRGNB respiratory tract colonisation and 21 for CRGNB rectal colonisation, identifying 19 RFs associated with pneumonia development and 44 RFs associated with infection progression, respectively. After discussion, the experts agreed on 13 RFs to be associated with pneumonia development after respiratory tract CRGNB colonisation and 33 RFs to be associated with infection progression after rectal CRGNB colonisation. Respiratory tract and rectal colonisation, previous stay in the ICU and longer stay in the ICU were classified as relevant RF independently of the pathogen and site of colonisation. Previous exposure to antibiotic therapy or previous carbapenem use were also common relevant RF for patients with CRGNB respiratory tract and rectal colonisation. Conclusion. The results of this study may contribute to the early identification of CRGNB colonized patients at higher risk of infection development, favouring time-to-effective therapy and improving health outcomes.This study was funded by Shionogi S.L.U

Pseudomonas aeruginosa antibiotic susceptibility profiles, genomic epidemiology and resistance mechanisms: a nation-wide five-year time lapse analysis

COVID-19; SARS-CoV-2; Electronic health recordsCOVID-19; SARS-CoV-2; Registros médicos electrónicosCOVID 19; SARS-CoV-2; Registres mèdics electrònicsBackground Pseudomonas aeruginosa healthcare-associated infections are one of the top antimicrobial resistance threats world-wide. In order to analyze the current trends, we performed a Spanish nation-wide high-resolution analysis of the susceptibility profiles, the genomic epidemiology and the resistome of P. aeruginosa over a five-year time lapse. Methods A total of 3.180 nonduplicated P. aeruginosa clinical isolates from two Spanish nation-wide surveys performed in October 2017 and 2022 were analyzed. MICs of 13 antipseudomonals were determined by ISO-EUCAST. Multidrug resistance (MDR)/extensively drug resistance (XDR)/difficult to treat resistance (DTR)/pandrug resistance (PDR) profiles were defined following established criteria. All XDR/DTR isolates were subjected to whole genome sequencing (WGS). Findings A decrease in resistance to all tested antibiotics, including older and newer antimicrobials, was observed in 2022 vs 2017. Likewise, a major reduction of XDR (15.2% vs 5.9%) and DTR (4.2 vs 2.1%) profiles was evidenced, and even more patent among ICU isolates [XDR (26.0% vs 6.0%) and DTR (8.9% vs 2.6%)] (p < 0.001). The prevalence of Extended-spectrum β-lactamase/carbapenemase production was slightly lower in 2022 (2.1%. vs 3.1%, p = 0.064). However, there was a significant increase in the proportion of carbapenemase production among carbapenem-resistant strains (29.4% vs 18.1%, p = 0.0246). While ST175 was still the most frequent clone among XDR, a slight reduction in its prevalence was noted (35.9% vs 45.5%, p = 0.106) as opposed to ST235 which increased significantly (24.3% vs 12.3%, p = 0.0062). Interpretation While the generalized decrease in P. aeruginosa resistance, linked to a major reduction in the prevalence of XDR strains, is encouraging, the negative counterpart is the increase in the proportion of XDR strains producing carbapenemases, associated to the significant advance of the concerning world-wide disseminated hypervirulent high-risk clone ST235. Continued high-resolution surveillance, integrating phenotypic and genomic data, is necessary for understanding resistance trends and analyzing the impact of national plans on antimicrobial resistance.This work was supported by MSD and by the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea—NextGenerationEU through grants PI21/00017 and Personalized and precision medicine grant (MePRAM Project, PMP22/00092)

CARB-ES-19 Multicenter Study of Carbapenemase-Producing Klebsiella pneumoniae and Escherichia coli From All Spanish Provinces Reveals Interregional Spread of High-Risk Clones Such as ST307/OXA-48 and ST512/KPC-3

