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Rumbo C.,Complejo Hospitalario Universitario runa | Gato E.,Complejo Hospitalario Universitario runa | Lopez M.,Complejo Hospitalario Universitario runa | Ruiz De Alegria C.,Hospital Universitario Marques Of Valdecilla Ifimav | And 9 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

Weinvestigated the mechanisms of resistance to carbapenems, aminoglycosides, glycylcyclines, tetracyclines, and quinolones in 90 multiresistant clinical strains of Acinetobacter baumannii isolated from two genetically unrelated A. baumannii clones: clone PFGEROC-1 (53 strains producing the OXA-58 β-lactamase enzyme and 18 strains with the OXA-24 β-lactamase) and clone PFGE-HUI-1 (19 strains susceptible to carbapenems).Weused real-time reverse transcriptase PCR to correlate antimicrobial resistance (MICs) with expression of genes encoding chromosomal β-lactamases (AmpC and OXA-51), porins (OmpA, CarO, Omp33, Dcap-like, OprB, Omp25, OprC, OprD, and OmpW), and proteins integral to six efflux systems (AdeABC, AdeIJK, AdeFGH, CraA, AbeM, and AmvA). Overexpression of the AdeABC system (level of expression relative to that by A. baumannii ATCC 17978, 30- to 45-fold) was significantly associated with resistance to tigecycline, minocycline, and gentamicin and other biological functions. However, hyperexpression of the AdeIJK efflux pump (level of expression relative to that by A. baumannii ATCC 17978, 8- to 10-fold) was significantly associated only with resistance to tigecycline and minocycline (to which the TetB efflux system also contributed). TetB and TetA(39) efflux pumps were detected in clinical strains and were associated with resistance to tetracyclines and doxycycline. The absence of the AdeABC system and the lack of expression of other mechanisms suggest that tigecycline-resistant strains of the PFGE-HUI-1 clone may be associated with a novel resistance-nodulation-cell efflux pump (decreased MICs in the presence of the inhibitor Phe-Argβ-naphthylamide dihydrochloride) and the TetA(39) system. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Mollejo M.,Hospital Virgen Of La Salud | Menarguez J.,Hospital Gregorio Maranon | Guisado-Vasco P.,Hospital Ramon y Cajal | Bento L.,Hospital Gregorio Maranon | And 7 more authors.
Modern Pathology | Year: 2014

We describe a retrospective series of B-cell lymphoproliferative disorders associated with hepatitis C virus infection. In addition to splenic marginal zone lymphoma, follicular lymphoma and diffuse large B-cell lymphoma, all of which showed some specific features, we found two poorly described groups of cases. The first featured disseminated marginal zone lymphoma without splenic marginal zone lymphoma features, defying the current marginal zone lymphoma classification; the other consisted of monoclonal B lymphocytes in the peripheral blood, bone marrow or other tissues, with no clinical or histological evidence of lymphoma, and exhibiting a pattern that requires proper identification in order to avoid the misdiagnosis of the lymphoma. Diagnosis of hepatitis C virus infection-associated lymphoproliferative disorders requires the integration of clinical, pathological and molecular findings to establish an adequate diagnosis and decide the appropriate therapy to be applied.


Ruiz Del Castillo B.,Hospital Universitario Marques Of Valdecilla Ifimav | Vinue L.,University of La Rioja | Roman E.J.,Hospital Universitario Marques Of Valdecilla Ifimav | Guerra B.,German Federal Institute for Risk Assessment | And 4 more authors.
BMC Microbiology | Year: 2013

Background: The prevalence and type of plasmids, resistance genes and integrons carried by two collections of multiresistant E. coli producing or not extended-spectrum β-lactamases have been compared. Rep-PCR was used to determine the clonal relationship of the organisms. Plasmids were classified according to their incompatibility. Class 1 and Class 2 integrons and antibiotic resistance genes were analysed by PCR and sequencing. Results: Both collections of organisms contained a large diversity of unrelated strains with some clones distributed in both groups of isolates. Large plasmids were identified in the two groups of organisms. Plasmids with replicons repK and repColE were more frequent among ESBL-producing isolates, while repFIA, repFII and repA/C replicons were more frequent in isolates lacking ESBL. Conjugative plasmids with repK and repA/C replicons coded for CTX-M-14 and CMY-2 β-lactamases, respectively. No significant differences were observed in the distribution of class 1 and class 2 integrons among multiresistant E. coli producing or not ESBL, and dfrA17-ant(3″)-Ie was the cassette arrangement most commonly found. Conclusions: In the concrete temporal and geographical context of this study, multiresistant E. coli producing ESBL or other mechanisms of resistance were largely clonally diverse and present some differences in the types of harboured plasmids. Still, some clones were found in both ESBL-producing and -lacking isolates. © 2013 Ruiz del Castillo et al.; licensee BioMed Central Ltd.


