Dispersal history of SARS-CoV-2 in Galicia, Spain.

The dynamics of SARS-CoV-2 transmission are influenced by a variety of factors, including social restrictions and the emergence of distinct variants. In this study, we delve into the origins and dissemination of the Alpha, Delta, and Omicron variants of concern in Galicia, northwest Spain. For this, we leveraged genomic data collected by the EPICOVIGAL Consortium and from the GISAID database, along with mobility information from other Spanish regions and foreign countries. Our analysis indicates that initial introductions during the Alpha phase were predominantly from other Spanish regions and France. However, as the pandemic progressed, introductions from Portugal and the USA became increasingly significant. Notably, Galicia's major coastal cities emerged as critical hubs for viral transmission, highlighting their role in sustaining and spreading the virus. This research emphasizes the critical role of regional connectivity in the spread of SARS-CoV-2 and offers essential insights for enhancing public health strategies and surveillance measures.

Mycoplasma pneumoniae at the rise not only in China: rapid increase of Mycoplasma pneumoniae cases also in Spain.

After the use of facemasks, other isolation measures enacted during the SARS-CoV-2 pandemic were lifted, respiratory pathogens, such as RSV, reappeared, but until the November 2023 WHO alert for China, M. pneumoniae had virtually disappeared. After observing a similar reappearance in our hospital, a retrospective analysis of the number of positive M. pneumoniae tests. Between 2018 and December 2023, 1619 PCR tests were ordered and 43 (2.6%) of them were positive. Two outbreaks, one in 2018 and one in 2023, accounted for the majority of cases. Tests were usually ordered in an outpatient setting (53.54%, n = 23) and most of them were paediatric patients with a mean age (sd) of 10.2 (6.2) years. As for the severity of the cases, in the 2018 outbreak, of 15 children who tested positive, 53.3% (n = 8) were admitted to the ward and 6.7% (n = 1) at the intensive care unit. Whereas in 2023, 2 patients were tested in the ward (10.5%) and one in the intensive care unit (5.2%) from a total of 19 patients. The positive rate in 2023 was significantly higher in comparison with years 2020, 2021 and 2022 and significantly lower in comparison with 2018 (P-value=0.003). The outbreak in late 2023 can be explained by the seasonality of Mycoplasma pneumonia alone, which has shown outbreaks every 3-5 years, and it does not appear to be more severe than the previous one.

Analysis of blood and nasal epithelial transcriptomes to identify mechanisms associated with control of SARS-CoV-2 viral load in the upper respiratory tract.

OBJECTIVES: The amount of SARS-CoV-2 detected in the upper respiratory tract (URT viral load) is a key driver of transmission of infection. Current evidence suggests that mechanisms constraining URT viral load are different from those controlling lower respiratory tract viral load and disease severity. Understanding such mechanisms may help to develop treatments and vaccine strategies to reduce transmission. Combining mathematical modelling of URT viral load dynamics with transcriptome analyses we aimed to identify mechanisms controlling URT viral load. METHODS: COVID-19 patients were recruited in Spain during the first wave of the pandemic. RNA sequencing of peripheral blood and targeted NanoString nCounter transcriptome analysis of nasal epithelium were performed and gene expression analysed in relation to paired URT viral load samples collected within 15 days of symptom onset. Proportions of major immune cells in blood were estimated from transcriptional data using computational differential estimation. Weighted correlation network analysis (adjusted for cell proportions) and fixed transcriptional repertoire analysis were used to identify associations with URT viral load, quantified as standard deviations (z-scores) from an expected trajectory over time. RESULTS: Eighty-two subjects (50% female, median age 54 years (range 3-73)) with COVID-19 were recruited. Paired URT viral load samples were available for 16 blood transcriptome samples, and 17 respiratory epithelial transcriptome samples. Natural Killer (NK) cells were the only blood cell type significantly correlated with URT viral load z-scores (r = -0.62, P = 0.010). Twenty-four blood gene expression modules were significantly correlated with URT viral load z-score, the most significant being a module of genes connected around IFNA14 (Interferon Alpha-14) expression (r = -0.60, P = 1e-10). In fixed repertoire analysis, prostanoid-related gene expression was significantly associated with higher viral load. In nasal epithelium, only GNLY (granulysin) gene expression showed significant negative correlation with viral load. CONCLUSIONS: Correlations between the transcriptional host response and inter-individual variations in SARS-CoV-2 URT viral load, revealed many molecular mechanisms plausibly favouring or constraining viral replication. Existing evidence corroborates many of these mechanisms, including likely roles for NK cells, granulysin, prostanoids and interferon alpha-14. Inhibition of prostanoid production and administration of interferon alpha-14 may be attractive transmission-blocking interventions.

