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WHAT IS KNOWN AND OBJECTIVE Betalactam antibiotics are the most frequent cause of hypersensitivity reactions. Rapid drug desensitization (RDD) is a technique that induces temporary tolerance to a drug allowing a patient to receive the optimal agent. The increased use of RDD and the lack of standardization among available protocols in terms of formulation, starting dose, number of steps and dosing frequency make it essential to determine the safety and appropriate management of these protocols, especially regarding reconstitution, diluents, stability and drug administration in order to guarantee reproducibility. We reviewed betalactam desensitization protocols in a tertiary hospital, in accordance with currently published practices and evaluated its use on patients over a period of three years. METHODS (a) We performed a literature search in PubMed, MEDLINE and Google Scholar databases for case reports and/or systematic reviews describing desensitization protocols for betalactam antibiotics. Pharmacokinetic parameters and physicochemical stability were checked for each antibiotic. (b) We retrospectively reviewed inpatients undergoing our antibiotic desensitization protocols from February 2018 to January 2021. Data and outcomes of desensitization procedures were analysed. RESULTS We developed nine RDD protocols: meropenem, ceftriaxone, ceftazidime, ampicillin, ceftolozane/tazobactam, cloxacillin, piperacillin/tazobactam, amoxicillin/clavulanate and penicillin G sodium. Five antibiotics have RDD protocols for two different doses, adjusted to patients with impaired renal function. Detailed data (diluent, total dose, volume, concentrations, duration and stability) of the protocol of each antibiotic used are provided. 28 desensitizations were performed in 17 patients, three of them with confirmed allergies by skin test. 26 out of 28 (92.9%) of them were successfully completed, including those three with positive skin results. The pathogens most frequently involved were E. faecalis and P. aeruginosa; both frequently associated with bacterial resistance. Meropenem, ceftriaxone and ceftazidime were the antibiotics most desensitized. 25 out of 26 (96.1%) procedures were successful in resolving the infection. WHAT IS NEW AND CONCLUSIONS Detailed information about compounding, dilution and stability is crucial to ensure safe and successful desensitization processes, as well as good coordination between the Allergy and Pharmacy departments. The increase in bacterial resistance to many of the commercially available antibiotics limits the therapeutic options for treating multidrug-resistant infections; in those situations, antibiotic desensitization may be a key therapeutic option. Although there is a broad consensus in limiting the use of RDD to patients with confirmed allergy, in usual clinical practice its application in those strongly suspected of having type I hypersensitivity is still observed. Our betalactam desensitization protocols have shown themselves to be safe and effective, as evidenced by data from the 17 patients on whom they have been tested.

Introducción: Voriconazol presenta una alta variabilidad interindividual en sus concentraciones plasmáticas (Cp). Los objetivos son: (i) describir sus Cp en una cohorte adulta, (ii) estudiar sus potenciales causas de variabilidad y (iii) relacionarlas con las recomendaciones de monitorización farmacocinética actuales. Método: Estudio observacional retrospectivo, incluyendo pacientes con ≥1 determinación de Cp mínima (Cmin) de voriconazol durante 2017. Resultados: Se analizaron 165 Cmin correspondientes a 51 pacientes. La mediana de Cmin fue de 2,4μg/mL (IQR:1,4-3,6), siendo 4μg/mL en 34. Se observaron Cmin significativamente superiores en >65 años (p=0,006) y en pacientes con albúmina, Introduction: Voriconazole presents a high interindividual variability in plasma concentrations. We aimed to: (i) describe plasma voriconazole concentrations (PVC) of an adult cohort, (ii) identify potential causes of variability and (iii) relate them with current pharmacokinetic monitoring recommendations. Method: Observational retrospective study. All patients with at least one determination of PVC during 2017 were included. Results: A total of 165 trough concentrations (Ctrough) were analyzed from 51 patients. The median Ctrough was 2.4μg/mL (IQR:1.4-3.6). Ctrough were 4 μg/mL in 34. Significantly higher concentrations were ob¬served in patients older than 65 years (p=0.006) and in patients with albumin levels

High temperatures during the summer season are a very important factor to be considered due to their possible influence on drug stability and effectiveness. This is especially important in those patients included in clinical trials, polymedicated or with long-term pharmacological therapies.

Objectives To investigate if the addition of cloxacillin to vancomycin enhances the activity of both monotherapies for treating MSSA and MRSA experimental endocarditis (EE) in rabbits. Methods Vancomycin plus cloxacillin was compared with the respective monotherapies and daptomycin. In vitro time–kill studies were performed using standard (105 cfu) and high (108 cfu) inocula of five MRSA, one glycopeptide-intermediate (GISA) and five MSSA strains. One MSSA (MSSA-678) and one MRSA (MRSA-277) strain were selected to be used in the in vivo model. A human-like pharmacokinetics model was applied and the equivalents of cloxacillin 2 g/4 h IV and daptomycin 6 mg/kg/day IV were administered. To optimize vancomycin activity, dosage was adjusted to achieve an AUC/MIC ≥400. Results Daptomycin sterilized significantly more vegetations than cloxacillin (13/13, 100% versus 9/15, 60%; P = 0.02) and showed a trend of better activity than vancomycin (10/14, 71%; P = 0.09) and vancomycin plus cloxacillin (10/14, 71%; P = 0.09) against MSSA-678. Addition of cloxacillin to vancomycin (13/15, 87%) was significantly more effective than vancomycin (8/16, 50%; P = 0.05) and showed similar activity to daptomycin (13/18, 72%; P = 0.6) against MRSA-277. In all treatment arms, the bacterial isolates recovered from vegetations were re-tested and showed the same daptomycin susceptibility as the original strains. Conclusions Vancomycin plus cloxacillin proved synergistic and bactericidal activity against MRSA. Daptomycin was the most efficacious option against MSSA and similar to vancomycin plus cloxacillin against MRSA. In settings with high MRSA prevalence, vancomycin plus cloxacillin might be a good alternative for empirical therapy of S. aureus IE.

