Vancomycin and daptomycin stability in heparin or sodium citrate lock solutions.

BACKGROUND: We investigated physical and chemical stability of daptomycin and vancomycin in heparin or sodium citrate lock solutions. The aim of this study was to find the optimal combination of antimicrobials and additives for lock solutions, which maximized patient safety. METHODS: Vancomycin and daptomycin were diluted with heparin or sodium citrate to achieve final concentrations of vancomycin-heparin 2.5 mg/mL-833.33 U/mL, vancomycin-citrate 2.5-33.3 mg/mL, daptomycin-heparin 5 mg/mL-800 U/mL, and daptomycin-citrate 5-32 mg/mL and they were stored at room temperature (+25°C), 4°C, -20°C, and 37°C. Physical and chemical stability were analyzed for each antibiotic-anticoagulant combination in all conditions immediately after preparation, at 24, 48, 72 h and at different time points until unstable concentrations were obtained. Daptomycin-sodium citrate microbiological activity was also studied by evaluating two Staphylococcus aureus cultures in a calcium enriched medium with a daptomycin E test, with and without sodium citrate. RESULTS: After incubation at 37°C vancomycin and daptomycin combined with heparin retained at least 90% of the initial concentration over 48 h. Vancomycin-sodium citrate solution stored at 37°C reduced more than 10% of the initial concentration at 24 h. On the other hand, daptomycin-sodium citrate preparation was stable at 37°C for 72 h but the microbiological activity of daptomycin was lower in the presence of sodium citrate. CONCLUSIONS: The purpose is to prepare vancomycin and daptomycin lock solutions combined with heparin. They should be changed at 48 h and its stability is over 3 days at 25°C and 7 days at 4°C, which allow Hospital Pharmacy Services to manage their stocks. Daptomycin-sodium citrate combination is more stable for extended periods but its bioactivity has not been demonstrated.

Design and validation of a predictive equation to estimate unbound valproic acid concentration.

OBJECTIVES: Total plasma levels of valproic acid (VPA) may mask an increased risk of adverse effects in hypoalbuminaemic patients since, in these patients, the free fraction is higher. The aim of this study is to analyse the relationship between plasma levels of total and free VPA (FVPA) in hypoalbuminaemic patients and define an equation that allows the estimation of FVPA concentration, as well as to validate the obtained equation. METHODS: This is a retrospective observational study conducted between January 2015 and January 2020. Hypoalbuminaemic adult patients with normal renal function were included. Serum VPA levels were determined using an automated enzyme immunoassay technique with a pre-treatment of the sample by ultrafiltration for the quantification of FVPA. Patients' determinations were randomised into two groups: first, to calculate the FVPA estimation equation (regression group) by multiple linear regression analysis; and second to validate the equation (validation group), calculating the agreement between experimental and estimated FVPA concentrations using Lin's coefficient and a Bland and Altman analysis. RESULTS: We included 51 determinations, corresponding to 33 patients: 26 in the regression group, and 25 in the validation group. The multiple linear regression analysis showed a statistically significant relationship between FVPA concentration (Y), total VPA concentration (X1) and albumin level (X2), explained by the equation Y=11.882 + 0.216*X1-4.722*X2. Pearson's correlation coefficient was 0.798 (p<0.001). Lin's coefficient was 0.82 (95% CI 0.63 to 0.92). The Bland and Altman analysis showed a bias of 0.32 mg/L, and the concordance limits were between -3.80 and 4.44. CONCLUSIONS: The calculated equation adequately predicts FVPA concentration, with a high degree of correlation between the variables. Despite Lin's coefficient outcome, Bland and Altman analysis showed a minimum bias that slightly underestimates FVPA concentration, positioning the calculated equation as a useful and validated estimation tool in hypoalbuminaemic patients with normal renal function.

Beta-lactam allergy in patients: an antibiotic stewardship challenge.

