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BACKGROUND: Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2 inflammation, including eosinophilic esophagitis in adults and adolescents. METHODS: In this phase 3 trial, we randomly assigned, in a 2:2:1:1 ratio, patients 1 to 11 years of age with active eosinophilic esophagitis who had had no response to proton-pump inhibitors to 16 weeks of a higher-exposure or lower-exposure subcutaneous dupilumab regimen or to placebo (two groups) (Part A). At the end of Part A, eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher-exposure or lower-exposure dupilumab for 36 weeks (Part B). At each level of exposure, dupilumab was administered in one of four doses tiered according to baseline body weight. The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤6 per high-power field) at week 16. Key secondary end points were tested hierarchically. RESULTS: In Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher-exposure group, in 18 of the 31 patients (58%) in the lower-exposure group, and in 1 of the 34 patients (3%) in the placebo group (difference between the higher-exposure regimen and placebo, 65 percentage points [95% confidence interval {CI}, 48 to 81; P<0.001]; difference between the lower-exposure regimen and placebo, 55 percentage points [95% CI, 37 to 73; P<0.001]). The higher-exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo. The improvements in histologic, endoscopic, and transcriptomic measures between baseline and week 52 in all the patients were generally similar to the improvements between baseline and week 16 in the patients who received dupilumab in Part A. In Part A, the incidence of coronavirus disease 2019, nausea, injection-site pain, and headache was at least 10 percentage points higher among the patients who received dupilumab (at either dose) than among those who received placebo. Serious adverse events were reported in 3 patients who received dupilumab during Part A and in 6 patients overall during Part B. CONCLUSIONS: Dupilumab resulted in histologic remission in a significantly higher percentage of children with eosinophilic esophagitis than placebo. The higher-exposure dupilumab regimen also led to improvements in measures of key secondary end points as compared with placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; EoE KIDS ClinicalTrials.gov number, NCT04394351.).
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Anticuerpos Monoclonales Humanizados , Esofagitis Eosinofílica , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esofagitis Eosinofílica/tratamiento farmacológico , Esofagitis Eosinofílica/inmunología , Esofagitis Eosinofílica/patología , Eosinófilos/inmunología , Eosinófilos/patología , Esófago/efectos de los fármacos , Esófago/inmunología , Esófago/patología , Inyecciones Subcutáneas , Interleucina-13/antagonistas & inhibidores , Interleucina-4/antagonistas & inhibidores , Inducción de Remisión , Inhibidores de la Bomba de Protones/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Dupilumab, a fully human monoclonal antibody, blocks interleukin-4 and interleukin-13 signaling, which have key roles in eosinophilic esophagitis. METHODS: We conducted a three-part, phase 3 trial in which patients 12 years of age or older underwent randomization in a 1:1 ratio to receive subcutaneous dupilumab at a weekly dose of 300 mg or placebo (Part A) or in a 1:1:1 ratio to receive 300 mg of dupilumab either weekly or every 2 weeks or weekly placebo (Part B) up to week 24. Eligible patients who completed Part A or Part B continued the trial in Part C, in which those who completed Part A received dupilumab at a weekly dose of 300 mg up to week 52 (the Part A-C group); Part C that included the eligible patients from Part B is ongoing. The two primary end points at week 24 were histologic remission (≤6 eosinophils per high-power field) and the change from baseline in the Dysphagia Symptom Questionnaire (DSQ) score (range, 0 to 84, with higher values indicating more frequent or more severe dysphagia). RESULTS: In Part A, histologic remission occurred in 25 of 42 patients (60%) who received weekly dupilumab and in 2 of 39 patients (5%) who received placebo (difference, 55 percentage points; 95% confidence interval [CI], 40 to 71; P<0.001). In Part B, histologic remission occurred in 47 of 80 patients (59%) with weekly dupilumab, in 49 of 81 patients (60%) with dupilumab every 2 weeks, and in 5 of 79 patients (6%) with placebo (difference between weekly dupilumab and placebo, 54 percentage points; 95% CI, 41 to 66 [P<0.001]; difference between dupilumab every 2 weeks and placebo, 56 percentage points; 95% CI, 43 to 69 [not significant per hierarchical testing]). The mean (±SD) DSQ scores at baseline were 33.6±12.41 in Part A and 36.7±11.22 in Part B; the scores improved with weekly dupilumab as compared with placebo, with differences of -12.32 (95% CI, -19.11 to -5.54) in Part A and -9.92 (95% CI, -14.81 to -5.02) in Part B (both P<0.001) but not with dupilumab every 2 weeks (difference in Part B, -0.51; 95% CI, -5.42 to 4.41). Serious adverse events occurred in 9 patients during the Part A or B treatment period (in 7 who received weekly dupilumab, 1 who received dupilumab every 2 weeks, and 1 who received placebo) and in 1 patient in the Part A-C group during the Part C treatment period who received placebo in Part A and weekly dupilumab in Part C. CONCLUSIONS: Among patients with eosinophilic esophagitis, subcutaneous dupilumab administered weekly improved histologic outcomes and alleviated symptoms of the disease. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03633617.).