Ceftriaxone total and unbound pharmacokinetics (PK) can be altered in critically ill patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration (CVVHDF). The objective of this study was to determine the dosing strategy of ceftriaxone that maximizes the probability of maintaining the concentration above the MIC of the susceptible bacteria (≤2 mg/L by the EUCAST) for a 100% of the dosing interval (100% ƒuT>MIC). In a prospective PK study in the intensive care units of two tertiary Spanish hospitals, six timed blood samples were collected per patient; for each sample, ceftriaxone total and unbound concentrations were measured using a liquid chromatography coupled to tandem mass spectrometry method. Population PK analysis and Monte-Carlo simulations were performed using NONMEMv.7.3®. We enrolled 8 critically ill patients that met the inclusion criteria (47 blood samples). Median age (range) was 70 years (47-85), weight 72.5 kg (40-95), albumin concentration 24.2 g/L (22-34), APACHE II score at admission 26 (17-36), and SOFA score on the day of study 12 (9-15). The unbound fraction (ƒu) of ceftriaxone was 44%, and total CL was 1.27 L/h, 25-30% higher than the CL reported in septic critically ill patients not receiving renal replacement therapies, and dependent on albumin concentration and weight. Despite this increment in ƒu and CL, Monte-Carlo simulations showed that a dose of 1 g once-daily ceftriaxone is sufficient to achieve a 100% ƒuT>MIC for MICs ≤2 mg/L for any range of weight and albumin concentration. Once-daily 1 g ceftriaxone provides optimal exposure in critically ill patients with septic shock and hypoalbuminemia receiving CVVHDF.

What is known and objective Dose banding is a strategy to optimize processing without reducing patient safety. Prescribed doses are rounded up or down to predetermined standard doses. Although it has been mostly used in chemotherapy, other drugs are suitable for this strategy, such as the antiviral ganciclovir. The aim of this work is to assess the safety and efficiency of a dose-rounding system for intravenous ganciclovir. Methods Dose bands were established for a maximum of 10% variation from the individualized dose. The number of annual preparations that expired before use and the number of ganciclovir vials saved were documented as indicators of efficiency. Toxicity was assessed comparing haematological parameters before and after ganciclovir treatment in a sample of patients who received doses above the theoretical dose (n = 121) and in the rest of the cohort (n = 129). Results and discussion Five ganciclovir standard doses were established. It was shown that the bulk of the preparations (83.7%) had a maximum variation between the exact dose prescribed and the adjusted dose of ±10%. Three years after its implementation, a mean of 2848 annual preparations were compounded. The average percentage of annual expired preparations was lower than 1% of the total compounded doses, and the dose-rounding system allowed for saving 699 manufactured ganciclovir vials annually. There was no significant difference between haemoglobin and leucocyte levels measured before and after ganciclovir treatment in both groups. What is new and conclusion Ganciclovir dose banding allows for efficient management of preparations without an increased risk of acute haematological side effects.

Personalized therapy in the treatment of infections is essential to ensure optimization of antimicrobial drug levels. This strategy, together with an understanding of the activity of these drugs, decreases the risk of bacterial resistance and improves the drugs' safety profile. Alternative outes of administration, such as inhalation, and the information provided by pharmacokinetic models, are essential given the limitation of antimicrobial activity allowed by the new antimicrobials.A non-systematic review of the literature is presented as a way of tackling and finding solutions to the problem. A search for high-quality articles on the research topic was conducted. Results: A total of 370 articles were detected, which were subjected to a further selection to discard low quality papers by a team of five clinical pharmacists and an intensivist. Finally, 153 articles were included in the review.The geriatric and the critical care patient population require the administration of antimicrobials with close monitoring. The routes of administration recommended for the first group are discouraged for the second. The inhaled route often results in high plasma concentrations in patients with respiratory infections. Pharmacokinetic models are a valuable tool in the treatment of geriatric patients, who are often excluded from clinical trials.La terapia personalizada en el tratamiento de las infecciones es esencial para garantizar la optimización de los niveles de fármaco lcanzados en el paciente tratado. Adicionalmente, esta estrategia, juntamente con el conocimiento de la actividad antimicrobiana de estos fármacos, isminuye la posibilidad de desarrollar resistencias bacterianas y mejora el perfil de seguridad de estos fármacos. Las terapias por vías alternativas, como la inhalada, y el soporte de la información facilitada por modelos farmacocinéticos son esenciales debido a la limitación de la actividad aportada por los nuevos antimicrobianos.Método: Se presenta una revisión no sistemática de la literatura como medida de orientación de la problemática y soluciones a lo expuesto anteriormente. Se ha efectuado una búsqueda de artículos de alta calidad sobre el tópico planteado.Se detectaron 231 artículos que sufrieron una selección posterior, en base a la calidad de los trabajos valorada por un equipo de cinco farmacéuticos clínicos y un médico intensivista. Finalmente, se incluyeron 153 artículos que soportan la revisión que se ha desarrollado.La población geriátrica y la integrada por pacientes críticos presenta la necesidad de utilización de los antimicrobianos con una estrecha monitorización. Vías de administración recomendadas en la primera, están desaconsejadas en la segunda. La vía inhalada es una vía que suele relacionarse con elevadas concentraciones en pacientes con infecciones respiratorias. Los modelos farmacocinéticos son un soporte de gran valor para poblaciones como la geriátrica debido a que es mayoritariamente excluida de los ensayos clínicos.

