Determining the burden of infectious diseases caused by carbapenem-resistant gram-negative bacteria in Spain / Determinación de la carga de las infecciones causadas por bacterias gramnegativas resistentes a carbapenemas en España

Objective: To estimate the burden of nosocomial infections induced by carbapenem resistant Gram-negative (CRGN) pathogens in Spain, focusing on both the clinical and economic impact. Methods: The burden of disease was estimated using data from 2017 according to the availability of data sources. The impact, both clinical and economic, of the most frequent CRGN nosocomial infections (those produced by Klebsiella pneumoniae, Pseudomonasaeruginosa and Acinetobacter baumannii) was analysed. Incidence and mortality of CRGN nosocomial infections were estimated, as well as the direct and indirect costs produced by this health problem. Results: Approximately 376,346 patients are believed to have suffered a nosocomial infection in Spain in 2017; 3.2% of them due to CRGN bacilli. Infections by carbapenem-resistant P. aeruginosa produced the highest mortality rates (2578 deaths) when compared with A. baumannii (1571) and K. pneumoniae (415). Total economic costs of CRGN nosocomial infections in Spain were estimated to be €472 million in 2017, with 83% of the total cost caused by direct costs. Conclusion: CRGN nosocomial infections have a high clinical impact on patients’ lives, high mortality rates, and represent one of the hospitalisation episodes with the most associated costs. Efforts should be focussed to implement preventive policies in order to avoid infections due to CRGN pathogens and the resulting burden, and to reduce direct costs due to morbimortality, specifically in those infections produced by P. aeruginosa.(AU)

Objetivo: Estimar la carga de las infecciones nosocomiales inducidas por patógenos gramnegativos resistentes a carbapenemas (GNRC) en España, focalizada tanto en el impacto clínico como en el económico. Métodos: La carga de la enfermedad se estimó utilizando datos del año 2017, de acuerdo con la disponibilidad de los mismos en bases de datos. Se analizó el impacto, tanto clínico como económico, de las infecciones nosocomiales GNRC más habituales (causadas por Klebsiella pneumoniae, Pseudomonas aeruginosa y Acinetobacter baumannii). Se estimaron la incidencia y la mortalidad de las infecciones nosocomiales GNRC, así como los costes directos e indirectos derivados de este problema de salud. Resultados: Aproximadamente 376.346 pacientes podrían haber sufrido una infección nosocomial en España durante el año 2017; siendo el 3,2% de ellas producidas por bacilos GNRC. Las infecciones causadas por P. aeruginosa resistente a carbapenemas produjeron las mayores tasas de mortalidad (2.578 muertes) en comparación con A. baumannii (1.571) y K. pneumoniae (415). Los costes económicos totales de las infecciones nosocomiales producidas por GNRC en España se estimaron en 472 M€ en 2017, siendo el 83% del coste total representado por los costes directos. Conclusión: Las infecciones nosocomiales producidas por GNRC tienen un gran impacto en la vida de los pacientes, altas tasas de mortalidad y representan uno de los episodios de hospitalización con más costes hospitalarios asociados. Se deben focalizar los esfuerzos en políticas de prevención para evitar las infecciones por patógenos GNRC y su carga, así como para reducir los costes directos producidos por la morbimortalidad, concretamente en aquellas infecciones producidas por P. aeruginosa.(AU)

Determining the burden of infectious diseases caused by carbapenem-resistant gram-negative bacteria in Spain.