Systematic influenza screening in cardiac intensive care units during the influenza season: A prospective study in Spain.

BACKGROUND: Little is known about the incidence of influenza among admissions to the cardiac intensive care unit (C-ICU), accuracy of clinical suspicion, and influenza vaccination uptake. We evaluated the incidence of influenza at C-ICU admission during the influenza season, potential underdiagnosis, and vaccination uptake. METHODS: Prospective study at five C-ICUs during the 2017-2020 influenza seasons. A nasopharyngeal swab was collected at admission from patients who consented (n = 788). Testing was with Xpert®XpressFlu/RSV. RESULTS: Influenza was detected in 43 patients (5.5%) (40 FluA; 3 FluB) and clinically suspected in 27 (62.8%). Compared to patients without influenza, patients with influenza more frequently had heart failure (37.2% vs 22.8%, P = 0.031), previous contact with relatives with influenza-like illnesses (23.3% vs 12.5%, P = 0.042), antimicrobial use (67.4% vs 23.2%, P <0.01), and need for mechanical ventilation (25.6% vs 14.5%, P = 0.048). Patients received oseltamivir promptly. We found no differences in mortality (11.6% vs 5.2%, P = 0.076). Patients with influenza more frequently had myocarditis (9.3% vs 0.9%, P <0.01) and pericarditis (7.0% vs 0.8%, P = 0.01). Overall, 43.0% of patients (339/788) were vaccinated (51.9% of those with a clear indication [303/584]). CONCLUSION: Influenza seems to be a frequently underdiagnosed underlying condition in admissions to the C-ICU. Influenza should be screened for at C-ICU admission during influenza epidemics.

Efficacy and Safety of Inhaled Ethanol in Early-Stage SARS-CoV-2 Infection in Older Adults: A Phase II Randomized Clinical Trial.

BACKGROUND: Inhaled ethanol in the early stages of SARS-CoV-2 infection may reduce the viral load, decreasing progression and improving prognosis. The ALCOVID-19 trial was designed to study the efficacy and safety of inhaled ethanol in older adults at initial phases of infection. METHODS: Randomized, triple-blind, placebo-controlled phase II clinical trial. Experimental group (n = 38) inhaled 65° ethanol through an oxygen flow, while in the control group (n = 37), water for injection was used. General endpoint was to evaluate disease progression according to the modified World Health Organization (WHO) Clinical Progression Scale. Specific effectiveness endpoints were body temperature, oxygen saturation, viral load assessed by cycle threshold (Ct) on real-time polymerase chain reaction (RT-PCR), analytical biomarkers and use of antibiotics or corticosteroids. Specific safety outcomes were the absence of ethanol in plasma, electrographic, analytical, or respiratory alterations. RESULTS: In the intention-to-treat population, no differences were found regarding disease progression. Mean Ct values increased over time in both groups, being numerically higher in the ethanol group, reaching a value above 33 only in the ethanol group on day 14, a value above which patients are considered non-infective. No differences were found in the other specific effectiveness endpoints. Inhaled ethanol was proven to be safe as no plasma ethanol was detected, and there were no electrocardiographic, analytical, or respiratory alterations. CONCLUSIONS: The efficacy of inhaled ethanol in terms of the progression of SARS-CoV-2 infection was not demonstrated in the present trial. However, it is positioned as a safe treatment for elderly patients with early-stage COVID-19.

Characterisation of the blood RNA host response underpinning severity in COVID-19 patients.