Martinez-Taboada V.M.,Hospital Universitario Marques Of Valdecilla Ifimav | Lopez-Hoyos M.,Hospital Universitario Marques Of Valdecilla Ifimav | Narvaez J.,Hospital Universitario Bellvitge | Munoz-Cacho P.,University of Cantabria
Autoimmunity Reviews | Year: 2014

Objective: To evaluate the effect of antiplatelet/anticoagulant therapy on the occurrence of severe ischemic complications in GCA patients at diagnosis and while on treatment with corticosteroids (CS), and the risk of bleeding in these patients. Methods: A comprehensive search of PubMed and the Cochrane Central Register of Controlled Trials databases was completed and supplemented by hand searching of the references of all selected articles published from 1992 through December 2012. The cumulative meta-analysis included 6 retrospective studies that provided a total of 914 GCA patients. The effect of established antiplatelet/anticoagulant therapy on the occurrence of severe ischemic complications in patients with GCA at diagnosis and on the development of new severe ischemic complications in patients with GCA after diagnosis and while on treatment with CS were evaluated; as well as the risk of bleeding in patients with GCA on concomitant treatment with CS and antiplatelet/anticoagulant therapy. Results: Antiplatelet/anticoagulant therapy before the diagnosis of GCA was not associated with a protection to develop severe ischemic complications (OR: 0.661; 95% CI [0.287-1.520]; p= 0.33). However, such a therapy may prevent from severe ischemic complications after the diagnosis of GCA (OR: 0.318; [0.101-0.996]; p= 0.049) without increasing the risk of bleeding in patients with GCA on concomitant treatment with CS (OR: 0.658; [0.089-4.856]; p= 0.682). Conclusions: Antiplatelet/anticoagulant therapy prior to the diagnosis of GCA was not associated with reduction in severe ischemic complications. However, antiplatelet/anticoagulant therapy demonstrated a marginal benefit when used together with CS therapy in patients with established GCA without associated bleeding risk. © 2014 Elsevier B.V.


Ocejo-Vinyals J.G.,Hospital Universitario Marques Of Valdecilla Ifimav | de Mateo E.P.,Hospital Universitario Marques Of Valdecilla Ifimav | Hoz M.T.,Hospital Universitario Marques Of Valdecilla Ifimav | Arroyo J.L.,Banco Regional de Sangre y Tejidos | And 3 more authors.
Cytokine | Year: 2013

Background: Interleukin 17 (IL-17) is induced during the early stages of tuberculosis infection, playing an important role in the defense against mycobacterial infection. To date, only one study performed in Chinese Han population has found an association between IL-17F sequence variants and susceptibility to tuberculosis, but no relationship has been found with another single nucleotide polymorphism (SNP) in IL-17A gene (rs2275913). Methods: To assess if rs2275913 (G-152A) SNP, could be associated with susceptibility to pulmonary tuberculosis (PTB) in a genetically homogeneous Caucasian population, we analyzed if its allele and genotype frequencies were statistically significant in a case-control study. One hundred and ninety-two patients with active PTB and 266 blood healthy donors were enrolled in this study. Results: The frequency of the GG versus GA. +. AA genotype was significantly more frequent in patients with PTB than in control subjects assuming a dominant model (50.52% versus 39.10% respectively, OR. = 1.59, 95%CI. = 1.09-2.31, p= 0.015). Despite patients with PTB had higher serum IL-17 levels, we did not find an association of this SNP with IL-17 ex vivo production after stimulation with Mycobacterium tuberculosis (Mtb) antigens or phytohemagglutinin (PHA). Conclusion: Our results would suggest an association between IL-17A rs2275913 - 152G allele and GG genotype with susceptibility to PTB for the first time. © 2013 Elsevier Ltd.


