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Prina E.,University of Barcelona | Prina E.,University of Sao Paulo | Pasini S.,University of Milan | Torres A.,University of Barcelona | Torres A.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes
Clinical Pulmonary Medicine | Year: 2015

One of the main concerns about the management of community-acquired pneumonia (CAP) is to choose an adequate empirical antibiotic treatment. Patients with CAP usually respond to the standard antibiotics suggested by CAP guidelines; however, a small percentage of patients need a different and more aggressive treatment because of the presence of resistant pathogens. The critical point is to identify this small subgroup of CAP patients and to avoid the overtreatment of the remaining CAP patients. Therefore, it is important to create a tool to stratify patients at risk for resistant pathogens. The definition of health care-associated pneumonia has not proven to be effective. Moreover, recent studies proposed new scores on the basis of specific factors to screen the population at risk. However, they presented limitations: there was a lack of strong external validation, they included immunosuppressed patients, and they used different definitions of multidrugresistant pathogens. In this review, we underline the limitations of the current approach to guide empirical antibiotic therapy in CAP. We propose to avoid the term multidrug resistant in favor of a novel definition called "PES concept," which includes the 3 most frequent resistant pathogens in CAP that are not susceptible to the antibiotics suggested by the guidelines: Pseudomonas aeruginosa, Enterobacteriaceae ESBL positive, and methicillin-resistant Staphylococcus aureus. This new concept is treatment oriented and classifies pathogens according to their response to a specific class of antibiotics. Thus, we present a conceptual framework to guide the empirical antibiotic selection considering 3 groups of patients: immunosuppressed patients with CAP, patients with CAP without risk factors for PES, and patients with CAP with high risk for PES pathogens. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source


Polverino E.,FSM | Polverino E.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes | Nava S.,Respiratory Intensive Care Unit | Ferrer M.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes | And 9 more authors.
Intensive Care Medicine | Year: 2010

Background: Respiratory intensive care units (RICU) dedicated to weaning could be suitable facilities for clinical management of "post-ICU" patients. Methods: We retrospectively analyzed the time course of patients' characteristics, clinical outcomes and medical staff utilization in five Italian RICUs by comparing three periods of 5 consecutive years (from 1991 to 2005). Results: A total of 3,106 patients (age 76 ± 4 years; 72% males) were analyzed. The number of co-morbidities per patient (from 1.8 to 3.0, p = 0.05) and the previous intensive care unit (ICU) stay (from 25 to 32 days, p = 0.002) increased over time. The doctor-to-patient ratio significantly decreased over time (from 1:3 to 1:5, p < 0.01), whereas the physiotherapist-to-patient ratio mildly increased (from 1:6 to 1:4.5, p < 0.05). The overall weaning success rate decreased (from 87 to 66%, p < 0.001), and the discharge destination changed (p < 0.001) over time; fewer patients were discharged to home (from 22 to 10%), and more patients to nursing home (from 3 to 6%), acute hospitals (from 6 to 10%) and rehabilitative units (from 70 to 75%). The mortality rate increased over time (from 9 to 15%). Significant correlations between the doctor-to-patient ratio and the rates of weaning success (r = 0.679, p = 0.005), home discharge (r = 0.722, p = 0.002) and the RICU length of stay (LOS) (r = -0.683, p = 0.005) were observed. Conclusions: The clinical outcomes of our units worsened over 15 years, likely as consequence of admitting more severely ill patients. The potential further negative influence of reduced medical staff availability on weaning success, home discharge and LOS warrants future prospective investigations. © 2009 Copyright jointly hold by Springer and ESICM. Source


Lopez-Rojas R.,University of Seville | Lopez-Rojas R.,Hospitales Universitarios Virgen del Rocio | Docobo-Perez F.,University of Seville | Pachon-Ibanez M.E.,University of Seville | And 7 more authors.
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2011

Pan-resistant Acinetobacter baumannii have prompted the search for therapeutic alternatives. We evaluate the efficacy of four cecropin A-melittin hybrid peptides (CA-M) in vivo. Toxicity was determined in mouse erythrocytes and in mice (lethal dose parameters were LD0, LD50, LD100). Protective dose 50 (PD50) was determined by inoculating groups of ten mice with the minimal lethal dose of A. baumannii (BMLD) and treating with doses of each CA-M from 0.5 mg/kg to LD0. The activity of CA-Ms against A. baumannii was assessed in a peritoneal sepsis model. Mice were sacrificed at 0 and 1, 3, 5, and 7-h post-treatment. Spleen and peritoneal fluid bacterial concentrations were measured. CA(1-8)M(1-18) was the less haemolytic on mouse erythrocytes. LD0 (mg/kg) was 32 for CA(1-8)M(1-18), CA(1-7)M(2-9), and Oct-CA(1-7)M(2-9), and 16 for CA(1-7)M(5-9). PD50 was not achieved with non-toxic doses (≤LD0). In the sepsis model, all CA-Ms were bacteriostatic in spleen, and decreased bacterial concentration (p<0.05) in peritoneal fluid, at 1-h post-treatment; at later times, bacterial regrowth was observed in peritoneal fluid. CA-Ms showed local short-term efficacy in the peritoneal sepsis model caused by pan-resistant Acinetobacter baumannii. © 2011 Springer-Verlag. Source


