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Background: Antimicrobial consumption (AMC) data in Latin America are scarce and usually spread out across different sources used to make AMC calculations, making it difficult to both standardize and compare regions through similar time frames. The main objective was to analyze AMC trends in Social Security tertiary care hospitals in Costa Rica in the period spanning January 2017 to December 2021, using both the defined daily dose (DDD)/100 bed days and DDD/100 discharges. Methods: This is a retrospective observational study of antimicrobial consumption. Global consumption trends were calculated and expressed as DDD/100 bed days and DDD/100 discharges. Trends in antimicrobial consumption were analyzed using a simple linear regression model to determine potential differences in antimicrobial usage throughout the study’s duration. Results: A statistically significant increase in the consumption expressed in DDD/100 discharges was observed in the following groups: carbapenems, 7.6% (trend: 64.68, p < 0.0001), trimethoprim-sulfamethoxazole: 12.6% (trend: 16.45, p < 0.0001), quinolones 9.4% (trend: 36.80, p = 0.02), vancomycin 2.0% (trend: 16.30, p = 0.03), echinocandins: 6.0% (trend: 15.17, p = 0.01) and azole antifungals: 12.10% (trend: 102.05, p < 0.0001). Additionally, a statistically significant increase of 10.30% in the consumption of azole antifungals expressed in DDD/100 bed days was observed (p = 0.0008). In contrast, a statistically significant decrease in consumption, expressed in DDD/100 discharges, was identified for cephalosporins −6.0% (p < 0.0001) and macrolides −16.5% (p < 0.0001). Macrolides also showed a downward trend in consumption, as expressed in DDD/100 bed days (−14.3%, p < 0.0001). According to World Health Organization (WHO) access, watch and reserve (AWaRe) classification trend analysis, only the reserve group showed a statistically significant upward change of 9.2% (p = 0.016). Conclusions: This five-year analysis demonstrated trends over time in overall antimicrobial consumption measured in DDD/100 bed days and DDD/100 discharge rates that correlate. In general, for all antimicrobials, after the implementation of antimicrobial stewardship programs (ASP), a downward trend is reported; in contrast, during the COVID-19 pandemic the AMC shows a general upward trend. The comparison between DDD/100 bed days and DDD/100 discharges allows for complementary comparisons to be made regarding antimicrobial exposure in a clinical setting.

GoalTo describe the experience of a dispensing model of outpatient hospital medicines (OHM) via collaboration of hospital and community pharmacies, and to explore patient satisfaction with the strategy as compared with the hospital pharmacy only service.BackgroundPatient satisfaction is an important component of the quality of health care.StudyA new model of dispensing OHM was conducted in the Outpatients Unit of the Service of Hospital Pharmacy of Hospital del Mar, in Barcelona, Spain. Participants were patients on stable chronic treatment with clinical or social fragility, immunocompromised patients, and those whose residence was located at a distance from the hospital that justified drug delivery through the community pharmacy. A cross sectional study was done using an ad hoc 14-item questionnaire collecting demographic data, duration of treatment, usual mode of collecting medication, and the degree of satisfaction regarding waiting time for the collection of medication, attention received by professionals, information received on treatment, and confidentiality.ResultsThe study population included a total of 4,057 patients (66.8% men) with a mean age of 53 (15.5) years, of whom 1,286 responded, with a response rate of 31.7%. Variables significantly associated with response to the survey were age over 44 years, particularly the age segment of 55–64 years (odds ratio [OR] 2.51) and receiving OHM via the community pharmacy (OR 12.76). Patients in the community pharmacy group (n = 927) as compared with those in the hospital pharmacy group (n = 359) showed significantly higher percentages of ‘satisfied’ and ‘very satisfied’ (p

Background: Liposomal amphotericin B (L-AmB) has become the mainstay of treatment for severe invasive fungal infections. However, the potential for renal toxicity must be considered. Aims: To evaluate the incidence of acute kidney injury (AKI) in critically ill patients receiving L-AmB for more than 48 h. Methods: Retrospective, observational, single-center study. Clinical, demographic and laboratory variables were obtained automatically from the electronic medical record. AKI incidence was analyzed in the entire population and in patients with a “low” or “high” risk of AKI based on their creatinine levels at the outset of the study. Factors associated with the development of AKI were studied using random forest models. Results: Finally, 67 patients with a median age of 61 (53–71) years, 67% male, a median SOFA of 4 (3–6.5) and a crude mortality of 34.3% were included. No variations in serum creatinine were observed during the observation period, except for a decrease in the high-risk subgroup. A total of 26.8% (total population), 25% (low risk) and 13% (high risk) of patients developed AKI. Norepinephrine, the SOFA score, furosemide (general model), potassium, C-reactive protein and procalcitonin (low-risk subgroup) were the variables identified by the random forest models as important contributing factors to the development of AKI other than L-AmB administration. Conclusions: The development of AKI is multifactorial and the administration of L-AmB appears to be safe in this group of patients.

ABSTRACT The objective of this study was to examine the relationship between colistin plasma concentrations and clinical outcomes in patients with hospital-acquired pneumonia (HAP) caused by extensively drug-resistant Pseudomonas aeruginosa (XDR-PA). A prospective observational cohort study was conducted at a tertiary care hospital. Patients diagnosed with HAP caused by XDR-PA between January 2010 and September 2018 were included. Steady-state plasma concentrations (C ss,avg) of colistin were measured by high performance liquid chromatography (HPLC). Based on the pharmacokinetic/pharmacodynamic data of colistin in animal models, previous clinical data, and the minimum inhibitory concentration (MIC) of the most prevalent strain in our center, an area under the ROC curve (AUC)/MIC24h between 30 and 60 mg·h/L was considered optimal. The primary outcome was 30-day mortality, and the secondary outcomes were clinical cure and colistin-associated nephrotoxicity. Seventy-five patients were included. The median C ss,avg was 1.1 (0.56–1.75) mg/L and only 23 (30.7%) patients achieved an AUC/MIC24h of 30–60 mg·h/L and the 30-day mortality was 30.7%. In multivariate analysis, sequential organ failure assessment score [adjusted hazard ratio (95% confidence interval, CI) 1.19 (1.07–1.32)] and high AUC/MIC24h (hazard ratio 1.55, 95% CI 1.17–2.04, P = 0.002) were associated with increased risk of death and clinical failure. Based on the maximally selected standardized log-rank statistic, the C ss,avg cutoff point that best predicted mortality was 1.5 mg/L. Nephrotoxicity at the end of treatment was 38.7%. High colistin exposure was not associated with improved clinical outcomes in the setting of HAP caused by XDR-PA. These data suggest that caution is required with intravenous colistin for the treatment of HAP caused by XDR-PA. IMPORTANCE In some cases, colistin is the only treatment option for infections caused by the very drug-resistant Pseudomonas aeruginosa. However, in the past decade, there have been questions concerning its pharmacokinetics and concentration at the site of infection. In this scenario, its use in a difficult-to-treat infection like pneumonia is currently debatable. This is a clinical pharmacokinetic study of colistin in patients with multidrug-resistant P. aeruginosa pneumonia. Our findings demonstrate that colistin exposure is associated with worse clinical outcomes rather than better clinical outcomes, implying that other therapeutic options should be explored in this clinical setting.