Carbapenemases; High-risk clones; Whole genome sequencingCarbapenemasas; Clones de alto riesgo; Secuenciación del genoma completoCarbapenemases; Clons d'alt risc; Seqüenciació del genoma sencerObjectives: CARB-ES-19 is a comprehensive, multicenter, nationwide study integrating whole-genome sequencing (WGS) in the surveillance of carbapenemase-producing K. pneumoniae (CP-Kpn) and E. coli (CP-Eco) to determine their incidence, geographical distribution, phylogeny, and resistance mechanisms in Spain. Methods: In total, 71 hospitals, representing all 50 Spanish provinces, collected the first 10 isolates per hospital (February to May 2019); CPE isolates were first identified according to EUCAST (meropenem MIC > 0.12 mg/L with immunochromatography, colorimetric tests, carbapenem inactivation, or carbapenem hydrolysis with MALDI-TOF). Prevalence and incidence were calculated according to population denominators. Antibiotic susceptibility testing was performed using the microdilution method (EUCAST). All 403 isolates collected were sequenced for high-resolution single-nucleotide polymorphism (SNP) typing, core genome multilocus sequence typing (cgMLST), and resistome analysis. Results: In total, 377 (93.5%) CP-Kpn and 26 (6.5%) CP-Eco isolates were collected from 62 (87.3%) hospitals in 46 (92%) provinces. CP-Kpn was more prevalent in the blood (5.8%, 50/853) than in the urine (1.4%, 201/14,464). The cumulative incidence for both CP-Kpn and CP-Eco was 0.05 per 100 admitted patients. The main carbapenemase genes identified in CP-Kpn were blaOXA–48 (263/377), blaKPC–3 (62/377), blaVIM–1 (28/377), and blaNDM–1 (12/377). All isolates were susceptible to at least two antibiotics. Interregional dissemination of eight high-risk CP-Kpn clones was detected, mainly ST307/OXA-48 (16.4%), ST11/OXA-48 (16.4%), and ST512-ST258/KPC (13.8%). ST512/KPC and ST15/OXA-48 were the most frequent bacteremia-causative clones. The average number of acquired resistance genes was higher in CP-Kpn (7.9) than in CP-Eco (5.5). Conclusion: This study serves as a first step toward WGS integration in the surveillance of carbapenemase-producing Enterobacterales in Spain. We detected important epidemiological changes, including increased CP-Kpn and CP-Eco prevalence and incidence compared to previous studies, wide interregional dissemination, and increased dissemination of high-risk clones, such as ST307/OXA-48 and ST512/KPC-3.This research was supported by grants from the Instituto de Salud Carlos III (numbers PI18CIII/00030 and PI21CIII/00039). It was also supported by Plan Nacional de I + D + i 2013–2016, Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía y Competitividad, Spanish Network for Research in Infectious Diseases (grants RD16CIII/0004/0002, RD16/0016/0001, RD16/0016/0003, RD16/0016/0004, RD16/0016/0006, RD16/0016/0007, RD16/0016/0008, RD16/0016/0010, and RD16/0016/0011). Cofinanced by the European Development Regional Fund “A way to achieve Europe,” Operative Program Intelligent Growth 2014–2020. CIBER – Consorcio Centro de Investigación Biomédica en Red (CB21/13/00095, CB21/13/00012, CB21/13/00049, CB21/13/00054, CB21/13/00055, CB21/13/00068, CB21/13/00081, CB21/13/00084, and CB21/13/00099) (CIBERINFEC) and Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea – NextGenerationEU also supported this work

An increase in erythromycin resistance in methicillin-susceptible Staphylococcus aureus from blood correlates with the use of macrolide/lincosamide/streptogramin antibiotics. EARS-Net Spain (2004–2020)