Infection with SARS-CoV-2 has highly variable clinical manifestations, ranging from asymptomatic infection through to life-threatening disease. Host whole blood transcriptomics can offer unique insights into the biological processes underpinning infection and disease, as well as severity. We performed whole blood RNA Sequencing of individuals with varying degrees of COVID-19 severity. We used differential expression analysis and pathway enrichment analysis to explore how the blood transcriptome differs between individuals with mild, moderate, and severe COVID-19, performing pairwise comparisons between groups. Increasing COVID-19 severity was characterised by an abundance of inflammatory immune response genes and pathways, including many related to neutrophils and macrophages, in addition to an upregulation of immunoglobulin genes. In this study, for the first time, we show how immunomodulatory treatments commonly administered to COVID-19 patients greatly alter the transcriptome. Our insights into COVID-19 severity reveal the role of immune dysregulation in the progression to severe disease and highlight the need for further research exploring the interplay between SARS-CoV-2 and the inflammatory immune response.

Oral microbiome and systemic antineoplastics in cancer treatment: A systematic review

Background: Oral mucositis is one of the most common side effects in cancer patients receiving systemic antineoplastics. However, the underlying biological mechanisms leading to this condition are still unclear. For this reason, it has been hypothesised that systemic antineoplastics may cause an imbalance on the oral microbiota that subsequently triggers oral mucosa damage. Material and Methods: A systematic review was performed following the PRISMA protocol and the PICO question established was: patients diagnosed with cancer, who are candidates for receiving systemic antineoplastics (P=Patients), that undergo oral microbiome determinations (I=Intervention), before and after systemic antineoplastics administration (C=Comparison), to analyse changes in the oral microbiome composition (O=Outcome). The bibliographic search was carried out in PubMed and other scientific repositories. Results: Out of 166 obtained articles, only 5 met eligibility criteria. Acute myeloid leukaemia (AML) was the most frequent type of cancer (40 %) among the participants. Only one of the studies included a control group of healthy subjects. Heterogeneity in the protocols and approaches of the included studies hindered a detailed comparison of the outcomes. However, it was stated that a decrease in bacteria α diversity is often associated with oral mucositis. On the other hand, fungal diversity was not associated with oral mucositis although α diversity was lower at baseline on patients developing oral candidiasis. Conclusions: There is insufficient scientific evidence of oral microbiological changes in patients undergoing systemic antineoplastics. Further investigations ought to be carried out to identify microorganisms that might play a key role in the pathogenesis of oral mucosa damage in patients undergoing systemic antineoplastics.(AU)

A multi-tissue study of immune gene expression profiling highlights the key role of the nasal epithelium in COVID-19 severity.

Coronavirus Disease-19 (COVID-19) symptoms range from mild to severe illness; the cause for this differential response to infection remains unknown. Unravelling the immune mechanisms acting at different levels of the colonization process might be key to understand these differences. We carried out a multi-tissue (nasal, buccal and blood; n = 156) gene expression analysis of immune-related genes from patients affected by different COVID-19 severities, and healthy controls through the nCounter technology. Mild and asymptomatic cases showed a powerful innate antiviral response in nasal epithelium, characterized by activation of interferon (IFN) pathway and downstream cascades, successfully controlling the infection at local level. In contrast, weak macrophage/monocyte driven innate antiviral response and lack of IFN signalling activity were present in severe cases. Consequently, oral mucosa from severe patients showed signals of viral activity, cell arresting and viral dissemination to the lower respiratory tract, which ultimately could explain the exacerbated innate immune response and impaired adaptative immune responses observed at systemic level. Results from saliva transcriptome suggest that the buccal cavity might play a key role in SARS-CoV-2 infection and dissemination in patients with worse prognosis. Co-expression network analysis adds further support to these findings, by detecting modules specifically correlated with severity involved in the abovementioned biological routes; this analysis also provides new candidate genes that might be tested as biomarkers in future studies. We also found tissue specific severity-related signatures mainly represented by genes involved in the innate immune system and cytokine/chemokine signalling. Local immune response could be key to determine the course of the systemic response and thus COVID-19 severity. Our findings provide a framework to investigate severity host gene biomarkers and pathways that might be relevant to diagnosis, prognosis, and therapy.

Development and Characterization of Inhaled Ethanol as a Novel Pharmacological Strategy Currently Evaluated in a Phase II Clinical Trial for Early-Stage SARS-CoV-2 Infection.