Introduction: Penicillin allergy labels (PAL) are common in the hospital setting and are associated with worse clinical outcomes. Desensitization can be a useful strategy for allergic patients when alternative options are suboptimal or not available. The aim was to compare clinical outcomes of patients with PAL managed with antibiotic desensitization vs. those who received alternative non-beta-lactam antibiotic treatments.Methods: A retrospective 3:1 case-control study was performed between 2015–2022. Cases were adult PAL patients with infection who required antibiotic desensitization; controls were PAL patients with infection managed with an alternative antibiotic treatment. Cases and controls were adjusted for age, sex, infection source, and critical or non-critical medical services.Results: Fifty-six patients were included: 14 in the desensitization group, 42 in the control group. Compared to the control group, desensitized PAL patients had more comorbidities, with a higher Charlson index (7.4 vs. 5; p = 0.00) and more infections caused by multidrug-resistant (MDR) pathogens (57.1% vs. 28.6%; p = 0.05). Thirty-day mortality was 14.3% in the desensitized group, 28.6% in the control group (p = 0.24). Clinical cure occurred in 71.4% cases and 54.8% controls (p = 0.22). Four control patients selected for MDR strains after alternative treatment; selection of MDR strains did not occur in desensitized patients. Five controls had antibiotic-related adverse events, including Clostridioides difficile or nephrotoxicity. No antibiotic-related adverse events were found in the study group. In multivariate analysis, no differences between groups were observed for main variables.Conclusion: Desensitization was not associated with worse clinical outcomes, despite more severe patients in this group. Our study suggests that antibiotic desensitization may be a useful Antimicrobial Stewardship tool for the management of selected PAL patients.

Abstract Ceftolozane/tazobactam (C/T) has emerged as a potential agent for the treatment of extensively drug-resistant (XDR) Pseudomonas aeruginosa infections. As it is a time-dependent antimicrobial, prolonged infusion may help achieve pharmacokinetic/pharmacodynamic (PK/PD) targets. To compare alternative steady-state concentrations (Css) of C/T in continuous infusion (CI) against three XDR P. aeruginosa ST175 isolates with C/T minimum inhibitory concentration (MIC) values of 2 to 16 mg/L in a hollow-fiber infection model (HFIM). Duplicate 10-day HFIM assays were performed to evaluate Css of C/T in CI: one compared 20 and 45 mg/L against the C/T-susceptible isolate while the other compared 45 and 80 mg/L against the two C/T-non-susceptible isolates. C/T resistance emerged when C/T-susceptible isolate was treated with C/T in CI at a Css of 20 mg/L; which showed a deletion in the gene encoding AmpC β-lactamase. The higher dosing regimen (80 mg/L) showed a slight advantage in effectiveness. The higher dosing regimen has the greatest bactericidal effect, regardless of C/T MIC. Exposure to the suboptimal Css of 20 mg/L led to the emergence of C/T resistance in the susceptible isolate. Antimicrobial regimens should be optimized through C/T levels monitoring and dose adjustments to improve clinical management.

Although several randomized clinical trials have confirmed that there is no difference in efficacy between etanercept and its biosimilar versions in the treatment of rheumatoid arthritis (RA), limited real-world evidence is available. We conducted a cohort study to compare the effectiveness and treatment persistence between the reference etanercept (ETN) and the biosimilar GP2015 in RA patients in a real-life setting. Adults with a diagnosis of RA who initiated treatment with ETN or GP2015, between January 2007 and December 2019, were included. The follow-up period was 52 weeks. The primary outcome was the mean of change in the DAS28-CRP values and the adjusted mean difference from baseline to 52 weeks between ETN and GP2015. Other effectiveness endpoints assessed were the rate of patients who achieved remission or low disease activity (LDA) at week 52, who showed a reduction of DAS28-CRP value greater than or equal to 1.2 from baseline to week 52 and rate of good responder patients (those meeting both effectiveness measures) at week 52. Treatment effectiveness over time (baseline, 26 and 52 weeks) was compared between the ETN and GP2015 groups using mixed effects models. Treatment persistence (probability of maintaining the same treatment over time) was also evaluated and shown using Kaplan–Meier survival curves. A total of 115 RA patients were included (ETN, n = 90; GP2015, n = 25). No differences were observed in the primary outcome: DAS28-CRP score decreased from baseline to week 52 [5.1 to 2.7 (mean of change -2.37) in ETN group and 5.0 to 2.2 (mean of change -2.84) in GP2015 group, p-value = 0.372] and the adjusted mean difference was −0.37 (−1.03 to 0.29). No differences were also observed in the other effectiveness endpoints assessed among patients treated with ETN or GP2015: rate of patients who achieved remission (54.1% vs. 66.7%, p-value = 0.303) and LDA (71.6% vs. 80.9%, p-value = 0.391) at week 52, reduction of DAS28-CRP value greater than or equal to 1.2 from baseline to week 52 (75.6% vs. 80.9%, p-value = 0.613) and rate of good responder patients (58.1% vs. 76.1%, p-value = 0.202). Drug survival was 82% and 80% for ETN and GP2015, respectively (log-rank p-value = 0.804). Etanercept and its biosimilar GP2015 show similar effectiveness and treatment persistence in RA patients in a real-life setting.

ABSTRACT The aim of this study was to compare the efficacy of intermittent (1-h), extended (4-h), and continuous ceftolozane-tazobactam (C/T) infusion against three extensively drug-resistant (XDR) sequence type (ST) 175 P. aeruginosa isolates with different susceptibilities to C/T (MIC = 2 to 16 mg/L) in a 7-day hollow-fiber infection model (HFIM). C/T in continuous infusion achieved the largest reduction in total number of bacterial colonies in the overall treatment arms for both C/T-susceptible and -resistant isolates. It was also the only regimen with bactericidal activity against all three isolates. These data suggest that continuous C/T infusion should be considered a potential treatment for infections caused by XDR P. aeruginosa isolates, including nonsusceptible ones. Proper use of C/T dosing regimens may lead to better clinical management of XDR P. aeruginosa infections. IMPORTANCE Ceftolozane-tazobactam (C/T) is an antipseudomonal antibiotic with a high clinical impact in treating infection caused by extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates, but resistance is emerging. Given its time-dependent behavior, C/T continuous infusion can improve exposure and therefore the pharmacokinetic/pharmacodynamic target attainment. We compared the efficacy of intermittent, extended, and continuous C/T infusion against three XDR ST175 P. aeruginosa isolates with different C/T MICs by means of an in vitro dynamic hollow-fiber model. We demonstrated that C/T in continuous infusion achieved the largest reduction in bacterial density in the overall treatment arms for both susceptible and resistant isolates. It was also the only regimen with bactericidal activity against all three isolates. Through this study, we want to demonstrate that developing individually tailored antimicrobial treatments is becoming essential. Our results support the role of C/T level monitoring and of dose adjustments for better clinical management and outcomes.

