Research Center Biomedica en Red Enfermedades Respiratorias

Barcelona, Spain

Research Center Biomedica en Red Enfermedades Respiratorias

Barcelona, Spain

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Rello J.,Hospital Universitari Vall dHebron | Rello J.,Research Center Biomedica en Red Enfermedades Respiratorias | Rello J.,Autonomous University of Barcelona | Lisboa T.,Federal University of Rio Grande do Sul | And 3 more authors.
The Lancet Respiratory Medicine | Year: 2014

Lower respiratory tract infections in mechanically ventilated patients are a frequent cause of antibiotic treatment in intensive-care units. These infections present as severe sepsis or septic shock with respiratory dysfunction in intubated patients. Purulent respiratory secretions are needed for diagnosis, but distinguishing between pneumonia and tracheobronchitis is not easy. Both presentations are associated with longlasting mechanical ventilation and extended intensive-care unit stay, providing a rationale for antibiotic treatment initiation. Differentiation of colonisers from true pathogens is difficult, and microbiological data show Staphylococcus aureus and Pseudomonas aeruginosa to be of great concern because of clinical outcomes and therapeutic challenges. Key management issues include identification of the pathogen, choice of initial empirical antibiotic, and decisions with regard to the resolution pattern. © 2014 Elsevier Ltd.


Torres A.,Institute dInvestigacions Biomediques August Pi i Sunyer | Torres A.,Research Center Biomedica En Red Enfermedades Respiratorias | Torres A.,University of Barcelona | Sibila O.,Hospital Of La Santa Creu I Sant Pau | And 19 more authors.
JAMA - Journal of the American Medical Association | Year: 2015

Importance: In patients with severe community-acquired pneumonia, treatment failure is associated with excessive inflammatory response and worse outcomes. Corticosteroids may modulate cytokine release in these patients, but the benefit of this adjunctive therapy remains controversial. Objective: To assess the effect of corticosteroids in patients with severe communityacquired pneumonia and high associated inflammatory response. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled trial conducted in 3 Spanish teaching hospitals involving patients with both severe community-acquired pneumonia and a high inflammatory response, which was defined as a level of C-reactive protein greater than 150mg/L at admission. Patients were recruited and followed up from June 2004 through February 2012. Interventions: Patients were randomized to receive either an intravenous bolus of 0.5mg/kg per 12 hours of methylprednisolone (n = 61) or placebo (n = 59) for 5 days started within 36 hours of hospital admission. Main Outcomes and Measures: The primary outcomewas treatment failure (composite outcome of early treatment failure defined as [1] clinical deterioration indicated by development of shock, [2] need for invasive mechanical ventilation not present at baseline, or [3] death within 72 hours of treatment; or composite outcome of late treatment failure defined as [1] radiographic progression, [2] persistence of severe respiratory failure, [3] development of shock, [4] need for invasive mechanical ventilation not present at baseline, or [5] death between 72 hours and 120 hours after treatment initiation; or both early and late treatment failure). In-hospital mortalitywas a secondary outcome and adverse eventswere assessed. Results: There was less treatment failure among patients from the methylprednisolone group (8 patients [13%]) compared with the placebo group (18 patients [31%]) (P = .02), with a difference between groups of 18% (95% CI, 3% to 32%). Corticosteroid treatment reduced the risk of treatment failure (odds ratio, 0.34 [95% CI, 0.14 to 0.87]; P = .02). In-hospital mortality did not differ between the 2 groups (6 patients [10%] in the methylprednisolone group vs 9 patients [15%] in the placebo group; P = .37); the difference between groups was 5% (95% CI, -6% to 17%). Hyperglycemia occurred in 11 patients (18%) in the methylprednisolone group and in 7 patients (12%) in the placebo group (P = .34). Conclusions and Relevance: Among patients with severe community-acquired pneumonia and high initial inflammatory response, the acute use of methylprednisolone compared with placebo decreased treatment failure. If replicated, these findings would support the use of corticosteroids as adjunctive treatment in this clinical population. Trial Registration: clinicaltrials.gov Identifier: NCT00908713. Copyright © 2015 American Medical Association. All rights reserved.