Inhaled administration of ethanol in the early stages of COVID-19 would favor its location on the initial replication sites, being able to reduce the progression of the disease and improving its prognosis. Before evaluating the efficacy and safety of this novel therapeutic strategy in humans, its characterization is required. The developed 65° ethanol formulation is stable at room temperature and protected from light for 15 days, maintaining its physicochemical and microbiological properties. Two oxygen flows have been tested for its administration (2 and 3 L/min) using an automated headspace gas chromatographic analysis technique (HS-GC-MS), with that of 2 L/min being the most appropriate one, ensuring the inhalation of an ethanol daily dose of 33.6 ± 3.6 mg/min and achieving more stable concentrations during the entire treatment (45 min). Under these conditions of administration, the formulation has proven to be safe, based on histological studies of the respiratory tracts and lungs of rats. On the other hand, these results are accompanied by the first preclinical molecular imaging study with radiolabeled ethanol administered by this route. The current ethanol formulation has received approval from the Spanish Agency of Medicines and Medical Devices for a phase II clinical trial for early-stage COVID-19 patients, which is currently in the recruitment phase (ALCOVID-19; EudraCT number: 2020-001760-29).

Non-tuberculous mycobacteria: beyond the magic mountain / Micobacterias no tuberculosas, más allá de la montaña mágica

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Leprosy in the twenty-first century: a microbiological, clinical, and epidemiological study in northwestern Spain.

Leprosy, or Hansen's disease, is a chronic granulomatous disease caused by Mycobacterium leprae and the recently discovered Mycobacterium lepromatosis. In Spain and other countries, where leprosy has been eliminated, an increasing number of imported cases have been documented, especially from South Africa and South America. The diagnosis of leprosy is mainly clinical, based on the signs established by the World Health Organization (WHO), although laboratory tools can be useful for diagnostic confirmation. The treatment is based on the administration of multi-drug therapy, and involves the multidisciplinary work of experts in ophthalmology, orthopedics, and physiotherapy. We studied the confirmed cases by microbiological and /or histopathological diagnosis in the health area of Santiago de Compostela (456,874 inhabitants in Galicia, in the Northwest of Spain), analyzing their clinical, microbiological, and epidemiological characteristics (2006-2015). In our study, we describe five cases of leprosy, four of them imported and one that, in the absence of more data, is native. Although we have only documented five cases during the 10 years of the study, our experience highlights the importance of considering the country of origin, travel history, and contacts in patients or staff working with leprosy patients. Despite the decrease of leprosy in our environment, it is important to enhance suspicion of the disease among health personnel, especially in those patients from countries where leprosy is endemic and those in close contact with the diagnosed patients.

Seroprevalencia de anticuerpos frente al virus del sarampión en Galicia: tendencias durante los últimos diez años en función de la edad y sexo / Seroprevalence of antibodies against measles virus in Galicia: trends during the last ten years depending on age and sex

OBJETIVOS: En 1998 la Región de Europa de la Organización Mundial de la Salud fijó el objetivo de eliminar el sarampión. En este estudio se analizó la prevalencia de la inmunidad frente al virus del sarampión en la población del área sanitaria de Santiago de Compostela a partir de los datos obtenidos entre 2008-2018. PACIENTES Y MÉTODOS: Se estudiaron 7.150 pacientes diferentes que se dividieron en grupos según su año de nacimiento: 2010-2017, 2000-2009, 1990-1999, 1980-1989, 1953-1979 y <1953. La determinación en suero de IgG frente al virus del sarampión se realizó mediante un inmunoensayo quimioluminiscente comercializado. RESULTADOS: Se observó un mínimo (76%) para las tasas de protección frente al virus del sarampión en los nacidos entre 1990-1999. Por grupo de edad se vio que en todos los grupos las mujeres presentaron un porcentaje superior de anticuerpos frente al sarampión. En un modelo de regresión logística con año de nacimiento y sexo se obtuvo una odds ratio para el año de nacimiento (p < 0,001) de 1,06 y para el sexo (p = 0,0013) de 0,82. CONCLUSIONES: Se observaron seroprevalencias inferiores a partir de la implantación de la vacuna, un cambio más acusado durante el periodo de implantación y desde el plan de vacunación para el sarampión del año 2000 en Galicia, las tasas de protección frente al virus del sarampión han ido aumentado en nuestra área. Aunque se observó una mayor proporción de mujeres protegidas frente a la de hombres, estas diferencias fueron escasas

