EVALUACIÓN A TRAVÉS DE CASOS CLÍNICOS DE LOS CONDICIONANTES IMPLICADOS EN EL USO DE ANTIBIÓTICOS POR LOS MÉDICOS DE FAMILIA DE ARAGÓN.

Introducción: La resistencia bacteriana a los antibióticos es uno de los principales problemas de salud pública en el mundo. Una de sus causas es el uso inadecuado de antibióticos en medicina animal y en los diferentes ámbitos asistenciales de la medicina humana, incluyendo atención primaria. Detectar y cambiar aquellos comportamientos erróneos en el proceso de prescripción antimicrobiana es uno de los retos de los Programas de Optimización de uso de Antibióticos (PROA). Objetivos: Explorar los condicionantes implicados en el uso de antibióticos y las actitudes diagnóstico-terapéuticas de médicos de familia que ejercen en Aragón. Metodología: Evaluación telemática a través de un cuestionario online a médicos de familia de Aragón a partir de tres supuestos prácticos de temática infecciosa. Se evaluó la influencia de variables sociodemográficas y percepción de resistencia antibiótica sobre el conocimiento implícito y factores asociados al uso de antibióticos. Resultados: Sobre un total de 287 encuestados, el 92.63% percibía la resistencia antibiótica como un problema de alta importancia en su práctica diaria. Un 95.8% percibieron oportunidades de mejora en el uso de antibióticos, especialmente en los que sentían mayor presión del paciente en la prescripción (p<0.04). Los condicionantes que mayor peso obtuvieron en un uso subóptimo de antibióticos fueron la incertidumbre diagnóstica, la prescripción por costumbre y la falta de tiempo. Conclusión: Los médicos de familia que ejercen en atención primaria en Aragón reconocen la importancia de la resistencia a los antibióticos en su práctica habitual y están receptivos a la realización de actividades de mejora de uso de antibióticos (PROA). Palabras clave: Resistencia antibiótica, atención primaria, entrevista, conocimientos, actitudes, percepciones.<br /

Resumen ejecutivo del documento de consenso de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC) sobre el diagnóstico y tratamiento antimicrobiano de las infecciones por bacterias gramnegativas resistentes a carbapenémicos

[EN] Infections caused by multidrug resistant Gram-negative bacteria are becoming a worldwide problem due to their increasing incidence and associated high mortality. Carbapenem-resistant bacteria such as Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii are the most important in clinical practice. The objective of these guidelines is to update the recommendations for the diagnosis and treatment of infections caused by these multidrug resistant bacteria. Although ‘old’ antibiotics such as aminoglycosides, colistin, or tigecycline are frequently used for therapy of these bacteria, the ‘new’ beta-lactams such as ceftazidime–avibactam, ceftolozane–tazobactam, meropenem–vaborbactam, imipenem–cilastatin–relebactam or cefiderocol are progressively becoming the first-line therapy for most of these microorganisms. The Spanish Society of Infectious Diseases and Clinical Microbiology (Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica) designated a panel of experts in the field to provide evidence-based recommendations in response to common clinical questions. This document is primarily focused on microbiological diagnosis, clinical management, and targeted antimicrobial therapy of these infections, with special attention to defining the role of the new antimicrobials in the treatment of these bacteria.[ES] Las infecciones causadas por bacterias gramnegativas multirresistentes se han convertido en un problema mundial debido a su creciente incidencia y alta mortalidad asociada. Las bacterias resistentes a carbapenémicos como Klebsiella pneumoniae, Pseudomonas aeruginosa y Acinetobacter baumannii son las más importantes en la práctica clínica. El objetivo de este documento de consenso es actualizar las recomendaciones sobre diagnóstico y tratamiento de las infecciones causadas por estas bacterias multirresistentes. Aunque los antibióticos ‘antiguos’ como aminoglucósidos, colistina o tigeciclina se utilizan con frecuencia en el tratamiento de estas bacterias, los ‘nuevos’ betalactámicos como ceftazidima-avibactam, ceftolozano-tazobactam, meropenem-vaborbactam, imipenem-cilastatina-relebactam o cefiderocol se están convirtiendo de forma progresiva en el tratamiento de primera elección para la mayoría de estos microorganismos. La Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica ha designado un grupo de expertos en la materia para elaborar una guía de recomendaciones basadas en la evidencia sobre las cuestiones clínicas más habituales. Este documento está principalmente centrado en el diagnóstico microbiológico, el manejo clínico y el tratamiento dirigido de estas infecciones, con especial referencia a definir el papel de los nuevos antimicrobianos en el tratamiento de estas bacterias.Peer reviewe