Staphylococcus aureus; Antibiotic resistance; MacrolidesStaphylococcus aureus; Resistència als antibiòtics; MacròlidsStaphylococcus aureus; Resistencia a los antibióticos; MacrólidosObjectives: To describe and analyse erythromycin resistance trends in blood isolates of Staphylococcus aureus (EARS-Net Spain, 2004–2020) and the association of these trends with the consumption of macrolide, lincosamide, and streptogramin B (MLSB) antibiotics. To assess molecular changes that could be involved in erythromycin resistance trends by whole genome analysis of representative isolates. Materials and methods: We collected antibiotic susceptibility data for all first-blood S. aureus isolates in patients from 47 Spanish hospitals according to EARS-Net criteria. MLSB antibiotic consumption was obtained from the Spanish Agency for Medicines and Medical Devices (2008–2020). We sequenced 137 representative isolates for core genome multilocus sequence typing, resistome and virulome analysis. Results: For the 36,612 invasive S. aureus isolates, methicillin resistance decreased from 26.4% in 2004 to 22.4% in 2020. Erythromycin resistance in methicillin-susceptible S. aureus (MSSA) increased from 13.6% in 2004 to 28.9% in 2020 (p < 0.001); however, it decreased from 68.7 to 61.8% (p < 0.0001) in methicillin-resistant S. aureus (MRSA). Total consumption of MLSB antibiotics increased from 2.72 defined daily doses per 1,000 inhabitants per day (DID) in 2014 to 3.24 DID in 2016. By WGS, the macrolide resistance genes detected were erm (59.8%), msrA (46%), and mphC (45.2%). The erm genes were more prevalent in MSSA (44/57, 77.2%) than in MRSA (38/80, 47.5%). Most of the erm genes identified in MSSA after 2013 differed from the predominant ermC gene (17/22, 77.3%), largely because ermT was significantly associated with MSSA after 2013 (11/29, 37.9%). All 13 ermT isolates in this study, except one, belonged to ST398 and came from 10 hospitals and six Spanish provinces. Conclusion: The significant increase in erythromycin resistance in blood MSSA correlated with the consumption of the MLSB antibiotics in Spain. These preliminary data seem support the hypothesis that the human ST398 MSSA clade with ermT-mediated resistance to erythromycin may be involved in this trend.This research was supported by CIBER—Consorcio Centro de Investigación Biomédica en Red (CB21/13/00095, CB21/13/00006, CB21/13/00054, CB21/13/00068, CB21/13/00084, CB21/13/00099 groups of CIBERINFEC; CB06/06/0058 group of CIBERES), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea-NextGenerationEU. This research was also supported by Personalized and precision medicine grant from the Instituto de Salud Carlos III (MePRAM Project, PMP22/00092), and by the Antibiotic Resistance and Staphylococcus aureus Surveillance Programs of the National Center for Microbiology, Instituto de Salud Carlos III

In Vitro Antibacterial Activity of Silver Nanoparticles Conjugated with Amikacin and Combined with Hyperthermia against Drug-Resistant and Biofilm-Producing Strains

Antibacterial activity; Biofilms; Silver nanoparticlesActividad antibacteriana; Biopelículas; Nanopartículas de plataActivitat antibacteriana; Biopel·lícules; Nanopartícules de plataIn view of the current increase and spread of antimicrobial resistance (AMR), there is an urgent need to find new strategies to combat it. This study had two aims. First, we synthesized highly monodispersed silver nanoparticles (AgNPs) of approximately 17 nm, and we functionalized them with mercaptopoly(ethylene glycol) carboxylic acid (mPEG-COOH) and amikacin (AK). Second, we evaluated the antibacterial activity of this treatment (AgNPs_mPEG_AK) alone and in combination with hyperthermia against planktonic and biofilm-growing strains. AgNPs, AgNPs_mPEG, and AgNPs_mPEG_AK were characterized using a suite of spectroscopy and microscopy methods. Susceptibility to these treatments and AK was determined after 24 h and over time against 12 clinical multidrug-resistant (MDR)/extensively drug-resistant (XDR) isolates of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The efficacy of the treatments alone and in combination with hyperthermia (1, 2, and 3 pulses at 41°C to 42°C for 15 min) was tested against the same planktonic strains using quantitative culture and against one P. aeruginosa strain growing on silicone disks using confocal laser scanning microscopy. The susceptibility studies showed that AgNPs_mPEG_AK was 10-fold more effective than AK alone, and bactericidal efficacy after 4, 8, 24, or 48 h was observed against 100% of the tested strains. The combination of AgNPs_mPEG_AK and hyperthermia eradicated 75% of the planktonic strains and exhibited significant reductions in biofilm formation by P. aeruginosa in comparison with the other treatments tested, except for AgNPs_mPEG_AK without hyperthermia. In conclusion, the combination of AgNPs_mPEG_AK and hyperthermia may be a promising therapy against MDR/XDR and biofilm-producing strains. IMPORTANCE Antimicrobial resistance (AMR) is one of the greatest public health challenges, accounting for 1.27 million deaths worldwide in 2019. Biofilms, a complex microbial community, directly contribute to increased AMR. Therefore, new strategies are urgently required to combat infections caused by AMR and biofilm-producing strains. Silver nanoparticles (AgNPs) exhibit antimicrobial activity and can be functionalized with antibiotics. Although AgNPs are very promising, their effectiveness in complex biological environments still falls below the concentrations at which AgNPs are stable in terms of aggregation. Thus, improving the antibacterial effectiveness of AgNPs by functionalizing them with antibiotics may be a significant change to consolidate AgNPs as an alternative to antibiotics. It has been reported that hyperthermia has a large effect on the growth of planktonic and biofilm-producing strains. Therefore, we propose a new strategy based on AgNPs functionalized with amikacin and combined with hyperthermia (41°C to 42°C) to treat AMR and biofilm-related infections.This study was supported by research grants from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (FIS 01162); la Marató TV3 (472/U/2018); the CaixaImpulse Program (Fundació LaCaixa); and the Spanish Network for Research in Infectious Diseases (REIPI RD19/0016)

