Search

Background Intravenous drug administration is associated with potential complications, such as phlebitis. The physiochemical characteristics of the infusate play a very important role in some of these problems. Aim The aim of this study was to standardize the dilutions of intravenous drugs most commonly used in hospitalized adult patients and to characterize their pH, osmolarity and cytotoxic nature to better guide the selection of the most appropriate vascular access. Methods The project was conducted in three phases: (i) standardization of intravenous therapy, which was conducted using a modified double-round Delphi method; (ii) characterization of the dilutions agreed on in the previous phase by means of determining the osmolarity and pH of each of the agreed concentrations, and recording the vesicant nature based on the information in literature; and (iii) algorithm proposal for selecting the most appropriate vascular access, taking into account the information gathered in the previous phases. Results In total, 112 drugs were standardized and 307 different admixtures were assessed for pH, osmolarity and vesicant nature. Of these, 123 admixtures (40%), had osmolarity values >600 mOsm/L, pH < 4 or > 9, or were classified as vesicants. In these cases, selection of the most suitable route of infusion and vascular access device is crucial to minimize the risk of phlebitis-type complications. Conclusions Increasing safety of intravenous therapy should be a priority in the healthcare settings. Knowing the characteristics of drugs to assess the risk involved in their administration related to their physicochemical nature may be useful to guide decision making regarding the most appropriate vascular access and devices.

Background Incorporating in the Intensive Care Unit (ICU) a clinical pharmacist who performs interventions on antimicrobials may be cost-effective. Objectives To evaluate the clinical and economic impact of clinical pharmacist interventions on antimicrobials in an ICU. To identify drug related problems and medication errors detected by the pharmacist. Methods A retrospective observational study was performed to analyze drug related problems, medication errors and clinical pharmacist interventions related to antimicrobials in adults admitted to an ICU in a 5-month period. The economic impact of pharmacist interventions was estimated considering difference in cost derived from antimicrobial treatment, adverse drug events and clinical pharmacist time. Results A total of 212 drug related problems were detected in 114 patients, 18 being medication errors. Clinical pharmacist developed one intervention for each problem identified. 204 interventions (96.2%) were considered important with improved patient care and 7 (3.3%) very important. No negative impact of any intervention was identified. Physicians accepted 97.6% of the interventions. A potential saving of 10,905 € was estimated as a result of pharmacist interventions and 4.8 € were avoided per euro invested in a clinical pharmacist. Conclusions A clinical pharmacist performing interventions on antimicrobials in the ICU has a positive impact on patient care and decreases costs.

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.

Background and importance Meropenem dose adjustment following pharmacokinetic/pharmacodynamic monitoring (TDM) in critical patients (CP) presents a clinical benefit. An economic analysis of this activity could facilitate its use in clinical practice. Aim and objectives To conduct a cost effectiveness analysis of meropenem TDM in CP versus standard dose (SD) according to the package insert recommendations. Material and methods We conducted a naturalistic, retrospective, observational cohort study of CP receiving meropenem between May 2011 and December 2017 in a university hospital. Two cohorts were analysed: patients with meropenem TDM (cohort A) and patients with SD meropenem (cohort B). The main effectiveness variable was the percentage of patients with a reduction of at least 80% in the procalcitonin value at the end of meropenem treatment compared with the maximum value during meropenem treatment. Costs included in the analysis were: meropenem, material for drug preparation, TDM, time for preparation, administration and infusion surveillance, meropenem adverse drug reactions (ADR), critical care hospitalisation days and re-entries. Propensity score (PS) matching was applied for patient selection. The χ2 was used to compare effectiveness and bootstrap to calculate the difference in costs between cohorts. A cost effectiveness analysis with deterministic and probabilistic sensitivity analyses was performed. Results A total of 154 patients were included (77 per cohort) after PS matching. Meropenem dose was changed in 51 (66.2%) patients with TDM, in most (90.2%) because they were overdosed. In cohort A, 71.4% of patients had reduced procalcitonin by at least 80% compared with 53.2% in cohort B (difference 18.2% (95% CI 3.1; 33.2; p=0.020)). No significant differences were found in ADR between the two cohorts. An average decrease in cost per patient of −1454€ (95% CI −4627;1720€) with TDM was observed, with lower cost per patient for meropenem −62€ (95% CI −116; −4), disposable material −12€ (95% CI −29; 4) and nursing time −38€ (95% CI −71; −4) in cohort A, that offset the TDM cost (47€). Mean hospitalisation cost in patients with TDM was 8912€ versus 10 325€ in cohort B. There was a 75% probability that TDM was more effective and cheaper (dominant) than SD according to the sensitivity analysis. Conclusion and relevance Meropenem dose adjustment following pharmacokinetic/pharmacodynamic criteria was more effective, with similar safety and lower costs, than dosing according to the package insert recommendations. References and/or acknowledgements 1. Schuetz P, et al. Procalcitonin-guided antibiotic stewardship. Clin Chem Lab Med 2019. No conflict of interest.

