National Survey and consensus document on dosing strategies for beta-lactam antibiotics against multidrug-resistant gram-negative bacilli (MDR-GNB) in critically ill patients undergoing extracorporeal life support techniques: The DOSEBL study protocol. / Encuesta nacional y elaboración de un documento de consenso sobre estrategias de dosificación de antibióticos beta-lactámicos frente a bacterias gramnegativas multirresistentes (BGN-MDR) en pacientes críticos que son tratados con técnicas de soporte vital extracorpóreas: protocolo de estudio DOSEBL.

INTRODUCTION: Infections caused by multidrug-resistant gram-negative bacilli (MDR-GNB) in critically ill patients present a challenge for timely and appropriate antibiotic treatment. This is particularly important in patients undergoing extracorporeal life support techniques such as renal replacement therapy and extracorporeal membrane oxygenation. These techniques can introduce additional pharmacokinetic alterations, potentially leading to suboptimal exposure to antibiotics. This study aims to outline dosing strategies and therapeutic drug monitoring protocols for new ß-lactam antibiotics effective against MDR-GNB in critically ill patients undergoing extracorporeal life support techniques at a national level. Additionally, the study seeks to develop a consensus document, based on available evidence. METHODS: The project will comprise two main phases: I) A national survey, and II) the development of a consensus document. This consensus document, undertaken according to ACCORD guidelines, will encompass: a) establishment of a multidisciplinary panel of experts, b) prospective registration of the consensus, c) evidence synthesis, d) modified Delphi rounds. The antimicrobials to be included will be: meropenem, ceftazidime/avibactam, ceftolozane/tazobactam, cefiderocol, meropenem/vaborbactam, imipenem/relebactam, and aztreonam. Extracorporeal life support techniques will include continuous renal replacement therapy, conventional intermittent hemodialysis, and extracorporeal membrane oxygenation. DISCUSSION: The availability of extracorporeal life support techniques has expanded significantly in recent years, alongside a rise in the prevalence of infections caused by multidrug-resistant gram-negative bacilli (MDR-GNB). There is a need to develop evidence-based tools of high quality to standardize dosing and monitoring strategies for new ß-lactam antibiotics.

Agreement between pharmacists and physicians on the assessment of appropriateness of antimicrobial prescribing.

INTRODUCTION: Audits for monitoring the quality of antimicrobial prescribing are a main tool in antimicrobial stewardship programs; however, interobserver reliability has not been conclusively assessed. Our objective was to measure the level of agreement between pharmacists and physicians on the appropriateness of antimicrobials prescribing in hospitals. METHODS: A national multicenter, cross-sectional study was conducted of patients who were receiving antimicrobials one day of April 2021. Hospital participation was voluntary, and the study population was randomly selected. Pharmacists and physicians performed a simultaneous, independent assessment of the quality of antimicrobial prescriptions. The observers used an assessment method by which all indicators of the quality of antimicrobial use were considered. Finally, an algorithm was used to rate overall antimicrobial prescribing as appropriate, suboptimal, inappropriate, or not assessable. Gwet's AC1 coefficient was used to assess interobserver agreement. RESULTS: In total, 101 hospitals participated, and 411 hospital antimicrobial prescriptions were reviewed. The strength of agreement was moderate regarding the overall quality of prescribing (AC1=0.51; 95%CI=[0.44-0.58]). A very good level of agreement (AC1>0.80) was observed between pharmacists and physicians in all indicators of the quality, except for duration of treatment, rated as good (AC1=0.79; 95%CI=[0.75-0.83]), and registration on the medical record, rated as fair (AC1=0.34; 95%CI=[0.26-0.43]). The agreement was greater in critical care, onco-hematology, and pediatric units than in medical and surgery units. CONCLUSIONS: In this point prevalence study, a moderate level of agreement was observed between pharmacists and physicians in the evaluation of the appropriateness of antimicrobials prescribing in hospitals.

Pharmacist care in hospital emergency departments: a consensus paper from the Spanish hospital pharmacy and emergency medicine associations. / Atención farmacéutica en los servicios de urgencias: documento de posicionamiento de la Sociedad Española de Farmacia Hospitalaria (SEFH) y la Sociedad Española de Medicina de Urgencias y Emergencias (SEMES).