Objectives Meropenem pharmacokinetics (PK) may be altered in patients with cirrhosis, hampering target attainment. We aimed to describe meropenem PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. Methods Serum concentrations and covariates were obtained from patients with severe infections under meropenem treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate meropenem exposure to assess the PTA. Results Fifty-four patients were enrolled in the study. Data were best described by a one-compartment linear model. The estimated typical mean value for clearance (CL) was 8.35 L/h and the estimated volume of distribution (V) was 28.2 L. Creatinine clearance (CLCR) and MELD score significantly influenced meropenem CL, and acute-on-chronic liver failure (ACLF) significantly affected V. Monte Carlo simulations showed that a lower meropenem dose would be needed as CLCR decreases and as the MELD score increases. Patients with ACLF would have lower peak meropenem concentrations but similar steady-state concentrations compared with patients with no ACLF. Conclusions Our study identified two new covariates that influence meropenem PK in patients with decompensated cirrhosis in addition to CLCR: MELD score and ACLF. Dosing regimens are recommended to reach several PK/PD targets considering these clinical variables and any MIC within the susceptibility range.

To improve the quality of the dispensing process and pharmaceutical care in the Outpatient Pharmacy through patient participation and Lean methodology, and to analyse the results obtained in terms of efficiency and patient satisfaction.Prospective observational single-centre study. A working group was organized with the health care staff involved in outpatient care to apply Lean methodology and detect improvement opportunities. We used a focus group technique to understand the patients' experience. The impact on patient satisfaction was measured through a mass survey mailed out in December 2019 (before introducing the main measures) and in December 2020.More than 30 improvement actions were identified after surveying the opinions of the patients and health care staff involved. Nine actions were prioritized, which were mainly related to structural and circuit changes. Waiting times significantly improved (35% of patients waited for more than 30 minutes before the improvement actions vs 4.5% afterward). The results showed that waiting times and overall satisfaction significantly improved in the period between the two surveys. In both cases, the degree of satisfaction was higher after introducing the improvement actions.We analysed the situation of our Outpatient Service and designed the most appropriate improvement actions according to the resources available. This initiative was achieved through patient participation (via a focus group and mass surveys), the participation of health care staff, and the application of Lean methodology.Objetivo: Mejorar la calidad del proceso de dispensación y atención farmacéutica a pacientes externos mediante la participación del paciente y la aplicación de la metodología Lean y analizar los resultados obtenidos en cuanto a eficiencia e impacto en la satisfacción de los pacientes. Método: Estudio observacional, prospectivo y unicéntrico. Se creó un grupo de trabajo con los diferentes profesionales implicados en la atención al paciente externo para aplicar la metodología Lean y detectar oportunidades de mejora. Para conocer la experiencia del paciente se utilizó la técnica del grupo focal. El impacto en la satisfacción de los pacientes se midió mediante encuestas de satisfacción que se enviaron a través del correo electrónico en diciembre de 2019 (antes de implantar las principales medidas) y en diciembre de 2020.Resultados: Teniendo en cuenta la perspectiva de los pacientes y de los profesionales sanitarios, se identificaron más de 30 acciones de mejora de las que se priorizaron 9, relacionadas fundamentalmente con cambios estructurales y de circuitos. Se consiguió mejorar significativamente los tiempos de espera (el 35% de los pacientes esperaban más de 30 minutos frente al 4,5% en el análisis realizado después de las intervenciones). Los aspectos que mostraron diferencias estadísticamente significativas en las encuestas entre los dos periodos fueron el tiempo de espera y la satisfacción global, en ambos casos el grado de satisfacción fue superior una vez implantadas las acciones de mejora.Conclusiones: La participación del paciente, a través del grupo focal y encuestas masivas, unido a la participación de los profesionales sanitarios implicados en el proceso, a través de la metodología Lean, ha permitido analizar la realidad de nuestro servicio y diseñar las acciones de mejora más adecuadas en función de los recursos disponibles.

Objectives Physiopathological changes in advanced cirrhosis could alter tigecycline pharmacokinetics (PK), thus affecting serum drug concentrations and compromising target attainment. We aimed to describe tigecycline PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. Methods Serum concentrations and covariates were obtained from patients with severe infections under tigecycline treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate tigecycline exposure to assess the PTA. Results Twenty critically ill patients were enrolled in the study. Data were best described by a two-compartment linear model. Mean ± SD parameter estimates for clearance (CL), intercompartmental clearance (Q), central and peripheral volumes of distribution (V1 and V2) were 14.8 ± 11 L/h, 38.4 ± 24 L/h, 63.7 ± 14 L and 233 ± 30 L, respectively. MELD score significantly influenced tigecycline CL, and total serum proteins significantly affected V1. Monte Carlo simulations showed that tigecycline elimination is hampered as MELD score values increase, consequently requiring lower drug doses. Patients with hypoproteinaemia would have lower peak tigecycline concentrations but similar steady-state concentrations compared with patients with normoproteinaemia. Conclusions Our study confirms that tigecycline dose adjustment is needed in severe hepatic dysfunction and suggests using the MELD score for dose optimization since it is identified as a covariate that significantly influences tigecycline CL. Dosing regimens are recommended to reach several PK/PD targets considering this clinical variable and any MIC within the susceptibility range.