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Anticuerpos Monoclonales Humanizados , Trastornos de Deglución , Esofagitis Eosinofílica , Adolescente , Adulto , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Trastornos de Deglución/tratamiento farmacológico , Trastornos de Deglución/etiología , Trastornos de Deglución/patología , Método Doble Ciego , Esofagitis Eosinofílica/complicaciones , Esofagitis Eosinofílica/tratamiento farmacológico , Esofagitis Eosinofílica/patología , Inyecciones Subcutáneas , Resultado del Tratamiento , Niño , Adulto JovenRESUMEN
INTRODUCTION: Improvements in symptomatic experience and health-related quality of life (HRQoL) are among the most important treatment benefits in patients with eosinophilic esophagitis (EoE). We assessed the impact of dupilumab treatment on HRQoL, patients' impression of dysphagia, and symptoms beyond dysphagia in adults/adolescents (≥12 years) with EoE in parts A and B of the LIBERTY EoE TREET (NCT03633617) study. METHODS: The EoE Symptom Questionnaire (EoE-SQ; frequency and severity of nondysphagia symptoms), EoE Impact Questionnaire (impact of EoE on HRQoL), and Patient Global Impression of Severity and Patient Global Impression of Change of dysphagia were used to assess the efficacy of weekly dupilumab 300 mg vs placebo. RESULTS: At week 24, dupilumab reduced EoE-SQ Frequency (least squares mean difference vs placebo [95% confidence interval] part A -1.7 [-2.9, -0.5], part B -1.4 [-2.3, -0.5]; both P < 0.01) and EoE-SQ Severity (part A -2.0 [-3.9, 0.0], P < 0.05, part B -1.5 [-3.0, 0.1], P = 0.07) overall scores, and improved scores across all individual items. Improvement in the dupilumab group was clinically meaningful to patients. Dupilumab also meaningfully improved EoE Impact Questionnaire average scores and improved individual item scores at week 24, particularly emotional and sleep disturbance. More dupilumab-treated patients reported improvement in the Patient Global Impression of Change of dysphagia vs placebo or reported having no symptoms per the Patient Global Impression of Severity of dysphagia at week 24. DISCUSSION: Dupilumab reduced the impact of EoE on multiple aspects of HRQoL, patients' impression of dysphagia, and frequency and severity of symptoms beyond dysphagia in adults/adolescents with EoE.
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G protein-coupled receptors (GPCRs) can interact with regulator of G protein signaling (RGS) proteins. However, the effects of such interactions on signal transduction and their physiological relevance have been largely undetermined. Ligand-bound GPCRs initiate by promoting exchange of GDP for GTP on the Gα subunit of heterotrimeric G proteins. Signaling is terminated by hydrolysis of GTP to GDP through intrinsic GTPase activity of the Gα subunit, a reaction catalyzed by RGS proteins. Using yeast as a tool to study GPCR signaling in isolation, we define an interaction between the cognate GPCR (Mam2) and RGS (Rgs1), mapping the interaction domains. This reaction tethers Rgs1 at the plasma membrane and is essential for physiological signaling response. In vivo quantitative data inform the development of a kinetic model of the GTPase cycle, which extends previous attempts by including GPCR-RGS interactions. In vivo and in silico data confirm that GPCR-RGS interactions can impose an additional layer of regulation through mediating RGS subcellular localization to compartmentalize RGS activity within a cell, thus highlighting their importance as potential targets to modulate GPCR signaling pathways.