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

7 figures, 1 table.[Aims]: Peritonitis is one of the most common causes of sepsis, a serious syndrome characterized by a dysregulated systemic inflammatory response. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role and the therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis.[Methods]: The level of extracellular GzmA as well as GzmA activity were analyzed in serum from healthy volunteers and patients with confirmed peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (WT) and GzmA-/- mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics alone or in combination serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days, levels of some proinflammatory cytokines were measured in serum and bacterial load and diversity was analyzed in blood and spleen at different times.[Results]: Clinically, elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen and GzmA did not affect bacterial replication in macrophages in vitro, indicating that GzmA has no role in bacterial control. Analysis of GzmA in lymphoid cells following CLP showed that it was mainly expressed by NK cells. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFα.[Conclusions]: Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis and provide solid evidences about its therapeutic potential for the treatment of this severe pathology.This work was supported by grant SAF2017-83120-C2-1-R and SAF2014-54763-C2-2-R from the Ministry of Science, Innovation and Universities and FEDER (Group B29_17R, Aragon Government). MG and LS were supported by a PhD fellowship (FPI) from the Ministry of Science, Innovation and Universities. IUM was supported by a PhD fellowship from Aragon Government, MA was supported by a post-doctoral fellowship “Juan de la Cierva-formación” from the Ministry of Science, Innovation and Universities. JP was supported by ARAID Foundation.Peer reviewe

A Large Multicenter Prospective Study of Community-Onset Healthcare Associated Bacteremic Urinary Tract Infections in the Era of Multidrug Resistance: Even Worse than Hospital Acquired Infections?

Introduction: Healthcare-associated (HCA) infections represent a growing public health problem. The aim of this study was to compare community-onset healthcare associated (CO-HCA) bacteremic urinary tract infections (BUTI) and hospital-acquired (HA)-BUTI with special focus on multidrug resistances (MDR) and outcomes. Methods: ITUBRAS-project is a prospective multicenter cohort study of patients with HCA-BUTI. All consecutive hospitalized adult patients with CO-HCA-BUTI or HA-BUTI episode were included in the study. Exclusion criteria were: patients \ 18 years old, non-hospitalized patients, bacteremia from another source or primary bacteremia, non-healthcare related infections and infections caused by unusual pathogens of the urinary tract. Th main outcome variable was 30-day all-cause mortality with day 1 as the first day of positive blood culture. Logistic regression was used to analyze factors associated with clinical cure at hospital discharge and with receiving inappropriate initial antibiotic treatment. Cox regression was used to evaluate 30-day all-cause mortality. Results: Four hundred forty-three episodes were included, 223 CO-HCA-BUTI. Patients with CO-HCA-BUTI were older (p \ 0.001) and had more underlying diseases (p = 0.029) than those with HA-BUTI. The severity of the acute illness (Pitt score) was also higher in CO-HCABUTI (p = 0.026). Overall, a very high rate of MDR profiles (271/443, 61.2%) was observed, with no statistical differences between groups. In multivariable analysis, inadequate empirical treatment was associated with MDR profile (aOR 3.35; 95% CI 1.77?6.35), Pseudomonas aeruginosa (aOR 2.86; 95% CI 1.27?6.44) and Charlson index (aOR 1.11; 95% CI 1.01?1.23). Mortality was not associated with the site of acquisition of the infection or the presence of MDR profile. However, in the logistic regression analyses patients with CO-HCA-BUTI (aOR 0.61; 95% CI 0.40?0.93) were less likely to present clinical cure. Conclusion: The rate of MDR infections was worryingly high in our study. No differences in MDR rates were found between CO-HCA-BUTI and HA-BUTI, in the probability of receiving inappropriate empirical treatment or in 30-day mortality. However, CO-HCA-BUTIs were associated with worse clinical cure.Funding. This study and the journal’s Rapid Service Fee are sponsored and funded by MSD Spain. The study was also supported by 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 (REIPI RD16/0016/0004, RD16/ 0016/0005, RD16/0016/0007, RD16/0016/0010, RD16/0016/0011 and RD16/0016/0015), co-financed by the European Development Regional Fund ‘A way to achieve Europe’ (ERDF), Operative program Intelligent Growth 2014–2020