Purpose To evaluate the stability of 5% vancomycin ophthalmic solution prepared using balanced salt solution (BSS) and stored at –20°C in polypropylene containers. Methods Six batches of vancomycin 50 mg/mL eyedrops were aseptically prepared. One bottle of each batch was analyzed immediately after preparation, and the rest were stored at –20°C and analyzed using high-performance liquid chromatography (HPLC) at 30, 60, and 90 days to test their physicochemical stability and sterility. Thereafter, bottles were removed from the freezer and stored at 5°C for 30 days, with HPLC and other analyses repeated 105 and 120 days after preparation. All samples were analyzed in triplicate. Stability was defined as the absence of particles, color variation, or changes in pH and a remaining vancomycin concentration of 90% to 110% of the initial concentration. The sterility of the ophthalmic solution was evaluated by using soybean-casein digest broth with resins; samples were incubated for 7 days and checked daily for signs of microbial growth. Results There was no particle formation or sign of precipitation in any of the solutions throughout the duration of the study, regardless of the storage conditions. No change in color or turbidity was observed. The pH and osmolarity remained unchanged during storage at –20°C and after thawing. The vancomycin concentration remained within 10% of the initial concentration during the 90-day period of storage at –20°C and the subsequent 30 days after thawing. Sterility was preserved in all samples. Conclusion A 5% solution of vancomycin prepared using BSS was physicochemically and microbiologically stable when stored at –20°C for 90 days. After thawing, this extemporaneous formulation remained stable when refrigerated at 5°C for 30 days.

Around 2·5 million deaths and more than 110 million COVID-19 cases have been reported globally. Although it initially appeared that HIV infection was not a risk factor for COVID-19 or more severe disease, more recent large studies suggest that people living with HIV (particularly with low CD4 cell counts or untreated HIV infection) might have a more severe clinical course than those who are HIV-negative. Moreover, the COVID-19 pandemic has disrupted HIV prevention and treatment services worldwide, creating huge challenges to the continuity of essential activities. We have reviewed the most relevant features of COVID-19 in people living with HIV and highlighted topics where further research is required.

Current guidelines recommend vancomycin and linezolid as first-line agents against methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. Telavancin is a potential new therapeutic alternative, specifically in monomicrobial MRSA pneumonia. This study compared the efficacies of telavancin versus linezolid in a porcine model of severe MRSA pneumonia. In 18 mechanically ventilated pigs (32.11 ± 1.18 kg), 75 ml of 10(6) CFU/ml of MRSA was administered into each pulmonary lobe. After the onset of pneumonia, pigs were randomized into three groups: a control group, a group receiving 22.5 mg/kg of body weight every 24 h (q24h) of telavancin, and a group receiving 10 mg/kg q12h of linezolid intravenously. Tracheal aspirate and bronchoalveolar lavage (BAL) fluids were cultured every 24 h. After 48 h of treatment, tissue samples were collected from the ventral and dorsal sections of each lobe. Microbiological and histopathological analyses were performed. Lung tissue concentrations differed among the groups (P = 0.019), with the lowest MRSA lung burden in the telavancin group (P

Ceftriaxone total and unbound pharmacokinetics (PK) can be altered in critically ill patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration (CVVHDF). The objective of this study was to determine the dosing strategy of ceftriaxone that maximizes the probability of maintaining the concentration above the MIC of the susceptible bacteria (≤2 mg/L by the EUCAST) for a 100% of the dosing interval (100% ƒIn a prospective PK study in the intensive care units of two tertiary Spanish hospitals, six timed blood samples were collected per patient; for each sample, ceftriaxone total and unbound concentrations were measured using a liquid chromatography coupled to tandem mass spectrometry method. Population PK analysis and Monte-Carlo simulations were performed using NONMEMv.7.3®.We enrolled 8 critically ill patients that met the inclusion criteria (47 blood samples). Median age (range) was 70 years (47-85), weight 72.5 kg (40-95), albumin concentration 24.2 g/L (22-34), APACHE II score at admission 26 (17-36), and SOFA score on the day of study 12 (9-15). The unbound fraction (ƒOnce-daily 1 g ceftriaxone provides optimal exposure in critically ill patients with septic shock and hypoalbuminemia receiving CVVHDF.

