Methotrexate Pharmacokinetics and Survival in Osteosarcomat

The aim of this study was to analyze the relationship between exposure to high-dose methotrexate (HDMTX) and tumor response in terms of survival in children with osteosarcoma. PROCEDURE: This study included 44 patients (479 courses) who received a median dose of 5.92 g/m2 of MTX (interquartile range (IQR) 2.37 g/m2) in a 4-hr infusion. The mean area under the concentration-time curve (AUC) estimated by parametric methods (non-parametric expectation maximization, NPEM), and the mean concentration at the end of the infusion were considered to be the exposure parameters. Tumor response was recorded as disease-free survival (DFS), overall survival (OS), and histologic tumor response. The relationship between MTX exposure and survival parameters was analyzed by Cox regression. RESULTS: The group of 11 patients who were the least exposed to MTX (AUC <2,400 micromol/L hr) presented a high DFS, probably due to the shorter interval of time between MTX courses that led to a higher dose density. In patients with AUC >2,400 micromol/L hr, an increase in the AUC was related to an increase in the DFS. Significant differences were observed in the DFS between patients whose mean AUC was below or above 4,000 micromol/L hr (P=0.024), such that 4,000 micromol/L hr was considered as the minimum AUC to be aimed at for future patients. CONCLUSIONS: Dose density seems to be an important factor in osteosarcoma response, but this must be confirmed in further studies. In order to improve the response to osteosarcoma in children, it is recommended that the dose of MTX to be increased such as to obtain an AUC higher than 4,000 micromol/L hr

Información de medicamentos a la población desde el Servicio de Farmacia a través de Internet

Objectives: To describe and discuss the work of a Pharmacy Department for the health-care portal www.viatusalud.com. Methods: Using a web portal, a Pharmacy Department develops and updates a vademecum on drugs, and answers enquiries by end-users. Results: On December 31, 2002 more than 750 records on drugs were available, and 3030 enquiries had been answered. Conclusions: With this drug information and online enquiry service, our Pharmacy Department helps meet the demand of health-care information posed by the community and by patients previously seen at Clínica Universitaria. In addition, it allows areas of improvement to be detected in the information to be offered to patients fron a Pharmacy Department, and represents a tertiary source of information for health-care professionals

Impacto clínico y económico de las intervenciones del farmacéutico clínico sobre antimicrobianos en el paciente crítico

Up to 52% of the patients in acute care hospitals may receive an antibiotic, and 30-50% of the treatments are estimated to be inadequate. Pharmacists have an important role in their optimization. In addition, critically ill patients may benefit more from pharmacist interventions (PIs). Few comparative studies have evaluated the clinical and the economic impact of PIs on antimicrobials in these patients, and none of them was conducted in Europe. Moreover, there have been no reviews analyzing the clinical and economic impact of interventions on antimicrobials conducted specifically by pharmacists (not by a multidisciplinary group, even though it includes a pharmacist) in the hospital setting. Therefore, our main objective was to determine the clinical and economic impact of PIs related to antimicrobials in critical care. Firstly we conducted a review of the evidence in Pubmed from 2003 to March 2016 of the clinical and economic impact of PIs in the hospital setting, in general. Secondly, we developed a retrospective observational study in the Critical Care Area (CCA) of our university hospital to analyze the clinical and economic impact of the clinical pharmacist (CP) interventions (CPI) on antimicrobials over a 5-month period. Thirdly, we conducted another retrospective observational cohort study to determine the effectiveness of a specific intervention promoted by the CP, which consisted of adding inhaled antibiotics in critically ill patients with respiratory infections, as the role of this therapy in these patients remained uncertain. In the review, 23 studies were included. All of them had high risk of bias. Patient-specific recommendations were included in every study; five also included policy strategies and four education. Significant impact of PIs was found in 14 of the 18 studies (77.8%) that evaluated costs, 15 of the 20 (75.0%) that assessed treatment related outcomes, 12 of the 22 (54.5%) that analyzed clinical outcomes and 1 of the 2 studies (50.0%) that evaluated microbiological outcomes. None of the studies found significant negative impact of PIs. It could not be concluded that adding other strategies to patient-specific recommendations improves results. Acceptance of recommendations varied from 70 to 97.5%. Therefore, PIs on antimicrobials in the hospital setting improve clinical and treatment related outcomes, and decrease costs. This positive clinical and economic impact of the PIs was confirmed in our CCA. The CP performed 212 interventions in response to 212 Drug Related Problems (DRPs) detected during the study period, corresponding to 114 patients. Eighteen DRPs (8.5%) were medication errors. A total of 96.2% of the CPIs were considered important with improvement in patient care. None of the CPIs had any negative impact on patients. Physicians accepted 98% of the CPIs. We estimated a 10,905 decrease in costs as a result of CPIs (the estimation could vary from 374 to 127,772 in the worst and best case scenarios, respectively). This means that 4.8 were avoided per euro invested in the CP. The CP initiative of adding inhaled antibiotics to critically ill patients was also positive. We analyzed data from adults admitted to the CCA during a 2-year period with respiratory infections in which respiratory fluid samples were obtained. A total of 136 patients were included: 43 in the treated group (that received inhaled antibiotics in addition to systemic antimicrobials), 93 in the control group (that only received systemic antimicrobials). After adjusting for confounders, treated group had higher odds of clinical improvement (adjusted odds ratio: 7.13; 95% confidence interval: 1.17-43.3). There were no significant differences in creatinine clearance reduction between groups. In conclusion, clinical pharmacist interventions on antimicrobials in the hospital and critical care setting have a positive impact on clinical and treatment related outcomes, and decrease costs