A Large Multicenter Prospective Study of Community-Onset Healthcare Associated Bacteremic Urinary Tract Infections in the Era of Multidrug Resistance: Even Worse than Hospital Acquired Infections?

Introduction: Healthcare-associated (HCA) infections represent a growing public health problem. The aim of this study was to compare community-onset healthcare associated (CO-HCA) bacteremic urinary tract infections (BUTI) and hospital-acquired (HA)-BUTI with special focus on multidrug resistances (MDR) and outcomes. Methods: ITUBRAS-project is a prospective multicenter cohort study of patients with HCA-BUTI. All consecutive hospitalized adult patients with CO-HCA-BUTI or HA-BUTI episode were included in the study. Exclusion criteria were: patients < 18 years old, non-hospitalized patients, bacteremia from another source or primary bacteremia, non-healthcare-related infections and infections caused by unusual pathogens of the urinary tract. The main outcome variable was 30-day all-cause mortality with day 1 as the first day of positive blood culture. Logistic regression was used to analyze factors associated with clinical cure at hospital discharge and with receiving inappropriate initial antibiotic treatment. Cox regression was used to evaluate 30-day all-cause mortality. Results: Four hundred forty-three episodes were included, 223 CO-HCA-BUTI. Patients with CO-HCA-BUTI were older (p < 0.001) and had more underlying diseases (p = 0.029) than those with HA-BUTI. The severity of the acute illness (Pitt score) was also higher in CO-HCA-BUTI (p = 0.026). Overall, a very high rate of MDR profiles (271/443, 61.2%) was observed, with no statistical differences between groups. In multivariable analysis, inadequate empirical treatment was associated with MDR profile (aOR 3.35; 95% CI 1.77–6.35), Pseudomonas aeruginosa (aOR 2.86; 95% CI 1.27–6.44) and Charlson index (aOR 1.11; 95% CI 1.01–1.23). Mortality was not associated with the site of acquisition of the infection or the presence of MDR profile. However, in the logistic regression analyses patients with CO-HCA-BUTI (aOR 0.61; 95% CI 0.40–0.93) were less likely to present clinical cure. Conclusion: The rate of MDR infections was worryingly high in our study. No differences in MDR rates were found between CO-HCA-BUTI and HA-BUTI, in the probability of receiving inappropriate empirical treatment or in 30-day mortality. However, CO-HCA-BUTIs were associated with worse clinical cure. © 2021, The Author(s)