Hyperthermia Prevents In Vitro and In Vivo Biofilm Formation on Endotracheal Tubes

Animal model; Biofilm; HyperthermiaModel animal; Biofilm; HipertèrmiaModelo animal; Biofilm; HipertermiaThere is currently an urgent need to find new strategies to tackle antimicrobial resistance and biofilm-related infections. This study has two aims. First, we evaluated the in vitro efficacy of hyperthermia in preventing biofilm formation on the surfaces of polyvinyl chloride discs. Second, we assessed the in vivo efficacy of hyperthermia in preventing biofilm formation in endotracheal tubes (ETTs) of a rabbit model. For the in vitro studies, nine clinical extensively drug-resistant/multidrug-resistant Gram-negative isolates of Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa and three clinical methicillin-resistant Staphylococcus aureus strains were studied. For biofilm formation, an adhesion step of 30 or 90 min followed by a growth step of 24 h were performed with application of one, two, and three pulses at 42°C for 15 min each pulse after the adhesion step. For the in vivo studies, New Zealand rabbits were intubated with ETTs previously colonized with K. pneumoniae or P. aeruginosa strains, and three pulses at 42°C for 15 min were applied after the adhesion step. The application of three pulses at 42°C for 15 min each pulse was needed to achieve the prevention of the in vitro biofilm formation of 100% of the tested strains. The application of heat pulses in a rabbit intubation model led to biofilm prevention of 85% against two K. pneumoniae strains and 80% against two P. aeruginosa strains compared to the control group. Hyperthermia application through pulses at 42°C could be a new nonantibiotic strategy to prevent biofilm formation in ETTs. IMPORTANCE Biofilm-producing microorganisms are considered medically crucial since they cause 80% of the infections that occur in the human body. Medical devices such as endotracheal tubes (ETTs) can act as a reservoir for pathogens providing the surface to which microorganisms can adhere and cause biofilm-associated infections in critically ill patients. This biofilm has been related with the development of ventilator-associated pneumonia (VAP), with an incidence of 8 to 28%, a mortality rate up to 17% and its associated high extra costs. Although some VAP-preventive measures have been reported, they have not demonstrated a significant reduction of VAP incidence. Therefore, we present a new nonantibiotic strategy based on hyperthermia application to prevent biofilm formation inside ETTs. This technology could reduce VAP incidence, intubation duration, hospital and intensive care unit (ICU) length stays, and mortality rates. Consequently, this could decrease the antibiotics administered and influence the impact of antibiotic resistance in the ICU.This study was supported by research grants from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (FIS 01162), la Marató TV3 (472/U/2018), the CaixaImpulse Program (Fundació “LaCaixa”), the Fundación para la Innovación y la Prospectiva en Salud en España (FIPSE 3932-21), and the Spanish Network for the Research in Infectious Diseases (REIPI RD19/0016)