We describe a Caucasian man in his late 60s who was admitted to the intensive care unit (ICU) with a history of cardiogenic shock secondary to an acute myocardial infarction. The patient’s baseline serum creatinine levels were 0.9–1 mg/dL. On day 7 of the admission treatment with quetiapine was initiated due to a delirium episode. The next day the patient developed an erythematous-maculopapular rash and fever, with eosinophilia in the blood count. Over the following days the patient experienced an acute deterioration of kidney function requiring continuous renal replacement therapy. The skin lesions and eosinophilia resolved after withdrawal of quetiapine and systemic steroid therapy was administered. The patient was discharged from the ICU with a serum creatinine level of 2.6 mg/dL. Three months later, blood tests showed no recovery of the kidney function. According to the Naranjo adverse drug reaction probability scale, this event would be classified as 9probable9 DRESS syndrome and, based on the RegiSCAR scoring system, was classified as 9definite9 DRESS syndrome.

The purpose of the study was to analyze the effectiveness of adding nebulized antibiotics to systemic antimicrobials in critically ill patients with respiratory tract infections (pneumonia or tracheobronchitis) and the effect on renal function. A retrospective observational cohort study including critically ill patients with respiratory tract infections during a 2-year period was conducted. Intervention group included patients that received nebulized and systemic antimicrobials. Patients in the control group received only systemic antimicrobials. Clinical resolution was the primary endpoint. Secondary outcomes included change in fever, inflammatory parameters, and creatinine clearance; length of hospital stay, systemic therapy, and mechanical ventilation; hospital readmission; and mortality. Regression models were performed to estimate the effect of nebulized antibiotics on outcome variables adjusted by potential confounders. A total of 136 patients were included (93 in control group and 43 in intervention group). The intervention group had higher odds of clinical resolution (adjusted odds ratio (OR): 7.1; 95% confidence interval (95% CI): 1.2, 43.3). Nebulized antibiotic therapy was independently associated with reduction in procalcitonin (adjusted OR: 12.4; 95% CI: 1.4, 109.7). There were no significant differences in the rest of the secondary outcomes or in creatinine clearance reduction. Adding nebulized antibiotics for the management of respiratory tract infections has a positive impact on clinical resolution without increasing the risk of renal toxicity. Electronic supplementary material The online version of this article (10.1007/s10096-019-03733-6) contains supplementary material, which is available to authorized users.

Purpose A case of severe bilateral sensorineural hearing loss associated with oral morphine is reported. Summary A 52-year-old Spanish man was admitted to the intensive care unit with a Glasgow Coma Scale score of 3, a fever, and sudden hearing loss with tinnitus in both ears. His medical history included type 2 diabetes mellitus, depression, sleep disorder, and hypertension. The patient also had pyelonephritis in 2011 and pulmonary embolism in 2014, requiring the placement of an inferior vena cava filter and chronic anticoagulation. His hearing loss appeared after the initiation of oral morphine, specifically on the eighth day of treatment, with increasing dosages of up to 120 mg daily. We did not find any other possible causes of the hearing loss. Ototoxicity is an adverse reaction of ibuprofen and acetaminophen, but the patient received only three doses of ibuprofen 600 mg and did not require acetaminophen. The patient’s other medications did not have ototoxicity as an adverse reaction, and the patient confirmed not to have received any salicylate product. Brain magnetic resonance imaging discarded other possible causes of hearing loss. Our patient’s hearing loss did not resolve after opioid discontinuation, and the use of hearing aids was necessary. According to the Naranjo et al. adverse drug reaction probability scale, this event would be classified as “probable.” Conclusion A 52-year-old man developed tinnitus and hearing loss after receiving high doses of oral morphine sulfate. His hearing loss did not fully resolve after the discontinuation of morphine, and he required the use of hearing aids.