BACKGROUND: Patients are commonly reported as being allergic to beta-lactam (BL) antibiotics. However, many patients with this reported allergy are able to receive BL treatments because they do not have true allergies. In many cases these are simply intolerances due to side effects reported as an allergy. Delabelling these patients leads to better clinical outcomes, optimal antibiotic usage, decreased bacterial resistance and reduced healthcare costs. Therefore, the aims of this study were to identify incorrectly labelled BL allergies in hospitalised patients and to assess antibiotic use in delabelled patients in order to establish a quality indicator to optimise antimicrobial treatments. METHODS: A prospective study was conducted in which hospitalised patients treated with antimicrobial drugs and labelled as 'BL-allergic' were identified by clinical pharmacists. An allergist assessed whether patients were suitable candidates for a skin test or oral challenge. The Allergy Service removed 'BL-allergic' labels if negative results were obtained. Delabelled patients were followed up by clinical pharmacists to study the use of BL antibiotics as a result of the delabelling programme. RESULTS: A total of 176 suspected allergic patients were identified and 91 (51.7%) were tested either by a skin test or oral challenge based on the patient indicators. Seven (16.4%) patients tested were allergic to BL antibiotics, 76 (83.5%) were totally delabelled and eight (0.1%) were partially delabelled. Thirty-two (38.1%) delabelled patients required antibiotic treatment in another inpatient or outpatient setting, of whom 27 (84.3%) patients with a new infectious episode received BL treatments while five (15.7%) continued to receive antimicrobial treatments without BL. CONCLUSION: After the implementation of a protocol to detect incorrect BL allergy labels, 83.5% of the patients in this cohort were completely delabelled. This shows that there is a clear opportunity to optimise the use of antibiotics by delabelling 'BL-allergic' patients.

Population Pharmacokinetic/Pharmacodynamic Modelling of Daptomycin for Schedule Optimization in Patients with Renal Impairment.

The aims of this study are (i) to develop a population pharmacokinetic/pharmacodynamic model of daptomycin in patients with normal and impaired renal function, and (ii) to establish the optimal dose recommendation of daptomycin in clinical practice. Several structural PK models including linear and non-linear binding kinetics were evaluated. Monte Carlo simulations were conducted with a fixed combination of creatinine clearance (30-90 mL/min/1.73 m2) and body weight (50-100 kg). The final dataset included 46 patients and 157 daptomycin observations. A two-compartment model with first-order peripheral distribution and elimination kinetics assuming non-linear protein-binding kinetics was selected. The bactericidal effect for Gram+ strains with MIC ≤ 0.5 mg/L could be achieved with 5-12 mg/kg daily daptomycin based on body weight and renal function. The administration of 10-17 mg/kg q48 h daptomycin allows to achieve bactericidal effect for Gram+ strains with MIC ≤ 1 mg/L. Four PK samples were selected as the optimal sampling strategy for an accurate AUC estimation. A quantitative framework has served to characterize the non-linear binding kinetics of daptomycin in patients with normal and impaired renal function. The impact of different dosing regimens on the efficacy and safety outcomes of daptomycin treatment based on the unbound exposure of daptomycin and individual patient characteristics has been evaluated.

Physicochemical and Microbiological Stability of Vancomycin 10-mg/mL Intravitreal Syringes.

Bacterial endophthalmitis constitutes a medical emergency due to the possibility of leading to blindness unless treatment is administered quickly. The usual treatment seeks to cover both gram-positive and gram-negative bacteria by intravitreal injections of vancomycin and ceftazidime. In the present work, we sought to determine the physicochemical and microbiological stability of intravitreal syringes of vancomycin 10 mg/mL in order to be able to store them as long as possible to have immediate stock. A study was carried out at different temperatures (room temperature, refrigerator, and freezer) for six months in which the concentration and osmolarity were determined and microbiological growth was observed. Also, an accelerated degradation study was carried out at 42°C for 51 days, where only the concentration was determined. The concentrations were quantified using a high-performance liquid chromatography technique. Vancomycin 10 mg/mL in polypropylene syringes is chemically, physically, and microbiologically stable for six months if stored at -20°C and stable for 14 weeks if stored at 4°C.

