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Resumen Introduccion El objetivo fue realizar la validacion clinica del sistema molecular AMR Direct Flow Chip® para la deteccion de genes de resistencia a antimicrobianos partiendo de aislados bacterianos en cultivo, asi como de hisopos de muestras nasales o rectales. Metodos El ensayo AMR es una PCR multiplex seguida de hibridacion reversa tipo dot blot en arrays de ADN completamente automatizada mediante la plataforma HS24, con un tiempo de realizacion de 3 h. Se realizo la validacion preclinica con 104 cepas bacterianas caracterizadas y posteriormente se analizaron 210 muestras de hisopos nasales o rectales. Resultados La sensibilidad y la especificidad del ensayo preclinico fueron del 100%, identificando correctamente las 104 cepas. En la validacion clinica, la sensibilidad fue del 100% y la especificidad fue del 100% en muestras rectales y del 97% en hisopos nasales. Conclusiones El sistema AMR Direct Flow Chip® es un sistema rapido y eficaz para la deteccion de microorganismos multirresistentes a partir de muestras rectales y nasales.

Background Differentiating between persistent infection with intermittent viral shedding and reinfection with severe acute respiratory syndrome coronavirus 2 remains challenging. Although a small number of cases with genomic evidence of second infection have been reported, limited information exists on frequency and determinants of reinfection, time between infections, and duration of immunity after the primary infection. Case presentation We report a reinfection with severe acute respiratory syndrome coronavirus 2 in a 52-year-old caucasian male whose primary infection was diagnosed in May 2020, during the first wave of the pandemic in Spain, and the second occurred 8 months later, in January 2021. We present a complete dataset including results from real-time polymerase chain reaction, serology, and genome sequencing confirming reinfection with a different clade. Noteworthy was that the patient was immunocompetent but had multiple cardiometabolic comorbidities, including refractory arterial hypertension, that might increase the individual risk in coronavirus disease 2019. Conclusions This case of reinfection with severe acute respiratory syndrome coronavirus 2 occurring several months after the primary infection reports the longest time interval between reinfection and initial infection described to date. It raises concerns on the duration of protective immunity, suggesting that it may begin to wane in patients who acquired the initial infection during the first wave of the pandemic. The potential contributing role of arterial hypertension and cardiometabolic comorbidities as risk factors for reinfection deserves investigation.

Objectives To assess the benefits of remdesivir in hospitalized COVID-19 patients receiving combined immunomodulatory therapy (CIT) with dexamethasone and tocilizumab. Methods This was a cohort study of microbiologically confirmed COVID-19 hospitalized patients. The primary outcome was all-cause 28 day mortality. Secondary outcomes were need for invasive mechanical ventilation (IMV) and IMV/death. Subgroup analyses according to SARS-CoV-2 cycle threshold (Ct) values and inflammation biomarkers were performed. Multivariable marginal structural Cox proportional hazards regression models were used to analyse the association between remdesivir therapy and the risk of outcomes of interest. Results Of 1368 hospitalized patients treated with corticosteroids, 1014 (74%) also received tocilizumab, 866 (63%) remdesivir and 767 (56%) tocilizumab + remdesivir. The 28 day mortality was 9% in the overall cohort, with an adjusted HR (aHR) of 0.32 (95% CI = 0.17–0.59) for patients receiving CIT. In the latter group, the 28 day mortality was 6.5%, with an aHR of 1.11 (95% CI = 0.57–2.16) for remdesivir use and there were no differences in secondary outcomes. The risk of primary and secondary outcomes with remdesivir differed by Ct and C-reactive protein (CRP) levels in patients receiving CIT: for 28 day mortality, the aHR was 0.48 (95% CI = 0.21–1.11) for Ct Conclusions The benefits of remdesivir administered with dexamethasone and tocilizumab in hospitalized COVID-19 patients differ depending on Ct and CRP. Remdesivir decreases the risk of mortality and need for IMV in patients with high viral loads and low-grade systemic inflammation.

