Evaluation of Current Amikacin Dosing Recommendations and Development of an Interactive Nomogram: The Role of Albumin.

This study aimed to evaluate the potential efficacy and safety of the amikacin dosage proposed by the main guidelines and to develop an interactive nomogram, especially focused on the potential impact of albumin on initial dosage recommendation. The probability of target attainment (PTA) for each of the different dosing recommendations was calculated through stochastic simulations based on pharmacokinetic/pharmacodynamic (PKPD) criteria. Large efficacy and safety differences were observed for the evaluated amikacin dosing guidelines together with a significant impact of albumin concentrations on efficacy and safety. For all recommended dosages evaluated, efficacy and safety criteria of amikacin dosage proposed were not achieved simultaneously in most of the clinical scenarios evaluated. Furthermore, a significant impact of albumin was identified: The higher is the albumin, (i) the higher will be the PTA for maximum concentration/minimum inhibitory concentration (Cmax/MIC), (ii) the lower will be the PTA for the time period with drug concentration exceeding MIC (T>MIC) and (iii) the lower will be the PTA for toxicity (minimum concentration). Thus, accounting for albumin effect might be of interest for future amikacin dosing guidelines updates. In addition, AMKnom, an amikacin nomogram builder based on PKPD criteria, has been developed and is freely available to help evaluating dosing recommendations.

Programa de atención a pacientes diabéticos y prediabéticos en farmacia comunitaria: 'DayBTS' / Treatment program for diabetic and prediabetic patients in community pharmacy: 'DayBTS'

JUSTIFICACIÓN: en España hay 6 millones de personas con diabetes. Canarias está 1,86 puntos porcentuales por encima de la media nacional. Aunque haya mejor conocimiento de la diabetes, el número de pacientes sigue aumentando. El farmacéutico comunitario puede jugar un papel importante a través de su formación académica como sanitario experto en el medicamento y por su cercanía al paciente. Por ello, son importantes proyectos de diseño y estandarización de servicios de seguimiento farmacoterapéutico en diabetes más un abordaje multidisciplinar. OBJETIVO: diseño de un servicio para atención a pacientes diabéticos y prediabéticos en farmacia comunitaria denominado DayBTS. Población diana: mayores de edad que acuden a la farmacia y cumplen al menos uno de estos requisitos: tratamiento con medicación antidiabética, presenten sobrepeso u obesidad, hipertensión arterial o hipercolesterolemia, presenten antecedentes familiares de diabetes o directamente soliciten el servicio. Estructura: serie de visitas divididas en dos fases. Fase inicio, comprende 5 visitas. Fase continuación, 2 visitas para seguimiento y nuevas dudas o problemas. Las actividades a realizar de forma general son: educación diabetológica, medición de variables clínicas (glucemia capilar, índice de masa corporal, hemoglobina glicosilada, patrones en glucemia), variables económicas (visitas a atención primaria, urgencias, número de medicamentos utilizados) y variables humanísticas (adherencia al tratamiento, calidad de vida, conocimientos sobre diabetes). Coste previsto: el coste por visita se estima en función de: tipo de visita, recursos materiales y tiempo del personal farmacéutico. Entre 5,95 € (paciente prediabético) a 20,90€ (paciente diabético) con precio propuesto de 7,44 € y 26,13 € para margen 20 %. El coste del servicio completo sería de 88,31-111 € (Prediabetes-Diabetes)

REASON: in Spain there are 6 million people with diabetes. The Canary Islands are 1.86 percentage points above the national average. Although information on diabetes has improved, the number of patients continues to increase. Community pharmacists can play a significant role thanks to their academic training as healthcare providers specialized in medications and their proximity to patients. For this reason, it is important to have projects for the design and standardization of pharmacotherapeutic monitoring services in diabetes, besides a multidisciplinary approach. OBJECTIVE: design of a treatment service for diabetic and prediabetic patients in community pharmacy called DayBTS. Target population: older people who visit the pharmacy and meet at least one of the following requirements: treatment with antidiabetic medication, are overweight or obese, arterial hypertension or hypercholesterolemia, with family history of diabetes or who ask for the service directly. Structure: series of visits in four phases. Initial phase, includes 5 visits. Continuation phase, 2 visits for monitoring and new doubts or issues. The activities to perform in general are as follows: diabetes education, measurement of clinical variables (blood glucose, body mass index, glycosylated hemoglobin, glycemic patterns), economic variables (visits at primary care, acute care, number of medications used) and human variables (treatment compliance, quality of life, knowledge of diabetes). Expected cost: the cost per visit is estimated according to: type of visit, material supplies and pharmaceutical staff time. Between 5.95 € (prediabetic patient) and 20.90 € (diabetic patient) with cost proposed 7.44 € and 26.13 € for a 20 % margin. The cost of the complete service would be 88.31-111 € (Prediabetes-Diabetes)