OBJECTIVE: To estimate the burden of nosocomial infections induced by carbapenem resistant Gram-negative (CRGN) pathogens in Spain, focusing on both the clinical and economic impact. METHODS: The burden of disease was estimated using data from 2017 according to the availability of data sources. The impact, both clinical and economic, of the most frequent CRGN nosocomial infections (those produced by Klebsiella pneumoniae, Pseudomonasaeruginosa and Acinetobacter baumannii) was analysed. Incidence and mortality of CRGN nosocomial infections were estimated, as well as the direct and indirect costs produced by this health problem. RESULTS: Approximately 376,346 patients are believed to have suffered a nosocomial infection in Spain in 2017; 3.2% of them due to CRGN bacilli. Infections by carbapenem-resistant P. aeruginosa produced the highest mortality rates (2578 deaths) when compared with A. baumannii (1571) and K. pneumoniae (415). Total economic costs of CRGN nosocomial infections in Spain were estimated to be €472 million in 2017, with 83% of the total cost caused by direct costs. CONCLUSION: CRGN nosocomial infections have a high clinical impact on patients' lives, high mortality rates, and represent one of the hospitalisation episodes with the most associated costs. Efforts should be focussed to implement preventive policies in order to avoid infections due to CRGN pathogens and the resulting burden, and to reduce direct costs due to morbimortality, specifically in those infections produced by P. aeruginosa.

Characterization of AmpC Beta-lactamase mutations of extensively drug-resistant Pseudomonas aeruginosa isolates that develop resistance to ceftolozane/tazobactam during therapy / Caracterización de las mutaciones en la betalactamasa AmpC de aislados de Pseudomonas aeruginosa XDR que desarrollaron resistencia a ceftolozano/tazobactam durante el tratamiento

INTRODUCTION: We characterized AmpC β-lactamase mutations that resulted in ceftolozane/tazobactam resistance in extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates recovered from patients treated with this agent from June 2016 to December 2018. METHODS: Five pairs of ceftolozane/tazobactam susceptible/resistant P. aeruginosa XDR isolates were included among a total of 49 patients treated. Clonal relationship among isolates was first evaluated by pulsed-field gel electrophoresis (PFGE). Multilocus sequence typing (MLST) was further performed. AmpC mutations were investigated by PCR amplification of the blaPDC gene followed by sequencing. RESULTS: The ST175 high-risk clone was detected in four of the pairs of isolates and the ST1182 in the remaining one. All resistant isolates showed a mutation in AmpC: T96I in two of the isolates, and E247K, G183V, and a deletion of 19 amino acids (G229-E247) in the other three. The G183V mutation had not been described before. The five isolates resistant to ceftolozane/tazobactam showed cross-resistance to ceftazidime/avibactam and lower MICs of imipenem and piperacillin/tazobactam than the susceptible isolates. CONCLUSIONS: Ceftolozane/tazobactam resistance was associated in all of the cases with AmpC mutations, including a novel mutation (G183V) not previously described. There is a vital need for surveillance and characterization of emerging ceftolozane/tazobactam resistance, in order to preserve this valuable antipseudomonal agent

INTRODUCCIÓN: Se han caracterizado las mutaciones en la betalactamasa AmpC que han producido resistencia a ceftolozano/tazobactam en aislados de Pseudomonas aeruginosa extremadamente resistente (XDR) en pacientes tratados con este agente desde junio de 2016 hasta diciembre de 2018. MÉTODOS: Se incluyeron 5 pares de aislados (sensibles/resistentes a ceftolozano/tazobactam) de P. aeruginosa XDR entre un total de 49 pacientes tratados. Se estudió la relación clonal mediante electroforesis en campo pulsado y MLST. Las mutaciones en AmpC se caracterizaron mediante amplificación por PCR del gen blaPDC y posterior secuenciación. RESULTADOS: Se detectó el clon de alto riesgo ST175 en 4 pares de aislados y el ST1182 en el restante. Todos los aislados resistentes mostraron una mutación en AmpC: T96I en 2 aislados, E247K, G183V y una deleción de 19 aminoácidos (G229-E247) en los otros 3. La mutación G183V no había sido descrita antes. Los 5 aislados resistentes a ceftolozano/tazobactam mostraron resistencia cruzada a ceftazidima/avibactam y CMI inferiores de imipenem y piperacilina/tazobactam que los aislados sensibles. CONCLUSIONES: La resistencia a ceftolozano/tazobactam se asoció con mutaciones en AmpC en todos los casos, incluida una nueva mutación G183V no descrita con anterioridad. La vigilancia y caracterización de la resistencia emergente a ceftolozano/tazobactam es de gran importancia para preservar este nuevo agente antipseudomónico

Characterization of AmpC ß-lactamase mutations of extensively drug-resistant Pseudomonas aeruginosa isolates that develop resistance to ceftolozane/tazobactam during therapy.