Manejo de afectación cutánea y sistémica por Candida auris / Management of cutaneous and systemic involvement by Candida auris

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Mapa de unidades de farmacocinética y farmacogenética clínica en España / Mapping the clinical pharmacokinetics and pharmacogenetic units operating in Spanish hospitals

Objetivo: Dar a conocer la actividad asistencial y docente de las unidades de farmacocinética y farmacogenética de los servicios de farmaciahospitalaria españoles y elaborar un mapa que refleje la situación actual.Método: Se diseñó una encuesta de 29 preguntas estructuradas encinco bloques: datos generales del hospital e información sobre la actividad asistencial y docente, tanto en el área de farmacocinética como defarmacogenética en los servicios de farmacia hospitalaria.Resultados: Respondieron la encuesta 69 hospitales. Las regiones geográficas con mayor número de respuestas fueron Cataluña, ComunidadValenciana y Andalucía. Los grupos farmacológicos que más se monitorizaron fueron los antibióticos clásicos (vancomicina y aminoglucósidos) (93%),digoxina (57%), antiepilépticos clásicos (51%) y biológicos (43%). Los programas informáticos que con más frecuencia se utilizaban fueron PKS yNONMEM, con un 93% y 22%, respectivamente. Respecto a la docenciaen farmacocinética, fue el segundo año de residencia cuando la mayoría delos farmacéuticos internos residentes rotaban por el área (40%) y un 44%de las unidades permitían rotantes externos. El responsable de la farmacogenética era el servicio de farmacia hospitalario en un 43% de los casos.Los ámbitos más frecuentes fueron oncohematología (72%) y psiquiatría(15%). Un 24% de los hospitales ofrecían rotación por la unidad de farmacogenética y sólo 7 servicios de farmacia ofertaron rotaciones externas. Conclusiones: Los resultados de la encuesta mostraron un incremento enla realización de actividades de farmacocinética y farmacogenética en losservicios de farmacia hospitalaria comparados con los datos de la encuesta basal de 2009. (AU)

Objective: The goal of this article is to analyze the situation of pharmacokinetics and pharmacogenetics units in the pharmacy departmentsof Spanish hospitals, evaluate their development both in the clinical andeducational areas, and draw up a map reflecting their current status.Method: A 29-item survey structured in five blocks was designed withgeneral questions about the respondents’ hospital and the clinical andeducational activities carried out by their pharmacy department, in thefields of both pharmacokinetics and pharmacogenetics.Results: Sixty-nine hospitals answered the survey. The highest response ratescorresponded to Catalonia, the Valencia region and Andalusia. The drugfamilies subject to closest monitoring were classic antibiotics (93%), digoxin(57%), classic antiepileptics (51%) and biologicals (43%). The most frequentlyused computer programs included PKS and NONMEM (93% and 22% ofhospitals, respectively). Regarding training in pharmacokinetics, second yearresidents were those who most frequently rotated through the pharmacokinetics unit (40%), while 44% of those units allowed external residents. Asfar as pharmacogenetics is concerned, in 42% of hospitals that engaged inpharmacogenetic work, the department in charge was pharmacy. The mostfrequent specialties covered were hemato-oncology (72%) and psychiatry(15%). Twenty-four percent of hospitals offered rotations through their pharmacogenetics unit but only seven of them allowed external residents.Conclusions: The results of the survey showed an increase in the performance of pharmacokinetic and pharmacogenetic activities by Spanishhospital pharmacies as compared with the data from a 2009 baseline survey, with many hospitals introducing the performance of therapeutic drugmonitoring of non-classical antibiotics, immunosuppressants and biologics. (AU)

Bacteriemia en pacientes con nutrición parenteral central: prevalencia, factores asociados y tratamiento / Catheter-related bloodstream infections in patients receiving central parenteral nutrition: prevalence, associated factors, and treatment