The purpose of this paper was to review the literature regarding the clinical and economic impact of pharmacist interventions (PIs) related to antimicrobials in the hospital setting. A PubMed literature search from January 2003 to March 2016 was conducted using the terms pharmacist* or clinical pharmacist* combined with antimicrobial* or antibiotic* or anti-infective*. Comparative studies that assessed the clinical and/or economic impact of PIs on antimicrobials in the hospital setting were reviewed. Outcomes were classified as: treatment-related outcomes (TROs), clinical outcomes (COs), cost and microbiological outcomes (MOs). Acceptance of pharmacist recommendations by physicians was collected. PIs were grouped into patient-specific recommendations (PSRs), policy, and education. Studies' risk of bias was analyzed using Cochrane's tool. Twenty-three studies were evaluated. All of them had high risk of bias. The design in most cases was uncontrolled before and after. PSRs were included in every study; five also included policy and four education. Significant impact of PI was found in 14 of the 18 studies (77.8%) that evaluated costs, 15 of the 20 studies (75.0%) that assessed TROs, 12 of the 22 studies (54.5%) that analyzed COs, and one of the two studies (50.0%) that evaluated MOs. None of the studies found significant negative impact of PIs. It could not be concluded that adding other strategies to PSRs would improve results. Acceptance of recommendations varied from 70 to 97.5%. Pharmacists improve TROs and COs, and decrease costs. Additional research with a lower risk of bias is unlikely to change this conclusion. Future research should focus on identifying the most efficient interventions.

OBJECTIVE: Electronic alert systems have shown their capacity for improving the detection of acute kidney injury (AKI). The aim of this study was to design and implement a clinical decision support system (CDSS) for improving drug selection and reducing nephrotoxic drug use in patients with AKI. METHODS: The study was designed as an intervention study comparing a pre and post cohort of patients admitted during April 2014 and April 2015, respectively (phase I and phase II). The intervention was a CDSS which provided kidney function and nephrotoxic drug information. Furthermore, an interruptive alert was designed to detect patients suffering an AKI event while taking a nephrotoxic drug and to see if the dose was then reduced or the drug was discontinued by the physicians. RESULTS: One-third of the inpatients were included in the analysis because they met the inclusion criteria (1004 and 1002 patients in phases I and II, respectively). 735 and 761 of them received at least one nephrotoxic alert (73% vs 76%; p=0.763). 65 and 88 patients suffered AKI during admission (6.5% vs 8.8%; p=0.051). In phase I, patients received 384 nephrotoxic alerts (55%) with 78 (20%) of them provoking a change or discontinuation of the nephrotoxic drug. In phase II this value increased to 154 out of 526 (29%) after implementation of the CDSS (p