Diseño e implantación de un sistema de alertas de medicamentos en insuficiencia renal asociado al sistema de prescripción electrónica asistida

INTRODUCTION. Renal disease is a worldwide health problem. The prevalence of chronic disease is between 10-16% in the general population and rises to 30% in hospitalized patients. Patients with renal disease have increased morbidity, mortality and costs. Chronic kidney disease(CKD) is defined as abnormalities of kidney structure or function, for more than three months, with implications for health. There are different type of factors that promote the development of this disease including the use of nephrotoxic drugs. GFR is generally accepted as the best overall index of kidney function and is estimated by different equations. The hypothesis for this research is that clinical decision support system(CDSS) which provides patients specific recommendations in real time would improve drug selection and the quality of drug prescribing, reducing adverse drugs events in patients with renal insufficiency. OBJECTIVES. To characterize inpatients according to renal function and determine the prescription habits of nephrotoxic drugs and drugs with renal elimination. To design a CDSS aids to guide drug prescription in renal impairment. To assess the impact of a CDSS in drug prescribing for patient with renal disease. PATIENTS AND METHODS. The setting for this study was an academic medical centre with an electronic medical record system including integrated computerized physician order entry(CPOE). The study was designed as an intervention study comparing pre and post implementation phases. Inclusion criteria were inpatients older than 18 years old with at least one reported SCr level. Patients were classified according to their GFR in the categories of CKD of the NKF guidelines (2002). AKI was defined as increase in SCr by 0,3 mg/dl within 48 hours or increase in SCr to 1,5 times baseline which is known or presumed to have occurred within the prior 7 days (KDIGO 2012). Drugs cleared by kidney and/or nephrotoxic drugs were selected from the hospital formulary. Four alert categories were defined and assigned to these drugs in corresponding renal stages: precaution, adjustment, contraindication and nephrotoxicity. A dosing guideline was drawn for drugs with adjustment alerts. The CDSS was designed and implemented in the hospital CPOE system after its diffusion among its users. RESULTS. 399 active substances where classified as renally cleared and 68 as nephrotoxic. The CDSS identified patients with potential acute or chronic renal disease and patients receiving nephrotoxic drugs. In these patients, it displayed a renal report with their renal function values and the corresponding alerts for the drugs prescribed. Alerts for precaution and adjustment had an informative design whereas alerts for contraindication or nephrotoxic in AKI were interruptive. More than 30% of inpatients included in the analysis suffered renal insufficiency and 7% presented at least an AKI episode. Patients with renal disease were older, had suffered any kind of renal damage previously and had other associated chronic diseases such as hypertension or diabetes mellitus. Every patient with renal impairment received drugs with precaution or adjustment alerts. More than 25% of patients were prescribed contraindicated drugs and one out of four nephrotoxic drugs. Alerts for nephrotoxic drugs in patients suffering AKI decreased the prescription of these drugs. CONCLUSIONS. Renal disease is a major health problem in hospitalized patients. CDSS implemented helps identifying these patients and eases the control of renally eliminated and nephrotoxic drugs use. Drug adjustment neglecting is more frequent during the prescription of antimicrobials drugs and in patients with cancer. Patients with chronic disease, patients undergoing renal therapy replacement, patients with worse renal function and patients who die during hospitalization receive more frequently drugs that should be avoided. Alerts for nephrotoxic drugs in patients suffering AKI have been the most effective alerts