Mulet X.,Hospital Universitario Son Espases | Cabot G.,Hospital Universitario Son Espases | Ocampo-Sosa A.A.,Hospital Universitario Marques Of Valdecilla Ifimav | Dominguez M.A.,Hospital Universitario Of Bellvitge | And 9 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

A limited number of Pseudomonas aeruginosa genotypes (mainly ST-111, ST-175, and ST-235), known as high-risk clones, are responsible for epidemics of nosocomial infections by multidrug-resistant (MDR) or extensively drug-resistant (XDR) strains worldwide. We explored the potential biological parameters that may explain the success of these clones. A total of 20 isolates from each of 4 resistance groups (XDR, MDR, ModR [resistant to 1 or 2 classes], and MultiS [susceptible to all antipseudomonals]), recovered from a multicenter study of P. aeruginosa bloodstream infections performed in 10 Spanish hospitals, were analyzed. A further set of 20 XDR isolates belonging to epidemic high-risk clones (ST-175 [n = 6], ST-111 [n = 7], and ST-235 [n = 7]) recovered from different geographical locations was also studied. When unknown, genotypes were documented through multilocus sequence typing. The biological parameters evaluated included twitching, swimming, and swarming motility, biofilm formation, production of pyoverdine and pyocyanin, spontaneous mutant frequencies, and the in vitro competition index (CI) obtained with a flow cytometry assay. All 20 (100%) XDR, 8 (40%) MDR, and 1 (5%) ModR bloodstream isolate from the multicenter study belonged to high-risk clones. No significant differences were observed between clonally diverse ModR and MultiS isolates for any of the parameters. In contrast, MDR/XDR high-risk clones showed significantly increased biofilm formation and mutant frequencies but significantly reduced motility (twitching, swimming, and swarming), production of pyoverdine and pyocyanin, and fitness. The defined biological markers of high-risk clones, which resemble those resulting from adaptation to chronic infections, could be useful for the design of specific treatment and infection control strategies. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Cabot G.,Hospital Universitario Son Espases | Ocampo-Sosa A.A.,Hospital Universitario Marques Of Valdecilla Ifimav | Dominguez M.A.,Hospital Universitario Of Bellvitge | Gago J.F.,Hospital Universitario Son Espases | And 7 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2012

Recent reports have revealed the existence of widespread extensively drug-resistant (XDR) P. aeruginosa high-risk clones in health care settings, but there is still scarce information on their specific chromosomal (mutational) and acquired resistance mechanisms. Up to 20 (10.5%) of 190 bloodstream isolates collected from 10 Spanish hospitals met the XDR criteria. A representative number (15 per group) of isolates classified as multidrug-resistant (MDR) (22.6%), resistant to 1 to 2 classes (moderately resistant [modR]) (23.7%), or susceptible to all antibiotics (multiS) (43.2%) were investigated in parallel. Multilocus sequence typing (MLST) analysis revealed that all XDR isolates belonged to sequence type 175 (ST175) (n = 19) or ST111 (n = 1), both recognized as international high-risk clones. Clonal diversity was higher among the 15 MDR isolates (4 ST175, 2 ST111, and 8 additional STs) and especially high among the 15 modR (13 different STs) and multiS (14 STs) isolates. The XDR/MDR pattern in ST111 isolates correlated with the production of VIM-2, but none of the ST175 isolates produced acquired β-lactamases. In contrast, the analysis of resistance markers in 12 representative isolates (from 7 hospitals) of ST175 revealed that the XDR pattern was driven by the combination of AmpC hyperproduction, OprD inactivation (Q142X), 3 mutations conferring high-level fluoroquinolone resistance (GyrA T83I and D87N and ParC S87W), a G195E mutation in MexZ (involved in MexXY-OprM overexpression), and the production of a class 1 integron harboring the aadB gene (gentamicin and tobramycin resistance). Of particular interest, in nearly all the ST175 isolates, AmpC hyperproduction was driven by a novel AmpR-activating mutation (G154R), as demonstrated by complementation studies using an ampR mutant of PAO1. This work is the first to describe the specific resistance markers of widespread P. aeruginosa XDR high-risk clones producing invasive infections. Copyright © 2012, American Society for Microbiology. All Rights Reserved.


Cabot G.,Hospital Universitario Son Espases | Ocampo-Sosa A.A.,Hospital Universitario Marques Of Valdecilla Ifimav | Tubau F.,Hospital Universitario Of Bellvitge | Macia M.D.,Hospital Universitario Son Espases | And 7 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2011