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Membrana Celular/metabolismo , Modelos Biológicos , Proteínas RGS/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/metabolismo , Transducción de Señal/fisiología , Membrana Celular/genética , Estructura Terciaria de Proteína , Proteínas RGS/genética , Receptores Acoplados a Proteínas G/genética , Schizosaccharomyces/citología , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/genéticaRESUMEN
Poor adherence to antiretroviral therapies (ARTs) in human immunodeficiency virus (HIV)-infected patients increases the risk of incomplete viral suppression, development of viral resistance, progression to acquired immune deficiency syndrome and death. This study assesses the impact of specific treatment-related adverse events (AEs) on adherence to ART in the adult HIV patient population. A systematic review of studies involving adult HIV-infected patients aged ≥ 16 years that reported an odds ratio (OR) for factors affecting adherence to ART was conducted through a search of the EMBASE(®) and Medline(®) databases. Database searches were complemented with a search of titles in the bibliographies of review papers. Studies conducted in populations limited to a particular demographic characteristic or behavioural risk were excluded. To qualify for inclusion into a meta-analysis, treatment-related AEs had to be defined similarly across studies. Also, multiple ORs from the same study were included where study sub-groups were distinct. Random effects models were used to pool ORs. In total, 19 studies and 18 ART-related AEs were included in meta-analyses. Adherence to ART was significantly lower in patients with non-specific AEs than in patients who did not experience AEs [OR = 0.623; 95% confidence interval (CI): 0.465-0.834]. Patients with specific AEs such as fatigue (OR = 0.631; 95% CI: 0.433-0.918), confusion (OR = 0.349; 95% CI: 0.184-0.661), taste disturbances (OR = 0.485; 95% CI: 0.303-0.775) and nausea (OR = 0.574; 95% CI: 0.427-0.772) were significantly less likely to adhere to ART compared to patients without these AEs. Knowledge of specific treatment-related AEs may allow for targeted management of these events and a careful consideration of well-tolerated treatment regimens to improve ART adherence and clinical outcomes.
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Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación , Adolescente , Adulto , Recuento de Linfocito CD4 , Confusión/inducido químicamente , Progresión de la Enfermedad , Esquema de Medicación , Farmacorresistencia Viral , Fatiga/inducido químicamente , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/inmunología , Humanos , Masculino , Cumplimiento de la Medicación/psicología , Cumplimiento de la Medicación/estadística & datos numéricos , Náusea/inducido químicamente , Educación del Paciente como Asunto , Trastornos del Gusto/inducido químicamenteRESUMEN
BACKGROUND: Eosinophilic esophagitis (EoE) has a detrimental effect on health-related quality of life (HRQOL). The Eosinophilic Esophagitis Impact Questionnaire (EoE-IQ) is a novel patient-reported outcome (PRO) measure assessing the impact of EoE on HRQOL. To assess suitability of the EoE-IQ, its measurement properties were evaluated. METHODS: Using baseline and week 24 data from the pivotal, randomized, placebo-controlled, multinational phase 3 R668-EE-1774 trial (NCT03633617) of dupilumab, we evaluated EoE-IQ's measurement properties (including reliability, construct and known-groups validity, and ability to detect change) and established the threshold for change in scores that can be considered clinically meaningful. RESULTS: The analysis population comprised 239 adults and adolescents with EoE. Mean age was 28.1 (standard deviation, 13.14) years; 63.6% were male, and 90.4% were White. Reliability estimates for the EoE-IQ average score exceeded acceptable thresholds for patients who were stable as indicated by ratings of Patient Global Impression of Severity (PGIS) and Change (PGIC) (intraclass correlation coefficients, 0.75 and 0.81). Construct validity correlations with other EoE-specific PRO scores were moderate at baseline (|r|= 0.44-0.60) and moderate to strong at week 24 (|r|= 0.61-0.72). In known-groups analysis, EoE-IQ average score discriminated among groups of patients at varying EoE severity levels defined by PGIS scores. A ≥ 0.6-point reduction in EoE-IQ average score (where scores range from 1 to 5, with higher scores indicating worse HRQOL) from baseline to week 24 can be considered clinically meaningful. CONCLUSIONS: The EoE-IQ's measurement properties are acceptable, making it a valid, reliable measure of the HRQOL impacts of EoE among adults and adolescents. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03633617. Registered August 14, 2018, https://clinicaltrials.gov/study/NCT03633617 .