Montes M.,Research Center Biomedica en Red Enfermedades Respiratorias | Montes M.,Hospital Donostia | Tamayo E.,Research Center Biomedica en Red Enfermedades Respiratorias | Orden B.,Hospital Universitario Puerta Of Hierro | And 4 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2010

The aim of this study was to determine the prevalence and characteristics of non-fluoroquinolone (FQ)-susceptible Streptococcus pyogenes isolates and to study their mechanisms of resistance. We performed a prospective prevalence study with 468 isolates collected from 2005 to 2007 and a retrospective study that was based on the examination of existing data collected from 1999 to 2008. The retrospective study included data for isolates with high-level resistance (HR) to ciprofloxacin (MIC ≥ 32 μg/ml) (HR isolates) and isolates with the same emm types as those reported in the literature with low-level resistance (LR) to ciprofloxacin (MICs, 2 to 8 μg/ml) (LR isolates, n = 205). Genetic characterization of the isolates was performed by means of emm typing and multilocus sequence typing. The prevalence of LR ranged from 1.9% in 2005 to 30.8% in 2007. This increase was mainly due to the circulation of an emm6 subtype (emm6.4) that represented 77.1% of the LR isolates in 2007. Notably, another emm6 subtype, also detected in 2007 (emm6.37), showed coresistance to 14-and 15-membered macrolides mediated by the mefA gene. Only three HR isolates were detected (isolates emm68.1/ST247/T3,13,B3264, emm77/ST399/T28, and emm28/ST52/T28), and all were identified in the retrospective study. Overall, the 673 isolates represented 25 emm types. All LR isolates were clustered into two emm types: emm6 (six emm6 subtypes) and emm75. All the 156 emm6 isolates had LR, harbored the Ser79/Ala mutation in the parC gene product, and had the same sequence type (ST), ST382. Most (21/33) of the emm75 isolates had LR, showed the Ser79/Phe plus Asp91/Asn double mutation in the parC gene product, and were ST150. The Asp91/Asn mutation by itself did not confer resistance to FQs. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Cilloniz C.,University of Barcelona | Cilloniz C.,Research Center Biomedica en Red Enfermedades Respiratorias | Polverino E.,University of Barcelona | Polverino E.,Research Center Biomedica en Red Enfermedades Respiratorias | And 10 more authors.
Chest | Year: 2013

Background: Prolonged life expectancy has currently increased the proportion of the very elderly among patients with community-acquired pneumonia (CAP). The aim of this study was to determine the infl uence of age and comorbidity on microbial patterns in patients over 65 years of age with CAP. Methods: This study was a prospective observational study of adult patients with CAP (excluding those in nursing homes) over a 12-year period. We compared patients aged 65 to 74 years, 75 to 84 years, and > 85 years for potential differences in clinical presentation, comorbidities, severity on admission, microbial investigations, causes, antimicrobial treatment, and outcomes. Results: We studied a total of 2,149 patients: 759 patients (35.3%) aged 65 to 74 years, 941 patients (43.7%) aged 75 to 84 years, and 449 patients (20.8%) aged > 85 years. At least one comorbidity was present in 1,710 patients (79.6%). Streptococcus pneumoniae was the most frequent pathogen in all age groups, regardless of comorbidity. Staphylococcus aureus, Enterobacteriaceae, and Pseudomonas aeruginosa accounted for 9.1% of isolates, and Haemophilus infl uenzae, 6.4%. All these pathogens were isolated only in patients with at least one comorbidity. Mortality increased with age (65-74 years, 6.9%; 75-84 years, 8.9%; > 85 years, 17.1%; P < .001) and was associated with increased comorbidities (neurologic; OR, 2.1; 95% CI, 1.5-2.1), Pneumonia Severity Index IV or V (OR, 3.2; 95% CI, 1.8-6.0), bacteremia (OR, 1.7; 95% CI, 1.1-2.7), the presence of a potential multidrug-resistant (MDR) pathogen (S aureus, P aeruginosa, Enterobacteriaceae; OR, 2.4; 95% CI, 1.3-4.3), and ICU admission (OR, 4.2; 95% CI, 2.9-6.1) on multivariate analysis. Conclusions: Age does not infl uence microbial cause itself, whereas comorbidities are associated with specifi c causes such as H infl uenzae and potential MDR pathogens. Mortality in the elderly is mainly driven by the presence of comorbidities and potential MDR pathogens.