OBJECTIVES: In 1998, the Europe Region of the World Health Organization set the goal of eliminating measles. In this study, the prevalence of immunity against measles virus in the population of the health area of Santiago de Compostela was analyzed based on data obtained between 2008-2018. METHODS: A total of 7,150 different patients were studied and divided into groups according to their year of birth: 2010-2017, 2000-2009, 1990-1999, 1980-1989, 1953-1979 and <1953. The serum determination of IgG against measles virus was performed using a commercialized chemiluminescent immunoassay. RESULTS: A minimum (76%) was observed for measles virus protection rates in those born between 1990-1999. By age group it was seen that in all groups the women presented a higher percentage of antibodies against measles. In a logistic regression model with year of birth and sex, an odds ratio of 1.06 (p < 0.001) was obtained for the year of birth and of 0.82 (p = 0.0013) for sex. CONCLUSIONS: It was observed lower seroprevalences from the implantation of the vaccine and a more pronounced change during the implantation period. From the vaccination plan for measles of the year 2000 in Galicia, the rates of protection against the virus of the measles have been increasing in our area. Although there is a greater proportion of women protected against men, these differences are small

A multicentre prospective study evaluating the impact of proton-pump inhibitors omeprazole and pantoprazole on voriconazole plasma concentrations.

Voriconazole is an antifungal metabolised by CYP2C19 enzyme, which can be inhibited by proton-pump inhibitors (PPIs). A prospective observational study was carried out to determine the influence of PPIs on voriconazole pharmacokinetic. The 78 patients included were divided into 4 groups: omeprazole (n = 32), pantoprazole (n = 25), esomeprazole (n = 3) and no PPI (n = 18). Patients with no PPI had no significant difference in plasma voriconazole concentration when compared with those with PPI (2.63 ± 2.13 µg/mL [95% confidence interval {CI} 1.57-3.69] vs 2.11 ± 1.73 µg/mL [95%CI 1.67-2.55], P > .05). However, voriconazole plasma concentration was significantly lower in patients treated with pantoprazole vs those treated with omeprazole (1.44 ± 1.22 µg/mL [95%CI 0.94-1.94) vs 2.67 ± 1.88 µg/mL [95%CI 2.02-3.32], P = .013) suggesting a greater CYP2C19 enzyme inhibitory effect of omeprazole. This study demonstrates the greater CYP inhibition capacity of omeprazole and should be helpful for the choice of PPIs for patients treated with voriconazole.

Factores clínicos asociados a enfermedad pulmonar por Aspergillus spp. en pacientes con enfermedad pulmonar obstructiva crónica / Clinical factors associated with pulmonary aspergillosis in patients with chronic obstructive pulmonary disease

OBJETIVO: Conocer las características clínicas y epidemiológicas de los pacientes con enfermedad pulmonar obstructiva crónica (EPOC) y aislamiento de especies de Aspergillus en muestra respiratoria e identificar factores que nos ayuden a diferenciar entre colonización e infección. MÉTODOS: Estudio de cohortes retrospectivo en el que se incluyeron todos los pacientes con EPOC y aislamiento de Aspergillus spp. en muestra respiratoria durante un periodo de 12 años. Se asignaron los pacientes a 2 categorías: colonización y aspergilosis pulmonar (AP), que incluye las diferentes formas de presentación clínica. Se aplicó un modelo de regresión logística binaria para identificar los factores predictores de desarrollo de AP. RESULTADOS: Un total de 123 pacientes fueron incluidos en el estudio: 48 (39%) colonizados y 75 (61%) con AP: 68 con AP invasiva probable y 7 con AP crónica. No hubo correlación entre el riesgo de AP y los estadios espirométricos de la clasificación GOLD. Se identificaron como factores predictores independientes de AP en pacientes con EPOC la oxigenoterapia domiciliaria (OR: 4,39; IC 95%: 1,60-12,01; p = 0,004), las bronquiectasias (OR: 3,61; IC 95%: 1,40-9,30; p = 0,008), la hospitalización en los 3 meses previos al ingreso (OR: 3,12; IC 95%: 1,24-7,87; p = 0,016) y la terapia antifúngica frente a Candida spp. en el mes previo (OR: 3,18; IC 95%: 1,16-8,73; p = 0,024). CONCLUSIONES: La oxigenoterapia continua domiciliaria, las bronquiectasias, la hospitalización en los 3 meses previos al ingreso y la utilización de terapia antifúngica frente a Candida spp. en el mes previo se asocian a mayor riesgo de AP en pacientes con EPOC