The health crisis situation we have experienced caused by the SARSCoV-2 virus has changed our daily life in numerous aspects, including those related to training (undergraduate, postgraduate, and continuing education, etc). Training activities, conferences, lectures, face-to-face workshops were suspended until the Health Situation was over. Alternatives to face-to-face training were needed to guarantee the continuity of these activities. Online training, teaching and evaluation emerged as a relatively fast, simple, operational and flexible solution. Universities and faculties promoted online teaching through virtual classes. The Spanish Society of Hospital Pharmacy supported this initiative by signing an agreement with the Board of Deans and Chancellors of Pharmacy to make it possible for undergraduate students to continue their studies and supervised practices in hospital pharmacy departments. Specialized training was affected. Pharmacy residency programs were significantly modified by hospital pharmacies to be able to provide the new clinical and research activities required, everyday, by the pandemic situation. Postgraduate and residency training were also negatively affected. Again, online activities made up for restrictions to face-to-face teaching and training. The Spanish Society of Hospital Pharmacy promoted continuing education and provided updated information on the SARS-CoV-2 virus through its website. Thus, numerous virtual sessions, lectures and webinars have been held, and high-quality material was offered to provide up-todate knowledge, on the pharmacological management of patients with COVID-19. Online teaching and education has demonstrated to be an invaluable tool for hard times. During the lockdown, technology has kept us closer and has emerged as an ally. Many of us have found a new means of communication, information, and training. The Spanish Society of Hospital Pharmacy has substantially contributed to make it possible.La situación de crisis sanitaria que hemos vivido con motivo de la pandemia causada por el virus SARS-CoV-2 ha cambiado nuestro día a día en muchos aspectos, incluidos los relacionados con nuestra formación (de pregrado, especializada, continuada, etc.). Se suspendieron las actividades docentes, congresos, charlas y talleres presenciales hasta la resolución de la situación sanitaria. Era necesario buscar alternativas a la presencialidad que garantizasen la continuidad de estas actividades. La formación, docencia y evaluación en línea se presentaba como una solución relativamente rápida, sencilla, operativa y flexible. Desde las universidades y facultades se promovía la docencia en remoto con material docente y clases virtuales. La Sociedad Española de Farmacia Hospitalaria ha facilitado esta iniciativa al firmar un convenio con la Conferencia de Decanos de Farmacia para que estudiantes matriculados en Prácticas tuteladas, y en formación en un servicio de farmacia hospitalaria, pudieran seguir con sus estudios de pregrado. La formación especializada resultó afectada. Los planes de formación de los farmacéuticos internos residentes requirieron cambios importantes por la necesidad de dar respuesta desde los servicios de farmacia a las nuevas actividades asistenciales y de investigación que se producían, cada día de manera cambiante, en la situación de pandemia. La formación continuada de los especialistas (y residentes) quedó también alterada. De nuevo, las actividades en línea permitieron salvar, en cierto grado, el déficit de actividades docentes y formativas. A través de su página web, la Sociedad Española de Farmacia Hospitalaria promovió la formación continuada y el seguimiento de la actualidad sobre la pandemia por el virus SARS-CoV-2; organizó sesiones virtuales, jornadas y talleres en formato webinar y proporcionó material de alta calidad que facilitaba el conocimiento, en tiempo real, de la gestión del tratamiento farmacológico en pacientes con COVID-19. La aplicación de la docencia y formación en línea ha demostrado ser una herramienta imprescindible en tiempos complicados, como los vividos. Durante el confinamiento, la tecnología nos ha acercado y se ha convertido en la gran aliada. También ha supuesto el descubrimiento, para muchos de nosotros, de una nueva manera de comunicarnos, informarnos y formarnos. La Sociedad Española de Farmacia Hospitalaria ha colaborado de manera importante a que esto sea así.

Aim: Older patients with chronic hepatitis C infection starting direct-acting antivirals (DAAs) are frequently prescribed multiple medications that may be categorized as inappropriate. Anticholinergic burden has been shown to be a predictor of adverse health and functional outcomes. Different scales are available to calculate anticholinergic burden. The aim of this study was to determine the prevalence of anticholinergic medication among older patients treated with DAAs and the risk factors associated using the Anticholinergic Cognitive Burden (ACB) scale, the Anticholinergic Risk Scale (ARS) and the Anticholinergic Drug Scale (ADS) and analyze the resulting safety consequences. Methods: Observational, retrospective cohort study of consecutive patients &ge, 65 years old receiving DAAs and taking concomitant medication. This study was conducted in accordance with the Strengthening the Reporting of observational studies in Epidemiology Statement. Results: 236 patients were included. The average age was 71.7 years, 73.3% cirrhotic, and 47% patients took &ge, 5 medicines. According to the ACB, ARS and ADS scales, 35.2% (n = 83), 10.6% (n = 25) and 34.3% (n = 81) of the patients were treated with anticholinergic medication. Two hundred-and-six (86%) patients presented any adverse events (AEs) during therapy. ARS scale showed a significant relationship between presence of anticholinergic medication and AEs. A large number of patients suffered anticholinergic events, with more events per patient in patients taking anticholinergic drugs. Conclusions: Older hepatitis C chronic patients are exposed to potentially inappropriate polypharmacy and anticholinergic risk, according to the ACB, ARS and ADS scales. The three scales showed different results. Only the ARS scale was associated with AEs, but the rate of anticholinergic effects per patient was significantly higher in patients with anticholinergic drugs, regardless of the scale used. Consider quality of pharmacotherapy when starting DAA with a multidisciplinary approach could improve health outcomes.

Introduction: Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide, and its prevalence continues to increase. Despite the efficacy of antimicrobials, their safety and tolerability remain topics of interest and concern for clinicians and patients alike.Areas covered: This review outlines the main antimicrobial classes recommended for the empirical treatment of CAP in current guidelines, together with a potential new class. Each pharmacological group underwent a safety evaluation based on all available data about drug-related toxicities. The authors also present their mechanisms of action, their pharmacokinetic and pharmacodynamic properties, and the main clinical studies.Expert opinion: Overall, antimicrobials currently marketed for the treatment of CAP are well tolerated and generally safe. However, unusual and sometimes serious adverse effects can occur in susceptible populations. Attention should be paid to identifying patients at risk of developing drug-related toxicities because, although most effects are transient, some could be disabling, permanent, or even fatal. Post-marketing surveillance remains crucial for gathering data to overcome the limitations of preclinical and clinical studies in estimating the true prevalence of drug-related adverse events.

GAMES Investigators., [Background] Enterococcal endocarditis (EE) is a growing entity in Western countries. However, quality data from large studies is lacking., [Objectives] The purpose of this study was to describe the characteristics and analyze the prognostic factors of EE in the GAMES cohort., [Methods] This was a post hoc analysis of a prospectively collected cohort of patients from 35 Spanish centers from 2008 to 2016. Characteristics and outcomes of 516 cases of EE were compared with those of 3,308 cases of nonenterococcal endocarditis (NEE). Logistic regression and Cox proportional hazards regression analysis were performed to investigate risk factors for in-hospital and 1-year mortality, as well as relapses., [Results] Patients with EE were significantly older; more frequently presented chronic lung disease, chronic heart failure, prior endocarditis, and degenerative valve disease; and had higher median age-adjusted Charlson score. EE more frequently involved the aortic valve and prosthesis (64.3% vs. 46.7%; p < 0.001; and 35.9% vs. 28.9%; p = 0.002, respectively) but less frequently pacemakers/defibrillators (1.5% vs. 10.5%; p < 0.001), and showed higher rates of acute heart failure (45% vs. 38.3%; p = 0.005). Cardiac surgery was less frequently performed in EE (40.7% vs. 45.9%; p = 0.024). No differences in in-hospital and 1-year mortality were found, whereas relapses were significantly higher in EE (3.5% vs. 1.7%; p = 0.035). Increasing Charlson score, LogEuroSCORE, acute heart failure, septic shock, and paravalvular complications were risk factors for mortality, whereas prior endocarditis was protective and persistent bacteremia constituted the sole risk factor for relapse., [Conclusions] Besides other baseline and clinical differences, EE more frequently affects prosthetic valves and less frequently pacemakers/defibrillators. EE presents higher rates of relapse than NEE.