Background A clinical pharmacist (CP), as part of the healthcare team (HT), can contribute to adequate anti-infective use. Few studies have evaluated the economic impact of CP´s interventions (CPI) in the intensive care unit (ICU), and most consider only drug costs. Purpose To analyse the economic impact of CPI regarding antimicrobial therapy (AT) in the ICU. Material and methods We conducted a retrospective analysis of CPI regarding AT in the ICU over a 5 month period. The CP spends 5 hours/day, 5 days/week in the ICU. 33% of CPI are anti-infective related. Information regarding CPI is recorded daily in the hospital´s information system and includes the drug involved, type of intervention, acceptance by physicians and estimated costs (incremental and avoided) as a consequence of the CPI. These costs include changes in drugs, time and products for drug preparations and administration, and the pharmacist’s time. To estimate costs (incremental or avoided) we assumed that the change to the recommended and accepted therapy would have happened 2 days later the without CPI (CPI contribute to earlier changes). For sensitivity analysis, we considered that the change would have happened in 1–4 days. The ratio ‘avoided cost to invested money’ was calculated. Results 212 interventions were recorded, corresponding to 114 patients. Most frequent types of CPI were: modification of drug dose and/or interval (MD) (50.9%), drug discontinuation (DD) (22.6%), change to a more cost effective administration route (CR) (14.6%), initiate a drug (7.5%) and change to a more cost effective drug (CD) (2.4%). Physicians´ acceptance rate was 97.6%. Over the 5-month period, we estimated a total decrease in costs as a consequence of CPI of €7013 (34.8% decrease), corresponding to €33.1/intervention and €61.5/patient. According to sensitivity analysis, total savings varied from €2779 to €19 011. This estimation included the cost of the CP’s time during the studied period (€2859). Therefore, €3.5 were avoided per €1 invested in the CP. Types of CPI associated with greater total savings were (in decreasing order): DD, MD and CR(and per intervention: CD, CR and DD). Conclusion Having a CP as a member of the HT in the ICU performing interventions related to antimicrobials is economically beneficial. References and/or acknowledgements Thanks to the pharmacy service. No conflict of interest

Background In hospital settings (HS), pharmacists´ interventions (PI) can contribute to rational use of antimicrobials. Due to scarce resources, the pharmacist’s time has to be dedicated to interventions with impact on patient outcomes and costs. Purpose A systematic review was conducted to summarise published evidence regarding clinical and/or economic outcomes of PI related to antimicrobials in HS to estimate the impact of PI and to identify strategies with higher impact. Material and methods A PubMed search of papers published from 2003 to March 2016 was conducted using the terms (’pharmacist*’ OR ‘clinical pharmacist*’) AND (’antimicrobial*’ OR ‘antibiotic*’ OR ‘anti infective*’). Additional references were identified from citations. Inclusion criteria were: comparative studies that assessed clinical or economic impact of PI regarding antimicrobials in HS or those that evaluated intermediate outcomes, microbiological impact or appropriate antimicrobial prescription (AAP). Exclusion criteria were: studies in paediatric, primary care or community settings, and evaluations of multidisciplinary teams. We collected: study design, type of PI, impact of PI and acceptance by physicians. Risk of bias of studies was analysed using Cochrane´s tool.1 Results 23 studies were included; all had a high risk of bias. Most frequent design was before and after without a control group (57%) and 83% were single centre studies. Identified PI were grouped into three types: specific recommendations (SR) (in 22 studies), policy (in 4) and education (in 3). Six studies combined various strategies. A significant positive impact of PI was found in 14 of 17 (82%) studies that evaluated costs, in 11 of 15 (73%) that studied AAP, in 9 of 18 (50%) that analysed clinical outcomes (CO), in 1 of 2 (50%) that assessed microbiological outcomes (MO) and in 3 of 7 (43%) that evaluated adverse drug events (ADE). A combination of SR, education and policy had the highest impact on AAP, CO and costs; SR and education on MO; and dose adjustment on ADE. 70–92% of recommendations were accepted. Conclusion Pharmacists´ interventions regarding antimicrobials had a positive impact on appropriate prescribing and patient outcomes, and decreased costs. Combinations of strategies seems to be superior to single strategies. Quality of published studies is poor and better studies are necessary to confirm these results. References and/or acknowledgements 1. Available at http://handbook.cochrane.org/chapter_8/8_5_the_cochrane_collaborations_tool_for_assessing_risk_of_bias.htm No conflict of interest