Background. Antimicrobial resistance killed 1.27 million people in 2019, so urgent actions are desperately needed. Antimicrobial stewardship programmes (ASPs) are essential to optimize antimicrobial use. The objective was to acknowledge the current role of clinical pharmacists engaged in ASP activities in Catalonia. Methods. This was a cross-sectional survey shared through the Catalan Infection Control Programme (VINCat). The survey consisted of four sections and was sent by e-mail. Results. A total of 69.0% of the centres answered. Pharmacists dedicated a median of 5.0 h per week (2.1 h/week/100 acute care beds), representing 0.15 full time equivalents. The ASP lacked information technology (IT) support, as only 16.3% of centres automatically calculated defined daily doses and days of therapy. Those with less than 15% of their time available for ASPs conducted fewer clinical activities, especially prospective audits and feedback. Those without official infectious diseases training also performed fewer clinical activities, but training was less determinant than IT support or time. Pharmacists performed interventions mostly through annotation in the medical records. Conclusions. Clinical pharmacists from Catalonia dedicated to ASPs present an important lack of time and IT support to perform clinical activities. Pharmacists should also improve their clinical skills and try to conduct clinical advice to prescribers, either by phone or face-to-face.

Abstract Introduction To assess the association between exposure to micafungin, other echinocandins, or azoles and the development of short-term liver injury (STLI) or long-term liver injury (LTLI) in patients with Child–Pugh B or C liver disease. Methods Multicenter case–control study of patients with Child–Pugh B or C liver disease who received antifungals (AF) for ≥ 72 h (May 2009–May 2015) in six Spanish and Italian hospitals. All micafungin patients were randomly matched with one patient who received another echinocandin and with one patient who received azole treatment. Primary outcome was development of STLI or LTLI (development of any type of liver tumor during the follow-up period). Results Of 2335 patients with chronic liver disease admitted to the six centers, 20 (0.85%) were found to have Child–Pugh B or C liver disease and received micafungin for ≥ 72 h. During AF treatment, the frequency of STLI was 10% in each group. Most cases of STLI were asymptomatic, and AFs had to be switched to another class of AF in only two patients (one micafungin and one azole). No patients developed acute liver insufficiency, were admitted to the ICU, or had to undergo transplantation. Follow-up data (median of 1.3 years) were available for 30 patients. LTLI was observed in only one patient, who had previously received treatment with azoles. Conclusions Our study suggests that the administration of micafungin to patients with end-stage liver disease does not imply a higher risk of developing STLI or LTLI.

Abstract Background Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia. Methods Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. Results The median (IQR) of meropenem AUC0–24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC

(1) Background: Patients with advanced chronic liver disease (ACLD) are living longer with more comorbidities because of improved medical and surgical management. However, patients with ACLD are at increased risk of perioperative morbidity and mortality; (2) Methods: We conducted a comprehensive review of the literature to support a narrative clinical guideline about the assessment of mortality risk and management of perioperative morbidity in patients with ACLD undergoing surgical procedures; (3) Results: Slight data exist to guide the perioperative management of patients with ACLD, and most recommendations are based on case series and expert opinion. The severity of liver dysfunction, portal hypertension, cardiopulmonary and renal comorbidities, and complexity of surgery and type (elective versus emergent) are predictors of perioperative morbidity and mortality. Expert multidisciplinary teams are necessary to evaluate and manage ACLD before, during, and after surgical procedures; (4) Conclusions: This clinical practice document updates the available data and recommendations to optimize the management of patients with advanced chronic liver disease who undergo surgical procedures.

Rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis are chronic progressive immune-mediated rheumatic diseases (IMRD) that can cause a progressive disability and joint deformation and thus can impact in healthcare resource utilization (HCRU) and costs. The main outcome of the study was to assess the effect of non-persistence to treatment with subcutaneous tumor necrosis factor-alpha inhibitors (SC-TNFis) on HCRU costs in naïve patients with IMRD who started treatment with adalimumab, etanercept, golimumab or certolizumab pegol during 12 months after initiation of treatment. The impact of persistence and non-persistence of SC-TNFis on HCRU costs was compared between 12 months before and 12 months after initiating SC-TNFis. Persistence was defined as the duration of time from initiation to discontinuation of therapy. The study was conducted in an acute care teaching hospital in Barcelona, Spain. Data for the period between 2015 and 2018 were extracted from the hospital cost management control database. HCRU costs comprised outpatient care, outpatient specialized rheumatology care, in-patient care, emergency care, laboratory testing and other non-biological therapies. The study population included 110 naïve SC-TNFis patients, divided into the cohorts of persistent (n = 85) and non-persistent (n = 25) patients. Fifty-six percent of patients were women, with a mean (standard deviation) age of 47.6 (14.8) years. Baseline clinical features and HCRU costs over the 12 months before the index prescription were similar in the two study groups. Before-and-after differences in mean (standard deviation) HCRU costs were significantly higher in the non-persistence group as compared to the persistence group for outpatient rheumatology care (€110.90 [234.56] vs. €20.80 [129.59], p = 0.023), laboratory testing (−€193.99 [195.88] vs. −€241.3 [217.88], p = 0.025), other non-biological drugs (€3849.03 [4046.14] vs. −€10.90 [157.42], p < 0.001) and total costs (€3268.90 [4821.55] vs. −€334.67 (905.44), p < 0.001). Treatment persistence with SC-TNFis may be associated with HCRU cost savings in naïve IMRD patients. Prescribing SC-TNFis with the best long-term persistence is beneficial.

ABSTRACT Ceftazidime-avibactam (CZA) has emerged as a promising solution to the lack of new antibiotics against Pseudomonas aeruginosa infections. Data from in vitro assays of CZA combinations, however, are scarce. The objective of our study was to perform a time-kill analysis of the effectiveness of CZA alone and in combination with other antibiotics against a collection of extensively drug-resistant (XDR) P. aeruginosa isolates. Twenty-one previously characterized representative XDR P. aeruginosa isolates were selected. Antibiotic susceptibility was tested by broth microdilution, and results were interpreted using CLSI criteria. The time-kill experiments were performed in duplicate for each isolate. Antibiotics were tested at clinically achievable free-drug concentrations. Different treatment options, including CZA alone and combined with amikacin, aztreonam, meropenem, and colistin, were evaluated to identify the most effective combinations. Seven isolates were resistant to CZA (MIC ≥ 16/4 mg/liter), including four metallo-β-lactamase (MBL)-carrying isolates and two class A carbapenemases. Five of them were resistant or intermediate to aztreonam (MIC ≥ 16 mg/liter). Three isolates were resistant to amikacin (MIC ≥ 64 mg/liter) and one to colistin (MIC ≥ 4 mg/liter). CZA monotherapy had a bactericidal effect in 100% (14/14) of the CZA-susceptible isolates. Combination therapies achieved a greater overall reduction in bacterial load than monotherapy for the CZA-resistant isolates. CZA plus colistin was additive or synergistic in 100% (7/7) of the CZA-resistant isolates, while CZA plus amikacin and CZA plus aztreonam were additive or synergistic in 85%. CZA combined with colistin, amikacin, or aztreonam was more effective than monotherapy against XDR P. aeruginosa isolates. A CZA combination could be useful for treating XDR P. aeruginosa infections, including those caused by CZA-resistant isolates. IMPORTANCE The emergence of resistance to antibiotics is a serious public health problem worldwide and can be a cause of mortality. For this reason, antibiotic treatment is compromised, and we have few therapeutic options to treat infections. The main goal of our study is to search for new treatment options for infections caused by difficult-to-treat resistant germs. Pseudomonas aeruginosa is a Gram-negative bacterium distributed throughout the world with the ability to become resistant to most available antibiotics. Ceftazidime-avibactam (CZA) emerged as a promising solution to the lack of new antibiotics against infections caused by P. aeruginosa strains. This study intended to analyze the effect of CZA alone or in combination with other available antibiotics against P. aeruginosa strains. The combination of CZA with other antibiotics could be more effective than monotherapy against extensively drug-resistant P. aeruginosa strains.