Transmission is a driver of tuberculosis (TB) epidemics in high-burden regions, with assumed negligible impact in low-burden areas. However, we still lack a full characterization of transmission dynamics in settings with similar and different burdens. Genomic epidemiology can greatly help to quantify transmission, but the lack of whole genome sequencing population-based studies has hampered its application. Here, we generate a population-based dataset from Valencia region and compare it with available datasets from different TB-burden settings to reveal transmission dynamics heterogeneity and its public health implications. We sequenced the whole genome of 785

Background: Differentiating between persistent infection with intermittent viral shedding and reinfection with SARS-CoV-2 remains challenging. Although a small number of cases with genomic evidence of second infection have been reported, limited information exists on frequency and determinants of reinfection, time between infections, and duration of immunity after the primary infection. Case presentation: We report a reinfection with SARS-CoV-2 in a 52-year old male whose primary infection was diagnosed in May 2020, during the first wave of the pandemic in Spain, and the second occurred eight months later, in January 2021. We present a complete data set including results from real-time polymerase chain reaction, serology and genome sequencing confirming reinfection with a different clade. Noteworthy was that the patient was immunocompetent but had multiple cardiometabolic comorbidities, including refractory arterial hypertension, that might increase the individual risk in COVID-19.Conclusions: This case of reinfection with SARS CoV-2 occurring several months after the primary infection reports the longest time interval between reinfection and initial infection described to date. It raises concerns on the duration of protective immunity, suggesting that it may begin to wane in patients who acquired the initial infection during the first wave of the pandemic. The potential contributing role of arterial hypertension and cardiometabolic comorbidities as risk factors for reinfection deserves investigation.

Data on the performance of saliva specimens for diagnosing coronavirus disease 2019 (COVID-19) in ambulatory patients are scarce and inconsistent. We assessed saliva-based specimens for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcriptase PCR (RT-PCR) in the community setting and compared three different collection methods., Data on the performance of saliva specimens for diagnosing coronavirus disease 2019 (COVID-19) in ambulatory patients are scarce and inconsistent. We assessed saliva-based specimens for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcriptase PCR (RT-PCR) in the community setting and compared three different collection methods. This prospective study was conducted in three primary care centers. RT-PCR was performed on paired nasopharyngeal swabs (NPS) and saliva samples collected from outpatients with a broad clinical spectrum of illness. To assess differences in collection methods, saliva specimens were obtained in a different way in each of the participating centers: supervised collection (SVC), oropharyngeal washing (OPW), and self-collection (SC). Pairs of NPS and saliva samples from 577 patients (median age, 39 years; 44% men; 42% asymptomatic) were collected and tested, and 120 (20.8%) gave positive results. The overall agreement with NPS results and kappa coefficients (κ) for saliva samples obtained by SVC, OPW, and SC were 95% (κ = 0.85), 93.4% (κ = 0.76), and 93.3% (κ = 0.76), respectively. The sensitivities (95% confidence intervals [95% CI]) of the saliva specimens ranged from 86% (72.6% to 93.7%) for SVC to 66.7% (50.4% to 80%) for SC samples. Sensitivity was higher for samples with lower cycle threshold (CT) values. The best RT-PCR performance was observed for SVC, with sensitivities (95% CI) of 100% (85.9% to 100%) in symptomatic individuals and 88.9% (50.7% to 99.4%) in asymptomatic individuals at CT values of ≤30. We conclude that saliva is an acceptable specimen for the detection of SARS-CoV-2 in the community setting. Specimens collected under supervision perform comparably to NPS and can effectively identify individuals at higher risk of transmission under real-life conditions.

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Introduction The prevalence of asthma in patients hospitalized with SARS-CoV-2 has been studied and varies widely in the different series. However, the prevalence in SARS-infected patients not requiring hospitalization is not known. The objective of this study was to analyze the presence of asthma in a consecutive series of patients who tested positive in the RT-PCR assay for SARS-CoV-2 and did not require hospital admission. Methods and results A total of 218 patients (58% of those who tested positive) did not require hospitalization; they had a median age of 45 years (IQR 34–57) and 57% were female. Six patients (2.8%) had a previous diagnosis of asthma. Only one patient developed a mild aggravation of asthma symptoms associated with SARS-CoV-2 infection. Conclusions Few patients with asthma were infected by SARS-CoV-2, and this infection was not a significant cause of asthma exacerbation.