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy, however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,071 tumors representing 33 cancer types from the PanCancer TCGA dataset. High ERBB2 mRNA was found associated with better response and progression-free survival in the metastatic setting and higher rates of pathological complete response in the neoadjuvant setting. ERBB2 expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20&ndash, 8.41% of tumors across 15 cancer types as ERBB2-high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified high ERBB2 mRNA in a patient with HER2+ advanced gastric cancer who achieved a long-lasting partial response to T-DM1. Our study demonstrates that the heterogeneity in response to T-DM1 is partly explained by ERBB2 levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.

Purpose: To analyze the influence of adding gentamicin to a regimen consisting of β-lactam or vancomycin plus rifampicin on survival in patients suffering from Staphylococcal prosthetic valve endocarditis (SPVE). Methods: From January 2008 to September 2016, 334 patients with definite SPVE were attended in the participating hospitals. Ninety-four patients (28.1%) received treatment based on β-lactam or vancomycin plus rifampicin and were included in the study. Variables were analyzed which related to patient survival during admission, including having received treatment with gentamicin. Results: Seventy-seven (81.9%) were treated with cloxacillin (or vancomycin) plus rifampicin plus gentamicin, and 17 patients (18.1%) received the same regimen without gentamicin. The causative microorganism was Staphylococcus aureus in 40 cases (42.6%) and coagulase-negative staphylococci in 54 cases (57.4%). Overall, 40 patients (42.6%) died during hospital admission, 33 patients (42.9%) in the group receiving gentamicin and 7 patients in the group that did not (41.2%, P = 0.899). Worsening renal function was observed in 42 patients (54.5%) who received gentamicin and in 9 patients (52.9%) who did not (p = 0.904). Heart failure as a complication of endocarditis (OR: 4.58; CI 95%: 1.84–11.42) and not performing surgery when indicated (OR: 2.68; CI 95%: 1.03–6.94) increased mortality. Gentamicin administration remained unrelated to mortality (OR: 1.001; CI 95%: 0.29–3.38) in the multivariable analysis. Conclusions: The addition of gentamicin to a regimen containing vancomycin or cloxacillin plus rifampicin in SPVE was not associated to better outcome.

FOSIMI Investigators., This work was supported by the Ministerio de Sanidad y Consumo of Spain (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Madrid, Spain, Grant #EC0800190). JMP received a “Rio Hortega” Research Grant (CM14/00135; 2015-16) from Instituto de Salud Carlos III and the Ministerio de Economia and Competitividad, Madrid (Spain) and the ESCMID/FEMS Research Fellowship 2016. JMM received a personal 80:20 research grant from the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, during 2017–19.

Aims Intravenous tocilizumab is currently dosed on body weight, although a weak correlation between body weight and clearance has been described. The aim of the study was to assess the current dosing strategy and provide a scientific rational for dosing using a modelling and simulation approach. Methods Serum concentrations and covariates were obtained from intravenous tocilizumab treated subjects at a dose of 4, 6 or 8 mg every 28 days. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling. The final model was used to simulate tocilizumab exposure to assess a dosing strategy based on body weight or fixed dosing, using as target a cumulative area under the curve at 24 weeks of treatment above 100 × 103 μg h ml-1 . Results A one-compartment disposition model with parallel linear and nonlinear elimination best described the concentration-time data. The typical population mean values for clearance, apparent volume of distribution, maximum elimination rate and Michaelis-Menten constant were 0.0104 l h-1 , 4.83 l, 0.239 mg h-1 and 4.22 μg ml-1 , respectively. Interindividual variability was included for clearance (17.0%) and volume of distribution (30.8%). Significant covariates for clearance were patient body weight and C-reactive protein serum levels. An estimated exponent for body weight of 0.360 confirms the weak relationship with tocilizumab clearance. Simulations demonstrate that patients with lower weights are at risk of underdosing if the weight-based dosing approach is used. However, fixed-dosing provides a more consistent drug exposure regardless of weight category. Conclusions Our study provides evidence to support fixed dosing of intravenous tocilizumab in rheumatoid arthritis patients since it reduces variability in tocilizumab exposure among weight categories compared to the current weight-based dosing approach.