This study correlates in vivo findings in a patient with an extensively drug-resistant (XDR) P. aeruginosa infection who developed resistance to ceftazidime-avibactam (CAZ-AVI) with in vitro results of a 7-day hollow-fiber infection model (HFIM) testing the same bacterial strain. The patient was critically ill with ventilator-associated pneumonia caused by XDR P. aeruginosa ST175 with CAZ-AVI MIC of 6 mg/L and was treated with CAZ-AVI in continuous infusion at doses adjusted for renal function. Plasma concentrations of CAZ-AVI were analyzed on days 3, 7, and 10. In the HIFM, the efficacy of different steady-state concentrations (Css) of CAZ-AVI (12, 18, 30 and 48 mg/L) was evaluated. In both models, a correlation was observed between the decreasing plasma levels of CAZ-AVI and the emergence of resistance. In the HIFM, a Css of 30 and 48 mg/L (corresponding to 5× and 8× MIC) had a bactericidal effect without selecting resistant mutants, whereas a Css of 12 and 18 mg/L (corresponding to 2× and 3× MIC) failed to prevent the emergence of resistance. CAZ/AVI resistance development was caused by the selection of a single ampC mutation in both patient and HFIM. Until further data are available, strategies to achieve plasma CAZ-AVI levels at least 4× MIC could be of interest, particularly in severe and high-inoculum infections caused by XDR P. aeruginosa with high CAZ-AVI MICs.

Resumen: Objetivo: Describir los problemas relacionados con la medicación detectados en pacientes ingresados y analizar el grado de aceptación de las recomendaciones propuestas. Método: Estudio observacional retrospectivo que incluyó los problemas relacionados con la medicación detectados en pacientes hospitalizados durante 2014-2015. Se realizó un análisis descriptivo y mediante regresión logística se analizó la asociación entre el grado de aceptación de la recomendación y la variable de interés. Resultados: Se detectaron 4587 problemas relacionados con la medicación en 44.870 pacientes ingresados. Los más frecuentes fueron errores de prescripción relacionados con el uso incorrecto de la orden médica informatizada (18,1%), seguidos por las interacciones (13,3%) y la necesidad de ajuste de dosis por alteración de la función renal o hepática (11,5%). El grado de aceptación de las recomendaciones realizadas que fueron valorables fue del 81,0%. El servicio médico frente al quirúrgico, determinadas intervenciones como la introducción o la suspensión de un fármaco, y la corrección de un error de prescripción, así como la comunicación verbal de la intervención al médico prescriptor, fueron las variables asociadas a un mayor grado de aceptación. Conclusiones: Los resultados de este estudio han permitido identificar áreas susceptibles de optimización mediante la introducción de estrategias de mejora, como formación sobre el modo de utilizar la orden médica informatizada, fármacos cuyo ajuste es necesario en insuficiencia renal e interacciones relevantes. Abstract: Objective: To describe drug-related problems identified in hospitalized patients and to assess physicians’ acceptance rate of pharmacists’ recommendations. Methods: Retrospective observational study that included all drug-related problems detected in hospitalized patients during 2014-2015. Statistical analysis included a descriptive analysis of the data and a multivariate logistic regression to evaluate the association between pharmacists’ recommendation acceptance rate and the variable of interest. Results: During the study period 4587 drug-related problems were identified in 44,870 hospitalized patients. Main drug-related problems were prescription errors due to incorrect use of the computerized physician order entry (18.1%), inappropriate drug-drug combination (13.3%) and dose adjustment by renal and/or hepatic function (11.5%). Acceptance rate of pharmacist therapy advice in evaluable cases was 81.0%. Medical versus surgical admitting department, specific types of intervention (addition of a new drug, drug discontinuation and correction of a prescription error) and oral communication of the recommendation were associated with a higher acceptance rate. Conclusions: The results of this study allow areas to be identified on which to implement optimization strategies. These include training courses for physicians on the computerized physician order entry, on drugs that need dose adjustment with renal impairment, and on relevant drug interactions. Palabras clave: Sistemas de prescripción electrónica, Seguridad del paciente, Farmacoepidemiología, España, Keywords: Medical order entry systems, Patient safety, Pharmacoepidemiology, Spain

The massive COVID-19 vaccine purchases made by high-income countries have resulted in important sample losses, mainly due to the complexity of their handling. Here, we evaluated the possibility of preserving the immunogenicity of COVID-19 mRNA vaccines after re-freezing vials, following the extraction of the maximum possible number of samples, as an alternative approach to minimizing their wastage. Thus, we exposed the vaccine vials to different re-freezing conditions and evaluated mRNA integrity and the effects in mice after in vivo administration. We reveal that the mRNA integrity of Comirnaty® and Spikevax® vaccines remained unaffected after re-freezing during 1 month at −20 °C or −80 °C. The immunological responses also remained unchanged in mice after these re-freezing conditions and no apparent side effects were revealed. The preservation of mRNA integrity and immunogenicity under these handling conditions opens the possibility of re-freezing the mRNA COVID-19 vaccine vials to limit their wastage and to facilitate vaccination processes.

ObjectivesTo identify factors associated with hospital admission and mortality within the first 30 days after enrolment in an outpatient parenteral antimicrobial therapy (OPAT) program, also analysing adequacy of the treatment regimen and clinical outcomes.Patients and methodsThis was a retrospective cohort study conducted between October 2016 and June 2017 in the state of São Paulo, Brazil. Variables related to hospital admission and mortality were subjected to bivariate analysis, and those with a PResultsWe evaluated 276 patients, of whom 80.5% were ≥60 years of age and 69.9% had more than one comorbidity. Of the patients evaluated, 41.3% had pneumonia and 35.1% had a urinary tract infection. The most common etiological agent, isolated in 18 (31.6%) cases, was Klebsiella pneumoniae, and 13 (72,2%) strains were carbapenem resistant. The OPAT was in accordance with the culture results in 76.6% of the cases and with the institutional protocols in 76.4%. The majority (64.5%) of the patients were not admitted, and a cure or clinical improvement was achieved in 78.6%. Multivariate analysis showed that, within the first 30 days after enrolment, the absence of a physician office visit was a predictor of hospital admission (PConclusionsThis study demonstrated the viability of OPAT in elderly patients with pulmonary or urinary tract infections in an area with a high prevalence of multidrug-resistant bacteria and that a post-discharge physician office visit is protective against hospital admission and mortality.