Biomarkers of disease activity and other factors as predictors of adalimumab pharmacokinetics in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is commonly treated with adalimumab. The main objective of the study was to develop a population pharmacokinetic model of adalimumab in IBD patients evaluating the potential biomarkers of disease activity and other factors and its implications in adalimumab dosing. A prospective observational study was performed in adult patients diagnosed with Crohn's disease and ulcerative colitis treated with adalimumab and following a proactive therapeutic drug monitoring of serum concentrations. Adalimumab serum concentrations (ASC) were quantified mainly prior the administration using an enzyme-linked immunosorbent assay (ELISA). A population pharmacokinetic model was developed based on 303 ASC data of 104 IBD patients using non-linear mixed effect modelling approach. Sixty-five ASC from 20 additional patients were randomly selected as an external validation group. A one-compartment model with first order absorption and elimination best describe the ASC time course. Body mass index (BMI), faecal calprotectin (FCP), unexplained decline in ASC and the specific administration pen device exhibited significant influence on apparent clearance (p-value < 0.001). FCP was the inflammatory activity biomarker showing the most relevant impact on adalimumab exposure, higher than C-reactive protein and albumin, and may be useful for adalimumab dosing adjustment. The population-based pharmacokinetic model developed adequately characterized adalimumab exposure in IBD patients. The unexplained decline in ASC, FCP, BMI and the specific administration pen device were identified as meaningful variables significantly influencing adalimumab pharmacokinetics.

Relationship between male moths of Cryptoblabes gnidiella (Millière) (Lepidoptera: Pyralidae) caught in sex pheromone traps and cumulative degree-days in vineyards in southern Uruguay.

Cryptoblabes gnidiella (Millière) (Lepidoptera: Pyralidae) has been known in Uruguay for 30 years and only in vineyards, despite being polyphagous. In recent years, this pest has caused sporadic but serious damage on some grapevine cultivars. Understanding the insect's phenology and developing a monitoring program are essential aspects of integrated pest management. We monitored males using sexual pheromone traps on four cultivars of vine, Pinot noir, Tannat, Gewürztraminer, and Cabernet Sauvignon, in two vine-growing establishments in the Department of Canelones and compiled data on the accumulated effective temperatures for the southern area of Uruguay. We determined that this species undergoes three generations per year and overwinters without diapause as larvae on dried grapes remaining after harvest. Using the proportion of cumulative male moths caught from December to May from 2003-2007 on the four cultivars and the sum of effective temperatures above two previously-published lower-threshold temperatures for development, 12.26°C and 13°C, statistically significant logistic models were estimated. Predictions based on the resulting models suggested that they would be acceptable tools to improve the efficiency of integrated management of this pest in Uruguay.

Clinical repercussions of analytical interferences due to aldosterone antagonists in digoxin immunoassays: an assessment.

