Activity of cefiderocol against high-risk clones of multidrug-resistant Enterobacterales, Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia

BACKGROUND: Cefiderocol is a novel siderophore cephalosporin, developed for activity against MDR Gram-negative bacilli (MDR-GNB). OBJECTIVES: To assess the in vitro antibacterial activity of cefiderocol against a collection of MDR-GNB clinical isolates from hospitals in southern Spain. METHODS: Two hundred and thirty-one isolates of successful clones were tested: 125 Enterobacterales (121 ESBL- and/or carbapenemase-producing Klebsiella pneumoniae and 4 carbapenemase-producing Enterobacter cloacae), 80 Acinetobacter baumannii, 6 Pseudomonas aeruginosa and 20 Stenotrophomonas maltophilia. Ceftolozane/tazobactam, ceftazidime, ceftazidime/avibactam, cefepime, aztreonam, meropenem, amikacin, ciprofloxacin, colistin and tigecycline were used as comparators against Enterobacterales, P. aeruginosa and A. baumannii. Minocycline, levofloxacin and trimethoprim/sulfamethoxazole were studied against S. maltophilia instead of aztreonam, ciprofloxacin and cefepime. MICs were determined by broth microdilution according to CLSI guidelines. MIC determination was performed in CAMHB for all antimicrobials except cefiderocol, where iron-depleted CAMHB was used. RESULTS: Cefiderocol showed potent in vitro activity against the isolates analysed. MIC50 and MIC90 values were in the ranges 0.125-8 mg/L and 0.5-8 mg/L, respectively, and 98% of isolates were inhibited at ≤4 mg/L. Only five isolates showed cefiderocol MICs of >4 mg/L: three ST2/OXA-24/40-producing A. baumannii, one ST114/VIM-1-producing E. cloacae and one ST114/VIM-1 + OXA-48-producing E. cloacae. All KPC-3-producing K. pneumoniae were susceptible to cefiderocol, even those resistant to ceftazidime/avibactam. P. aeruginosa isolates showed cefiderocol MICs of <4 mg/L, including those resistant to ceftolozane/tazobactam. S. maltophilia isolates displayed cefiderocol MICs of <4 mg/L, including those resistant to levofloxacin and/or trimethoprim/sulfamethoxazole. CONCLUSIONS: Cefiderocol showed excellent activity against MDR-GNB, including carbapenem-resistant isolates, and was the most active antimicrobial tested against this collection

Virulence Profiles of Bacteremic Extended-Spectrum β-Lactamase-Producing Escherichia coli: Association with Epidemiological and Clinical Features

There is scarce data about the importance of phylogroups and virulence factors (VF) in bloodstream infections (BSI) caused by extended-spectrum β-lactamase-producing Escherichia coli (ESBLEC). A prospective multicenter Spanish cohort including 191 cases of BSI due to ESBLEC was studied. Phylogroups and 25 VF genes were investigated by PCR. ESBLEC were classified into clusters according to their virulence profiles. The association of phylogropus, VF, and clusters with epidemiological features were studied using multivariate analysis. Overall, 57.6%, 26.7%, and 15.7% of isolates belonged to A/B1, D and B2 phylogroups, respectively. By multivariate analysis (adjusted OR [95% CI]), virulence cluster C2 was independently associated with urinary tract source (5.05 [0.96-25.48]); cluster C4 with sources other than urinary of biliary tract (2.89 [1.05-7.93]), and cluster C5 with BSI in non-predisposed patients (2.80 [0.99-7.93]). Isolates producing CTX-M-9 group ESBLs and from phylogroup D predominated among cluster C2 and C5, while CTX-M-1 group of ESBL and phylogroup B2 predominantes among C4 isolates. These results suggest that host factors and previous antimicrobial use were more important than phylogroup or specific VF in the occurrence of BSI due to ESBLEC. However, some associations between virulence clusters and some specific epidemiological features were foundSpanish Network for Research in Infectious Diseases REIPI RD06/0008Fondo de Investigación Sanitaria 070190, 10/02021, 10/01955, y 10/00795Junta de Andalucía 0048/2008 y CTS-525