Ranzani O.T.,University of Barcelona | Ranzani O.T.,Research Center Biomedica en Red Enfermedades Respiratorias | Ranzani O.T.,University of Sao Paulo | Ferrer M.,University of Barcelona | And 9 more authors.
Critical Care Medicine | Year: 2012

Objective: The use of corticosteroids is frequent in critically-ill patients. However, little information is available on their effects in patients with intensive care unit-acquired pneumonia. We assessed patients' characteristics, microbial etiology, inflammatory response, and outcomes of previous corticosteroid use in patients with intensive care unit-acquired pneumonia. Design: Prospective observational study. Setting: Intensive care units of a university teaching hospital. Patients: Three hundred sixteen patients with intensive care unit-acquired pneumonia. Patients were divided according to previous systemic steroid use at onset of pneumonia. Interventions: None. Measurements and Main Results: Survival at 28 days was analyzed using Cox regression, with adjustment for the propensity for receiving steroid therapy. One hundred twenty-five (40%) patients were receiving steroids at onset of pneumonia. Despite similar baseline clinical severity, steroid treatment was associated with decreased 28-day survival (adjusted hazard ratio for propensity score and mortality predictors 2.503; 95% confidence interval 1.176-5.330; p = .017) and decreased systemic inflammatory response. In post hoc analyses, steroid treatment had an impact on survival in patients with nonventilator intensive care unit-acquired pneumonia, those with lower baseline severity and organ dysfunction, and those without etiologic diagnosis or bacteremia. The cumulative dosage of corticosteroids had no significant effect on the risk of death, but bacterial burden upon diagnosis was higher in patients receiving steroid therapy. Conclusions: In critically-ill patients, systemic corticosteroids should be used very cautiously because this treatment is strongly associated with increased risk of death in patients with intensive care unit-acquired pneumonia, particularly in the absence of established indications and in patients with lower baseline severity. Decreased inflammatory response may result in delayed clinical suspicion of intensive care unit-acquired pneumonia and higher bacterial count. © 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.


Hoiby N.,Rigshospitalet | Hoiby N.,Copenhagen University | Bjarnsholt T.,Rigshospitalet | Bjarnsholt T.,Copenhagen University | And 18 more authors.
Clinical Microbiology and Infection | Year: 2015

Biofilms cause chronic infections in tissues or by developing on the surfaces of medical devices. Biofilm infections persist despite both antibiotic therapy and the innate and adaptive defence mechanisms of the patient. Biofilm infections are characterized by persisting and progressive pathology due primarily to the inflammatory response surrounding the biofilm. For this reason, many biofilm infections may be difficult to diagnose and treat efficiently. It is the purpose of the guideline to bring the current knowledge of biofilm diagnosis and therapy to the attention of clinical microbiologists and infectious disease specialists. Selected hallmark biofilm infections in tissues (e.g. cystic fibrosis with chronic lung infection, patients with chronic wound infections) or associated with devices (e.g. orthopaedic alloplastic devices, endotracheal tubes, intravenous catheters, indwelling urinary catheters, tissue fillers) are the main focus of the guideline, but experience gained from the biofilm infections included in the guideline may inspire similar work in other biofilm infections. The clinical and laboratory parameters for diagnosing biofilm infections are outlined based on the patient's history, signs and symptoms, microscopic findings, culture-based or culture-independent diagnostic techniques and specific immune responses to identify microorganisms known to cause biofilm infections. First, recommendations are given for the collection of appropriate clinical samples, for reliable methods to specifically detect biofilms, for the evaluation of antibody responses to biofilms, for antibiotic susceptibility testing and for improvement of laboratory reports of biofilm findings in the clinical microbiology laboratory. Second, recommendations are given for the prevention and treatment of biofilm infections and for monitoring treatment effectiveness. Finally, suggestions for future research are given to improve diagnosis and treatment of biofilm infections. © 2014 European Society of Clinical Microbiology and Infectious Diseases.


Agusti A.,University of Barcelona | Agusti A.,Research Center Biomedica en Red Enfermedades Respiratorias | Barbera J.A.,University of Barcelona | Barbera J.A.,Research Center Biomedica en Red Enfermedades Respiratorias | And 3 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Patients with chronic obstructive pulmonary disease (COPD) often suffer other concomitant disorders, such as cardiovascular diseases and metabolic disorders, that influence significantly (and independently of lung function) their health status and prognosis. Thus, COPD is not a single organ condition, and disturbances of a complex network of interorgan connected responses occur and modulate the natural history of the disease. Here, we propose a novel hypothesis that considers a vascularly connected network with (1) the lungs as themain external sensor of the systemand a major source of "danger signals"; (2) the endothelium as an internal sensor of the system (alsoa potential target tissue);and(3)twokey responding elements, bone marrow and adipose tissue, which produce both inflammatory and repair signals. According to the model, the development of COPD, and associated multimorbidities (herewe focus on cardiovascular disease as an important example), depend on the manner in which the vascular connected network responds, adapts, or fails to adapt (dictated by the genetic and epigenetic background of the individual) to the inhalation of particles and gases, mainly in cigarette smoke. The caveats and limitations of the hypothesis, as well as the experimental and clinical research needed to test and explore the proposed model, are also briefly discussed. Copyright © 2013 by the American Thoracic Society.