Optimización con criterios PK/PD de la terapia con meropenem en el paciente crítico. Análisis farmacoeconómico de resultados

Meropenem is a broad-spectrum antibiotic. It is a drug usually reserved for the treatment of infections caused by multi-drug resistant microorganisms or in the empirical treatment of patients with risk factors for multi-drug resistant microorganisms. Therefore, its use is frequent in intensive care units (ICU). Critical patients features including physiopathological and pharmacokinetic changes and infected by microorganisms with high minimum inhibitory concentration (MIC) make difficult calculating the optimal meropenem dose. The objective of our study was to analyze the use of clinical pharmacokinetics to optimize the therapy with meropenem in critically ill patients and assess a possible pharmacoeconomic benefit. This retrospective, observational, naturalistic, cohort single-centre study was conducted in critically ill patients treated with meropenem admitted in the ICU at a universitary hospital. Subjects were divided into two cohorts; cohort A if they had pharmacokinetic intervention or cohort B if not. For the pharmacokinetic analysis, two serum samples were drawn from each patient (a peak sampled at the end of the infusion and a sample in the elimination phase) for quantification of the total and (for some patients) free meropenem concentrations. Meropenem was administered in infusions of 3 hours theoretically. Individual pharmacokinetic parameters were estimated by the method of Sawchuk and Zaske. The percentage of time in which the free drug concentration exceeded 4 times the MIC of the isolated microorganism was estimated, and dose adjustment was made when necessary. All the variables required for the study were obtained from the electronic medical record and the pharmacokinetic history. The objectives of this study were to analyze and compare clinical and microbiological effectiveness and the safety of meropenem treatment in critically ill patients in both cohorts. We evaluated the type of pharmacokinetic interventions (IFs) recommended in monitored patients according to the real MICs of the isolated germs. A cost-effectiveness analysis was carried out to analyze if pharmacokinetic monitoring of meropenem, in addition to having a clinical benefit, is associated with an economic saving. In addition, a non-parametric model of meropenem was developed for critically ill patients based on values derived from our actual clinical practice. Monte Carlo simulations were used to evaluate what meropenem dosage regimens achieved the PK/PD index associated with therapeutic efficacy in this subgroup of patients. This study shows a great clinical and bacteriological benefit associated with the use of pharmacokinetic monitoring of meropenem in the infectious pathology in critically ill patients. Procalcitonin has proven to be a very useful biomarker for the use of antibiotics. In this review, it was necessary to optimize meropenem therapy in 66.23 % of the patients who were pharmacokinetic monitored (CA) and 90.19 % of these patients required a decrease in the daily dose of meropenem, which led to an important economic saving in the cohort A. There are no statistically significant differences in aspects related to safety between both cohorts. These results show that empirical dose of meropenem in critical patients usually proposed in the literature is not always adequate for real-world populations and tends to overdose this population, especially when MIC of the isolated germ is very low

Optimización con criterios PK/PD de la terapia con meropenem en el paciente crítico. Análisis farmacoeconómico de resultados

