OTAC: Optimization of Antibiotic Therapy in Critically ill Patients. Using beta-lactam antibiotics by continuous infusion

Objective: To determine the percentage of patients given standard doses of piperacillin/tazobactam or meropenem by continuous infusion who achieved the target pharmacokinetic/pharmacodynamic (PK/PD) index, which was defined as free concentrations four times more than the minimum inhibitory KEYWORDS Beta-lactams; Critical care; Pharmacokinetics; Drug monitoring; Piperacillin; Meropenem

Tuberculosi, infecció i malatia en relació amb nivells de vitamina D

La vitamina D té un paper important en patologies infeccioses, entre les quals la tuberculosi. El present estudi pretén avaluar aspectes clínics i epidemiològics de pacients amb infecció tuberculosa en els quals s'han determinat nivells sèrics de vitamina D, i veure si existeix relació entre el dèficit de vitamina D i el risc de desenvolupar malaltia activa, i si aquest dèficit es relaciona més amb malaltia extrapulmonar o greu. És un estudi observacional retrospectiu, en el qual s'han inclós un total de 86 pacients amb malaltia activa i 80 amb infecció latent. No s'objectivà una associació entre major dèficit de vitamina D i malaltia extrapulmonar, ni amb malaltia més greu. En canvi, destacà una associació significativa entre el dèficit greu de vitamina D i la malaltia tuberculosa activa quan es compara amb pacients amb infecció latent

Clinical and Economic Impact of Community-Onset Urinary Tract Infections Caused by ESBL-Producing Klebsiella pneumoniae Requiring Hospitalization in Spain : An Observational Cohort Study

Objective : To analyze the clinical and economic impact of community-onset urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae requiring hospitalization. Methods : A retrospective cohort study that included all adults with a UTI caused by K. pneumoniae that were admitted to a tertiary care hospital in Barcelona, Spain, between 2011 and 2015. Demographic, clinical, and economic data were analyzed. Results : One hundred and seventy-three episodes of UTIs caused by K. pneumoniae were studied; 112 were non-ESBL-producing and 61 were ESBL-producing. Multivariate analysis identified ESBL production, acute confusional state associated with UTI, shock, and the time taken to obtain adequate treatment as risk factors for clinical failure during the first seven days. An economic analysis showed differences between ESBL-producing and non-ESBL-producing K. pneumoniae for the total cost of hospitalization per episode (mean EUR 6718 vs EUR 3688, respectively). Multivariate analysis of the higher costs of UTI episodes found statistically significant differences for ESBL production and the time taken to obtain adequate treatment. Conclusion : UTIs caused by ESBL-producing K. pneumoniae requiring hospitalization and the time taken to obtain adequate antimicrobial therapy are associated with worse clinical and economic outcomes

Predictive Factors of Piperacillin Exposure and the Impact on Target Attainment after Continuous Infusion Administration to Critically Ill Patients

Critically ill patients undergo significant pathophysiological changes that affect antibiotic pharmacokinetics. Piperacillin/tazobactam administered by continuous infusion (CI) improves pharmacokinetic/pharmacodynamic (PK/PD) target attainment. This study aimed to characterize piperacillin PK after CI administration of piperacillin/tazobactam in critically ill adult patients with preserved renal function and to determine the empirical optimal dosing regimen. A total of 218 piperacillin concentrations from 106 patients were simultaneously analyzed through the population PK approach. A two-compartment linear model best described the data. Creatinine clearance (CLCR) estimated by CKD-EPI was the covariate, the most predictive factor of piperacillin clearance (CL) interindividual variability. The mean (relative standard error) parameter estimates for the final model were: CL: 12.0 L/h (6.03%); central and peripheral compartment distribution volumes: 20.7 L (8.94%) and 62.4 L (50.80%), respectively; intercompartmental clearance: 4.8 L/h (26.4%). For the PK/PD target of 100% fT(>1xMIC), 12 g of piperacillin provide a probability of target attainment > 90% for MIC 100 mL/min. For 100% fT(>4xMIC), the highest dose (24 g/24 h) was not sufficient to ensure adequate exposure, except for MICs of 1 and 4 mg/L. Our model can be used as a support tool for initial dose guidance and during therapeutic drug monitoring

Executive summary of the Consensus Document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and of the Spanish Association of Surgeons (AEC) in antibiotic prophylaxis in surgery