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Esofagitis Eosinofílica , Adolescente , Adulto , Femenino , Humanos , Masculino , Esofagitis Eosinofílica/diagnóstico , Calidad de Vida , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
BACKGROUND: Long-term management options that specifically target the underlying inflammation in eosinophilic oesophagitis are needed. Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13; we aimed to assess its long-term efficacy and safety in adults and adolescents with eosinophilic oesophagitis enrolled in part B of the LIBERTY EoE TREET study who continued to part C (part B-C). METHODS: LIBERTY EoE TREET was a three-part, double-blind, randomised, placebo-controlled, phase 3 study conducted at 65 hospitals and private clinics across ten countries in Australia, Canada, Europe, and the USA. Adults or adolescents (aged ≥12 years) with a diagnosis of eosinophilic oesophagitis by endoscopic biopsy (peak oesophageal intraepithelial eosinophil count ≥15 eosinophils per high-power field [eos/hpf]) from at least one oesophageal region despite 8 weeks of high-dose proton-pump inhibitors (PPIs) and a Dysphagia Symptom Questionnaire (DSQ) score of at least 10 at baseline were eligible. In part B, patients were randomly (1:1:1) assigned to receive subcutaneous dupilumab 300 mg either weekly or every 2 weeks or weekly placebo until week 24. Randomisation was done centrally by interactive voice response system/web response system (IVRS/IWRS) in blocks and stratified according to age (<18 years vs ≥18 years) and use of PPI at randomisation (yes vs no). Patients, study sponsors, and investigators involved in the study were masked to the randomisation outcome. Eligible patients who received placebo in part B and continued to part C were randomly assigned again (1:1) to either weekly dupilumab (placebo/weekly dupilumab group) or dupilumab every 2 weeks (placebo/dupilumab every 2 weeks), with matching placebo alternating with dupilumab doses. Patients who were randomly assigned to one of the dupilumab dose regimens in part B remained on the same regimen in part C for an additional 28 weeks (weekly dupilumab/weekly dupilumab group or dupilumab every 2 weeks/dupilumab every 2 weeks group). Treatment assignment in part C was managed by IVRS/IWRS to maintain blinding of treatment assignment in part B. The primary endpoint of this trial has been reported; here, we report the week 52 outcomes of part B-C. Efficacy and safety analyses were done in the part C safety-analysis set, which included all patients who were randomised in part B, entered part C, and received any study drug in part C. This completed trial is registered with ClinicalTrials.gov, number NCT03633617. FINDINGS: Between Aug 12, 2019, and March 11, 2021, 240 patients were randomly assigned into part B, of whom 227 (74 in placebo group, 74 in weekly dupilumab group, and 79 in dupilumab every 2 weeks group) continued into part B-C and were included in the current analysis. 37 patients switched from placebo to weekly dupilumab, and 37 from placebo to dupilumab every 2 weeks; 74 patients continued on weekly dupilumab and 79 continued on dupilumab every 2 weeks. Of the patients who entered part B-C, 75 (33%) were adolescents, 145 (64%) male, 82 (36%) female, and 206 (91%) White. At week 52, 55 (85%) patients in the weekly dupilumab/weekly dupilumab group, 25 (68%) in the placebo/weekly dupilumab group, 54 (74%) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and 23 (72%) in the placebo/every 2 weeks dupilumab group achieved a peak oesophageal intraepithelial eosinophil count of 6 eos/hpf or less. Mean percent change from part B baseline in peak eosinophil count was -95·9% (95% CI -96·9 to -94·9) in the weekly dupilumab/weekly dupilumab group, -84·2% (-98·3 to -70·2) in the placebo/weekly dupilumab group, -84·8% (-94·3 to -75·2) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -91·2% (-95·9 to -86·5) in the placebo/every 2 weeks dupilumab group at week 52. At week 52, mean change from part B baseline in eosinophilic oesophagitis Histology Scoring System (HSS) grade score was -1·0 point (95% CI -1·1 to -0·9) in the weekly dupilumab/weekly dupilumab group and -0·9 points (-1·0 to -0·8) in the placebo/weekly dupilumab group; mean change in eosinophilic oesophagitis HSS stage score was -0·9 points (-1·0 to -0·8) in the weekly dupilumab/weekly dupilumab group and -0·9 points (-1·0 to -0·8) in the placebo/weekly dupilumab group. Similar improvements were observed in the every 2 weeks dupilumab groups. Mean absolute change from part B baseline in DSQ score was -30·3 points (95% CI -34·5 to -26·1) in the weekly dupilumab/weekly dupilumab group, -27·3 points (-32·1 to -22·4) in the placebo/weekly dupilumab group, -20·9% (-25·4 to -16·3) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -23·7% (-29·1 to -18·3) in the placebo/every 2 weeks dupilumab group at week 52. Mean change from part B baseline in endoscopic reference score was -5·4 points (95% CI -6·1 to -4·6) in the weekly dupilumab/weekly dupilumab group, -6·1 points (-7·3 to -4·9) in the placebo/weekly dupilumab group, -5·2% (-6·0 to -4·4) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -4·3% (-5·4 to -3·1) in