OBJECTIVES: To draft a list of actions and quality indicators for pharmacist care in hospital emergency departments, based on consensus among a panel of experts regarding which actions to prioritize in this setting. MATERIAL AND METHODS: A panel of experts from the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Emergency Medicine (SEMES) evaluated a preliminary list of potential actions and quality of care indicators. The experts used a questionnaire to assess the proposals on the basis of available evidence. In the first round, each expert individually assessed the importance of each proposed action based on 4 dimensions: evidence base, impact on clinical response and patient safety, ease of implementation, and priority. In the second round the experts attended a virtual meeting to reach consensus on a revised list of proposals; suggestions and comments that had been made anonymously in the first round were included. The group then prioritized each action as basic, intermediate, or advanced. RESULTS: The experts evaluated a total of 26 potential actions and associated quality indicators. No items were eliminated in the analysis of scores and comments from the first round. After the second round, 25 actions survived. Nine were considered basic, 10 intermediate, and 6 advanced. CONCLUSION: The expert panel's list of pharmacist actions and care quality indicators provides a basis for developing a pharmacist care program in Spanish emergency departments on 3 levels of priority. The list can serve as a guide to pharmacists, managers, physicians, and nurses involved in the effort to improve drug therapy in this hospital setting.

OBJETIVO: Desarrollar un conjunto de actividades e indicadores de atención farmacéutica en los servicios de urgencias hospitalarios mediante un consenso colectivo de un panel de expertos que permita priorizar las actividades a realizar por los farmacéuticos en estas unidades. METODO: Un comité formado por miembros de la Sociedad Española de Farmacia Hospitalaria (SEFH) y de la Sociedad Española de Medicina de Urgencias y Emergencias (SEMES) evaluó una propuesta inicial de actividades e indicadores potenciales, basados en la evidencia científica disponible, en formato de cuestionario. En una primera ronda, cada uno de los expertos del panel clasificó de forma individual la relevancia de cada una de las actividades propuestas en cuatro dimensiones: evidencia científica, impacto en la respuesta clínica y seguridad para el paciente, facilidad de implementación y grado de prioridad. La segunda ronda se realizó mediante una reunión grupal de forma virtual, a partir del cuestionario modificado de acuerdo con las sugerencias planteadas, así como los comentarios vertidos por los participantes del panel de forma anónima. En esta ronda, cada actividad fue clasificada por consenso como básica, intermedia o avanzada en función del grado de prioridad de implantación considerado por el grupo de expertos. RESULTADOS: Se propusieron un total de 26 potenciales actividades a los expertos, con indicadores asociados. Tras el análisis de las puntuaciones y los comentarios realizados en la primera ronda, no se eliminó ninguna de las actividades propuestas. Tras la segunda ronda, se mantuvieron 25 actividades, de las cuales se puntuaron 9 como actividades básicas, 10 actividades como intermedias y 6 actividades como avanzadas. CONCLUSIONES: El desarrollo del conjunto de actividades e indicadores de atención farmacéutica en urgencias, priorizados por grado de relevancia para la unidad, es la base para el desarrollo de esta cartera de servicios en los hospitales españoles, y sirve como guía tanto para farmacéuticos como para gestores, médicos y enfermeros de la unidad a fin de mejorar la farmacoterapia los pacientes atendidos en los servicios de urgencias.

Dexamethasone for the treatment of traumatic brain injured patients with brain contusions and pericontusional edema: Study protocol for a prospective, randomized and double blind trial.

BACKGROUND: Traumatic brain injury (TBI) constitutes a leading cause of death and disability. Patients with TBI and cerebral contusions developing pericontusional edema are occasionally given dexamethasone on the belief that this edema is similar to that of tumors, in which the beneficial effect of dexamethasone has been demonstrated. METHODS: The DEXCON TBI trial is a multicenter, pragmatic, randomized, triple-blind, placebo controlled trial to quantify the effects of dexamethasone on the prognosis of TBI patients with brain contusions and pericontusional edema. Adult patients who fulfill the elegibility criteria will be randomized to dexamethasone/placebo in a short and descending course: 4 mg/6 h (2 days); 4 mg/8 hours (2 days); 2 mg/6 hours (2 days); 2 mg/8 hours (2 days); 1 mg/8 hours (2 days); 1 mg/12 hours (2 days). The primary outcome is the Glasgow Scale Outcome Extended (GOSE) performed 1 month and 6 months after TBI. Secondary outcomes are: number of episodes of neurological deterioration; symptoms associated with TBI; adverse events; volume of pericontusional edema before and after 12 days of treatment; results of the neuropsychological tests one month and 6 months after TBI. The main analysis will be on an "intention-to-treat" basis. Logistic regression will estimate the effect of dexamethasone/placebo on GOSE at one month and at 6 months, dichotomized in unfavorable outcome (GOSE 1-6) and favorable outcome (GOSE 7-8). Efficacy will also be analyzed using the 'sliding dichotomy'. An interim and safety analysis will be performed including patients recruited during the first year to calculate the conditional power. A study with 600 patients would have 80% power (2 sided alpha = 5%) to detect a 12% absolute increase (from 50% to 62%) in good recovery. DISCUSSION: This is a confirmative trial to elucidate the therapeutic efficacy of dexamethasone in a very specific group of TBI patients: patients with brain contusions and pericontusional edema. This trial could become an important milestone for TBI patients as nowadays there is no effective treatment in this type of patients. TRIAL REGISTRATION: eudraCT: 2019-004038-41; Clinical Trials.gov: NCT04303065.