IntroductionChagas disease (CD) affects ~7 million people worldwide. Benznidazole (BZN) and nifurtimox (NFX) are the only approved drugs for CD chemotherapy. Although both drugs are highly effective in acute and paediatric infections, their efficacy in adults with chronic CD (CCD) is lower and variable. Moreover, the high incidence of adverse events (AEs) with both drugs has hampered their widespread use. Trials in CCD adults showed that quantitative PCR (qPCR) assays remain negative for 12 months after standard-of-care (SoC) BZN treatment in ~80% patients. BZN pharmacokinetic data and the nonsynchronous nature of the proliferative mammal-dwelling parasite stage suggested that a lower BZN/NFX dosing frequency, combined with standard or extended treatment duration, might have the same or better efficacy than either drug SoC, with fewer AEs.Methods and analysisNew ThErapies and Biomarkers for ChagaS infEctiOn (TESEO) is an open-label, randomised, prospective, phase-2 clinical trial, with six treatment arms (75 patients/arm, 450 patients). Primary objectives are to compare the safety and efficacy of two new proposed chemotherapy regimens of BZN and NFX in adults with CCD with the current SoC for BZN and NFX, evaluated by qPCR and biomarkers for 36 months posttreatment and correlated with CD conventional serology. Recruitment of patients was initiated on 18 December 2019 and on 20 May 2021, 450 patients (study goal) were randomised among the six treatment arms. The treatment phase was finalised on 18 August 2021. Secondary objectives include evaluation of population pharmacokinetics of both drugs in all treatment arms, the incidence of AEs, and parasite genotyping.Ethics and disseminationThe TESEO study was approved by the National Institutes of Health (NIH), U.S. Food and Drug Administration (FDA), federal regulatory agency of the Plurinational State of Bolivia and the Ethics Committees of the participating institutions. The results will be disseminated via publications in peer-reviewed journals, conferences and reports to the NIH, FDA and participating institutions.Trial registration numberNCT03981523.

Objective: To investigate the rate of colorectal neoplasms (CRNs) in patients who have Enterococcus faecalis infective endocarditis (EFIE) with available colonoscopies and to assess whether this is associated with the identification of a focus the infection. Patients and Methods: Retrospective analysis of data from a prospective multicenter study involving 35 centers who are members of the Grupo de Apoyo para el Manejo de la Endocarditis en Espana [Support Group for the Management of Infective Endocarditis in Spain] cohort. A specific set of queries regarding information on colonoscopy and histopathology of colorectal diseases was sent to each participating center. Four-hundred sixty-seven patients with EFIE were included from January 1, 2008, to December 31, 2017, from whom data on colonoscopy performance and results were available in 411 patients. Results: One hundred forty-two (34.5%) patients had a colonoscopy close to the EFIE episode. The overall rate of colorectal diseases was 70.4% (100 of 142), whereas the prevalence of CRN (advanced adenomas and colorectal carcinoma) was 14.8% (21 of 142), with no significant differences between the group of EFIE of unknown focus and that with an identified focus. Conclusion: Our study adds to prior evidence suggesting a much higher rate of CRN among patients with EFIE than in the general population of the same age and sex. In addition, our findings suggest that this phenomenon might take place both in EFIE with an unknown and an identified source of infection.

Tocilizumab is a humanized monoclonal antibody approved for rheumatoid arthritis treatment. In clinical practice, empirical dose-tapering strategies are implemented in patients showing sustained remission or low disease activity (LDA) to avoid overtreatment and reduce costs. Since rational adaptive-dosing algorithms taking the full pharmacokinetic (PK)/pharmacodynamic (PD) characteristics into account are currently lacking, we aimed to develop novel tapering strategies and compare them with currently used empirical ones.Four strategies were simulated on a virtual population. In all of them, the same initial dose was administered every 28 days for six consecutive months. Then, different strategies were considered: (1) label-dosing; (2) mild empirical dose-tapering; (3) intense empirical dose-tapering; (4) therapeutic drug monitoring (TDM)-guided dose-tapering. The different strategies were evaluated on the proportion of patients who maintain remission/LDA 1 year after the intervention. Cost-savings of direct drug costs were also estimated as relative dose intensity.The overall proportion of simulated patients in remission/LDA after 1 year of the intervention was comparable between the mild empirical and the TDM-guided dose-tapering strategies, and much lower for the intense empirical dose-tapering strategy (80.3%, 78.2%, and 69.0%, respectively). Likewise, 1-year flare rates were lower for the mild empirical and TDM-guided tapering strategies. The relative dose intensity was lowest for the intense empirical dose-tapering, followed by the TDM-guided and the mild empirical dose-tapering approaches (61.2%, 71.0%, and 80.4%, respectively).We demonstrated that the TDM-guided strategy using model-based algorithms performed similarly to mild empirical dose-tapering strategies in overall remission/LDA rates but is superior in cost-savings.

Objective There is scarce data with regard to the effectiveness and safety of direct-acting antivirals and possible drug-drug interactions between antiviral therapy and the multiple drugs frequently assumed by older patients. The aim is to evaluate the impact of comorbidities and drug-drug interactions on the efficacy and tolerability of direct-acting antivirals in this population. Methods Observational retrospective study of patients at least 65 years old receiving all-oral antiviral therapy between April 2015 and March 2016. Results Two hundred sixty-one patients were identified. Age distribution: 65-74 (73.9%), 75-79 (18.4%) and ≥80 (7.7%) years. Average age was 71 years, 38.7% were male, and 90% of patients took concomitant medication (43% patients taking ≥ 5 medicines). Predicted clinically significant drug-drug interactions were present in 72.8% of patients. The sustained viral response 12 weeks after end of treatment was 96.9%. Patients with serious adverse events received more concomitant drugs and all of them presented a clinical risk group ≥06/5. Conclusions Direct antiviral agents are highly effective also in older patients with advanced liver disease, comorbidities and concomitant medications. Serious adverse events increased with the number of concomitant medications and the severity of comorbidity. A clinical risk group score ≥06/5 may help to decide the indication of antiviral therapy in this difficult-to-treat population.