the placebo/every 2 weeks dupilumab group at week 52. During part B-C, one (3%) patient in the placebo/weekly dupilumab group, one (1%) in the weekly dupilumab/weekly dupilumab group, and one (3%) in the placebo/every 2 weeks dupilumab group received rescue medication. One (3%) patient in the placebo/every 2 weeks dupilumab group and one (1%) in the dupilumab every 2 weeks/dupilumab every 2 weeks group underwent a rescue oesophageal dilation procedure. The most common treatment-emergent adverse events were injection-site reactions (ten [14%] in the weekly dupilumab/weekly dupilumab group and four [11%] in the placebo/weekly dupilumab group). INTERPRETATION: Improvements in histological, symptomatic, endoscopic, and molecular features of eosinophilic oesophagitis observed after 24 weeks of weekly dupilumab treatment were maintained or continued to improve to week 52. These findings reinforce the importance of weekly dupilumab, rather than every 2 weeks, for the improvement of symptoms in adults and adolescents with eosinophilic oesophagitis. FUNDING: Sanofi and Regeneron Pharmaceuticals Inc.
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Aim: To determine the suitability of network meta-analysis (NMA) using antibacterial treatment evidence in complicated urinary tract infection. Materials & methods: We conducted a systematic literature review to identify published clinical trial data for complicated urinary tract infection treatments. We performed a feasibility assessment to determine whether the available evidence would support the creation of a robust NMA, considering key assumptions of homogeneity, similarity and consistency. Results: Twenty-five trials met eligibility criteria. Risk of bias was low, and individual studies met their primary end point(s). Assumptions central to the conduct of a robust NMA were not met. Heterogeneity was ubiquitous, including baseline pathogen, treatment and patient characteristics. Conclusion: Limited and heterogeneous data identified make the use of NMA to compare novel antibacterial agents impractical and likely unreliable.
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Infecciones Urinarias , Antibacterianos/uso terapéutico , Humanos , Metaanálisis en Red , Infecciones Urinarias/tratamiento farmacológicoRESUMEN
INTRODUCTION: Efforts to curb a growing prevalence of carbapenem resistance are prominent worldwide and especially in countries where high levels of carbapenem resistance are reported, such as Italy. Complicated infections, including complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI), and hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), are often caused by carbapenem-resistant Gram-negative (CRGN) bacteria and as such, these infection sites and their causative bacteria are important areas of focus for healthcare practitioners seeking to follow good antimicrobial stewardship practices. The aim of this study was to assess the clinical management and associated clinical and economic outcomes of patients with cUTI, cIAI, and HABP/VABP resulting from CRGN bacteria in Italy. METHODS: We first conducted a hospital survey focusing on Gram-negative infections and their antibacterial susceptibility profile in four participating Italian hospitals. The second part of the study involved a non-interventional, retrospective single cohort chart review of 100 patients with cUTI, cIAI, or HABP/VABP caused by CRGN bacteria, in which patient characteristics, index hospitalization characteristics, infection characteristics, patient outcomes, treatment pathways, and healthcare resource use were assessed. RESULTS: The hospital survey demonstrated carbapenem resistance in approximately 17% of complicated infections, mostly associated with Acinetobacter baumannii. The non-interventional, retrospective cohort component showed that complicated CRGN infections were hospital- or healthcare-acquired in 99.0% of cases and were most often caused by Klebsiella pneumoniae (66.0%). Despite the carbapenem-resistant nature of the included infections, carbapenems were used in 19.0% of patients as empirical therapy, in 43.0% as late empirical (i.e. immediately before receipt of susceptibility test results), and in 64.0% as targeted therapy (post-susceptibility test result receipt). Colistin was used in 61.0% of patients after susceptibility results were available. High clinical and economic burden was evident, with the average length of hospital stay being greater than 50 days, clinical cure achievement in only 43.0% of patients, and an overall mortality rate of 65.0% by the end of the follow-up period. CONCLUSION: Our results reflect the considerable burden associated with complicated CRGN infections in Italy and the limitations in current treatment strategies. Our study pinpoints potential areas for improvement. For example, regular and detailed local surveillance and state of the art microbial diagnostic capabilities might aid and hasten clinical decision-making and facilitate improved antimicrobial stewardship when treating complex CRGN infections. New therapeutic options which more appropriately address CRGN infections may assist in improving outcomes which are important to both patients and healthcare providers.