[ES] La profilaxis antibiótica en cirugía es una de las medidas más eficaces para la prevención de la infección de localización quirúrgica, aunque su uso es con frecuencia inadecuado, pudiendo incrementar el riesgo de infección, toxicidades y resistencias bacterianas. Debido al avance en las técnicas quirúrgicas y la emergencia de microorganismos multirresistentes las actuales pautas de profilaxis precisan ser revisadas. La Sociedad Española de Enfermedades Infecciosas (SEIMC), conjuntamente con la Asociación Española de Cirujanos (AEC) ha revisado y actualizado las recomendaciones de profilaxis antimicrobiana para adaptarlas a cada tipo de intervención quirúrgica y a la epidemiología actual. En este documento se recogen las recomendaciones de los antimicrobianos utilizados en profilaxis en los diferentes procedimientos, las dosis, la duración, la profilaxis en huéspedes especiales, y en situación epidemiológica de multirresistencia, de tal forma que permitan un manejo estandarizado, un uso racional, seguro y efectivo de los mismos en la cirugía electiva.[EN] Antibiotic prophylaxis in surgery is one of the most effective measures for preventing surgical site infection, although its use is frequently inadequate and may even increase the risk of infection, toxicities and antimicrobial resistance. As a result of advances in surgical techniques and the emergence of multidrug-resistant organisms, the current guidelines for prophylaxis need to be revised. The Sociedad Española de Enfermedades Infecciosas (Spanish Society of Infectious Diseases and Clinical Microbiology) (SEIMC) together with the Asociación Española de Cirujanos (Spanish Association of Surgeons) (AEC) have revised and updated the recommendations for antibiotic prophylaxis in surgery to adapt them to any type of surgical intervention and to current epidemiology. This document gathers together the recommendations on antimicrobial prophylaxis in the various procedures, with doses, duration, prophylaxis in special patient groups, and in epidemiological settings of multidrug resistance to facilitate standardized management and the safe, effective and rational use of antibiotics in elective surgery

Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene-Driven Myeloid Leukemia.

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2-GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2-GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2-GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. SIGNIFICANCE: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state.See related commentary by Cruz Hernandez and Vyas, p. 1653.This article is highlighted in the In This Issue feature, p. 1631

Genetic and Chemical Evaluation of Trypanosoma brucei Oleate Desaturase as a Candidate Drug Target

Background: Trypanosomes can synthesize polyunsaturated fatty acids. Previously, we have shown that they possess stearoyl-CoA desaturase (SCD) and oleate desaturase (OD) to convert stearate (C18) into oleate (C18:1) and linoleate (C18:2), respectively. Here we examine if OD is essential to these parasites. Methodology: Cultured procyclic (insect-stage) form (PCF) and bloodstream-form (BSF) Trypanosoma brucei cells were treated with 12- and 13-thiastearic acid (12-TS and 13-TS), inhibitors of OD, and the expression of the enzyme was knocked down by RNA interference. The phenotype of these cells was studied. Principal Findings: Growth of PCF T. brucei was totally inhibited by 100 mM of 12-TS and 13-TS, with EC50 values of 4062 and 3062 mM, respectively. The BSF was more sensitive, with EC50 values of 763 and 261 mM, respectively. This growth phenotype was due to the inhibitory effect of thiastearates on OD and, to a lesser extent, on SCD. The enzyme inhibition caused a drop in total unsaturated fatty-acid level of the cells, with a slight increase in oleate but a drastic decrease in linoleate level, most probably affecting membrane fluidity. After knocking down OD expression in PCF, the linoleate content was notably reduced, whereas that of oleate drastically increased, maintaining the total unsaturated fatty-acid level unchanged. Interestingly, the growth phenotype of the RNAi-induced cells was similar to that found for thiastearate-treated trypanosomes, with the former cells growing twofold slower than the latter ones, indicating that the linoleate content itsel

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Impacte clínic i econòmic de les infeccions urinàries per E.Coli Blee i de l’aplicació d’un programa d’optimització d’antimicrobians (PROA) en el seu abordatge terapèutic