Aims Tocilizumab has a direct effect on inflammatory markers. Therefore, composite measures for disease activity assessment in rheumatoid arthritis (RA) using these inflammatory markers may not be suitable for tocilizumab treatment. We used a modelling approach to describe the tocilizumab exposure-response relationship and to investigate the different dynamics of the individual components of the routinely used continuous composite measures. Methods Pharmacokinetic (PK), clinical and laboratory data were obtained from a prospective, observational, single-centre study involving 35 subjects with RA treated with intravenous tocilizumab. A population PK/pharmacodynamic analysis was performed using nonlinear mixed effects models. Results The population for model development comprised 1086, 1083 and 1082 observations calculated with the disease activity score based on 28 joint (DAS28) and the simplified and clinical disease activity scores (SDAI, CDAI). The tocilizumab exposure-response relationship was described with an indirect-response model. Two main groups of individual components were identified based on their different dynamics under tocilizumab treatment: (i) tender and swollen joint counts and patient and evaluator global assessment showed a slower decrease of their baseline value (half-life: 4.6 weeks, RSE: 24%) and the need for higher serum drug concentration (EC50 : 4.60 μg/mL, RSE: 103%, IIV: 359%) than (ii) C-reactive protein and erythrocyte sedimentation rate (half-life: 2.3 weeks, RSE 19%; EC50 : 0.878 μg/mL, RSE: 41%, IIV: 238%). Conclusion Our study confirms a different dynamics of the individual components of the most frequently used continuous composite measures under tocilizumab treatment which should be taken into account to avoid misassessment of disease activity.

Background Robots arrived a few years ago to compounding units and, as a new health technology, it is necessary to assess their implications on safety and efficiency Purpose Evaluate the impact on safety and productivity issues after the implementation of Kiro® Oncology. Material and methods Failure mode, effect and criticality analysis were used to identify all risks related to the manual and robotic compounding processes. Criticality index (CI) was calculated for all of them, using a 1–4 scale. The percentage of preparations within the ±5% accuracy range was evaluated by gravimetric control for nine common drugs prepared manually and using the robotic system. To evaluate the role of the robot avoiding high-volume syringe handling, the number of preparations suitable to use 50 mL syringes (dose volume >20 mL) was estimated in a 6 month period (March–August 2018). Robot productivity (mean and maximum number of preparations) was evaluated during 6 months. Results Twenty-three failure modes were identified in the manual system, ahead of 14 for the robotic process, with a global decrease in CI of 32%. Risks with the highest scores were related to labelling errors. Dosing accuracy was compared for 1031 manual preparations and 756 robotic preparations of carboplatin, cyclophosphamide, doxorubicin, epirrubicin, 5-fluorouracil, gemcitabine, irinotecan, oxaliplatin and paclitaxel. No statistically significant difference was observed between manual and robotic preparations (percentage within ±5%: 99.8% manual vs 96.9% robot; χ2=1.11, p=0.29). Doses above 20 mL prepared during the evaluation period were 730±56 (mean ±SD) per month. The mean number of daily preparations by the robot during the period studied was 50 (40% of total daily production), with a maximum of 90. Technical incidences and workflow interruptions were major obstacles in improving productivity. Conclusion Robotic compounding might decrease the global risk of the process by the suppression of human intervention in some tasks. It showed similar accuracy rates to manual compounding in our setting. It has a major potential role avoiding stress injuries due to the repeated handling of high-volume syringes. Regarding productivity, the percentage of preparations assumed by the robot is still under expected; so, different strategies based on technical improvements and optimisation of cycle management should be implemented in the near future. References and/or acknowledgements EJHP 2012;19:148. https://ejhp.bmj.com/content/19/2/148.2.info AJHP 2015;72(12):1036–45. No conflict of interest.

Background Glecaprevir/pibrentasvir (G/P) is a pangenotypic, once-daily, ribavirin-free direct-acting antiviral treatment for hepatitis C virus (HCV) infection in patients with and without compensated cirrhosis. Purpose Our aim was to assess the effectiveness of G/P treatment in patients with HCV infection in clinical practice. Material and methods Observational retrospective study in a tertiary hospital. Patients with HCV infection treated with G/P between November 2017 and April 2018 were included. Demographic data such as age, gender, race and adjusted morbidity group (AMG) were collected. AMG is a new morbidity tool adapted to the Spanish Healthcare System that classifies the population into four groups depending on the severity of their diseases. Clinical registered variables were: transmission route of HCV infection, previous treatment status, stages of liver fibrosis, HCV genotype, baseline viral load, viral load measured after 4 weeks of treatment (VL4) categorised as undetectable, detectable below quantification (DBQ) and detectable above quantification (DAQ) with viral load >15 IU/mL, and sustained virological response defined as an undetectable HCV RNA level 12 weeks after stopping antiviral treatment (SVR12). Results A total of 110 patients completed the treatment (55±12 years, 46% males, 95% Europeans). The most frequent AMG were group 2 (42%) and 3 (23%). Transmission route was unknown in 57 patients (52%), blood transfusion in 19 patients (17%), intravenous drug use in 14 patients (13%), nosocomial in 11 patients (10%) and other routes in nine patients (8%). Eighty-two patients (75%) were naive. Fibrosis degree was F0–F1 in 86 patients (78%), F2 in 20 (18%), F3 in 2 (2%) and F4 in 2 (2%). Most common HCV genotypes were 1b (72 patients, 65%) and 1a (21 patients, 19%). Mean baseline viral load was 3.18×106 IU/mL. VL4 was determined in 55 patients: in 75% of them it was undetectable, in 15% it was DBQ and in 10% it was DAQ. SVR12 was achieved by 109 patients (99%) and in one patient results were not available due to loss of follow-up. Conclusion G/P is associated with high SVR12 rates in a real-world setting. Similar results were obtained in clinical trials. References and/or acknowledgements No conflict of interest.