RESUMEN
Streptococcus pneumoniae (the pneumococcus) is the major cause of bacterial meningitis globally, and pneumococcal meningitis is associated with increased risk of long-term neurological sequelae. These include several sensorimotor functions that are controlled by specific brain regions which, during bacterial meningitis, are damaged by a neuroinflammatory response and the deleterious action of bacterial toxins in the brain. However, little is known about the invasion pattern of the pneumococcus into the brain. Using a bacteremia-derived meningitis mouse model, we combined 3D whole brain imaging with brain microdissection to show that all brain regions were equally affected during disease progression, with the presence of pneumococci closely associated to the microvasculature. In the hippocampus, the invasion provoked microglial activation, while the neurogenic niche showed increased proliferation and migration of neuroblasts. Our results indicate that, even before the outbreak of symptoms, the bacterial load throughout the brain is high and causes neuroinflammation and cell death, a pathological scenario which ultimately leads to a failing regeneration of new neurons.
Asunto(s)
Bacteriemia , Encéfalo , Meningitis Neumocócica , Streptococcus pneumoniae , Animales , Meningitis Neumocócica/patología , Ratones , Encéfalo/patología , Encéfalo/microbiología , Bacteriemia/patología , Bacteriemia/microbiología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Masculino , FemeninoRESUMEN
Pasteurella multocida is an important zoonotic respiratory pathogen capable of infecting a diverse range of hosts, including humans, farm animals, and wild animals. However, the precise mechanisms by which P. multocida compromises the pulmonary integrity of mammals and subsequently induces systemic infection remain largely unexplored. In this study, based on mouse and rabbit models, we found that P. multocida causes not only lung damage but also bacteremia due to the loss of lung integrity. Furthermore, we demonstrated that bacteremia is an important aspect of P. multocida pathogenesis, as evidenced by the observed multiorgan damage and systemic inflammation, and ultimately found that this systemic infection leads to a cytokine storm that can be mitigated by IL-6-neutralizing antibodies. As a result, we divided the pathogenesis of P. multocida into two phases: the pulmonary infection phase and the systemic infection phase. Based on unbiased RNA-seq data, we discovered that P. multocida-induced apoptosis leads to the loss of pulmonary epithelial integrity. These findings have been validated in both TC-1 murine lung epithelial cells and the lungs of model mice. Conversely, the administration of Ac-DEVD-CHO, an apoptosis inhibitor, effectively restored pulmonary epithelial integrity, significantly mitigated lung damage, inhibited bacteremia, attenuated the cytokine storm, and reduced mortality in mouse models. At the molecular level, we demonstrated that the FAK-AKT-FOXO1 axis is involved in P. multocida-induced lung epithelial cell apoptosis in both cells and animals. Thus, our research provides crucial information with regard to the pathogenesis of P. multocida as well as potential treatment options for this and other respiratory bacterial diseases.
Asunto(s)
Bacteriemia , Infecciones por Pasteurella , Pasteurella multocida , Enfermedades de los Roedores , Humanos , Animales , Conejos , Ratones , Infecciones por Pasteurella/veterinaria , Infecciones por Pasteurella/microbiología , Proteínas Proto-Oncogénicas c-akt , Síndrome de Liberación de Citoquinas/patología , Síndrome de Liberación de Citoquinas/veterinaria , Pulmón/patología , Bacteriemia/veterinaria , Bacteriemia/patología , Apoptosis , Mamíferos , Proteína Forkhead Box O1RESUMEN
Neisseria meningitidis (the meningococcus) remains a major cause of bacterial meningitis and fatal sepsis. This commensal bacterium of the human nasopharynx can cause invasive diseases when it leaves its niche and reaches the bloodstream. Blood-borne meningococci have the ability to adhere to human endothelial cells and rapidly colonize microvessels. This crucial step enables dissemination into tissues and promotes deregulated inflammation and coagulation, leading to extensive necrotic purpura in the most severe cases. Adhesion to blood vessels relies on type IV pili (TFP). These long filamentous structures are highly dynamic as they can rapidly elongate and retract by the antagonistic action of two ATPases, PilF and PilT. However, the consequences of TFP dynamics on the pathophysiology and the outcome of meningococcal sepsis in vivo have been poorly studied. Here, we show that human graft microvessels are replicative niches for meningococci, that seed the bloodstream and promote sustained bacteremia and lethality in a humanized mouse model. Intriguingly, although pilus-retraction deficient N. meningitidis strain (ΔpilT) efficiently colonizes human graft tissue, this mutant did not promote sustained bacteremia nor induce mouse lethality. This effect was not due to a decreased inflammatory response, nor defects in bacterial clearance by the innate immune system. Rather, TFP-retraction was necessary to promote the release of TFP-dependent contacts between bacteria and, in turn, the detachment from colonized microvessels. The resulting sustained bacteremia was directly correlated with lethality. Altogether, these results demonstrate that pilus retraction plays a key role in the occurrence and outcome of meningococcal sepsis by supporting sustained bacteremia. These findings open new perspectives on the role of circulating bacteria in the pathological alterations leading to lethal sepsis.