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BACKGROUND: Owing to their resistance to an important class of antibiotics, the prevention and treatment of carbapenem-resistant (CR)/non-susceptible Gram-negative (GN) infections has become an important public health objective. We conducted a systematic review and meta-analysis of published literature to evaluate the burden of CR GN infections, focusing on high-risk patients such as transplant recipients, or patients with cancer, renal impairment, or sepsis. METHODS: MEDLINE®, Cochrane Central, and Embase® were searched between 2010 and March 2019. Abstracts and full-text articles were screened in duplicate. Random effects meta-analysis was conducted when reported outcomes were sufficiently similar. RESULTS: Twenty-six publications were eligible. Meta-analyses found increased mortality associated with CR infections among high-risk patients in both unadjusted analysis (8 studies; summary unadjusted odds ratio [OR]: 5.85; 95% confidence interval [CI]: 3.69, 9.26; I2 = 19.8%) and adjusted analysis (5 studies; summary hazard ratio [HR]: 4.67; 95% CI: 2.18, 9.99; I2 = 77.7%), compared to patients with carbapenem-susceptible (CS) infections or no infection. Increased mortality was also seen in subgroup analyses by length of follow-up (either short-term or long-term) or causative pathogen. A limited number of studies found that CR GN infections increased the risk for mechanical ventilation, adverse events such as graft failure or acute rejection in solid organ transplant recipients, increased renal failure or nephrotoxicity, and an increase in readmissions and costs, though the findings reported in the literature were not consistent. CONCLUSION: This systematic literature review and meta-analysis indicates that CR GN infections in high-risk patients are associated with increased mortality, emphasizing the need for antimicrobial stewardship and infection control in hospitals which treat high-risk patients and for the development of effective antimicrobials with favorable efficacy and safety profiles for the treatment of CR GN infections.
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Carbapenémicos/uso terapéutico , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Anciano , Costo de Enfermedad , Farmacorresistencia Bacteriana , Femenino , Infecciones por Bacterias Gramnegativas/mortalidad , Humanos , Tiempo de Internación , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: We explored patient- and hospital-level predictor variables for worse clinical and economic outcomes in carbapenem-nonsusceptible urinary tract infections (UTIs). PATIENTS AND METHODS: We used electronic data (January 2013-September 2015; 78 US hospitals) from a large multicenter clinical database. Nonduplicate gram-negative isolates were considered carbapenem-nonsusceptible if they had resistant/intermediate susceptibility. Potential predictors of outcomes (mortality, 30-day readmissions, length of stay [LOS], hospital total cost, and net gain/loss per case) were examined using generalized linear mixed models. Significant predictors were identified based on statistical significance and model goodness-of-fit criteria. RESULTS: A total of 1439 carbapenem-nonsusceptible urine cases were identified. The mortality rate was 5.5%; the hospital readmission rate was 25.0%. Mean (standard deviation [SD]) LOS, total cost, and loss per case were 12 (14) days, $21,502 ($37,172), and $5828 ($26,540), respectively. Hospital-onset (vs community-onset) infection significantly impacted all outcomes: mortality (odds ratio [OR], 2.21; 95% confidence interval [CI], 1.19-4.11; P=.01), 30-day readmissions (OR, 2.35; 95% CI, 1.49-3.71; P<.001), LOS (25.7 vs 10.2 days; P<.001), hospital total cost ($67,810 vs $22,141; P<.001), and loss per case (-$28,054 vs -$10,809; P<.001). Mechanical ventilation/intensive care unit status, neoplasms, and other underlying diseases were also common predictors for worse outcomes overall; polymicrobial infection was significantly associated with worse economic outcomes. Other key predictors were >1 prior hospitalization for 30-day readmissions, high Acute Laboratory Risk of Mortality Score for mortality, LOS, cost, and hospital teaching status for cost. CONCLUSION: Hospital-onset infections, polymicrobial infections, higher clinical severity, and underlying diseases are key predictors for worsened overall burden of carbapenem-nonsusceptible gram-negative UTIs.