Padilla E.,University of the Balearic Islands | Llobet E.,Research Center Biomedica en Red Enfermedades Respiratorias | Domenech-Sanchez A.,University of the Balearic Islands | Martinez-Martinez L.,Hospital Universitario Marques Of Valdecilla | And 4 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2010

Respiratory infections caused by Klebsiella pneumoniae are characterized by high rates of mortality and morbidity. Management of these infections is often difficult, due to the high frequency of strains that are resistant to multiple antimicrobial agents. Multidrug efflux pumps play a major role as a mechanism of antimicrobial resistance in Gram-negative pathogens. In the present study, we investigated the role of the K. pneumoniae AcrRAB operon in antimicrobial resistance and virulence by using isogenic knockouts deficient in the AcrB component and the AcrR repressor, both derived from the virulent strain 52145R. We demonstrated that the AcrB knockout was more susceptible, not only to quinolones, but also to other antimicrobial agents, including β-lactams, than the wild-type strain and the AcrR knockout. We further showed that the AcrB knockout was more susceptible to antimicrobial agents present in human bronchoalveolar lavage fluid and to human antimicrobial peptides than the wild-type strain and the AcrR knockout. Finally, the AcrB knockout exhibited a reduced capacity to cause pneumonia in a murine model, in contrast to the wild-type strain. The results of this study suggest that, in addition to contributing to the multidrug resistance phenotype, the AcrAB efflux pump may represent a novel virulence factor required for K. pneumoniae to resist innate immune defense mechanisms of the lung, thus facilitating the onset of pneumonia. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Llobet E.,Recinto Hospital Joan March | Llobet E.,Research Center Biomedica en Red Enfermedades Respiratorias | Campos M.A.,Recinto Hospital Joan March | Gimenez P.,Recinto Hospital Joan March | And 5 more authors.
Infection and Immunity | Year: 2011

Antimicrobial peptides (APs) impose a threat to the survival of pathogens, and it is reasonable to postulate that bacteria have developed strategies to counteract them. Polymyxins are becoming the last resort to treat infections caused by multidrug-resistant Gram-negative bacteria and, similar to APs, they interact with the anionic lipopolysaccharide. Given that polymyxins and APs share the initial target, it is possible that bacterial defense mechanisms against polymyxins will be also effective against host APs. We sought to determine whether exposure to polymyxin will increase Klebsiella pneumoniae resistance to host APs. Indeed, exposure of K. pneumoniae to polymyxin induces cross-resistance not only to polymyxin itself but also to APs present in the airways. Polymyxin treatment upregulates the expression of the capsule polysaccharide operon and the loci required to modify the lipid A with aminoarabinose and palmitate with a concomitant increase in capsule and lipid A species containing such modifications. Moreover, these surface changes contribute to APs resistance and also to polymyxin-induced cross-resistance to APs. Bacterial loads of lipid A mutants in trachea and lungs of intranasally infected mice were lower than those of wild-type strain. PhoPQ, PmrAB, and the Rcs system govern polymyxin-induced transcriptional changes, and there is a cross talk between PhoPQ and the Rcs system. Our findings support the notion that Klebsiella activates a defense program against APs that is controlled by three signaling systems. Therapeutic strategies directed to prevent the activation of this program could be a new approach worth exploring to facilitate the clearance of the pathogen from the airways. © 2011, American Society for Microbiology.


Faner R.,Research Center Biomedica en Red Enfermedades Respiratorias | Faner R.,Institute dInvestigacions Biomediques August Pi I Sunyer IDIBAPS | Rojas M.,McGowan Institute for Regenerative Medicine | MacNee W.,Queens Medical Research Institute | And 3 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2012

Aging is a natural process characterized by progressive functional impairment and reduced capacity to respond appropriately to environmental stimuli and injury. The incidence of two common chronic respiratory diseases (chronic obstructive pulmonary disease [COPD] and idiopathic pulmonary fibrosis [IPF]) increaseswith advanced age. It is plausible, therefore, that abnormal regulation of themechanisms of normal aging may contribute to the pathobiology of both COPD and IPF. This review discusses the available evidence supporting a number of aging mechanisms, including oxidative stress, telomere length regulation, cellular and immunosenescence, aswell as changes inanumberofantiagingmoleculesandtheextracellularmatrix,which are abnormal in COPD and/or IPF. A better understanding of these abnormalitiesmay help in the design of novel and better therapeutic interventions for these patients. Copyright © 2012 by the American Thoracic Society.

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