Monthly Continuous Erythropoietin Receptor Activator Versus Weekly Epoetin-Beta, Similar Hemoglobinization but Different Anisocytosis Degree in Hemodialysis Patients: A Randomized Controlled Trial.

BACKGROUND: The monthly continuous erythropoietin receptor activator (CERA) utilization maintains stable hemoglobin (Hb) after conversion from weekly epoetin-ß (EB); however, how the different pharmacologic properties affect the red blood cell (RBC) size determined by RBC distribution width (RDW) has not been evaluated yet. We assess the potential differences in iron metabolism, plasma erythropoietin (EPO), hepcidin, and soluble α-Klotho (α-Klotho) levels as an emergent hematopoiesis factor. METHODS: Thirty-seven chronic hemodialysis patients were included from January 2010 to November 2011 and randomized (1:1) to continue with EB or to convert to monthly CERA. Primary outcome was the mean change in Hb between groups at months 0, 3 and 6, and the percentage of patients who maintained stable Hb (Hb ± 1 g/dL from baseline level to month 6). Secondary outcomes were the influence on the erythropoietic process and iron metabolism markers. Thirty-one patients completed the study (CERA: n = 15, EB: n = 16). RESULTS: The mean (95% confidence interval (CI)) Hb difference between groups was 0.28 g/dL (-0.36 to 0.93). There was no difference between the percentages of patients with stable Hb levels. In the CERA group RDW values increased progressively (interaction erythropoietin-stimulating agent (ESA) type and time on RDW values, F (1.57, 45.60) = 17.17, P < 0.01, partial η2 = 0.37) and the mean corpuscular volume changed at the different time points, (F (2, 28) = 29.12, P = 0.03, partial η2 = 0.23). During the evaluation period, in the CERA group, EPO was higher, and hepcidin and ferritin decreased significantly. α-Klotho decreased in both groups and correlated negatively with the changes on the RDW and positively with transferrin and serum iron. The number of serious adverse events was higher at the CERA group. CONCLUSIONS: Monthly CERA maintained Hb concentrations; however, it showed a significant effect on RDW, probably due to its impact on the EPO and hepcidin levels. α-Klotho decreased significantly in both groups, and its changes correlated with the changes in iron metabolism. Whether the RDW evolution was associated with the serious adverse events (SAEs) is a feasible hypothesis that needs to be confirmed in large studies.

Nationwide current situation of hospital pharmacists in intensive care units.

OBJECTIVE: To describe the current situation of the hospital pharmacist in intensive care units and their activity in care, in teaching  and in research. METHOD: Multicenter and prospective study through a survey  disseminated by the Spanish Society of Hospital Pharmacy, which  consisted of several sections: personal and hospital's data, hospital's  characteristics, pharmacist's involvement in intensive care units and  teaching. RESULTS: A number of 58 completed surveys were obtained. The  number of pharmacists involved in intensive care units was 1 in 77.6%  of cases, assisting an average of 30.8 beds (5-70). Experience of  pharmacists in the intensive care unit was 5 years on average (2  months-25 years). Visitor's pass assistance and shift changes were  between "never" by 36.2% to "daily" by 22.4%. Out of respondents,  93.1% reported a part-time intensive care unit involvement. Regarding  activities undertaken, between 40-60% of pharmacists manage  narcotics, teaching at intensive care unit, conciliation and safety.  Between 60-80%, pharmacists cover clinical nutrition, notarization,  optimization of pharmacokinetics and antibiotics; and 84.5% perform  pharmacotherapy follow-up. Out of the surveyed pharmacists, 77.6%  have specialized medical training, rotating intensive care unit residents  in 86% of cases. CONCLUSIONS: Most of the surveyed hospitals have one part-time  pharmacist in these units. In order to improve the quality of  pharmaceutical care of critically ill patients, it would be necessary to  extend the involvement in time and staff, regarding the current  situation, and a greater number of hospitals should include pharmacists  in hospital intensive care units.