Objective: To quantify the impact of the incorporation of a hospital pharmacy resident into a healthcare team. To describe the work schedule followed. Method: The resident was integrated for 8 months in Medical Oncology, Intensive Care Unit, and Oncology Day Hospital. Interventions were recorded and evaluated using Atefarm®‚ software. Problem characteristics, type, and severity were recorded, as were acceptance, and costs avoided by interventions. Results: In all, 2,415 drug-related problems were detected (10 per day, and 3.6 per patient), and 2,545 interventions for 672 patients were carried out. Most common problems were inadequate treatment duration, and conversion to oral route. Sixty- one percent of errors were prevented. Sixty-five percent of interventions influenced safety, 35% efficiency, and 25% effectiveness. Ninety-four percent of interventions were accepted. Costs avoided by the pharmacist amounted to 3,133 per month. Conclusions: The integration of a pharmacist in the healthcare teams optimizes therapy, reduces costs, prevents adverse events, and offers healthcare education.

Background 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 μmol/Lhr, 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 μmol/Lhr (P = 0.024), such that 4,000 μmol/Lhr 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 μmol/Lhr. © 2003 Wiley-Liss, Inc.

OBJECTIVE:To establish a relationship between the pharmacokinetics of high-dose methotrexate (MTX) and toxicity in children of a pediatric oncology department and to reassess MTX concentrations at which the patients would be at high risk for toxic effects.METHODS:This study included 37 patients (227 treatment courses) who received a median dose of 4.87 g/m2of MTX in a 4-hour infusion. The population pharmacokinetic parameters of MTX were estimated by parametric (IT2B) and nonparametric methods (NPEM). Gastrointestinal, renal, and hematologic toxicity were evaluated. The relationship between pharmacokinetic parameters and toxicity was analyzed by logistic regression and multiple linear regression.RESULTS:Equations to predict hematologic and nonhematologic toxicity were obtained. An increase of 100 μmol/L in the MTX peak concentration meant a 12% (p = 0.03) higher risk of vomiting; a significant delay in MTX elimination implied a 5.76-fold higher risk of mucositis (p < 0.001). An increase of 1 μmol/L in the MTX concentration 24 hours after the end of the infusion (Cp24h) led to a 43% increase in the risk of renal toxicity (p < 0.001). Hematologic toxicity was significantly conditioned by the baseline leukocyte count and Cp24h(p < 0.001).CONCLUSIONS:The analysis of high-dose MTX pharmacokinetic/pharmacodynamic relationship to toxicity has led to equations able to predict toxicity that are easily applicable to daily practice. Cp24h>3.5 μmol/L was confirmed as an indicator of high risk of toxicity.

The use of high dose of methotrexate (HDM), has been suggested as a mean of obtaining potentially cytotoxic cerebrospinal fluid (CSF) drug levels. The present study describes the pharmacokinetics in plasma and CSF for at least 65 hours after administratrion of HDM, and allows the simultaneous interpretation of the CSF and plasma available data. Methotrexate (MTX) concentrations in plasma and CSF were monitored and analyzed in a child suffering from a protuberancial primitive neuroectodermal tumor (PNET) wearing an external ventricular derivation of CSF. The pharmacokinetic parameters obtained allow us to predict CSF MTX concentrations from a more accessible fluid (plasma). Moreover, this study would allow to theoretically calculate different dose regimens in order to reach specific CSF concentrations.

BACKGROUND: Hospitalized patients are complex and institutions have to face the high cost of critical care and the limited resources of the ward. Intermediate care appears as an attractive strategy to provide rational care according to patient needs. It is an interesting scenario to expand co-management and teaching. STUDY DESIGN: Retrospective observational study. SETTING: Intermediate care unit (ImCU) of a single academic hospital. PATIENTS AND METHODS: 456 patients admitted from April 2006 to April 2010 were included in the study. Demographics, admission physiologic parameters and in-hospital mortality were recorded. We used the Simplified Acute Physiology Score II (SAPS II) as prognostic score system. Co-management with medical and surgical teams, and the number of training residents were evaluated. RESULTS: In-hospital mortality was 20.6%, whereas the expected mortality was 23.2% based on SAPS II score. The correlation between SAPS II predicted and observed death rates was accurate and statistically significant (Rho = 1.0, p < 0.001). Co-management was performed with several medical and surgical teams, with an increase in perioperative comanagement of 22.7% (p = 0.014). The number of training residents in ImCU increased from 4.3% to 30.4% (p = 0.002) CONCLUSIONS: An ImCU led by hospitalists showed encouraging results regarding patient survival and SAPS II is an useful tool for prognostic evaluation in this population. Intermediate care serves as an expansion of role for hospitalists; and clinicians, trainees and patients may benefit from co-management and teaching opportunities at this unique level of care. Journal of Hospital Medicine 2012; © 2012 Society of Hospital Medicine