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PURPOSE: This study examined patient- and hospital-level predictor variables that contribute to worse clinical and economic outcomes in patients with carbapenem-nonsusceptible respiratory infections. PATIENTS AND METHODS: Electronic data (January 2013 to September 2015) were from 78 US hospitals. Nonduplicate, gram-negative respiratory isolates were considered carbapenem-nonsusceptible if they tested resistant/intermediate to imipenem, meropenem, doripenem, or ertapenem. Potential predictors of outcomes (in-hospital mortality, 30-day readmission, length of stay [LOS], hospital total cost, and net gain/loss per patient) were examined using univariate analysis and generalized linear mixed models. Statistical significance and model goodness-of-fit criteria were used to identify significant predictors. RESULTS: A total of 1488 carbapenem-nonsusceptible respiratory patients were identified. Overall, the mortality rate was 13.7%, 30-day readmission rate was 20.6%, mean LOS was 20 days, mean total cost was $54,158, and mean net loss was $139 per patient. Our models showed that hospital-onset infection, higher clinical severity, mechanical ventilation/intensive care unit status, polymicrobial infection, and underlying diseases were all significant predictors for mortality, LOS, and total cost. Hospital-onset infections were also associated with a significantly greater net loss (P≤.01), and underlying disease significantly impacted readmissions (P=.03). The number of prior admissions, hospital characteristics, and payer type were also found to significantly impact measured outcomes. CONCLUSION: Carbapenem-nonsusceptible respiratory infections are associated with a considerable clinical and economic burden. The impact of hospital-onset infections on both clinical and economic outcomes highlights the continued need for action on this modifiable risk factor through antimicrobial stewardship and optimal therapy, thereby reducing the burden in this patient population.
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OBJECTIVE: We aimed to describe the clinical and economic burden attributable to carbapenem-nonsusceptible (C-NS) respiratory infections. METHODS: This retrospective matched cohort study assessed clinical and economic outcomes of adult patients (aged ≥18 years) who were admitted to one of 78 acute care hospitals in the United States with nonduplicate C-NS and carbapenem-susceptible (C-S) isolates from a respiratory source. A subset analysis of patients with principal diagnosis codes denoting bacterial pneumonia or other diagnoses was also conducted. Isolates were classified as community- or hospital-onset based on collection time. A generalized linear mixed model method was used to estimate the attributable burden for mortality, 30-day readmission, length of stay (LOS), cost, and net gain/loss (payment minus cost) using propensity score-matched C-NS versus C-S cohorts. RESULTS: For C-NS cases, mortality (25.7%), LOS (29.4 days), and costs ($81,574) were highest in the other principal diagnosis, hospital-onset subgroup; readmissions (19.4%) and net loss (-$9522) were greatest in the bacterial pneumonia, hospital-onset subgroup. Mortality and readmissions were not significantly higher for C-NS cases in any propensity score-matched subgroup. Significant C-NS-attributable burden was found for both other principal diagnosis subgroups for LOS (hospital-onset: 3.7 days, P = 0.006; community-onset: 1.5 days, P<0.001) and cost (hospital-onset: $12,777, P<0.01; community-onset: $2681, P<0.001). CONCLUSIONS: Increased LOS and cost burden were observed in propensity score-matched patients with C-NS compared with C-S respiratory infections; the C-NS-attributable burden was significant only for patients with other principal diagnoses.