Les betalactamases d'espectre estès (BLEE) són enzims produïts per bacils gramnegatius capaços d'hidrolitzar l'anell betalactàmic inactivant certs antibiòtics com les oximino-cefalosporines i monobactams, i són inhibides per inhibidors de betalactamases com l'àcid clavulànic, el sulbactam, el tazobactam o l'avibactam. A més, els microorganismes productors d'aquestes betalactamases, sovint presenten co-resistència a altres antibiòtics. Aquesta peculiaritat redueix les opcions terapèutiques en les infeccions produïdes per bacteris productors de BLEE, la qual cosa es correlaciona amb uns pitjors resultats clínics. La prevalença d'enterobacteris productors de BLEE ha anat en augment en els darrers anys, tant a Espanya com a la resta d'Europa, objectivant-se igualment un increment en les soques d'adquisició comunitària. Aquesta situació dificulta el tractament de les infeccions urinàries produïdes per enterobacteris productors de BLEE i resulta en un major consum de recursos sanitaris. Resulta imprescindible un abordatge multidisciplinar per aquest tipus d'infeccions, de cara a optimitzar-ne el maneig per assegurar l'èxit terapèutic, tenint en compte l'impacte ecològic que poden tenir els tractaments antibiòtic, així com assegurar l'ús de tractaments cost-efectius. Per a tal efecte, en els darrers anys s'han anat implementat arreu de l'Estat els Programes d'Optimtizació d'Antimicrobians (PROA). El present treball ha focalitzat en l'impacte clínic i econòmic que han tingut les infeccions urinàries per E.coli productor de BLEE a l'Hospital del Mar de Barcelona en els darrers anys, així com l'impacte que la implementació d'un Programa d'Optimització d'Antimicrobians ha tingut en les mateixes, tant en termes clínics com econòmics. Es van analitzar les infeccions urinàries per E.coli productor de BLEE que van requerir hospitalització entre agost de 2010 i juliol de 2013 mitjançant un estudi de cohorts retrospectiu, observant-se una pitjor evolució clínica comparat amb les produïdes per E.coli no BLEE (major fracàs clínic al 7è dia; p = 0.002), a més de suposar un increment en els costos atribuïts a les mateixes (4980€ vs 2612€ per episodi). Amb aquestes dades, es va decidir avaluar l'impacte que la progressiva implementació d'un PROA estava tenint en aquestes infeccions. Per aquest propòsit, es van revisar tots els pacients amb diagnòstic d'infecció urinària per E.coli BLEE que havien consultat a l'Hospital del Mar entre gener de 2014 i desembre de 2015, i es va avaluar l'impacte clínic i econòmic que havien tingut els casos en els quals s'havia realitzat algun tipus d'intervenció comparat amb els que no l'havien rebut. Les intervencions per part de l'equip de PROA van tenir un impacte positiu quant a curació clínica (p = 0.008). No es va poder demostrar que aquestes intervencions tinguessin un impacte econòmic en les infeccions urinàries per E.coli BLEE.Extended-spectrum betalactamases (ESBL) are enzymes produced by gram-negative bacilli capable of hydrolyzing the betalactamic ring by inactivating certain antibiotics such as oximinum-cephalosporins and monobactams, and are inhibited by betalactamase inhibitors such as clavulanic acid, sulbactam, tazobactam or avibactam. In addition, the microorganisms producing these betalactamases often present co-resistance to other antibiotics. This peculiarity reduces the therapeutic options in infections produced by ESBL-producing bacteria, which correlates with worse clinical outcomes. The prevalence of ESBL-producing enterobacteria has been increasing in recent years, both in Spain and in the rest of Europe, with an increase in community strains. This situation hinders the treatment of urinary infections produced by ESBL-producing enterobacteria and results in a greater consumption of health resources. A multidisciplinary approach for these infections is essential, in order to optimize its management to ensure therapeutic success, taking into account the ecological impact that antibiotic treatments can have on them, as well as ensuring the use of cost effective treatments. For this purpose, in recent years, Antimicrobial Stewardship Programs (ASP) have been implemented throughout the Country. The present work has focused on the clinical and economic impact that ESBL-producing E.coli urinary tract infections had at the Hospital del Mar in Barcelona in recent years, as well as the impact of the implementation of an ASP in these infections, both clinical and economic. We analysed the episodes of urinary tract infections caused by ESBL-producing E.coli that required hospitalization between August 2010 and July 2013 by a retrospective cohort study, showing a poorer clinical outcome compared to non-ESBL-producing E.coli infections (higher clinical failure at day 7; p = 0.002), as well as an increase in the attributable costs (€ 4980 versus 2612 € per episode). With these results, we decided to analyse the impact that the progressive implementation of an ASP was having on these infections. For this purpose, all patients diagnosed with urinary tract infection by ESBL E.coli who had consulted at Hospital del Mar between January 2014 and December 2015 were reviewed, and assessed the clinical and economic impact that ASP interventions had on them. The interventions by the ASP team had a positive impact on clinical cure (p = 0.008). It was not possible to demonstrate an economic impact of these interventions on ESLB E.coli urinary tract infections