Abstract Background Dosing in obese critically ill patients is challenging due to pathophysiological changes derived from obesity and/or critical illness, and it remains fully unexplored. This study estimated the micafungin probability of reaching adequate 24-h area under the curve (AUC0–24h)/minimum inhibitory concentration (MIC) values against Candida spp. for an obese/nonobese, critically ill/noncritically ill, large population. Methods Blood samples for pharmacokinetic analyses were collected from 10 critically ill nonobese patients, 10 noncritically ill obese patients, and 11 critically ill morbidly obese patients under empirical/directed micafungin treatment. Patients received once daily 100–150 mg micafungin at the discretion of the treating physician following the prescribing information and hospital guidelines. Total micafungin concentrations were determined by high-performance liquid chromatography (HPLC). Monte-Carlo simulations were performed and the probability of target attainment (PTA) was calculated using the AUC0–24/MIC cut-offs 285 (C. parapsilosis), 3000 (all Candida spp.), and 5000 (nonparapsilosis Candida spp.). Intravenous once-daily 100-mg, 150-mg, and 200-mg doses were simulated at different body weights (45, 80, 115, 150, and 185 kg) and age (30, 50, 70 and 90 years old). PTAs ≥ 90% were considered optimal. Fractional target attainment (FTA) was calculated using published MIC distributions. A dosing regimen was considered successful if the FTA was ≥ 90%. Results Overall, 100 mg of micafungin was once-daily administered for nonobese and obese patients with body mass index (BMI) ≤ 45 kg/m2 and 150 mg for morbidly obese patients with BMI > 45 kg/m2 (except two noncritically ill obese patients with BMI ~ 35 kg/m2 receiving 150 mg, and one critically ill patient with BMI > 45 kg/m2 receiving 100 mg). Micafungin concentrations in plasma were best described using a two-compartment model. Weight and age (but not severity score) were significant covariates and improved the model. FTAs > 90% were obtained against C. albicans with the 200 mg/24 h dose for all body weights (up to 185 kg), and with the 150 mg/24 h for body weights

Dalbavancin is a new antibiotic that is effective against Gram-positive microorganisms, including methicillin-resistant Staphylococci, and offers the possibility of administering intravenous therapy once weekly in an ambulatory setting. We conducted a multicenter observational case-control study, comparing all patients who received dalbavancin (cases) with hospitalized patients who were treated instead with daptomycin, linezolid or vancomycin (controls), based on clinical diagnosis, main microorganism involved, and age. The primary outcome was the length of hospital stay after starting the study antimicrobial. Secondary outcomes were 7-day and 30-day efficacy, 30-day mortality, 90-day recurrence, 90-day and 6-month hospitalization, presence of adverse events and healthcare-associated infections; 161 patients (44 cases and 117 controls) were included. Bivariate analysis showed that dalbavancin reduced the total length of hospital stay (p < 0.001), with fewer 90-day recurrences (p = 0.005), 6-month hospitalizations related to the same infection (p = 0.004) and non-related hospitalizations (p = 0.035). Multivariate analyses showed that length of hospital stay was significantly shorter in patients treated with dalbavancin (−12.05 days 95% CI [−17.00, −7.11], p < 0.001), and 30-day efficacy was higher in the dalbavancin group (OR 2.62 95% CI [1.07, 6.37], p = 0.034). Although sample size of the study may be a limitation, we can conclude that Dalbavancin is a useful antimicrobial drug against Gram-positive infections, including multidrug-resistant pathogens, and allows for a remarkable reduction in length of hospital stay with greater 30-day efficacy.

Background: The impact of antimicrobials generic entry (GE) is controversial. Their introduction could provide an economic benefit yet may also increase their consumption, leading to a higher risk of resistance. Our aim was to analyze the impact of GE on trends of antimicrobial consumption in an acute-care hospital. Methods: A retrospective quasi-experimental interrupted time series analysis was conducted at a 400-bed tertiary hospital in Barcelona, Spain. All antimicrobials for systemic use for which a generic product entered the hospital from January 2000 to December 2019 were included. Antimicrobial consumption was expressed as DDD/100 bed days. Results: After GE, the consumption of cefotaxime (0.09, p < 0.001), meropenem (0.54, p < 0.001), and piperacillin-tazobactam (0.13, p < 0.001) increased, whereas the use of clindamycin (−0.03, p < 0.001) and itraconazole (−0.02, p = 0.01) was reduced. An alarming rise in cefepime (0.004), daptomycin (1.02), and cloxacillin (0.05) prescriptions was observed, despite not achieving statistical significance. On the contrary, the use of amoxicillin (−0.07), ampicillin (−0.02), cefixime (−0.06), fluconazole (−0.13), imipenem–cilastatin (−0.50) and levofloxacin (−0.35) decreased. These effects were noticed beyond the first year post GE. Conclusions: GE led to an increase in the consumption of broad-spectrum molecules. The potential economic benefit of generic antibiotics could be diluted by an increase in resistance. Antimicrobial stewardship should continue to monitor these molecules despite GE.

Background: Antimicrobials have been widely used during the COVID-19 pandemic. This study aimed to analyze the impact of the COVID-19 pandemic on the antimicrobial consumption of 66 hospitals in Catalonia. Methods: Adult antibacterial and antimycotic consumption was calculated as defined daily doses (DDD)/100 bed-days and DDD/100 discharges. Firstly, overall and ICU consumption in 2019 and 2020 were compared. Secondly, observed ICU 2020 consumptions were compared with non-COVID-19 2020 estimated consumptions (based on the trend from 2008–2019). Results: Overall, antibacterial consumption increased by 2.31% and 4.15% DDD/100 bed-days and DDD/100 discharges, respectively. Azithromycin (105.4% and 109.08% DDD/100 bed-days and DDD/100 discharges, respectively) and ceftriaxone (25.72% and 27.97% DDD/100 bed-days and DDD/100 discharges, respectively) mainly accounted for this finding. Likewise, antifungal consumption increased by 10.25% DDD/100 bed-days and 12.22% DDD/100 discharges, mainly due to echinocandins or amphotericin B. ICU antibacterial and antimycotic consumption decreased by 1.28% and 4.35% DDD/100 bed-days, respectively. On the contrary, antibacterial and antifungal use, expressed in DDD/100 discharges, increased by 23.42% and 19.58%. Azithromycin (275.09%), ceftriaxone (55.11%), cefepime (106.35%), vancomycin (29.81%), linezolid (31.28%), amphotericin B (87.98%), and voriconazole (96.17%) use changed the most. Observed consumption of amphotericin B, azithromycin, caspofungin, ceftriaxone, vancomycin, and voriconazole were higher than estimated values. Conclusions: The consumption indicators for most antimicrobials deviated from the expected trend pattern. A worrisome increase in antibacterial and antifungal consumption was observed in ICUs in Catalonia.

Background: Pathophysiological changes such as extreme body weights in critically ill patients with severe infections may alter the pharmacokinetics (PK) of antimicrobials, leading to treatment failure or toxicity. There are almost no PK data on meropenem in critically ill patients with low body weight (LwBW) and therefore information is lacking on the most appropriate dosing regimens, especially when administered by extended infusion. Objectives: To assess if the current administered doses of meropenem could lead to supratherapeutic concentrations in LwBW patients and to identify the factors independently associated with overexposure. Methods: A matched case-control 1:1 study of surgical critically ill patients treated with meropenem administered by extended or continuous infusion and undergoing therapeutic drug monitoring was conducted. Cases (patients with LwBW (body mass index (BMI) < 18.5 kg/m2)) were matched with normal body weight controls (NBW) (patients with BMI ≥ 18.5 kg/m2 and ≤30 kg/m2)) by age, gender, baseline renal function and severity status (APACHE II score). A 100% fT > MIC was considered an optimal pharmacokinetic/pharmacodynamic (PK/PD) target and 100% fT > 10 × MIC as supratherapeutic exposure. Results: Thirty-six patients (18 cases and 18 controls) were included (median (range) age, 57.5 (26–75) years; 20 (55.6% male)). Meropenem was administered by 6 h (extended) or 8 h (continuous) infusion at a median (range) daily dose of 5 (1–6) g/day. Similar median meropenem trough plasma concentrations (Cmin,ss), measured pre-dose on day three to four of treatment) were observed in the two groups (19.9 (22.2) mg/L vs 22.4 (25.8) mg/L, p > 0.999). No differences in the proportion of patients with an optimal or a supratherapeutic PKPD target between cases and controls were observed. A baseline estimated glomerular filtration rate (eGFR) < 90 mL/min was the only factor independently associated with a supratherapeutic PK/PD target. Conclusions: LwBW seems not to be a risk factor for achieving a supratherapeutic PK/PD target in critically ill patients receiving meropenem at standard doses by extended or continuous infusion.