Objetivo: Describir la situación actual del farmacéutico de hospital en las unidades de cuidados intensivos, su actividad asistencial, docente  e investigadora.Método: Estudio multicéntrico, prospectivo mediante encuesta  difundida por la Sociedad Española de Farmacia Hospitalaria, la cual  constaba de varios apartados: datos personales y del hospital,  características del hospital, implicación del farmacéutico en la unidad de  cuidados intensivos y docencia.Resultados: Se obtuvieron 58 encuestas completadas. El número de farmacéuticos implicados en unidades de cuidados intensivos era 1  en el 77,6% de los casos, atendiendo una media de 30,8 camas (5-70).  La experiencia en la unidad de cuidados intensivos del farmacéutico fue  de 5 años de mediana (2 meses-25 años). La asistencia al pase de visita  o cambios de guardia fue entre "nunca" en un 36,2% a  "diariamente" en un 22,4%. El 93,1% de los encuestados reportaron  dedicación a tiempo parcial en la unidad de cuidados intensivos.  Respecto a actividades desarrolladas, entre el 40-60% gestiona  estupefacientes, docencia en unidad de cuidados intensivos, conciliación  y seguridad; entre el 60-80% abarca nutrición clínica,  protocolización, optimización de antibióticos y farmacocinética, y un  84,5% realizan seguimiento farmacoterapéutico. Un 77,6% cuenta con  formación sanitaria especializada, rotando los residentes en la unidad de  cuidados intensivos en un 86% de los casos.Conclusiones: La mayor parte de los hospitales encuestados cuenta con un solo farmacéutico a tiempo parcial en estas unidades. Con objeto de mejorar la calidad de la atención farmacéutica del paciente crítico sería necesario ampliar la dedicación en tiempo y personal respecto a la  situación actual y que más centros incluyan al farmacéutico en las unidades de cuidados intensivos hospitalarias.

Higher MICs (>2 mg/L) Predict 30-Day Mortality in Patients With Lower Respiratory Tract Infections Caused by Multidrug- and Extensively Drug-Resistant Pseudomonas aeruginosa Treated With Ceftolozane/Tazobactam.

BACKGROUND: Ceftolozane/tazobactam (C/T) efficacy and safety in ventilator-associated pneumonia (VAP) is being evaluated at a double dose by several trials. This dosing is based on a pharmacokinetic (PK) model that demonstrated that 3 g q8h achieved ≥90% probability of target attainment (50% ƒT > minimal inhibitory concentration [MIC]) in plasma and epithelial lining fluid against C/T-susceptible P. aeruginosa. The aim of this study was to evaluate the efficacy of different C/T doses in patients with lower respiratory infection (LRI) due to MDR- or XDR-P. aeruginosa considering the C/T MIC. METHODS: This was a multicenter retrospective study of 90 patients with LRI caused by resistant P. aeruginosa who received a standard or high dose (HDo) of C/T. Univariable and multivariable analyses were performed to identify independent predictors of 30-day mortality. RESULTS: The median age (interquartile range) was 65 (51-74) years. Sixty-three (70%) patients had pneumonia, and 27 (30%) had tracheobronchitis. Thirty-three (36.7%) were ventilator-associated respiratory infections. The median C/T MIC (range) was 2 (0.5-4) mg/L. Fifty-four (60%) patients received HDo. Thirty-day mortality was 27.8% (25/90). Mortality was significantly lower in patients with P. aeruginosa strains with MIC ≤2 mg/L and receiving HDo compared with the groups with the same or higher MIC and dosage (16.2% vs 35.8%; P = .041). Multivariate analysis identified septic shock (P < .001), C/T MIC >2 mg/L (P = .045), and increasing Charlson Comorbidity Index (P = .019) as independent predictors of mortality. CONCLUSIONS: The effectiveness of C/T in P. aeruginosa LRI was associated with an MIC ≤2 mg/L, and the lowest mortality was observed when HDo was administered for strains with C/T MIC ≤2 mg/L. HDo was not statistically associated with a better outcome.

Indicators of the hospital use of antimicrobial agents based on consumption.