Respuesta inmune en la infección por SARS-CoV-2

La infección por SARS-CoV-2 ha sido la primera gran pandemia del siglo XXI y ha puesto a prueba al mundo en múltiples sentidos. Conocer la respuesta inmune generada está suponiendo un reto para la población científica. Especialmente, entender mejor la dicotomía entre las vías moleculares que regulan la respuesta inmunológica responsable de la eliminación de la infección y de la patogénesis de la enfermedad. Además, el espectro clínico y evolutivo tan amplio hace pensar en un patrón inmunológico distinto entre infecciones leves-moderadas y graves. Es en estas formas graves donde una respuesta inflamatoria descontrolada podría ser el sustrato de la enfermedad. Se han propuesto numerosas teorías que explican la fisiopatología de las formas graves y el amplio espectro clínico. Entre ellas se encuentran la variabilidad en el inóculo viral, la susceptibilidad individual genética al virus, posibles deficiencias funcionales en la respuesta inmune innata mediada por interferón I o la variabilidad en la producción de citoquinas. En otros modelos de infección como la sepsis bacteriana se ha demostrado el papel patogénico de las granzimas (Gzms). Se trata de una familia de serin proteasas producidas por linfocitos T y células natural killer (NK) con actividad citotóxica e inflamatoria. Producidas de forma descontrolada, dan lugar a un estado de hiperinflamación que provoca daño tisular y orgánico, característico de una respuesta desproporcionada a la infección, como en la sepsis o el shock séptico. En modelos animales y humanos, sus niveles se encuentran elevados en este tipo de infecciones, lo cual se ha asociado a un peor pronóstico. Ratones deficientes en GzmA mostraban una mayor supervivencia tras provocarles una infección intraabdominal, con menor expresión de marcadores inflamatorios en suero y líquido peritoneal, sin verse afectado el control de la carga bacteriana. En el caso de la infección por SARS-CoV-2, todavía se desconoce el papel que pueden tener estas proteasas. En este trabajo hemos analizado múltiples parámetros de la respuesta inmune mediante el análisis de sangre periférica en pacientes valorados en urgencias por COVID-19, comparados con donantes sanos (HDs, del inglés health donors) y otros pacientes atendidos por infecciones respiratorias en las que se descartó SARS-CoV-2 (no-COV-ITR) y otras patologías no respiratorias (ID). Se han estudiado las principales células responsables de la inmunidad viral: monocitos, linfocitos T CD8+ (LTCD8+), NK, y diferentes familias de factores solubles inflamatorios que regulan su actividad: interleuquinas (IL), quimioquinas (CC), granzimas y ligandos de células NK y LTCD8+. Se evalúo su correlación con marcadores analíticos rutinarios (ferritina, PCR y Dímero D). Dentro del grupo de COVID-19, se analizaron las diferencias entre los pacientes afectos de infección leve – moderada frente a grave-crítica. La hipótesis principal es que la respuesta inmune en pacientes con COVID-19 leve-moderada difiere de aquellos con infección más grave y, por tanto, se podrían diferenciar en función del tipo y/o niveles de marcadores inflamatorios solubles y de la respuesta inmune celular. Otras hipótesis secundarias son: • La COVID-19 genera una respuesta inmune diferente a la encontrada en otras infecciones respiratorias no provocadas por SARS-CoV-2 pero con un patrón clínico similar y a la de otras patologías sin afectación respiratoria. • La identificación de patrones inflamatorios puede ayudar a predecir qué pacientes tienen mayor riesgo de fracaso respiratorio y muerte. • La granzima A extracelular puede ser responsable de la situación de hiperinflamación encontrada en los pacientes más graves de la infección. El objetivo principal es la caracterización del perfil inmunológico de los pacientes con infección por SARS-CoV-2 al momento de la hospitalización, tratando de encontrar patrones inmunológicos útiles para diferenciar COVID-19 de otras infecciones y predecir la gravedad y el riesgo de muerte.Se trata de un estudio observacional, descriptivo y analítico multiparamétrico. Los criterios de inclusión fueron pacientes de dieciocho años o más, valorados en el servicio de urgencias del Hospital Clínico Universitario Lozano Blesa por sospecha clínica de infección por SARS-CoV-2, confirmada o no por pruebas microbiológicas (PCR, Test de antígenos, serología IgM y/o IgG). Se seleccionaron 150 pacientes con sospecha de COVID-19 y se escogieron 48 controles sanos adultos que no presentaban sintomatología compatible y en los cuales se descartó esta infección mediante serología. Las muestras de sangre periférica fueron obtenidas de los participantes en las primeras 24 horas tras valoración en urgencias y antes del inicio de cualquier tratamiento. Se incluyeron un total de 150 pacientes que cumplían los criterios de selección: 87 de ellos (57.4%) tuvieron una infección por SARS-CoV-2 confirmada microbiológicamente (COVID-19), 27 (17.4%) mostraban clínica, analítica y radiografía compatibles con infección viral pero las pruebas microbiológicas fueron negativas (no-COV-ITR) y en 37 de ellos (24.7%) se descartó la infección y requirieron valoración en urgencias u hospitalización por otros motivos (ID). Se analizaron muestras de 48 sujetos sanos. En el grupo de infección por SARS-CoV-2 se documentó una intensa activación de LTCD8+ y células NK, lo cual podría justificar parte del daño tisular y la lesión orgánica. Esta activación iba acompañada por la aparición precoz de varios marcadores de control inmunes inhibitorios, con la presencia simultánea de células que producían Gzms y de marcadores de activación, junto con células que no expresaban Gzms, lo que apuntaba a un mantenimiento parcial de su funcionalidad. Éstas y otras características diferenciaban la infección por SARS-CoV-2 de otras infecciones no-COVI-ITR, de HDs y de ID. COVID-19 se caracterizó por una agresiva producción de IL y CC, algunas de ellas con capacidad diagnóstica y pronóstica respecto a otras infecciones y patologías no respiratorias. También la infección por SARS-CoV-2 presentaba una actividad elevada de GzmA y GzmB, mayor a la encontrada en los otros grupos, lo cual podría contribuir al daño citotóxico y ser responsables de la atracción y producción de otras citoquinas. Ferritina, PCR y Dímero D se correlacionaron adecuadamente con otros marcadores inmunológicos sugestivos de infección grave. • Arias MA, Jiménez de Bagües MP, Aguiló N, Menao S, Hervás-Stubbs S, de Martino A, et al. Elucidating sources and roles of granzymes A and B during bacterial infection and sepsis. Cell Rep [Internet]. 2014 Jul 24 [cited 2021 Sep 25];8(2):420–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25017060• Garzón-Tituaña M, Arias MA, Sierra-Monzón JL, Morte-Romea E, Santiago L, Ramirez-Labrada A, et al. The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover. Front Immunol. 2020;11(June):1–12. • Garzón-Tituaña, Marcela, Sierra Monzón J.L., Comas l, Santiago Llipsy et al. Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis. Theranostics. 2021 Jan 30; 11 (8): 3781 – 3795. • Carvalho T, Krammer F, Iwasaki A. The first 12 months of COVID-19: a timeline of immunological insights. Nat Rev Immunol [Internet]. 2021; Apr; 21 (4): 245 -256. Available from: http://www.ncbi.nlm.nih.gov/pubmed/33723416<br /