Background: Ampicillin resistant and glycopeptide susceptible Enterococcus faecium bloodstream infection (GSEF-BSI) incidence has risen. However, the treatment of choice remains unknown. Daptomycin use for the treatment of enterococcal infections has increased, despite effectiveness and safety concerns. The objective was to compare the effectiveness and safety of daptomycin and glycopeptides in the treatment of GSEF-BSI. Methods: This was a single-centre, retrospective observational cohort study performed at Hospital del Mar (Barcelona, Spain), from January 2006–May 2018. The primary outcome was clinical cure at the end of the therapy, and secondary outcomes included 14-day, 30-day, in-hospital mortality, and length of stay. Results: From a total of 192 patients with GSEF-BSI, 54 (28.1%) were treated with glycopeptides and 17 (8.9%) with daptomycin. Patients treated with daptomycin presented a lower clinical cure than patients treated with glycopeptides (58.8% vs. 83.3%, RR 0.416 (95% CI 0.189–0.915)). After controlling for confounding variables by means of multivariate analysis the significative difference was confirmed (aOR 4.313, 95% CI, 1.053–17.660). The need for treatment discontinuation due to adverse events was similar. Conclusions: Patients with GSEF-BSI treated with glycopeptides showed a higher clinical cure than those treated with daptomycin.

Background: High rates of amoxicillin-clavulanate (AMC) resistance among Enterobacterales isolated from urinary tract infections (UTIs) were observed in our area. The aim of this study was to identify risk factors associated with AMC resistance in patients with community-onset UTI in emergency departments (EDs). Methods: A retrospective study was performed of all ED patients with positive urine cultures for Escherichia coli or Klebsiella pneumoniae in a Spanish tertiary-care hospital. Results: 330 urine cultures in all were included: 261 (79.1%) for E. coli and 69 (20.90%) for K. pneumonia. Rates of AMC resistance were 14.94% and 34.78%, respectively. UTI was clinically confirmed in 212 (64.24%) cases. Previous antimicrobial exposure was independently associated with AMC resistance development in E. coli and K. pneumoniae urinary isolates (OR = 2.94, 95% CI = 1.55–5.58). Analyses of infected patients revealed that previous exposure to fluoroquinolones (OR = 3.33, 95% CI = 1.10–10.12, p = 0.034) and to AMC (OR = 5.68, 95% CI = 1.97–16.44, p = 0.001) was significantly associated with isolation of AMC-resistant strains. Conclusions: Prior antibiotic exposure, particularly to AMC or fluoroquinolones, was the only independent risk factor associated with development of AMC resistance in E. coli and K. pneumoniae urinary isolates from patients attending the ED.

Objective: To analyze the clinical and economic impact of community-onset urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae requiring hospitalization. Methods: A retrospective cohort study that included all adults with a UTI caused by K. pneumoniae that were admitted to a tertiary care hospital in Barcelona, Spain, between 2011 and 2015. Demographic, clinical, and economic data were analyzed. Results: One hundred and seventy-three episodes of UTIs caused by K. pneumoniae were studied; 112 were non-ESBL-producing and 61 were ESBL-producing. Multivariate analysis identified ESBL production, acute confusional state associated with UTI, shock, and the time taken to obtain adequate treatment as risk factors for clinical failure during the first seven days. An economic analysis showed differences between ESBL-producing and non-ESBL-producing K. pneumoniae for the total cost of hospitalization per episode (mean EUR 6718 vs EUR 3688, respectively). Multivariate analysis of the higher costs of UTI episodes found statistically significant differences for ESBL production and the time taken to obtain adequate treatment. Conclusion: UTIs caused by ESBL-producing K. pneumoniae requiring hospitalization and the time taken to obtain adequate antimicrobial therapy are associated with worse clinical and economic outcomes.

Maintenance in restricted cold temperature conditions is a mandatory requirement to preserve the stability of mRNA vaccines [...]

Background: The first wave of COVID-19 pandemic may have significantly impacted antimicrobial consumption in hospitals. The objective of this study was to assess the evolution of antimicrobial consumption during this period. Methods: A retrospective quasi-experimental before–after study was conducted in a Spanish tertiary care hospital. The study compared two periods: pre-pandemic, from January 2018 to February 2020, and during the COVID-19 pandemic from March to June 2020. Antimicrobial consumption was analyzed monthly as defined daily doses (DDD)/100 bed-days and overall hospital and ICU consumption were evaluated. Results: An increase in the hospital consumption was noticed. Although only ceftaroline achieved statistical significance (p = 0.014), a rise was observed in most of the studied antimicrobials. A clear temporal pattern was detected. While an increase in ceftriaxone and azithromycin was observed during March, an increment in the consumption of daptomycin, carbapenems, linezolid, ceftaroline, novel cephalosporin/β-lactamase inhibitors or triazoles during April–May was noticed. In the ICU, these findings were more evident, namely ceftriaxone (p = 0.029), carbapenems (p = 0.002), daptomycin (p = 0.002), azithromycin (p = 0.030), and linezolid (p = 0.011) but followed a similar temporal pattern. Conclusion: An increase in the antimicrobial consumption during the first wave of COVID-19 pandemic was noticed, especially in the ICU. Availability of updated protocols and antimicrobial stewardship programs are essential to optimize these outcomes.

Background: Ceftolozane-tazobactam is a new antibiotic against multidrug-resistant pathogens such as Pseudomonas aeruginosas. Ceftolozane-tazobactam dosage is still uncertain in children, especially in those with renal impairment or undergoing continuous renal replacement therapy (CRRT). Methods: Evaluation of different ceftolozane-tazobactam dosing regimens in three critically ill children. Ceftolozane pharmacokinetics (PK) were characterized by obtaining the patient’s specific parameters by Bayesian estimation based on a population PK model. The clearance (CL) in patient C undergoing CRRT was estimated using the prefilter, postfilter, and ultrafiltrate concentrations simultaneously. Variables such as blood, dialysate, replacement, and ultrafiltrate flow rates, and hematocrit were integrated in the model. All PK analyses were performed using NONMEM v.7.4. Results: Patient A (8 months of age, 8.7 kg) with normal renal function received 40 mg/kg every 6 h: renal clearance (CLR) was 0.88 L/h; volume of distribution (Vd) Vd1 = 3.45 L, Vd2 = 0.942 L; terminal halflife (t1/2,β) = 3.51 h, dosing interval area under the drug concentration vs. time curve at steady-state (AUCτ,SS) 397.73 mg × h × L−1. Patient B (19 months of age, 11 kg) with eGFR of 22 mL/min/1.73 m2 received 36 mg/kg every 8 h: CLR = 0.27 L/h; Vd1 = 1.13 L; Vd2 = 1.36; t1/2,β = 6.62 h; AUCSS 1481.48 mg × h × L−1. Patient C (9 months of age, 5.8 kg), with severe renal impairment undergoing CRRT received 30 mg/kg every 8 h: renal replacement therapy clearance (CLRRT) 0.39 L/h; Vd1 = 0.74 L; Vd2= 1.17; t 1/2,β = 3.51 h; AUCτ,SS 448.72 mg × h × L−1. No adverse effects attributable to antibiotic treatment were observed. Conclusions: Our results suggest that a dose of 35 mg/kg every 8 h can be appropriate in critically ill septic children with multi-drug resistance Pseudomonas aeruginosa infections. A lower dose of 10 mg/kg every 8 h could be considered for children with severe AKI. For patients with CRRT and a high effluent rate, a dose of 30 mg/kg every 8 h can be considered.