INTRODUCTION: We characterized AmpC ß-lactamase mutations that resulted in ceftolozane/tazobactam resistance in extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates recovered from patients treated with this agent from June 2016 to December 2018. METHODS: Five pairs of ceftolozane/tazobactam susceptible/resistant P. aeruginosa XDR isolates were included among a total of 49 patients treated. Clonal relationship among isolates was first evaluated by pulsed-field gel electrophoresis (PFGE). Multilocus sequence typing (MLST) was further performed. AmpC mutations were investigated by PCR amplification of the blaPDC gene followed by sequencing. RESULTS: The ST175 high-risk clone was detected in four of the pairs of isolates and the ST1182 in the remaining one. All resistant isolates showed a mutation in AmpC: T96I in two of the isolates, and E247K, G183V, and a deletion of 19 amino acids (G229-E247) in the other three. The G183V mutation had not been described before. The five isolates resistant to ceftolozane/tazobactam showed cross-resistance to ceftazidime/avibactam and lower MICs of imipenem and piperacillin/tazobactam than the susceptible isolates. CONCLUSIONS: Ceftolozane/tazobactam resistance was associated in all of the cases with AmpC mutations, including a novel mutation (G183V) not previously described. There is a vital need for surveillance and characterization of emerging ceftolozane/tazobactam resistance, in order to preserve this valuable antipseudomonal agent.

EPICO 3.0. Management of non-neutropenic patients in medical wards / EPICO 3.0. Tratamiento del paciente no neutropénico en la planta de medicina interna

Background. Although the management of invasive fungal infection (IFI) has improved, a number of controversies persist regarding the approach to invasive fungal infection in non-neutropenic medical ward patients. Aims. To identify the essential clinical knowledge to elaborate a set of recommendations with a high level of consensus necessary for the management of IFI in non-neutropenic medical ward patients. Methods. A prospective, Spanish questionnaire, which measures consensus through the Delphi technique, was anonymously answered and e-mailed by 30 multidisciplinary national experts, all specialists (intensivists, anesthesiologists, microbiologists, pharmacologists and specialists in infectious diseases) in IFI and belonging to six scientific national societies. They responded to five questions prepared by the coordination group after a thorough review of the literature published in the last few years. For a category to be selected, the level of agreement among the experts in each category had to be equal to or greater than 70%. In a second round, 73 specialists attended a face-to-face meeting held after extracting the recommendations from the chosen topics, and validated the pre-selected recommendations and derived algorithm. Results. The following recommendations were validated and included in the algorithm: 1. several elements were identified as risk factors for invasive candidiasis (IC) in non-hematologic medical patients; 2. no agreement on the use of the colonization index to decide whether prescribing an early antifungal treatment to stable patients (no shock), with sepsis and no other evident focus and IC risk factors; 3. agreement on the use of the Candida Score to decide whether prescribing early antifungal treatment to stable patients (no shock) with sepsis and no other evident focus and IC risk factors; 4. agreement on initiating early antifungal treatment in stable patients (no shock) with a colonization index>0.4, sepsis with no other evident focus and IC risk factors; 5. agreement on the performance of additional procedures in stable patients (no shock) with sepsis and no other evident focus, IC risk factors, without colonization index>0.4, but with a high degree of suspicion. Conclusions. Based on the expert's recommendations, an algorithm for the management of non-neutropenic medical patients was constructed and validated. This algorithm may be useful to support bedside prescription (AU)