The multifaceted function of granzymes in sepsis: some facts and a lot to discover

1 figure, 1 tableSepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy, increasing the risk of secondary infections. Granzymes (Gzms) are a family of serine proteases classified according to their cleavage specificity. Traditionally, it was assumed that all Gzms acted as cytotoxic proteases. However, recent evidence suggests that GzmB is the one with the greatest cytotoxic capacity, while the cytotoxicity of others such as GzmA and GzmK is not clear. Recent studies have found that GzmA, GzmB, GzmK, and GzmM act as pro-inflammatory mediators. Specially, solid evidences show that GzmA and GzmK function as extracellular proteases that regulate the inflammatory response irrespectively of its ability to induce cell death. Indeed, studies in animal models indicate that GzmA is involved in the cytokine release syndrome characteristic of sepsis. Moreover, the GZM family also could regulate other biological processes involved in sepsis pathophysiology like the coagulation cascade, platelet function, endothelial barrier permeability, and, in addition, could be involved in the immunosuppressive stage of sepsis. In this review, we provide a comprehensive overview on the contribution of these novel functions of Gzms to sepsis and the new therapeutic opportunities emerging from targeting these proteases for the treatment of this serious health problem.This work was supported in part by FEDER/Gobierno de Aragón (group B29), Ministerio de Economia y Competitividad [SAF2014-54763-C2-1 and SAF2017-83120-C2-1-R (JP-P), SAF2014-54763-C2-2-R (EG)] and Instituto de Salud Carlos III (PI16-00526, LM-L; PI18/00527, JP-P). Predoctoral grants/contracts from Fundacion Santander/Universidad de Zaragoza (LS and MA), Ministerio de Ciencia, Innovación y Universidades (MG-T). MA has a Juan de la Cierva Contract (Ministerio de Ciencia, Innovación y Universidades) and JS-M a Rio Hortega Contract (Instituto de Salud Carlos III). JP was supported by Fundación Aragon I+D (ARAID).Peer reviewe