Objective: To assess the impact of Clostridium difficile infection (CDI) on hospital resources and costs in Spain and Italy. Methods: CDI data were collected from institutions in Spain and Italy. Each patient was matched with two randomly selected uninfected controls in the same institution. Patient outcomes were assessed for the first and second episodes of CDI and for patients aged ≤65 and >65 years. The impact of CDI on hospital length of stay (LOS) was used to calculate CDI-attributable costs. A multivariate analysis using duration of stay as the continuous outcome variable assessed the independent effect of CDI on hospital costs and LOS. Results: LOS attributable to CDI ranged from 7.6–19.0 days in adults and was 5.0 days in children; the increases were greater in adults in Italy than in Spain. Attributable costs per adult patient ranged from €4396 in Madrid to €14 023 in Rome, with the majority of the cost being due to hospitalization. For children, the total attributable cost was €3545/patient. Conclusions: These data show that the burden of CDI is considerable in Spain and Italy. Treatments that can reduce LOS, disease severity, and recurrence rates, as well as effective infection control measures to prevent transmission, have the potential to reduce the burden of CDI.

Colistin is administered as its inactive prodrug colistimethate (CMS). Selection of an individualized CMS dose for each patient is difficult due to its narrow therapeutic window, especially in patients with chronic kidney disease (CKD). Our aim was to analyze CMS use in patients with CKD. Secondary objectives were to assess the safety and efficacy of CMS in this special population. In this prospective observational cohort study of CMS-treated CKD patients, CKD was defined as the presence of a glomerular filtration rate (GFR) < 60 mL/min/m2 for more than 3 months. The administered doses of CMS were compared with those recently published in the literature. Worsened CKD at the end of treatment (EOT) was evaluated with the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria. Colistin plasma concentrations (Css) were measured using high-performance liquid chromatography. Fifty-nine patients were included. Thirty-six (61.2%) were male. The median age was 76 (45⁻95) years and baseline GFR was 36.6 ± 13.6. The daily mean CMS dosage used was compared with recently recommended doses (3.36 vs. 6.07; p < 0.001). Mean Css was 0.9 (0.2⁻2.9) mg/L, and Css was ss were under the recommended target of 2 mg/dL. Despite this, clinical cure rate was high. In this patient cohort, the incidence of nephrotoxicity was similar to those found in other recent studies performed in the general population and was reversible in 52.6%. These results suggest that CMS is safe and effective in patients with CKD and may encourage physicians to adjust dosage regimens to recent recommendations in order to optimize CMS treatments.

Fundamentos: No se dispone de estudios adecuados del coste de las diarreas asociadas a Clostridium difficile (DACD) en España. El objetivo del estudio es estimar el coste de las DACD para el Sistema Nacional de Salud (SNS). Métodos: Se realizó un modelo económico para calcular el coste por episodio de DACD (por antibióticos, prolongación del ingreso hospitalario, procedimientos quirúrgicos, medidas de control de la infección, recurrencias de las infecciones tratadas) y el coste anual de la DACD. El uso de recursos en la práctica clínica se obtuvo mediante un panel Delphi de clínicos españoles con experiencia en la DACD y los costes unitarios (€ 2012) de fuentes españolas. Resultados: Se estimó que anualmente se produjeron 7.601 episodios de DACD en España (incidencia de 17,1 episodios/año/10.000 altas hospitalarias) con un gasto anual para el SNS de 32.157.093 €. Coste por episodio de DACD: 3.901 € (infección inicial), 4.875 € (primera recurrencia) y 5.916 € (segunda recurrencia). Coste total de las recurrencias: 10.426.750 € anuales. El 95,6% del gasto se debería a la prolongación de la duración de la estancia hospitalaria, el 0,5% a tratamientos antibióticos, el 2,8% a intervenciones quirúrgicas y el 1,1% a las medidas de control de la infección. Los resultados del estudio fueron sensibles a la incidencia y tasa de letalidad de la DACD en España y a la duración de la prolongación de la duración de la estancia hospitalaria debida a la DACD. Conclusiones: Según este estudio, el gasto asociado a la DACD se debe fundamentalmente a la prolongación de los ingresos hospitalarios y tiene un gran impacto económico en el SNS.

**Objective:** The aim of this study was to evaluate, from the Spanish National Health System perspective, the cost-effectiveness of rivaroxaban (20 mg/day) versus use of acenocoumarol (5 mg/day) for the treatment of patients with non-valvular atrial fibrillation (NVAF) at moderate to high risk for stroke. **Methods:** A Markov model was designed and populated with local cost estimates, efficacy and safety of rivaroxaban in stroke prevention in NVAF compared with adjusted-dose warfarin clinical results from the pivotal phase III ROCKET AF trial and utility values obtained from the literature. Warfarin and acenocoumarol were assumed to have therapeutic equivalence. **Results:** Rivaroxaban treatment was associated with fewer ischemic strokes and systemic embolisms (0.289 vs. 0.300 events), intracranial bleeds (0.051 vs. 0.067), and myocardial infarctions (0.088 vs. 0.102) per patient compared with acenocoumarol. Over a lifetime time horizon, rivaroxaban led to a reduction of 0.041 life-threatening events per patient, and increases of 0.103 life-years and 0.155 quality-adjusted lifeyears (QALYs) versus acenocoumarol treatment. This resulted in an incremental cost-effectiveness ratio of €7045 per QALY and €10 602 per life-year gained. Sensitivity analysis indicated that these results were robust and that rivaroxaban is cost-effective compared with acenocoumarol in 89.4% of cases should a willingness-to-pay threshold of €30 000/QALY gained be considered. **Conclusions:** The present analysis suggests that rivaroxaban is a cost-effective alternative to acenocoumarol therapy for the prevention of stroke and systemic embolisms in patients with NVAF in the Spanish healthcare setting.