OBJECTIVE: To identify indicators of hospital use of antimicrobials from the  benchmark analysis of consumption data between hospitals at the same level  through the collective judgement of a group of experts. METHOD: A committee formed by members of the Spanish Societies of Hospital Pharmacy and Infectious Diseases and Clinical Microbiology prepared a proposal of indicators which was submitted to  consensus by a panel of 21 experts on infectious diseases, microbiology and  antimicrobial therapy, through a modified Delphi method. The panel  underwent two rounds of scores by e-mail. Participants assigned a score  from 1 (completely disagree) to 9 (completely agree) to the relevance of  each indicator in four dimensions: scientific evidence, efficacy and safety,  ecological impact and cost. Scores were processed according to the RAND- UCLA method. An indicator was considered to be relevant if at least one  dimension other than cost obtained a median score equal to or higher than 7 without disagreement among the panel. RESULTS: The committee submitted an initial proposal of 14 indicators. After the first round of panel scores, one indicator was ruled out and two  were  modified for moving on to the second round. Finally, 13 indicators  were considered relevant. CONCLUSIONS: Determining indicators of the hospital use of antimicrobial agents based on consumption can allow the antimicrobial  stewardship programs to detect any potential problems with the use of  antimicrobial agents, and to help guide their efforts in order to implement actions of improvement, as well as to assess the impact of the  measures implemented.

Objetivo: Identificar unos indicadores del uso hospitalario de  antimicrobianos a partir del análisis comparativo de los datos de consumo  entre hospitales del mismo nivel por medio del juicio colectivo de un grupo  de expertos.Método: Un comité formado por miembros de la Sociedad Española de Farmacia Hospitalaria y de la Sociedad Española de Enfermedades  Infecciosas y Microbiología Clínica preparó una propuesta de indicadores que  fue sometida a consenso por un panel de 21 expertos en enfermedades infecciosas, microbiología y terapéutica antimicrobiana  mediante un método Delphi modificado. El panel se sometió a dos rondas de  puntuaciones por correo electrónico. Los participantes puntuaron de 1  (completamente en desacuerdo) a 9 (completamente de acuerdo) la  relevancia de cada indicador en cuatro dimensiones: evidencia científica,  eficacia y seguridad, repercusión ecológica y coste. Las puntuaciones fueron  procesadas según el método UCLA-RAND. Un indicador fue juzgado como relevante si al menos una dimensión distinta al coste obtenía una  mediana de puntuación igual o superior a 7 sin haber desacuerdo entre el  panel.Resultados: El comité planteó una propuesta inicial de 14 indicadores. Tras  la primera ronda de puntuaciones del panel, un indicador fue desestimado y  dos fueron modificados para el paso a la segunda ronda. Finalmente, 13  indicadores fueron considerados relevantes.Conclusiones: El establecimiento de indicadores del uso hospitalario de  antimicrobianos basados en el consumo puede permitir a los programas de  optimización de antimicrobianos detectar cuáles son los problemas potenciales de uso de los antimicrobianos, y ayudar a orientar sus esfuerzos para emprender acciones de mejora, así como para valorar el impacto de las medidas efectuadas.

Drug dosage recommendations in patients with chronic liver disease.

Chronic liver diseases (CLD) alter the kinetics of drugs. Despite dosage adjustment is based on Child-Pugh scores, there are no available recommendations and/or algorithms of reference to facilitate dosage regimens. A literature review about dose adjustment of the drugs from the hospital guide -which are included in the list of the WHO recommended drugs to be avoided or used with caution in patients with liver disease- was carried out. The therapeutic novelties from the last few years were also included. In order to do so, the summary of product characteristics (SPC), the database DrugDex-Micromedex, the WHO recommendations and the review articles from the last 10 years in Medline were reviewed. Moreover, the kinetic parameters of each drug were calculated with the aim of establishing a theoretical recommendation based on the proposal of Delcò and Huet. Recommendations for 186 drugs are presented according to the SPC (49.5%), DrugDex-Micromedex (26.3%) and WHO (18.8%) indications; six recommendations were based on specific publications; the theoretical recommendation based on pharmacokinetic parameters was proposed in four drugs. The final recommendations for clinical management were: dosage modification (26.9%), hepatic/analytical monitoring of the patient (8.6%), contraindication (18.8%), use with caution (19.3%) and no adjustment required (26.3%). In this review, specific recommendations for the practical management of patients with chronic liver disease are presented. It has been elaborated through a synthesis of the published bibliography and completed by following a theoretical methodology.