OBJECTIVE: To explore the clinical and epidemiological characteristics of chronic obstructive pulmonary disease (COPD) patients with Aspergillus spp. isolation from respiratory samples, and to identify which factors may help us to distinguish between colonisation and infection. METHODS: A retrospective cohort study was performed. All patients with COPD and respiratory isolation of Aspergillus spp. over a 12-year period were included. Patients were assigned to 2 categories: colonisation and pulmonary aspergillosis (PA), which includes the different clinical forms of aspergillosis. A binary logistic regression model was performed to identify the predictive factors of PA. RESULTS: A total of 123 patients were included in the study: 48 (39.0%) with colonisation and 75 (61.0%) with PA: 68 with probable invasive pulmonary aspergillosis and 7 with chronic pulmonary aspergillosis. Spirometric stages of the GOLD classification were not correlated with a higher risk of PA. Four independent predictive factors of PA in COPD patients were identified: home oxygen therapy (OR: 4.39; 95% CI: 1.60-12.01; P = .004), bronchiectasis (OR: 3.61; 95% CI: 1.40-9.30; P = .008), hospital admission in the previous three months (OR: 3.12; 95% CI: 1.24-7.87; P = .016) and antifungal therapy against Candida spp. in the previous month (OR: 3.18; 95% CI: 1.16-8.73; P = .024). CONCLUSIONS: Continuous home oxygen therapy, bronchiectasis, hospital admission in the previous three months and administration of antifungal medication against Candida spp. in the previous month were associated with a higher risk of pulmonary aspergillosis in patients with COPD

Clinical factors associated with pulmonary aspergillosis in patients with chronic obstructive pulmonary disease. / Factores clínicos asociados a enfermedad pulmonar por Aspergillus spp. en pacientes con enfermedad pulmonar obstructiva crónica.

OBJECTIVE: To explore the clinical and epidemiological characteristics of chronic obstructive pulmonary disease (COPD) patients with Aspergillus spp. isolation from respiratory samples, and to identify which factors may help us to distinguish between colonisation and infection. METHODS: A retrospective cohort study was performed. All patients with COPD and respiratory isolation of Aspergillus spp. over a 12-year period were included. Patients were assigned to 2 categories: colonisation and pulmonary aspergillosis (PA), which includes the different clinical forms of aspergillosis. A binary logistic regression model was performed to identify the predictive factors of PA. RESULTS: A total of 123 patients were included in the study: 48 (39.0%) with colonisation and 75 (61.0%) with PA: 68 with probable invasive pulmonary aspergillosis and 7 with chronic pulmonary aspergillosis. Spirometric stages of the GOLD classification were not correlated with a higher risk of PA. Four independent predictive factors of PA in COPD patients were identified: home oxygen therapy (OR: 4.39; 95% CI: 1.60-12.01; P=.004), bronchiectasis (OR: 3.61; 95% CI: 1.40-9.30; P=.008), hospital admission in the previous three months (OR: 3.12; 95% CI: 1.24-7.87; P=.016) and antifungal therapy against Candida spp. in the previous month (OR: 3.18; 95% CI: 1.16-8.73; P=.024). CONCLUSIONS: Continuous home oxygen therapy, bronchiectasis, hospital admission in the previous three months and administration of antifungal medication against Candida spp. in the previous month were associated with a higher risk of pulmonary aspergillosis in patients with COPD.

Impact of CYP2C19 Genotype and Drug Interactions on Voriconazole Plasma Concentrations: A Spain Pharmacogenetic-Pharmacokinetic Prospective Multicenter Study.