Analytical interferences in digoxin immunoassays constitute a well-known problem, with repercussions for therapeutic drug monitoring. Clinically effective doses of spironolactone and potassium canrenoate cross-react in several digoxin immunoassays, producing falsely elevated or lowered concentrations. This study evaluates the interferences caused by these drugs in the microparticle enzyme immunoassay (MEIA III) in comparison with another 3 immunoassays used for digoxin therapeutic drug monitoring: MEIA II, fluorescence polarization immunoassay, and enzyme multiplied immunoassay. The potential clinical implications of assay discrepancies in patient care are also assessed. To evaluate assay performance, in vitro specimens and real patient samples were measured using the 4 assays. Five serum pools were spiked with digoxin to achieve concentrations of 1 and 2.25 ng/mL digoxin and measured with the immunoassays before and after supplementation. Real samples from patients receiving digoxin (n = 39), digoxin and spironolactone (n = 35), or digoxin and potassium canrenoate (n = 4) were also quantified. The influence of ultrafiltration was evaluated in 3 pools from 29 additional patients. The implications of assay discrepancies for dose recommendations were also evaluated. In general, the results obtained for the in vitro and in vivo approaches coincided, confirming statistically significant differences in the assays regardless of the type of sample. MEIA III showed positive interference against the well-known negative interference attributed to MEIA II. According to Bland-Altman analysis, it is not possible to assume the interchangeability of the immunoassays evaluated. Thus, individual patients must be monitored with the same technique even in the absence of potential interferences. Discordant digoxin dose recommendations were estimated in 31% of patients not treated with interfering drugs and in 43% of cotreated patients. From a clinical perspective, analytical interferences in digoxin immunoassays are a real and frequent problem, which seems even more important in view of the lower therapeutic range now recommended.

[Recommendations for antibiotic monitoring in ICU patients]. / Recomendaciones para la monitorización de antibióticos en pacientes críticos ingresados en UCI.

UNLABELLED: Monitoring plasma concentrations of antimicrobial agents used to treat infection in critically ill patients is one of the recommended strategies for improving clinical outcome. Drug monitoring has a double AIM: to limit adverse events and to increase the effectiveness of the drugs. In clinical practice, however, this approach is mainly limited to monitoring plasma concentrations of vancomycin and aminoglycosides, although future extension to other antimicrobial agents would be desirable. Application of this technique varies considerably between hospitals, and this makes interpretation and comparison of the results obtained difficult. For this reason, representatives of various scientific societies related to the pharmacokinetic area have developed a series of recommendations for monitoring plasma concentrations of antimicrobials using vancomycin and several aminoglycosides as the reference. The recommendations are based on 14 questions encompassing all steps of the process: indication for the test, blood sampling (timing of blood collection, blood volume, tubes), transport to the laboratory, techniques applied, normal values, dose adjustment, and reporting the RESULTS: The purpose of these guidelines is to develop a process of monitoring plasma antimicrobial concentrations that is as homogeneous as possible to facilitate the design of multicenter studies, as well as the interpretation and comparison of results.

Recomendaciones para la monitorización de antibióticos en pacientes críticos ingresados en UCI / Recommendations for antibiotic monitoring in ICU patients

La monitorización de concentraciones plasmáticas de los antimicrobianos utilizados para el tratamiento de infecciones en pacientes críticos es una de las estrategias planteadas para mejorar los resultados clínicos. El objetivo de la monitorización es doble: limitar los efectos adversos y aumentar la efectividad de los antimicrobianos. Su desarrollo clínico se limita prácticamente a la monitorización de vancomicina y aminoglucósidos, aunque es deseable su extensión, en el futuro, al resto de antimicrobianos. La aplicación de esta técnica está sometida a múltiples variaciones entre hospitales, lo que dificulta la interpretación y comparación de resultados. Por este motivo, representantes de diversas sociedades científicas relacionadas con el área de la farmacocinética han elaborado un conjunto de recomendaciones para la monitorización plasmática de antimicrobianos utilizando como referencia la vancomicina y los distintos aminoglucósidos. La recomendaciones se realizan en torno a 14 preguntas que abarcan todas las etapas de proceso: indicación de la prueba, extracción de la muestra (tiempo de extracción, cantidad de sangre, tubos), traslado al laboratorio, técnicas aplicables, valores de normalidad, ajuste de dosis y comunicación de resultados. El objetivo de las recomendaciones es homogeneizar en la medida de lo posible el proceso de la monitorización de estos antimicrobianos y facilitar con ello la realización de estudios multicéntricos y la comparación e interpretación de los resultados (AU)