Objectives Durability of the humoral immune response to SARS-CoV-2 has yet to be defined. We longitudinally evaluated during a 12-month period the antibody responses to SARS-CoV-2, and analysed predictors of antibody titres decline and seroreversion. Methods Prospective study conducted in a cohort of patients hospitalized for microbiologically-confirmed COVID-19. Blood and nasopharyngeal samples were sequentially obtained during hospital stay and at 1, 2, 6 and 12 months after patients’ discharge for measuring anti-spike (S) and anti-nucleocapsid (N) IgG antibody levels and SARS-CoV-2 RNA, respectively. Results 80 non-vaccinated patients were analysed. At month 12 after discharge, 73 (91.2%) patients exhibited detectable S-IgG and 35 (43.8%) N-IgG antibody titres. A gradual wane was observed in S-IgG and N-IgG antibody titres. Linear regression showed that S-IgG decline was positively associated with peak antibody titres (coefficient [95% CI] 0.059 [0.05–0.067], p

Balancing access to antibiotics with the control of antibiotic resistance is a global public health priority. At present, antibiotic stewardship is informed by a ‘use it and lose it’ principle, in which antibiotic use by the population is linearly related to resistance rates. However, theoretical and mathematical models suggest that use–resistance relationships are nonlinear. One explanation for this is that resistance genes are commonly associated with ‘fitness costs’ that impair the replication or transmissibility of the pathogen. Therefore, resistant genes and pathogens may only gain a survival advantage where antibiotic selection pressures exceed critical thresholds. These thresholds may provide quantitative targets for stewardship—optimizing the control of resistance while avoiding over-restriction of antibiotics. Here, we evaluated the generalizability of a nonlinear time-series analysis approach for identifying thresholds using historical prescribing and microbiological data from five populations in Europe. We identified minimum thresholds in temporal relationships between the use of selected antibiotics and incidence rates of carbapenem-resistant Acinetobacter baumannii (Hungary), extended-spectrum β-lactamase-producing Escherichia coli (Spain), cefepime-resistant E. coli (Spain), gentamicin-resistant Pseudomonas aeruginosa (France) and methicillin-resistant Staphylococcus aureus (Northern Ireland) in different epidemiological phases. Using routinely generated data, our approach can identify context-specific quantitative targets for rationalizing population antibiotic use and controlling resistance. Prospective intervention studies that restrict antibiotic consumption are needed to validate these thresholds., G.K. was supported by a Bolyai Research Scholarship of the Hungarian Academy of Sciences. T.L. was supported by the Wellcome Trust. J.R.B. and P.R. received funding for research from Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (RD16/0016/0001), co-financed by European Development Regional Fund ‘A way to achieve Europe’, Operative Programme Intelligent Growth 2014–2020.

Balancing access to antibiotics with the control of antibiotic resistance is a global public health priority. At present, antibiotic stewardship is informed by a 'use it and lose it' principle, in which antibiotic use by the population is linearly related to resistance rates. However, theoretical and mathematical models suggest that use-resistance relationships are nonlinear. One explanation for this is that resistance genes are commonly associated with 'fitness costs' that impair the replication or transmissibility of the pathogen. Therefore, resistant genes and pathogens may only gain a survival advantage where antibiotic selection pressures exceed critical thresholds. These thresholds may provide quantitative targets for stewardship-optimizing the control of resistance while avoiding over-restriction of antibiotics. Here, we evaluated the generalizability of a nonlinear time-series analysis approach for identifying thresholds using historical prescribing and microbiological data from five populations in Europe. We identified minimum thresholds in temporal relationships between the use of selected antibiotics and incidence rates of carbapenem-resistant Acinetobacter baumannii (Hungary), extended-spectrum β-lactamase-producing Escherichia coli (Spain), cefepime-resistant E. coli (Spain), gentamicin-resistant Pseudomonas aeruginosa (France) and methicillin-resistant Staphylococcus aureus (Northern Ireland) in different epidemiological phases. Using routinely generated data, our approach can identify context-specific quantitative targets for rationalizing population antibiotic use and controlling resistance. Prospective intervention studies that restrict antibiotic consumption are needed to validate these thresholds.