Brain structures identification based on feature descriptor

Traumatic Brain Injury -TBI- -1- is defined as an acute event that causes certain damage to areas of the brain. TBI may result in a significant impairment of an individuals physical, cognitive and psychosocial functioning. The main consequence of TBI is a dramatic change in the individuals daily life involving a profound disruption of the family, a loss of future income capacity and an increase of lifetime cost. One of the main challenges of TBI Neuroimaging is to develop robust automated image analysis methods to detect signatures of TBI, such as: hyper-intensity areas, changes in image contrast and in brain shape. The final goal of this research is to develop a method to identify the altered brain structures by automatically detecting landmarks on the image where signal changes and to provide comprehensive information to the clinician about them. These landmarks identify injured structures by co-registering the patient?s image with an atlas where landmarks have been previously detected. The research work has been initiated by identifying brain structures on healthy subjects to validate the proposed method. Later, this method will be used to identify modified structures on TBI imaging studies

Neuroanatomic-based detection algorithm for automatic labeling of brain structures in brain injury

The number and grade of injured neuroanatomic structures and the type of injury determine the degree of impairment after a brain injury event and the recovery options of the patient. However, the body of knowledge and clinical intervention guides are basically focused on functional disorder and they still do not take into account the location of injuries. The prognostic value of location information is not known in detail either. This paper proposes a feature-based detection algorithm, named Neuroanatomic-Based Detection Algorithm (NBDA), based on SURF (Speeded Up Robust Feature) to label anatomical brain structures on cortical and sub-cortical areas. Themain goal is to register injured neuroanatomic structures to generate a database containing patient?s structural impairment profile. This kind of information permits to establish a relation with functional disorders and the prognostic evolution during neurorehabilitation procedures

Renal Function Impact in the Prognostic Value of Galectin-3 in Acute Heart Failure

[Abstract] Introduction: Galectin-3 (Gal-3) is an inflammatory marker associated with the development and progression of heart failure (HF). A close relationship between Gal-3 levels and renal function has been observed, but data on their interaction in patients with acute HF (AHF) are scarce. We aim to assess the prognostic relationship between renal function and Gal-3 during an AHF episode. Materials and methods: This is an observational, prospective, multicenter registry of patients hospitalized for AHF. Patients were divided into two groups according to estimated glomerular filtration rate (eGFR): preserved renal function (eGFR ≥ 60 mL/min/1.73 m2) and renal dysfunction (eGFR <60 mL/min/1.73 m2). Cox regression analysis was performed to evaluate the association between Gal-3 and 12-month mortality. Results: We included 1,201 patients in whom Gal-3 values were assessed at admission. The median value of Gal-3 in our population was 23.2 ng/mL (17.3-32.1). Gal-3 showed a negative correlation with eGFR (rho = -0.51; p < 0.001). Gal-3 concentrations were associated with higher mortality risk in the multivariate analysis after adjusting for eGFR and other prognostic variables [HR = 1.010 (95%-CI: 1.001-1.018); p = 0.038]. However, the prognostic value of Gal-3 was restricted to patients with renal dysfunction [HR = 1.010 (95%-CI: 1.001-1.019), p = 0.033] with optimal cutoff point of 31.5 ng/mL, with no prognostic value in the group with preserved renal function [HR = 0.990 (95%-CI: 0.964-1.017); p = 0.472]. Conclusions: Gal-3 is a marker of high mortality in patients with acute HF and renal dysfunction. Renal function influences the prognostic value of Gal-3 levels, which should be adjusted by eGFR for a correct interpretation.Grant No. RD06-0003-0000 Grant No. RD12/0042/000

Molecular method for the characterization of Coxiella burnetii from clinical and environmental samples: variability of genotypes in Spain