March C.,Laboratory Microbial Pathogenesis | March C.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes | Cano V.,Laboratory Microbial Pathogenesis | Cano V.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes | And 14 more authors.
PLoS ONE | Year: 2013

Phagocytosis is a key process of the immune system. The human pathogen Klebsiella pneumoniae is a well known example of a pathogen highly resistant to phagocytosis. A wealth of evidence demonstrates that the capsule polysaccharide (CPS) plays a crucial role in resistance to phagocytosis. The amoeba Dictyostelium discoideum shares with mammalian macrophages the ability to phagocytose and kill bacteria. The fact that K. pneumoniae is ubiquitous in nature and, therefore, should avoid predation by amoebae, poses the question whether K. pneumoniae employs similar means to counteract amoebae and mammalian phagocytes. Here we developed an assay to evaluate K. pneumoniae-D. discoideum interaction. The richness of the growth medium affected the threshold at which the cps mutant was permissive for Dictyostelium and only at lower nutrient concentrations the cps mutant was susceptible to predation by amoebae. Given the critical role of bacterial surface elements on host-pathogen interactions, we explored the possible contribution of the lipopolysaccharide (LPS) and outer membrane proteins (OMPs) to combat phagoyctosis by D. discoideum. We uncover that, in addition to the CPS, the LPS O-polysaccharide and the first core sugar participate in Klebsiella resistance to predation by D. discoideum. K. pneumoniae LPS lipid A decorations are also necessary to avoid predation by amoebae although PagP-dependent palmitoylation plays a more important role than the lipid A modification with aminoarabinose. Mutants lacking OMPs OmpA or OmpK36 were also permissive for D. discoideium growth. Except the LPS O-polysaccharide mutants, all mutants were more susceptible to phagocytosis by mouse alveolar macrophages. Finally, we found a correlation between virulence, using the pneumonia mouse model, and resistance to phagocytosis. Altogether, this work reveals novel K. pneumoniae determinants involved in resistance to phagocytosis and supports the notion that Dictyostelium amoebae might be useful as host model to measure K. pneumoniae virulence and not only phagocytosis. © 2013 March et al. Source


Moranta D.,Program Infection and Immunity | Moranta D.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes | Regueiro V.,Program Infection and Immunity | Regueiro V.,Research Center Biomedica en Red Enfermedades Respiratorias CibeRes | And 11 more authors.
Infection and Immunity | Year: 2010

Human β-defensins (hBDs) contribute to the protection of the respiratory tract against pathogens. It is reasonable to postulate that pathogens have developed countermeasures to resist them. Klebsiella pneumoniae capsule polysaccharide (CPS), but not the lipopolysaccharide O antigen, mediated resistance against hBD1 and hBD2. hBD3 was the most potent hBD against Klebsiella. We investigated the possibility that as a strategy for survival in the lung, K. pneumoniae may not activate the expression of hBDs. Infection of A549 and normal human bronchial cells with 52145-ΔwcaK2, a CPS mutant, increased the expression of hBD2 and hBD3. Neither the wild type nor the lipopolysaccharide O antigen mutant increased the expression of hBDs. In vivo, 52145-ΔwcaK2 induced higher levels of mBD4 and mBD14, possible mouse orthologues of hBD2 and hBD3, respectively, than the wild type. 52145-ΔwcaK2-dependent upregulation of hBD2 occurred via NF-κB and mitogen-activated protein kinases (MAPKs) p44/42, Jun N-terminal protein kinase (JNK)-dependent pathways. The increase in hBD3 expression was dependent on the MAPK JNK. 52145-ΔwcaK2 engaged Toll-like receptors 2 and 4 (TLR2 and TLR4) to activate hBD2, whereas hBD3 expression was dependent on NOD1. K. pneumoniae induced the expression of CYLD and MKP-1, which act as negative regulators for 52145-ΔwcaK2-induced expression of hBDs. Bacterial engagement of pattern recognition receptors induced CYLD and MKP-1, which may initiate the attenuation of proinflammatory pathways. The results of this study indicate that K. pneumoniae CPS not only protects the pathogen from the bactericidal action of defensins but also impedes their expression. These features of K. pneumoniae CPS may facilitate pathogen survival in the hostile environment of the lung. Copyright © 2010, American Society for Microbiology. All Rights Reserved. Source

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