Asunto(s)
Carbapenémicos/farmacología , Farmacorresistencia Bacteriana , Infecciones por Bacterias Gramnegativas/economía , Infecciones por Bacterias Gramnegativas/mortalidad , Costos de la Atención en Salud/estadística & datos numéricos , Infecciones del Sistema Respiratorio/economía , Infecciones del Sistema Respiratorio/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/crecimiento & desarrollo , Bacterias Gramnegativas/aislamiento & purificación , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Hospitalización/estadística & datos numéricos , Humanos , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Pronóstico , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/microbiología , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
INTRODUCTION: The aim of this study is to assess the cost-effectiveness of golimumab for the treatment of non-radiographic axial spondyloarthritis (nr-axSpA) vs. conventional therapy and other tumor necrosis factor inhibitors from the Scottish payer perspective. METHODS: A model comprising a short-term decision tree and a long-term Markov model was developed to compare cost-effectiveness (incremental costs per quality-adjusted life-year [QALY]) for patients in Scotland with nr-axSpA treated by conventional therapy, adalimumab, certolizumab pegol, etanercept, or golimumab for a lifetime period. A network meta-analysis (NMA) was conducted to identify clinical and safety data for treatments and synthesize the available evidence into relative treatment effects between comparators. The probability of patients achieving an Assessment of SpondyloArthritis International Society 20/40% response criteria (ASAS20/ASAS40) or a 50% improvement in Bath Ankylosing Spondylitis Disease Activity Index score (BASDAI50) at week 12 was obtained from the NMA for each of the comparators. Baseline health state utilities were based on the EQ-5D questionnaire collected in the golimumab GO-AHEAD study. The cost of treatment was calculated based on drug acquisition, drug administration, and initiation/monitoring costs. RESULTS: Golimumab resulted in an increase of 2.06 QALYs and additional cost of £39,770 compared with conventional therapy. Incremental cost per QALY gained was £19,280 for golimumab, which was lower than adalimumab (£19,737), etanercept (£20,089), and higher than certolizumab pegol (£18,710). Golimumab remained cost-effective throughout a range of sensitivity analyses where key assumptions were tested. CONCLUSIONS: From a Scottish perspective, golimumab was a cost-effective treatment for nr-axSpA compared with conventional therapy at a willingness-to-pay threshold of £30,000 per QALY. FUNDING: Merck & Co., Inc.
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BACKGROUND: Infections caused by Gram-negative pathogens resistant to carbapenems have limited treatment options and are associated with increased morbidity and mortality. We evaluated the rates, infection sources, and pathogen types associated with carbapenem-nonsusceptible (Carb-NS) Gram-negative isolates in intensive care unit (ICU) and non-ICU settings in a large US hospital database. METHODS: We conducted a retrospective cross-sectional analysis of carbapenem susceptibility of all nonduplicate isolates of Gram-negative pathogens collected from January 1, 2017, to December 31, 2017, at 358 US hospitals in the BD Insights Research Database. Carb-NS isolates included all pathogens reported at the institutional level as intermediate or resistant. RESULTS: Of 312 075 nonduplicate Gram-negative isolates, 10 698 (3.4%) were Carb-NS. Respiratory samples were the most frequent source of Carb-NS isolates (35.2%); skin/wound accounted for 23.6%. Pseudomonas aeruginosa was the most common Carb-NS pathogen (58.5% of isolates), and about 30% were Enterobacteriaceae. The highest rates of Carb-NS were found in Acinetobacter spp. (35.6%) and P. aeruginosa (14.6%). The rate of Carb-NS was significantly higher in ICU (5.4%) vs non-ICU settings (2.7%; P < .0001 in univariate analysis). This difference remained significant in multivariable analysis after adjusting for infection and hospital characteristics (odds ratio, 1.35; 95% confidence interval, 1.17-1.56; P < .0001). CONCLUSIONS: Infections caused by Carb-NS isolates pose a significant clinical problem across different sources of infection, species of pathogen, and hospital settings. Widespread infection prevention and antimicrobial stewardship initiatives, in combination with new treatment options, may be required to reduce the burden of carbapenem resistance in health care settings.
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OBJECTIVE: To describe the real-world use of adalimumab for maintenance treatment of ulcerative colitis (UC) and associated healthcare costs in English hospitals. DESIGN: Retrospective cohort study. SETTING: Analysis of NHS Hospital Episode Statistics linked with pharmacy dispensing data in English hospitals. PATIENTS: Adult UC patients receiving ≥240mg during adalimumab treatment induction, subsequently maintained on adalimumab. OUTCOMES: Frequency and pattern of adalimumab use and dose escalation during maintenance treatment and associated healthcare costs (prescriptions and hospital visits). RESULTS: 191 UC patients completed adalimumab treatment induction. 83 (43.46%) dose escalated during maintenance treatment by ≥100% (equivalent to weekly dosing) (median time to dose escalation: 139 days). 56 patients (67.47%) subsequently de-escalated by ≥50% (median time to dose de-escalation: 21 days). Mean all-cause healthcare costs for all patients ≤12 months of index were £13,892. Dose escalators incurred greater mean healthcare costs than non-escalators ≤12 months of index (£14,596 vs. £13,351). Prescriptions accounted for 96.49% of UC-related healthcare costs (£11,090 of £11,494 in all patients). CONCLUSIONS: Within the cohort, 43.46% of UC patients escalated their adalimumab dose by ≥100% and incurred greater costs than non-escalators. The apparent underestimation of adalimumab dose escalation in previous studies may have resulted in underestimated costs in healthcare systems.