TIM3, LAG3, CXCL10 and GzmA reveal as main hallmarks of inflammatory profiles in Covid-19 patiens

Comunicación oral presentada en el 42º SEI Congreso de la Sociedad Española de Inmunología, 24-26 marzo 2021, Madrid, formato virtual.Peer reviewe

CAR immunotherapy for the treatment of infectious diseases: a systematic review

Immunotherapy treatments aim to modulate the host’s immune response to either mitigate it in inflammatory/autoimmune disease or enhance it against infection or cancer. Among different immunotherapies reaching clinical application during the last years, chimeric antigen receptor (CAR) immunotherapy has emerged as an effective treatment for cancer where different CAR T cells have already been approved. Yet their use against infectious diseases is an area still relatively poorly explored, albeit with tremendous potential for research and clinical application. Infectious diseases represent a global health challenge, with the escalating threat of antimicrobial resistance underscoring the need for alternative therapeutic approaches. This review aims to systematically evaluate the current applications of CAR immunotherapy in infectious diseases and discuss its potential for future applications. Notably, CAR cell therapies, initially developed for cancer treatment, are gaining recognition as potential remedies for infectious diseases. The review sheds light on significant progress in CAR T cell therapy directed at viral and opportunistic fungal infections

Serum active Granzyme A: a new biomarker that contributes to the pathogenesis of peritoneal sepsis

Abstract of the work presented at the 30th ECCMID 2020, European Congress of Clinical Microbiology and Infectious Diseases, organized by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).-- www.eccmid.org .-- www.escmid.org.-- Accepted abstract 1508.[Background] Peritonitis is one of the most common leading cause of sepsis. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed in NK cells and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role of serum GzmA as a biomarker and therapeutic target in peritoneal sepsis.[Materials/methods] Concentration and enzyme activity of soluble GzmA were sequentially analyzed in serum from healthy donors and patients with peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (Wt) and GzmA-KO mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics and with serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days and the levels of serum proinflammatory cytokines and bacterial load in blood and spleen were analyzed at 6 and 24h from CLP.[Results] We have found high levels of GzmA in serum of patient with peritonitis. Most importantly, we observed that GzmA activity in serum correlates with SOFA score, suggesting that active GzmA could play an important role in sepsis development in peritonitis patients and could be a new biomarker of sepsis severity. In order to analyze the therapeutical potential of soluble GzmA in peritoneal sepsis, we used the CLP mouse model. After peritonitis induction, GzmA-KO mice exhibit increased survival compared with Wt mice, which correlated with reduced levels of proinflammatory cytokines in serum. The analysis of bacterial load in blood and spleen showed no differences between Wt and GzmA-KO mice suggesting that GzmA does not play an important role in bacterial control. Treatment with serpinb6b reduced mortality, which correlated with reduced cytokine serum levels in serum, confirming the therapeutical potential of gzmA to treat peritoneal sepsis.[Conclusions] Our findings confirm that soluble GzmA plays an important role in the pathogenesis of sepsis and could be a new therapeutic target and a biomarker for the treatment of peritoneal sepsis.Peer reviewe