Background: Adverse drug reaction (ADR) spontaneous reporting is the primary method of postmarketing drug surveillance: although it is an important part of postmarketing drug surveillance, it is underused. Before 2004, almost no ADRs were reported in our 400-bed hospital. As an electronic hospital information system was available in our hospital, we developed a tool (ADR-RS-IHIS) for ADR reporting integrated into the hospital information system to facilitate reporting through easy use, automatic input of certain information, increased accessibility, real-time review, and intervention. Objective: To analyze the efficacy of the ADR-RS-IHIS in increasing ADR reporting to the national drug surveillance system, propose and implement improvements to increase ADR reporting, and evaluate the impact of these improvements, Methods: Every ADR reported through the ADR-RS-IHIS was evaluated retrospectively. Two study phases for evaluating ADR-RS-IHIS efficacy were identified. Phase I took place April 2004-August 2006; in April 2006, an interim analysis was performed to propose improvements. Phase II took place September 2006-April 2007 for evaluation of the impact made by the proposed improvements. Efficacy in the phase I and improvement impact on phase II were measured as the number of ADRs reported to the national drug surveillance system Results: The rate of ADRs reported per month to the national system increased from 0 before 2004 to 0.91 in phase I and 1.62 in phase II (2.25 if delayed reporting was considered). Improvement measures included: allowing nurses to report ADRs in the same way as physicians and pharmacists, automatic form filling of certain information from the electronic hospital information system, easier ADR report analysis, and automatic notification to the allergy department regarding suspected allergies. Conclusions: An ADR reporting system integrated into the electronic hospital information system is effective for increasing the number of ADRs reported to the national drug surveillance system. Allowing nurses to report ADRs in a manner similar to that of physicians and pharmacists, as well as automatic entry of certain data into the form, contributes to the improvement of the system.

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.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.The group of 11 patients who were the least exposed to MTX (AUC2,400 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 AUC2,400 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.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.

OBJECTIVE: To report a case of delayed elimination of high-dose methotrexate (MTX) associated with concomitant omeprazole administration. CASE SUMMARY: Delayed MTX elimination was observed in an 11-year-old white boy who concomitantly received high-dose MTX and omeprazole. The patient's serum creatinine and liver function tests were normal during treatment and follow-up. The only medication we suspected of inhibiting MTX elimination was omeprazole 20 mg every 12 hours. Twenty-four hours after the first high-dose MTX cycle (15 g), omeprazole was discontinued. Thereafter, the patient received one high-dose MTX cycle without omeprazole every month for five months; MTX elimination was normal throughout MTX cycles 2 to 5. DISCUSSION: MTX is actively secreted in the distal tubules. The renal hydrogen/potassium adenosine triphosphatase (H+/K+-ATPase) pump makes the urine more acidic, by secreting hydrogen ions into the renal tubule and reabsorbing potassium ions. Active tubular secretion of MTX requires the activity of this pump because MTX is excreted with hydrogen ions. Omeprazole can inhibit renal elimination of the hydrogen ion and block the active tubular secretion of MTX. Therefore, the elimination half-life of MTX increases, which may result in potentially toxic concentrations of MTX. At a pH of approximately 5, as found in the renal tubules, pantoprazole is more slowly activated than omeprazole, reducing the incidence of unwanted reactions with sulfhydryl groups and adverse effects occurring outside of the gastric hydrogen pump. CONCLUSIONS: Based on the Naranjo probability scale, a probable drug interaction was observed. Omeprazole may delay MTX elimination; therefore, when prescribing MTX, an alternative to omeprazole should be considered.