BACKGROUND: Voriconazole, a first-line agent for the treatment of invasive fungal infections, is mainly metabolized by cytochrome P450 (CYP) 2C19. A significant portion of patients fail to achieve therapeutic voriconazole trough concentrations, with a consequently increased risk of therapeutic failure. OBJECTIVE: To show the association between subtherapeutic voriconazole concentrations and factors affecting voriconazole pharmacokinetics: CYP2C19 genotype and drug-drug interactions. METHODS: Adults receiving voriconazole for antifungal treatment or prophylaxis were included in a multicenter prospective study conducted in Spain. The prevalence of subtherapeutic voriconazole troughs was analyzed in the rapid metabolizer and ultra-rapid metabolizer patients (RMs and UMs, respectively), and compared with the rest of the patients. The relationship between voriconazole concentration, CYP2C19 phenotype, adverse events (AEs), and drug-drug interactions was also assessed. RESULTS: In this study 78 patients were included with a wide variability in voriconazole plasma levels with only 44.8% of patients attaining trough concentrations within the therapeutic range of 1 and 5.5 µg/ml. The allele frequency of *17 variant was found to be 29.5%. Compared with patients with other phenotypes, RMs and UMs had a lower voriconazole plasma concentration (RM/UM: 1.85 ± 0.24 µg/ml vs other phenotypes: 2.36 ± 0.26 µg/ml). Adverse events were more common in patients with higher voriconazole concentrations (p<0.05). No association between voriconazole trough concentration and other factors (age, weight, route of administration, and concomitant administration of enzyme inducer, enzyme inhibitor, glucocorticoids, or proton pump inhibitors) was found. CONCLUSION: These results suggest the potential clinical utility of using CYP2C19 genotype-guided voriconazole dosing to achieve concentrations in the therapeutic range in the early course of therapy. Larger studies are needed to confirm the impact of pharmacogenetics on voriconazole pharmacokinetics.

Comparative evaluation of the identification of rapidly growing non-tuberculous mycobacteria by mass spectrometry (MALDI-TOF MS), GenoType Mycobacterium CM/AS assay and partial sequencing of the rpoBeta gene with phylogenetic analysis as a reference method / Evaluación comparativa de la identificación de micobacterias no tuberculosas de crecimiento rápido mediante espectrometría de masas (MALDI-TOF MS), GenoType(R) Mycobacterium CM/AS assay y la secuenciación parcial del gen rpoBeta con análisis filogenético como método de referencia

Introduction: The American Thoracic Society and the Infectious Diseases Society of America recommend that clinically significant non-tuberculous mycobacteria (NTM) should be identified to the species level in order to determine their clinical significance. The aim of this study was to evaluate identification of rapidly growing NTM (RGM) isolated from clinical samples by using MALDI-TOF MS and a commercial molecular system. The results were compared with identification using a reference method. Methods: We included 46 clinical isolates of RGM and identified them using the commercial molecular system GenoType(R) CM/AS (Hain, Lifescience, Germany), MALDI-TOF MS (Bruker) and, as reference method, partial rpoBeta gene sequencing followed by BLAST and phylogenetic analysis with the 1093 sequences available in the GeneBank. Results: The degree of agreement between GenoType(R) and MALDI-TOF MS and the reference method, partial rpoBeta sequencing, was 27/43 (62.8%) and 38/43 cases (88.3%) respectively. For all the samples correctly classified by GenoType(R), we obtained the same result with MALDI-TOF MS (27/27). However, MALDI-TOF MS also correctly identified 68.75% (11/16) of the samples that GenoType(R) had misclassified (p = 0.005). Conclusions: MALDI-TOF MS classified significantly better than GenoType(R). When a MALDI-TOF MS score >1.85 was achieved, MALDI-TOF MS and partial rpoBeta gene sequencing were equivalent. GenoType(R) was not able to distinguish between species belonging to the M. fortuitum complex. MALDI-TOF MS methodology is simple, rapid and associated with lower consumable costs than GenoType(R). The partial rpoBeta sequencing methods with BLAST and phylogenetic analysis were not able to identify some RGM unequivocally. Therefore, sequencing of additional regions would be indicated in these cases