The prevalence and impact of the overexpression of AmpC and efflux pumps were evaluated with a collection of 190 Pseudomonas aeruginosa isolates recovered from bloodstream infections in a 2008 multicenter study (10 hospitals) in Spain. The MICs of a panel of 13 antipseudomonal agents were determined by microdilution, and the expressions of ampC, mexB, mexY, mexD, and mexF were determined by real-time reverse transcription (RT)-PCR. Up to 39% of the isolates overexpressed at least one of the mechanisms. ampC overexpression (24.2%) was the most prevalent mechanism, followed by mexY (13.2%), mexB (12.6%), mexF (4.2%), and mexD (2.2%). The overexpression of mexB plus mexY, documented for 5.3% of the isolates, was the only combination showing a significantly (P = 0.02) higher prevalence than expected from the frequencies of the individual mechanisms (1.6%). Additionally, all imipenem-resistant isolates studied (25 representative isolates) showed inactivating mutations in oprD. Most of the isolates nonsusceptible to piperacillin-tazobactam (96%) and ceftazidime (84%) overexpressed ampC, while mexB (25%) and mexY (29%) overexpressions gained relevance among cefepime-nonsusceptible isolates. Nevertheless, the prevalence of mexY overexpression was highest among tobramycin-nonsusceptible isolates (37%), and that of mexB was highest among meropenem-nonsusceptible isolates (33%). Regarding ciprofloxacin-resistant isolates, besides the expected increased prevalence of efflux pump overexpression, a highly significant link to ampC overexpression was documented for the first time: up to 52% of ciprofloxacin-nonsusceptible isolates overexpressed ampC, sharply contrasting with the 24% documented for the complete collection (P < 0.001). In summary, mutation-driven resistance was frequent in P. aeruginosa isolates from bloodstream infections, whereas metallo-β-lactamases, detected in 2 isolates (1%) producing VIM-2, although with increasing prevalences, were still uncommon. Copyright © 2011, American Society for Microbiology. All Rights Reserved.


Farinas M.C.,Hospital Universitario Marques Of Valdecilla Ifimav | Farinas M.C.,University of Cantabria | Martinez-Martinez L.,Hospital Universitario Marques Of Valdecilla Ifimav | Martinez-Martinez L.,University of Cantabria
Enfermedades Infecciosas y Microbiologia Clinica | Year: 2013

Multiresistant Gram-negative bacteria represent a major health problem worldwide. This is related to the severity of the infections they cause, the difficulties for empiric (even directed) treatment, the ease of multiresistance spread, and the absence of new antimicrobial agents active against this group of pathogens. Accordingly, antimicrobial therapy should be based on the results of susceptibility testing, and may require using antimicrobial combinations. The production of extended-spectrum beta-lactamases represents the most important current problem of resistance among enterobacteria; these organisms cause nosocomial infections, but can also be cultured from non-hospitalised patients. In our country, enterobacteria producing plasmid-mediated AmpC enzymes or most carbapenemases are still uncommon, at the moment. Enterobacteria expressing these types of beta-lactamases present high rates of resistance to aminoglycosides and quinolones, because plasmids coding for beta-lactamases also contain other genes involved in additional resistances and/or the selection of additional chromosomal mutations. Among multiresistant Gram-negative non-fermenting bacteria, the most clinically relevant organism is Pseudomonas aeruginosa, an organism with intrinsic resistance to multiple agents and with ability to capture acquired resistance mechanisms. Other organisms in the latter group include Acinetobacter baumannii, with increasing rates of resistance to antimicrobial agents, and to a lesser extent Stenotrophomonas maltophilia. © 2013 Elsevier España, S.L. All rights reserved.


Martinez-Martinez L.,Hospital Universitario Marques Of Valdecilla Ifimav | Martinez-Martinez L.,University of Cantabria | Calvo J.,Hospital Universitario Marques Of Valdecilla Ifimav
Enfermedades Infecciosas y Microbiologia Clinica | Year: 2010

Most bacteria contain genes involved in natural resistance to antimicrobial agents. Resistance has clinical importance when the organism is able to survive in the presence of in vivo concentrations of antimicrobial agents. Antimicrobial agents can select individual bacteria or bacterial populations that present natural or acquired resistance to them. Resistance is due to multiple genetic and biochemical causes. Two of the most important genetic processes in bacterial resistance are mutagenesis and the acquisition of new genes by horizontal transfer (usually by conjugation, and to a lesser extent transformation or transduction). Biochemical mechanisms of resistance include decreased permeability, antimicrobial modification, target change, protection or over-production, expression of efflux pumps and modifications of certain metabolic pathways. Resistance impacts the health care system in many ways: it requires that clinical microbiologists have reliable tools to detect and analyse the problem; it results in reduced options for empirical and targeted antimicrobial treatment; it forces the use of broad-spectrum antimicrobials; it increases infectious morbidity and mortality and health expenses; and it demands new antimicrobials to control this serious problem in the short term. © 2010 Elsevier España, S.L. All rights reserved.

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