INTRODUCCIÓN: la infección relacionada con el catéter es una de las complicaciones del tratamiento con nutrición parenteral central (NPC) que generan una mayor morbimortalidad. OBJETIVOS: el objetivo principal fue analizar la prevalencia de la bacteriemia asociada al catéter en pacientes con nutrición parenteral central. Los objetivos secundarios fueron: a) evaluar si el tipo de catéter central, la duración de la nutrición parenteral central, el índice de masa corporal o la estancia en la unidad de cuidados intensivos son factores asociados al desarrollo de bacteriemia; b) analizar el manejo terapéutico de la infección. MATERIAL Y MÉTODOS: se trata de un estudio observacional retrospectivo. Se incluyeron los pacientes que recibieron nutrición parenteral central tras una intervención quirúrgica entre julio de 2018 y marzo de 2019. La asociación de las variables con el desarrollo de la bacteriemia se analizó mediante regresión logística. RESULTADOS: el 7,3 % (IC 95 %: 3,9-13,3) (n = 9/123) de los pacientes desarrollaron bacteriemia relacionada con el catéter. El único factor asociado al desarrollo de la infección fue la duración de la nutrición parenteral central (OR = 1,12; IC 95 %: 1,05-1,20; p = 0,001). CONCLUSIONES: la prevalencia de la bacteriemia relacionada con el catéter en este estudio es baja. La duración del tratamiento con nutrición parenteral central parece estar relacionada con el desarrollo de la bacteriemia. Sin embargo, se necesitan más estudios para identificar factores de riesgo que permitan minimizar este tipo de complicaciones

BACKGROUND: catheter-related infection is one of the complications of central parenteral nutrition treatment with the highest morbidity and mortality. OBJECTIVES: the primary endpoint of this study was to analyze the prevalence of bloodstream infection in patients with central parenteral nutrition. Secondary objectives included: a) an assessment of whether type of central catheter, duration of parenteral nutrition treatment, body mass index, or being admitted to the intensive care unit are factors associated with the development of bloodstream infection; b) an analysis of the therapeutic approach. MATERIAL AND METHODS: this was a retrospective observational study. All patients who received central parenteral nutrition after surgery between July 2018 and March 2019 were included. The association between the different variables and the development of bloodstream infection was analyzed by logistic regression. RESULTS: the prevalence of bloodstream infection was 7.3 % (95 % CI: 3.9-13.3) (n = 9/123 patients). The duration of central parenteral nutrition was the only variable associated with the development of bloodstream infection (OR = 1.12; 95 % CI:1.05-1.20; p = 0.001). CONCLUSIONS: the prevalence of catheter-related bloodstream infection in this study is low, and the duration of central parenteral nutrition seems to be related to its development. However, further studies are needed to identify risk factors that might help reduce this kind of complications

[Catheter-related bloodstream infections in patients receiving central parenteral nutrition: prevalence, associated factors, and treatment]. / Bacteriemia en pacientes con nutrición parenteral central: prevalencia, factores asociados y tratamiento.

INTRODUCTION: Background: catheter-related infection is one of the complications of central parenteral nutrition treatment with the highest morbidity and mortality. Objectives: the primary endpoint of this study was to analyze the prevalence of bloodstream infection in patients with central parenteral nutrition. Secondary objectives included: a) an assessment of whether type of central catheter, duration of parenteral nutrition treatment, body mass index, or being admitted to the intensive care unit are factors associated with the development of bloodstream infection; b) an analysis of the therapeutic approach. Methods: this was a retrospective observational study. All patients who received central parenteral nutrition after surgery between July 2018 and March 2019 were included. The association between the different variables and the development of bloodstream infection was analyzed by logistic regression. Results: the prevalence of bloodstream infection was 7.3 % (95 % CI: 3.9-13.3) (n = 9/123 patients). The duration of central parenteral nutrition was the only variable associated with the development of bloodstream infection (OR = 1.12; 95 % CI:1.05-1.20; p = 0.001). Conclusions: the prevalence of catheter-related bloodstream infection in this study is low, and the duration of central parenteral nutrition seems to be related to its development. However, further studies are needed to identify risk factors that might help reduce this kind of complications.