Monitoring plasma concentrations of antimicrobial agents used to treat infection in critically ill patients is one of the recommended strategies for improving clinical outcome. Drug monitoring has a double aim: to limit adverse events and to increase the effectiveness of the drugs. In clinical practice, however, this approach is mainly limited to monitoring plasma concentrations of vancomycin and aminoglycosides, although future extension to other antimicrobial agents would be desirable. Application of this technique varies considerably between hospitals, and this makes interpretation and comparison of the results obtained difficult. For this reason, representatives of various scientific societies related to the pharmacokinetic area have developed a series of recommendations for monitoring plasma concentrations of antimicrobials using vancomycin and several aminoglycosides as the reference. The recommendations are based on 14 questions encompassing all steps of the process: indication for the test, blood sampling (timing of blood collection, blood volume, tubes), transport to the laboratory, techniques applied, normal values, dose adjustment, and reporting the results. The purpose of these guidelines is to develop a process of monitoring plasma antimicrobial concentrations that is as homogeneous as possible to facilitate the design of multicenter studies, as well as the interpretation and comparison of results (AU)

Pharmacokinetic/pharmacodynamic analysis of vancomycin in ICU patients.

AIMS: To identify the variables affecting vancomycin pharmacokinetics in medical ICU patients and to evaluate the potential efficacy of dosage schedules by PK/PD analysis. DESIGN: A retrospective pharmacokinetic analysis of serum levels obtained in routine vancomycin monitoring was performed. SETTING: A 12-bed general ICU of a university teaching hospital. PATIENTS: Forty-six vancomycin-treated ICU patients fitting the following criteria: over 18 years old; more than three concentration data per patient; absence of renal replacement support, cardiac surgery and neoplastic disorders. INTERVENTIONS: Clinical information was collected from the patients' medical records. Details of vancomycin therapy, dosage and blood sampling times were obtained from pharmacokinetic reports. Population analysis were made by the standard two-stage approach. MEASUREMENTS AND MAIN RESULTS: Vancomycin clearance and distribution volume were estimated individually assuming a one-compartment pharmacokinetic model. PK/PD analysis was performed by Monte Carlo simulation. In the ICU patients, higher Vd (nearly twice the quoted value of 0.72 l/kg) and different vancomycin clearance-creatinine clearance relationship were found. Renal function, the APACHE score, age and serum albumin accounted for more than 65% of drug clearance variability. Vancomycin standard dosages led to a 33% risk of not achieving the recommended AUC(24h)/MIC breakpoint for Staphylococcus aureus. CONCLUSIONS: The population kinetics and PK/PD analyses based on Monte Carlo simulation procedures offer an excellent tool for selecting the therapeutic option with the highest probability of clinical success in ICU patients.

Pharmacokinetic basis for the use of extended interval dosage regimens of gentamicin in neonates.

OBJECTIVES: To analyse the pharmacokinetic basis for the use of extended-interval dosage regimens of gentamicin in neonates using population pharmacokinetics. PATIENTS AND METHODS: The population pharmacokinetics of gentamicin was studied retrospectively in a population of 113 neonates divided into two groups: one for computing the population model (n=97) and another for validation (n=36). A one-compartment pharmacokinetic model and non-linear mixed-effects modelling were used to assess the population pharmacokinetic model. RESULTS: Weight (W) and postnatal age (PA) were the covariates that influenced the pharmacokinetic parameters of gentamicin. The final population model obtained was: distribution volume, V (L)=0.636 x W (kg)0.852; clearance, Cl (L/h)=0.032 x W (kg)1.482+0.0024 x PA (days). The predictive performance of the model in the population validation was adequate for clinical purposes. The optimized population model allowed us to simulate gentamicin serum levels and their variability, in this kind of patient, when extended-interval dosage administration regimens were implemented. CONCLUSIONS: According to our pharmacokinetic population model, initial doses of gentamicin of 10 mg/kg, and dosage intervals between 36-48 h, appear to be appropriate to achieve target peak and trough serum levels of 15-20 and <0.5 mg/L, respectively, when extended-interval dosage regimens are implemented in newborns. The half-life of gentamicin in premature babies of very low weight and gestational age <31 weeks is long. Thus, to achieve serum concentrations in the 1-10 mg/L range, the use of dosage regimens of 5 mg/kg at 36-48 h dosage intervals seems suitable.