Antecedentes. A pesar de que el manejo de la micosis invasiva ha mejorado, persisten ciertas controversias en su tratamiento en pacientes no neutropénicos. Objetivos. Identificar el conocimiento clínico esencial y elaborar, con un alto nivel de consenso, las recomendaciones necesarias para el manejo de la micosis invasiva en pacientes no neutropénicos. Métodos. Treinta expertos multidisciplinarios españoles en micosis invasiva (intensivistas, anestesistas, microbiólogos, farmacólogos y especialistas en enfermedades infecciosas) pertenecientes a 6 sociedades científicas contestaron anónimamente un cuestionario que evaluaba el grado de consenso mediante la técnica Delphi. Los expertos respondieron a 5 preguntas elaboradas por los coordinadores después de una revisión exhaustiva de la bibligorafía reciente. El grado de acuerdo necesario para seleccionar una categoría fue igual o superior al 70%. Posteriormente, 73 especialistas asistieron a una reunión en que se extrajeron las recomendaciones que se utilizaron en la elaboración de un algoritmo para la ayuda en la toma de una decisión clínica. Resultados. Las recomendaciones validadas e incluidas en el algoritmo fueron las siguientes: 1) varias situaciones se definieron como factores de riesgo para la candidiasis invasiva (CI) en pacientes no hematológicos; 2) no hubo acuerdo sobre el uso del índice de colonización para decidir la prescripción de tratamiento antifúngico precoz en pacientes estables (sin shock) con septicemia, sin foco evidente y con factores de riesgo para CI; 3) hubo acuerdo en el uso del Candida Score para decidir la prescripción de tratamiento antifúngico precoz en pacientes estables (sin shock) con septicemia, sin foco evidente y con factores de riesgo para CI; 4) hubo acuerdo en el inicio de tratamiento antifúngico precoz en pacientes estables (sin shock) con sepsis, sin foco evidente e índice de colonización >0,4 y con factores de riesgo para CI; 5) hubo acuerdo para realizar los procedimientos diagnósticos adicionales en pacientes estables (sin shock) con septicemia, sin foco evidente, factores de riesgo para CI e índice de colonización <0,4, pero con alto índice de sospecha. Conclusiones. Se ha elaborado un algoritmo de manejo de la CI en pacientes no neutropénicos basado en las recomendaciones de expertos. Este algoritmo puede ser útil como soporte a la prescripción a pie de cama (AU)

EPICO 3.0. Management of non-neutropenic patients in medical wards.

BACKGROUND: Although the management of invasive fungal infection (IFI) has improved, a number of controversies persist regarding the approach to invasive fungal infection in non-neutropenic medical ward patients. AIMS: To identify the essential clinical knowledge to elaborate a set of recommendations with a high level of consensus necessary for the management of IFI in non-neutropenic medical ward patients. METHODS: A prospective, Spanish questionnaire, which measures consensus through the Delphi technique, was anonymously answered and e-mailed by 30 multidisciplinary national experts, all specialists (intensivists, anesthesiologists, microbiologists, pharmacologists and specialists in infectious diseases) in IFI and belonging to six scientific national societies. They responded to five questions prepared by the coordination group after a thorough review of the literature published in the last few years. For a category to be selected, the level of agreement among the experts in each category had to be equal to or greater than 70%. In a second round, 73 specialists attended a face-to-face meeting held after extracting the recommendations from the chosen topics, and validated the pre-selected recommendations and derived algorithm. RESULTS: The following recommendations were validated and included in the algorithm: 1. several elements were identified as risk factors for invasive candidiasis (IC) in non-hematologic medical patients; 2. no agreement on the use of the colonization index to decide whether prescribing an early antifungal treatment to stable patients (no shock), with sepsis and no other evident focus and IC risk factors; 3. agreement on the use of the Candida Score to decide whether prescribing early antifungal treatment to stable patients (no shock) with sepsis and no other evident focus and IC risk factors; 4. agreement on initiating early antifungal treatment in stable patients (no shock) with a colonization index>0.4, sepsis with no other evident focus and IC risk factors; 5. agreement on the performance of additional procedures in stable patients (no shock) with sepsis and no other evident focus, IC risk factors, without colonization index>0.4, but with a high degree of suspicion. CONCLUSIONS: Based on the expert's recommendations, an algorithm for the management of non-neutropenic medical patients was constructed and validated. This algorithm may be useful to support bedside prescription.