Meropenem is a broad-spectrum antibiotic. It is a drug usually reserved for the treatment of infections caused by multi-drug resistant microorganisms or in the empirical treatment of patients with risk factors for multi-drug resistant microorganisms. Therefore, its use is frequent in intensive care units (ICU). Critical patients features including physiopathological and pharmacokinetic changes and infected by microorganisms with high minimum inhibitory concentration (MIC) make difficult calculating the optimal meropenem dose. The objective of our study was to analyze the use of clinical pharmacokinetics to optimize the therapy with meropenem in critically ill patients and assess a possible pharmacoeconomic benefit. This retrospective, observational, naturalistic, cohort single-centre study was conducted in critically ill patients treated with meropenem admitted in the ICU at a universitary hospital. Subjects were divided into two cohorts; cohort A if they had pharmacokinetic intervention or cohort B if not. For the pharmacokinetic analysis, two serum samples were drawn from each patient (a peak sampled at the end of the infusion and a sample in the elimination phase) for quantification of the total and (for some patients) free meropenem concentrations. Meropenem was administered in infusions of 3 hours theoretically. Individual pharmacokinetic parameters were estimated by the method of Sawchuk and Zaske. The percentage of time in which the free drug concentration exceeded 4 times the MIC of the isolated microorganism was estimated, and dose adjustment was made when necessary. All the variables required for the study were obtained from the electronic medical record and the pharmacokinetic history. The objectives of this study were to analyze and compare clinical and microbiological effectiveness and the safety of meropenem treatment in critically ill patients in both cohorts. We evaluated the type of pharmacokinetic interventions (IFs) recommended in monitored patients according to the real MICs of the isolated germs. A cost-effectiveness analysis was carried out to analyze if pharmacokinetic monitoring of meropenem, in addition to having a clinical benefit, is associated with an economic saving. In addition, a non-parametric model of meropenem was developed for critically ill patients based on values derived from our actual clinical practice. Monte Carlo simulations were used to evaluate what meropenem dosage regimens achieved the PK/PD index associated with therapeutic efficacy in this subgroup of patients. This study shows a great clinical and bacteriological benefit associated with the use of pharmacokinetic monitoring of meropenem in the infectious pathology in critically ill patients. Procalcitonin has proven to be a very useful biomarker for the use of antibiotics. In this review, it was necessary to optimize meropenem therapy in 66.23 % of the patients who were pharmacokinetic monitored (CA) and 90.19 % of these patients required a decrease in the daily dose of meropenem, which led to an important economic saving in the cohort A. There are no statistically significant differences in aspects related to safety between both cohorts. These results show that empirical dose of meropenem in critical patients usually proposed in the literature is not always adequate for real-world populations and tends to overdose this population, especially when MIC of the isolated germ is very low

Effectiveness of pharmacokinetic / pharmacodynamic-guided meropenem treatment in critically ill patients: A comparative cohort study

Background: The proper dosage of antibiotics is a key element in the effective treatment of infection, especially in critically ill patients. This study aimed to evaluate the efficacy of optimized meropenem regimens based on pharmacokinetic/pharmacodynamic criteria in patients admitted to the intensive care unit. Methods: This observational, naturalistic, retrospective, unicentric cohort study was performed between May 2011 and December 2017. The clinical and bacteriologic responses of 77 control intensive care unit patients receiving meropenem were compared with those of 77 propensity score-balanced patients who received meropenem dose adjusted by therapeutic drug monitoring. The primary end point of clinical response was a reduction at the end of treatment of at least 80% of the maximum procalcitonin (PCT) value recorded during the meropenem treatment. Results: The primary end point was met by 55 patients (71.4%) in the adjusted group compared with 41 (53.3%) patients in the control group (mean difference 18.1%, P = 0.02). Fifty-one patients (66.2%) in the adjusted group required a meropenem dose adjustment, being necessary in 46 of them (90.2%) to decrease the dose. The reduction of PCT was the greatest in the adjusted group compared with the unadjusted group (93% versus 85%, P = 0.004); a greater percentage of patients reached a PCT level < 0.5 ng/mL (63.6% versus 41.6%, P = 0.006), and there was a trend toward an improved bacteriologic response (relative risk = 1.27; 95% confidence interval: 0.92-1.56). There were no differences in early mortality or safety between groups. Conclusions: Adjustment of meropenem therapy by monitoring is a useful strategy for improving meropenem effectiveness in the treatment of infection in critically ill patients, with no impact on safety

Información de medicamentos a la población desde el Servicio de Farmacia a través de Internet

Objectives: To describe and discuss the work of a Pharmacy Department for the health-care portal www.viatusalud.com. Methods: Using a web portal, a Pharmacy Department develops and updates a vademecum on drugs, and answers enquiries by end-users. Results: On December 31, 2002 more than 750 records on drugs were available, and 3030 enquiries had been answered. Conclusions: With this drug information and online enquiry service, our Pharmacy Department helps meet the demand of health-care information posed by the community and by patients previously seen at Clínica Universitaria. In addition, it allows areas of improvement to be detected in the information to be offered to patients fron a Pharmacy Department, and represents a tertiary source of information for health-care professionals