AIM:To calculate the incremental cost of nosocomial bacteremia caused by the most common organisms, classified by their antimicrobial susceptibility. METHODS:We selected patients who developed nosocomial bacteremia caused by Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Pseudomonas aeruginosa. These microorganisms were analyzed because of their high prevalence and they frequently present multidrug resistance. A control group consisted of patients classified within the same all-patient refined-diagnosis related group without bacteremia. Our hospital has an established cost accounting system (full-costing) that uses activity-based criteria to analyze cost distribution. A logistic regression model was fitted to estimate the probability of developing bacteremia for each admission (propensity score) and was used for propensity score matching adjustment. Subsequently, the propensity score was included in an econometric model to adjust the incremental cost of patients who developed bacteremia, as well as differences in this cost, depending on whether the microorganism was multidrug-resistant or multidrug-sensitive. RESULTS:A total of 571 admissions with bacteremia matched the inclusion criteria and 82,022 were included in the control group. The mean cost was € 25,891 for admissions with bacteremia and € 6,750 for those without bacteremia. The mean incremental cost was estimated at € 15,151 (CI, € 11,570 to € 18,733). Multidrug-resistant P. aeruginosa bacteremia had the highest mean incremental cost, € 44,709 (CI, € 34,559 to € 54,859). Antimicrobial-susceptible E. coli nosocomial bacteremia had the lowest mean incremental cost, € 10,481 (CI, € 8,752 to € 12,210). Despite their lower cost, episodes of antimicrobial-susceptible E. coli nosocomial bacteremia had a major impact due to their high frequency. CONCLUSIONS:Adjustment of hospital cost according to the organism causing bacteremia and antibiotic sensitivity could improve prevention strategies and allow their prioritization according to their overall impact and costs. Infection reduction is a strategy to reduce resistance.

The objective of this study was to identify risk factors for bacteremia by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae. Retrospective case-control study performed in a 450-bed acute care academic tertiary hospital in Barcelona, Spain. Cases included 53 patients with ESBL-producing E. coli or K. pneumoniae bacteremia, and 159 controls with non-ESBL-producing E. coli or K. pneumoniae bacteremia. Controls were matched in a 3:1 ratio to case patients according to species of infecting organism, age, and severity of illness in the 24-48h before blood sample collection for culture calculated by the Simplified Acute Physiology Score (SAPS II) system. Previous antimicrobials were more frequently administered to cases than to controls (56.5% vs 17%, p 2) of different families of antimicrobials received within 90 days before bloodstream infection was the only predictor of ESBL-producing E. coli or K. pneumoniae in blood culture (OR = 2.29, 95% CI 1.35−3.88, p = 0.002). Conclusion: Previous use of different families of antimicrobials (more than two) in patients with bloodstream infection caused by E. coli or K. pneumoniae increased the risk for ESBL-producing strains. Keywords: bacteremia, β-lactamases, risk factors

Francisco Alvarez-Lerma1, Santiago Grau2, Olivia Ferrández21Intensive Care Unit, 2Pharmacy Department, Hospital Del Mar, Barcelona, SpainAbstract: Doripenem (S-4661) is a new parenteral antibiotic from the carbapenem class; similarly to imipenem and meropenem, it has a broad-spectrum activity against Gram-positive, Gram-negative, and anaerobic bacteria. It is active against multiresistant Gram-negative bacilli such as extended-spectrum beta-lactamase-producing (ESBL) Gram-negative Enterobacteriaceae and nonfermentative Gram-negative bacilli including some strains of Pseudomonas aeruginosa that are resistant to other carbapenems. Doripenem’s chemical structure is similar to that of meropenem (substitution of one sulfamoxil-aminomethyl chain for the dimethyl-carboxyl chain), and has one 1-beta-methyl chain which provides resistance to dehydropeptidase-I enzyme. The clinical trials conducted so far have focused on the treatment of severe infections such as complicated intra-abdominal infections, complicated urinary tract infections and pyelonephritis, nosocomial pneumonia, and ventilator-associated pneumonia. Given its activity profile and the results from the clinical trials, this antibiotic may be used for empirical treatment of multibacterial infections produced by potentially multiresistant Gram-negative bacilli. In 2007, the US Food and Drug Administration approved the use of doripenem for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. The European Medicines Agency has approved the use of doripenem for the same indications in addition to nosocomial pneumonia regardless of whether it is ventilator-associated or not.Keywords: doripenem, antimicrobial activity, clinical efficacy, pharmacokinetics, tolerability

**Objectives:** Compare the cost of the primary prophylaxis of invasive fungal infections (IFI) with voriconazole, posaconazole, and micafungin in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in hospitals of the National Health System (NHS) in Spain. **Methods:** A cost analysis was made for 100 days and 180 days of prophylaxis and a decision tree model was developed. The efficacy rate of IFI prophylaxis and survival rate with liposomal amphotericin B treatment of prophylaxis failures were obtained from randomized trials and a meta-analysis of mixed treatment comparisons. The model simulation was interrupted with IFI treatment (prophylaxis failures). The costs of medication and its intravenous administration in the hospital (in the case of micafungin) were considered. **Results:** In the non-modeled analysis, the savings per patient of prophylaxis with voriconazole ranged from €1,709 to €9,655 compared with posaconazole oral solution, from €1,811 to €9,767 compared with posaconazole gastro-resistant tablets and from €3,376 to €7,713 compared with micafungin. In the modeled analysis, the mean cost per patient of the prophylaxis and treatment of IFIs was €6,987 to €7,619 with voriconazole, €7,749 with posaconazole, and €22,424 with micafungin. Therefore, the savings per patient of prophylaxis with voriconazole was €130 to €3,664 and €11,132 to €30,374 compared with posaconazole and micafungin, respectively. The result remained stable after modification of the number of days of antifungal prophylaxis and the cost of antifungal treatment of failures. **Conclusion:** Taking into account this model, antifungal prophylaxis with voriconazole in recipients of hematopoietic progenitor transplants, compared with posaconazole or micafungin, may represent savings for hospitals in Spain.

INTRODUCTION: There is scarce evidence on the use of eosinophil count as a marker of outcome in patients with infection. The aim of this study was to evaluate whether changes in eosinophil count, as well as the neutrophil-lymphocyte count ratio (NLCR), could be used as clinical markers of outcome in patients with bacteremia. METHODS: We performed a retrospective study of patients with a first episode of community-acquired or healthcare-related bacteremia during hospital admission between 2004 and 2009. A total of 2,311 patients were included. Cox regression was used to analyze the behaviour of eosinophil count and the NLCR in survivors and non-survivors. RESULTS: In the adjusted analysis, the main independent risk factor for mortality was persistence of an eosinophil count below 0.0454·10(3)/uL (HR = 4.20; 95% CI 2.66-6.62). An NLCR value >7 was also an independent risk factor but was of lesser importance. The mean eosinophil count in survivors showed a tendency to increase rapidly and to achieve normal values between the second and third day. In these patients, the NLCR was 7 were independent markers of mortality in patients with bacteremia.

The objective of this study was to identify risk factors for bacteremia by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae. Retrospective case-control study performed in a 450-bed acute care academic tertiary hospital in Barcelona, Spain. Cases included 53 patients with ESBL-producing E. coli or K. pneumoniae bacteremia, and 159 controls with non-ESBL-producing E. coli or K. pneumoniae bacteremia. Controls were matched in a 3:1 ratio to case patients according to species of infecting organism, age, and severity of illness in the 24-48h before blood sample collection for culture calculated by the Simplified Acute Physiology Score (SAPS II) system. Previous antimicrobials were more frequently administered to cases than to controls (56.5% vs 17%, p < 0.001). Binary logistic regression showed that the number (> 2) of different families of antimicrobials received within 90 days before bloodstream infection was the only predictor of ESBL-producing E. coli or K. pneumoniae in blood culture (OR = 2.29, 95% CI 1.35-3.88, p = 0.002). Conclusion: Previous use of different families of antimicrobials (more than two) in patients with bloodstream infection caused by E. coli or K. pneumoniae increased the risk for ESBL-producing strains.