Introducción: La American Thoracic Society y la Infectious Diseases Society of America recomiendan que las micobacterias no tuberculosas (MNT) clínicamente relevantes sean identificadas a nivel de especie para determinar su significado clínico. El propósito de este estudio fue a partir de MNT de crecimiento rápido (MCR) aisladas en muestras clínicas, evaluar su identificación mediante MALDI-TOF MS y un método molecular comercial, comparando estos resultados con la identificación obtenida usando un método de referencia. Métodos: Se incluyeron 46 aislados clínicos de MCR. Estos aislados se identificaron mediante el método molecular comercial GenoType(R) Mycobacterium CM/AS (Hain, Lifescience, Alemania), MALDI-TOF MS (Bruker) y, como método de referencia, la secuenciación parcial del gen rpoBeta seguido de BLAST y análisis filogenético. Para el análisis filogenético se utilizaron 1.093 secuencias disponibles en el GeneBank. Resultados: Entre GenoType(R) o MALDI-TOF MS, la concordancia respecto al método de referencia, secuenciación parcial de rpoB, fue 27/43 (62,8%) y 38/43 casos (88,3%), respectivamente. En todas las muestras que GenoType(R) clasificó correctamente con MALDI-TOF MS se obtuvo el mismo resultado (27/27). Pero además MALDI-TOF MS identificó bien 68,75% (11/16) de las muestras que GenoType(R) no clasificó correctamente (p = 0,005). Conclusiones: MALDI-TOF MS clasificó significativamente mejor que GenoType(R). Cuando MALDI-TOF MS alcanzó una puntuación >1,85, MALDI-TOF y la secuenciación parcial del gen rpoβ fueron equivalentes. GenoType(R) no distinguió dentro del M. fortuitum complex. La metodología MALDI-TOF MS es simple, rápida y se asocia a un menor coste de consumibles que GenoType(R). La secuenciación parcial del gen rpoBeta con BLAST y análisis filogenético no lograron identificar de manera inequívoca algunas MCR. Para estas MCR estaría indicado la secuenciación de regiones adicionales

Comparative evaluation of the identification of rapidly growing non-tuberculous mycobacteria by mass spectrometry (MALDI-TOF MS), GenoType Mycobacterium CM/AS assay and partial sequencing of the rpoß gene with phylogenetic analysis as a reference method.

INTRODUCTION: The American Thoracic Society and the Infectious Diseases Society of America recommend that clinically significant non-tuberculous mycobacteria (NTM) should be identified to the species level in order to determine their clinical significance. The aim of this study was to evaluate identification of rapidly growing NTM (RGM) isolated from clinical samples by using MALDI-TOF MS and a commercial molecular system. The results were compared with identification using a reference method. METHODS: We included 46 clinical isolates of RGM and identified them using the commercial molecular system GenoType® CM/AS (Hain, Lifescience, Germany), MALDI-TOF MS (Bruker) and, as reference method, partial rpoß gene sequencing followed by BLAST and phylogenetic analysis with the 1093 sequences available in the GeneBank. RESULTS: The degree of agreement between GenoType® and MALDI-TOF MS and the reference method, partial rpoß sequencing, was 27/43 (62.8%) and 38/43 cases (88.3%) respectively. For all the samples correctly classified by GenoType®, we obtained the same result with MALDI-TOF MS (27/27). However, MALDI-TOF MS also correctly identified 68.75% (11/16) of the samples that GenoType® had misclassified (p=0.005). CONCLUSIONS: MALDI-TOF MS classified significantly better than GenoType®. When a MALDI-TOF MS score >1.85 was achieved, MALDI-TOF MS and partial rpoß gene sequencing were equivalent. GenoType® was not able to distinguish between species belonging to the M. fortuitum complex. MALDI-TOF MS methodology is simple, rapid and associated with lower consumable costs than GenoType®. The partial rpoß sequencing methods with BLAST and phylogenetic analysis were not able to identify some RGM unequivocally. Therefore, sequencing of additional regions would be indicated in these cases.

An Observational Study of the Efficacy and Safety of Voriconazole in a Real-Life Clinical Setting.

An observational retrospective study in patients treated with voriconazole was made to evaluate outcomes, safety, drug interactions and characteristics of the treatment. A total of 96 patients were included. In 78.12%, at least one inducer or enzyme inhibitor was detected. The most frequently observed potential interaction was the simultaneous administration of omeprazole. A large number of patients were concurrently treated with corticosteroids. The simultaneous administration of drugs acting as CYP450 enzyme inhibitors was associated with a higher risk of toxicity while concomitant administration of corticosteroids seemed a protective factor. Our study is one of the few ones, which evaluate the use of voriconazole in a real life clinical setting. We demonstrate the wide variety of strategies in the voriconazole using and the large number of dugs that are susceptible to pharmacokinetic interactions. This study reinforces the need to implement voriconazole pharmacokinetic monitoring in order to optimize antifungal treatment.