Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections

IMPORTANCE The consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option. OBJECTIVE To determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli. DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021. INTERVENTIONS Patients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or pa renteral ertapenem for the comparator group after 4 days. MAIN OUTCOMES AND MEASURES The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered. RESULTS Among 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, -9.4 percentage points; 1-sided 95% CI, -21.5 to infinity percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, -5.4 percentage points; 1-sided 95% CI. -infinity to 4.9; percentage points; P = .19), an increased rate of adverse event-related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01). CONCLUSIONS AND RELEVANCE This study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event-related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections

The economics of debt clearing mechanisms

We examine the evolution of decentralized clearinghouse mechanisms from the 13th to the 18th century; in particular, we explore the clearing of non- or limitedtradable debts like bills of exchange. We construct a theoretical model of these clearinghouse mechanisms, similar to the models in the theoretical matching literature, and show that specific decentralized multilateral clearing algorithms known as rescontre, skontrieren or virement des parties used by merchants were efficient in specific historical contexts. We can explain both the evolutionary self-organizing emergence of late medieval and early modern fairs, and its robustness during the 17th and 18th century

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Estudos latino-americanos sobre melancolia: um transtorno do humor melhor definido para o CID-11 Melancholia in Latin American studies: a distinct mood disorder for the ICD-11

OBJETIVO: A depressão melancólica é um diagnóstico psiquiátrico de história de vida, geralmente com episódios recorrentes. Melancolia é uma síndrome com longa duração e características específicas de psicopatologia, insuficientemente diferenciada de depressão maior por um especificador no DSM-IV e parcialmente descrito nos critérios da Classificação Internacional de Doenças-10ª Edição. Dentro da classificação atual, é frequentemente vista em pacientes gravemente doentes com depressão e transtorno bipolar. No entanto, a melancolia possui uma homogeneidade psicopatológica e biológica distinta na experiência clínica e nos marcadores de testes laboratoriais, e é diferencialmente sensível às intervenções terapêuticas específicas. O objetivo deste estudo é revisar a literatura de artigos publicados por autores latino-americanos sobre a melancolia. MÉTODO: Realizou-se busca de artigos latino-americanos de informações relevantes para a revisão da Classificação Internacional de Doenças-10ª Edição de transtornos mentais e comportamentais em pacientes com depressão melancólica. Foi avaliada a qualidade do design de todos os estudos e realizada uma revisão abrangente sobre o assunto, com o objetivo de considerar a contribuição latino-americana para inclusão da melancolia como uma entidade distinta na futura Classificação Internacional de Doenças-11ª Edição. RESULTADOS E CONCLUSÃO: Os estudos latino-americanos fundamentam o diagnóstico da melancolia com uma psicopatologia e psiconeuroendocrinologia própria que fundamentam ser reconhecida como um transtorno de humor identificável e merecedor de uma atenção específica nos sistemas de classificação, como um transtorno de humor distinto, identificável e especificamente tratável.<br>OBJECTIVE: Melancholic depression is a lifetime diagnosis, typically with recurrent episodes. Melancholia, a syndrome with a long history and distinctive psychopathological features, is differentiated from major depression by the DSM-IV specifiers and partly described in the International Classification of Diseases - 10th edition. Within the present classification, it is frequently seen in severely ill patients with major depression and bipolar disorder. Nevertheless, it has a distinctive psychopathology and biological homogeneity in clinical experience and laboratory test markers, and it is differentially responsive to specific treatment interventions according to international studies. The objective of this study is to review the literature published by Latin American authors about Melancholia. METHOD: We conducted a systematic search to identify scientific literature published by Latin American authors gathering information relevant to the revision of the classification of mental and behavioral disorders in patients with melancholic depression of the International Classification of Diseases - 10th edition. The review was specifically focused on literature from Brazil and Latin America in order to examine the specific Latin American contribution for the study of melancholia as a distinct entity. RESULTS AND CONCLUSION: Melancholia can be identified as a separate mood disorder with unique psychopathology and psychoneuroendocrinology, worthy of separate attention in the classification systems. We therefore suggest that melancholia be positioned as a distinct, identifiable mood disorder that requires specific treatment