BACKGROUND: Coxiella burnetii is a highly clonal microorganism which is difficult to culture, requiring BSL3 conditions for its propagation. This leads to a scarce availability of isolates worldwide. On the other hand, published methods of characterization have delineated up to 8 different genomic groups and 36 genotypes. However, all these methodologies, with the exception of one that exhibited limited discriminatory power (3 genotypes), rely on performing between 10 and 20 PCR amplifications or sequencing long fragments of DNA, which make their direct application to clinical samples impracticable and leads to a scarce accessibility of data on the circulation of C. burnetii genotypes. RESULTS: To assess the variability of this organism in Spain, we have developed a novel method that consists of a multiplex (8 targets) PCR and hybridization with specific probes that reproduce the previous classification of this organism into 8 genomic groups, and up to 16 genotypes. It allows for a direct characterization from clinical and environmental samples in a single run, which will help in the study of the different genotypes circulating in wild and domestic cycles as well as from sporadic human cases and outbreaks. The method has been validated with reference isolates. A high variability of C. burnetii has been found in Spain among 90 samples tested, detecting 10 different genotypes, being those adaA negative associated with acute Q fever cases presenting as fever of intermediate duration with liver involvement and with chronic cases. Genotypes infecting humans are also found in sheep, goats, rats, wild boar and ticks, and the only genotype found in cattle has never been found among our clinical samples. CONCLUSIONS: This newly developed methodology has permitted to demonstrate that C. burnetii is highly variable in Spain. With the data presented here, cattle seem not to participate in the transmission of C. burnetii to humans in the samples studied, while sheep, goats, wild boar, rats and ticks share genotypes with the human population

The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation

The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT)15) for the (GT)n polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD) in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08-0.82, p = 0.021); without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients

Validation of a Novel, Sensitive, and Specific Urine-Based Test for Recurrence Surveillance of Patients With Non-Muscle-Invasive Bladder Cancer in a Comprehensive Multicenter Study

Bladder cancer (BC), the most frequent malignancy of the urinary system, is ranked the sixth most prevalent cancer worldwide. Of all newly diagnosed patients with BC, 70-75% will present disease confined to the mucosa or submucosa, the non-muscle-invasive BC (NMIBC) subtype. Of those, approximately 70% will recur after transurethral resection (TUR). Due to high rate of recurrence, patients are submitted to an intensive follow-up program maintained throughout many years, or even throughout life, resulting in an expensive follow-up, with cystoscopy being the most cost-effective procedure for NMIBC screening. Currently, the gold standard procedure for detection and follow-up of NMIBC is based on the association of cystoscopy and urine cytology. As cystoscopy is a very invasive approach, over the years, many different noninvasive assays (both based in serum and urine samples) have been developed in order to search genetic and protein alterations related to the development, progression, and recurrence of BC. TERT promoter mutations and FGFR3 hotspot mutations are the most frequent somatic alterations in BC and constitute the most reliable biomarkers for BC. Based on these, we developed an ultra-sensitive, urine-based assay called Uromonitor®, capable of detecting trace amounts of TERT promoter (c.1-124C > T and c.1-146C > T) and FGFR3 (p.R248C and p.S249C) hotspot mutations, in tumor cells exfoliated to urine samples. Cells present in urine were concentrated by the filtration of urine through filters where tumor cells are trapped and stored until analysis, presenting long-term stability. Detection of the alterations was achieved through a custom-made, robust, and highly sensitive multiplex competitive allele-specific discrimination PCR allowing clear interpretation of results. In this study, we validate a test for NMIBC recurrence detection, using for technical validation a total of 331 urine samples and 41 formalin-fixed paraffin-embedded tissues of the primary tumor and recurrence lesions from a large cluster of urology centers. In the clinical validation, we used 185 samples to assess sensitivity/specificity in the detection of NMIBC recurrence vs. cystoscopy/cytology and in a smaller cohort its potential as a primary diagnostic tool for NMIBC. Our results show this test to be highly sensitive (73.5%) and specific (93.2%) in detecting recurrence of BC in patients under surveillance of NMIBC.info:eu-repo/semantics/publishedVersio

Safety and Efficacy of Sofosbuvir plus Simeprevir in a Spanish Cohort of 622 Cirrhotic Patients Infected with Genotypes 1 or 4

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