Introduccion En los ultimos anos observamos la aparicion, cada vez mas frecuente, de bacterias, y singularmente de Escherichia coli, productoras de betalactamasas de espectro extendido (BLEE), que confieren resistencia a las cefalosporinas (excepto cefamicinas) y aztreonam. Estas bacterias son frecuentemente resistentes tambien a antibioticos no betalactamicos, lo que plantea un importante problema clinico. Metodos Estudio descriptivo de las cepas de E. coli productoras de BLEE aisladas en todo tipo de muestras en dos hospitales del sur de la provincia de Alicante en un periodo de 57 meses (de enero de 1999 a septiembre de 2003), con especial atencion a su origen (intrahospitalario o extrahospitalario), a las corresistencias a antibioticos no betalactamicos y a la evolucion cronologica de su incidencia. Resultados Respectivamente, 3 y 2,25% de las cepas de E. coli aisladas en cada hospital son productoras de BLEE (3,83 y 2,85% de las cepas procedentes de ingresados y 2,74 y 2,1% de las de pacientes ambulatorios). El 30,73 y 24,58% de las cepas productoras de BLEE se aislaron en pacientes hospitalizados. En ambos hospitales se encontraron porcentajes de corresistencia a ciprofloxacino, gentamicina y cotrimoxazol muy superiores en cepas productoras de BLEE. Conclusion El porcentaje de cepas de E. coli productoras de BLEE es elevado en nuestro medio, pero es mas notable su clara tendencia al incremento. Es resenable el elevado porcentaje de cepas productoras procedentes del ambito extrahospitalario. Por ultimo, resaltamos los elevados indices de corresistencia a antibioticos no betalactamicos.

In the last years, we have verified the increasing emergence of bacteria, specially Escherichia coli, that produce expanded spectrum beta-lactamases (ESBL), enzymes which confer resistance to all cephalosporins (except cephamycins) and aztreonam. These bacteria are frequently resistant also to non-beta-lactam antibiotics, a fact which poses an important clinical problem.Descriptive study of ESBL-producing strains of E. coli isolated in all kind of specimens in two hospitals of Southern Alicante (Spain), throughout a period of 57 months (January 1999 to September 2003), paying a close attention to their origin (outpatients or admitted patients), co-resistance to non beta-lactam antibiotics and evolution of their incidence.Respectively, 3% and 2.25% of E. coli strains isolated in each hospital produce ESBL (3.83% and 2.85% of strains from admitted and 2.74% and 2.1% from outpatients). 30.73% and 24.58% of strains ESBL were isolated in admitted patients. We found in both hospitals much higher percentages of co-resistance to ciprofloxacin, gentamicin and trimetoprim-sulfamethoxazole in ESBL-producing strains.The percentage of ESBL-producing E. coli is high in our environment, but it is even more noteworthy its clear trend to increase. It is very remarkable the high percentage of ESBL-producing strains isolated from outpatients. Finally, we emphasize the high percentages of co-resistance to non-beta-lactam antibiotics.

During the past 20 years, there have been numerous attempts to study the relationship between antimicrobial use and resistance using surveillance data. The method presented here represents another of those attempts. It proved helpful to demonstrate a temporal relationship between antimicrobial use and resistance and unlike most other methods,this method can take into account the use of several antimicrobials to explain specific types of resistance, quantify the effect of use on resistance,and estimate the delay between variations in use and subsequent variations in resistance.Additionally, it has allowed us to predict future levels of resistance based on past antimicrobial use and resistance data. Our observations show that ecologic systems such as that within the hospital tend to react to changes in antimicrobial use much faster than previously thought, that is, within a few months rather than several years. This finding has recently been confirmed by Corbella et al. who reported rapid variations in the percentage of imipenem-resistant Acinetobacter baumannii following changes in carbapenem use in a Spanish hospital (Corbella et al., 2000),and by Lepper et al. who also reported changes in P. aeruginosa resistance to imipenem following changes in hospital imipenem use (Lepper et al., 2002). The recent application of time-series analysis to antimicrobial use and resistance data from the primary healthcare sector in Denmark shows that this is probably also true outside hospitals (Monnet, 2000a). In conclusion, time-series analysis is a new tool that can help us make sense of antimicrobial use and resistance surveillance data,an area where modeling has proven difficult. Future developments must include confirmation of the usefulness of this method in other hospitals and in other countries.