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

Human neutrophils synthesize IL-8 in an IgE-mediated activation

It has been demonstrated that neutrophils are responsible for the release of large amounts of the inflammatory chemokine interleukin-8 (IL-8), associated with inflammation. To further define the mechanisms implicated, we have analyzed the response of human neutrophils from allergic patients to specific antigens or challenge with anti-immunoglobulin (Ig)E antibodies. Neutrophils showed a dose- and time-dependent production of IL-8. The release of the cytokine was parallel to expression of IL-8 mRNA analyzed by the polymerase chain reaction. This expression was transient—it occurred after 3 h of anti-IgE treatment and was maintained for 18 h. Trifluoperazine, EGTA, reduced nicotinamide adenine dinucleotide phosphate-oxidase inhibitors, and reactive oxygen species (ROS) scavengers inhibited IL-8 production, indicating a critical dependence of calcium and oxidative stress. Moreover, an inhibitory effect of cyclosporin A, an immunosuppressor that inhibits calcineurin activity, on IL-8 release and IL-8 mRNA expression was observed. This is the first evidence of the involvement of ROS and calcium/calcineurin in IgE-dependent IL-8 production. These findings open new perspectives into the functional role of neutrophils in IgE-associated diseases

A new role for monoamine oxidases in the modulation of macrophage-inducible nitric oxide synthase gene expression

This report focuses on the modulatory role of endogenous H2O2 on lipopolysaccharide (LPS)/interferon-γ (IFN-γ)-induced inducible nitric oxide synthase (NOS2) gene expression in rat peritoneal macrophages. Exogenously added H2O2 was initially found to inhibit the synthesis of NOS2, which prompted us to assess the effect of the activity of monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) as H2O2-forming enzymes on NOS2 gene expression. In the presence of their substrates, tyramine for MAO and benzylamine for SSAO, intracellular synthesis of H2O2 took place with concomitant inhibition of LPS/IFN-γ-induced NOS2 protein synthesis, as detected by Western blotting, flow cytometry, and immunofluorescence microscopy analyses. Pargyline and semicarbazide, specific inhibitors of MAO and SSAO, respectively, canceled this negative effect of MAO substrates on NOS2 expression. In the presence of Fe2+ and Cu2+ ions, inhibition of NOS2 expression was enhanced, suggesting the participation in this regulation of species derived from Fenton chemistry. In addition, the negative effect of H2O2, generated by MAOs, was found to be exerted on NOS2 mRNA levels. These data offer a new insight in the control of NOS2 expression through the intracellular levels of H2O2 and other reactive oxygen species (ROS). The hypothesis can be raised that the inhibition of NOS by H2O2 could constitute a protective mechanism against the cytotoxic consequences of the activation of ROS-generating enzymes, thus providing a new, singular role for the MAO family of proteins

Comparing quantile residual life functions by confidence bands

In this article we present a nonparametric method for constructing confidence bands for the difference of two quantile residual life (qrl) functions. These bands provide evidence for two random variables ordering with respect to the qrl order. The comparison of qrl functions is of importance, specially in the treatment of cancer when there exists a possibility of benefiting from a new secondary therapy. A qrl function is the quantile of the remaining life of a surviving subject, as it varies with time. We show the applicability of this approach in Medicine and Ecology. A simulation study has been carried out to evaluate and illustrate the performance and the consistency of this new methodology

7-Keto-cholesterol and 25-hydroxy-1 cholesterol rapidly enhance ROS production in human neutrophils

Purpose. Oxysterols are cholesterol-oxygenated derivatives generated in the organism and also present in foods because of cholesterol oxidation during processing and storage. They are the natural ligands of liver X receptors (LXRs) and are generally recognized as hypocholesterolemic and anti-inflammatory molecules although this latter property is still controversial. Most oxysterol studies have been performed in macrophages, whereas the effects of oxysterols in neutrophils are poorly known. In this study, human neutrophils were exposed to two different oxysterols, 7-keto-cholesterol (7-k-chol) and 25-hydroxy-cholesterol (25-OH-chol), and their possible participation in inflammatory process was evaluated. Methods. Human neutrophils were incubated with 7-k-chol and 25-OH-chol, and ROS production, translocation of the NADPH oxidase cytosolic components, hemoxygenase-1 (HO-1) expression and lysozyme secretion were analyzed. Results. An increase in ROS production was observed within a short period of time (minutes) with both molecules. These oxysterols also stimulated the cellular membrane translocation of the NADPH oxidase cytosolic components, p47phox and p67phox. On the other hand, HO-1 expression, a cytoprotector enzyme, is inhibited in human neutrophils upon oxysterols treatment. Moreover, both oxysterols were associated with high lysozyme enzyme secretion at 5 and 18 h of incubation. Conclusions. The present paper describes for the first time that two oxysterols (7-k-chol and 25-OH-chol) enhance the ROS production within a short period of time in human neutrophils, stimulate the translocation of the cytosolic components of NADPH oxidase to the cellular membrane and increase lysozyme secretion. These data suggest that both oxysterols are able to activate pro-inflammatory effects in human neutrophils which contrasts with the role assigned to the oxysterols when they act through LXR at long time of incubation.M.E.R-Q was supported by a fellowship from the Asociación Virgen Macarena, Hospital Universitario Virgen Macarena, Sevilla. G.A. was supported by fellowships from the Ministerio de Educación y Ciencia (BFU2006-13802) and the Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía (P08-CVI-03550). This work was funded by Grants from the latter (P06-CTS-01936 and P08-CVI-03550) to F.S., and from the Consejería de Salud, Junta de Andalucía (CS 0116/2007) to E. P