INTRODUCCIÓN: Introducción: la infección relacionada con el catéter es una de las complicaciones del tratamiento con nutrición parenteral central (NPC) que generan una mayor morbimortalidad. Objetivos: el objetivo principal fue analizar la prevalencia de la bacteriemia asociada al catéter en pacientes con nutrición parenteral central. Los objetivos secundarios fueron: a) evaluar si el tipo de catéter central, la duración de la nutrición parenteral central, el índice de masa corporal o la estancia en la unidad de cuidados intensivos son factores asociados al desarrollo de bacteriemia; b) analizar el manejo terapéutico de la infección. Material y métodos: se trata de un estudio observacional retrospectivo. Se incluyeron los pacientes que recibieron nutrición parenteral central tras una intervención quirúrgica entre julio de 2018 y marzo de 2019. La asociación de las variables con el desarrollo de la bacteriemia se analizó mediante regresión logística. Resultados: el 7,3 % (IC 95 %: 3,9-13,3) (n = 9/123) de los pacientes desarrollaron bacteriemia relacionada con el catéter. El único factor asociado al desarrollo de la infección fue la duración de la nutrición parenteral central (OR = 1,12; IC 95 %: 1,05-1,20; p = 0,001). Conclusiones: la prevalencia de la bacteriemia relacionada con el catéter en este estudio es baja. La duración del tratamiento con nutrición parenteral central parece estar relacionada con el desarrollo de la bacteriemia. Sin embargo, se necesitan más estudios para identificar factores de riesgo que permitan minimizar este tipo de complicaciones.

Therapeutic drug monitoring of levetiracetam in daily clinical practice: high-performance liquid chromatography versus immunoassay.

Objectives: Although levetiracetam presents an easy dosing and tolerability, therapeutic drug monitoring may be recommended in certain situations. Measurement of levetiracetam in serum plasma is commonly done by high performance liquid chromatography (HPLC). After ARK Diagnostics marketed an enzyme immunoassay (IA) for levetiracetam in serum or plasma, automated determinations are possible. In this study, the performance of this immunoassay and the impact of automation on the follow-up in patients treated with levetiracetam is evaluated. We also detected those subpopulations of patients who may benefit the most from this therapeutic drug monitoring. Methods: Samples from 50 outpatients diagnosed with epilepsy and treated with levetiracetam were collected. This new IA was performed on the Architect c4000 analyser and compared with the HPLC. Then, a retrospective observational study that included serum samples of levetiracetam for 24 months, was conducted to evaluate the impact of automattion and the influence of some variables (age, sex, renal function, and co-administration of valproic acid and glucuronidation-inducing drugs) in levetiracetam apparent oral clearance (CLp/F) by a multivariate linear regression. Results: The mean high-performance liquid chromatography quantified concentration (CpHPLC) was 18.43 mcg/mL (95% CI: 15.48 to 21.39) and immunoassay concentration (CpEI) was 18.35 mcg/mL (95% CI: 15.20 to 21.50) (P=0.861). The Pearson's linear correlation coefficient obtained in the analysis was r2=0.88, according to the following equation: CpHPLC=-0.29+1.01 CpEI. The intraclass correlation coefficient was 0.95 (95% CI: 0.91 to 0.97). After IA implementation, the number of levetiracetam determinations increased in 76.27%. The median of Clp/F was higher (P<0.001) in inducers (4.36 L/h; IQR:3.29-5.44) and lower (P<0.001) in glomerular filtration rate (GFR) <60 mL/min (2.7 L/h; IQR: 0.58-3.85). Conclusions: The Ark method performed on the Architect is fully acceptable and can be used routinely to measure levetiracetam plasmatic concentration levels. It has demonstrated the need for closer monitoring in patients with renal failure or co-administration of glucuronidation-inducing drugs.