Asunto(s)
Bacteriemia/microbiología , Modelos Animales de Enfermedad , Proteínas Fimbrias/metabolismo , Fimbrias Bacterianas/fisiología , Infecciones Meningocócicas/microbiología , Neisseria meningitidis/patogenicidad , Sepsis/microbiología , Animales , Bacteriemia/metabolismo , Bacteriemia/patología , Adhesión Bacteriana , Células Endoteliales , Femenino , Proteínas Fimbrias/genética , Humanos , Infecciones Meningocócicas/metabolismo , Infecciones Meningocócicas/patología , Ratones , Ratones SCID , Sepsis/metabolismo , Sepsis/patología , Trasplante de PielRESUMEN
The break of the epithelial barrier of gingiva has been a subject of minor interest, albeit playing a key role in periodontal pathology, transitory bacteraemia, and subsequent systemic low-grade inflammation (LGI). The significance of mechanically induced bacterial translocation in gingiva (e.g., via mastication and teeth brushing) has been disregarded despite the accumulated knowledge of mechanical force effects on tight junctions (TJs) and subsequent pathology in other epithelial tissues. Transitory bacteraemia is observed as a rule in gingival inflammation, but is rarely observed in clinically healthy gingiva. This implies that TJs of inflamed gingiva deteriorate, e.g., via a surplus of lipopolysaccharide (LPS), bacterial proteases, toxins, Oncostatin M (OSM), and neutrophil proteases. The inflammation-deteriorated gingival TJs rupture when exposed to physiological mechanical forces. This rupture is characterised by bacteraemia during and briefly after mastication and teeth brushing, i.e., it appears to be a dynamic process of short duration, endowed with quick repair mechanisms. In this review, we consider the bacterial, immune, and mechanical factors responsible for the increased permeability and break of the epithelial barrier of inflamed gingiva and the subsequent translocation of both viable bacteria and bacterial LPS during physiological mechanical forces, such as mastication and teeth brushing.
Asunto(s)
Bacteriemia , Periodontitis , Humanos , Encía , Lipopolisacáridos/farmacología , Periodontitis/patología , Inflamación/patología , Bacteriemia/patologíaRESUMEN
Enterococcus faecalis is a significant cause of hospital-acquired bacteremia. Herein, the discovery is reported that cardiac microlesions form during severe bacteremic E. faecalis infection in mice. The cardiac microlesions were identical in appearance to those formed by Streptococcus pneumoniae during invasive pneumococcal disease. However, E. faecalis does not encode the virulence determinants implicated in pneumococcal microlesion formation. Rather, disulfide bond forming protein A (DsbA) was found to be required for E. faecalis virulence in a Caenorhabditis elegans model and was necessary for efficient cardiac microlesion formation. Furthermore, E. faecalis promoted cardiomyocyte apoptotic and necroptotic cell death at sites of microlesion formation. Additionally, loss of DsbA caused an increase in proinflammatory cytokines, unlike the wild-type strain, which suppressed the immune response. In conclusion, we establish that E. faecalis is capable of forming cardiac microlesions and identify features of both the bacterium and the host response that are mechanistically involved.
Asunto(s)
Bacteriemia/microbiología , Bacteriemia/patología , Enterococcus faecalis/patogenicidad , Cardiopatías/microbiología , Cardiopatías/patología , Corazón , Animales , Apoptosis , Proteínas Bacterianas/metabolismo , Caenorhabditis elegans/microbiología , Muerte Celular , Citocinas , Modelos Animales de Enfermedad , Infecciones por Bacterias Grampositivas/microbiología , Infecciones por Bacterias Grampositivas/patología , Ratones , Necroptosis , Infecciones Neumocócicas/microbiología , Streptococcus pneumoniae/patogenicidad , Tiorredoxinas , Virulencia , Factores de VirulenciaRESUMEN
Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease affecting primarily premature infants. The disease is characterized by intestinal inflammation and leucocyte infiltration, often progressing to necrosis, perforation, systemic inflammatory response and death. Neutrophil extracellular traps (NETs), denoting nuclear DNA, histone and antimicrobial protein release, have been suggested to play a role in NEC. This study aimed to determine the role of NETs in NEC and explore the effect of chloramidine, a NET inhibitor, on a murine NEC-like intestinal injury model. Blood and intestinal tissues were collected from infants diagnosed with ≥ Stage II NEC, and levels of nucleosomes and NETs, respectively, were compared with those of case-matched controls. In mice, NEC was induced with dithizone/Klebsiella, and mice in the treatment group received 40 mg/kg chloramidine. Bacterial load, intestinal histology, plasma myeloperoxidase and cytokine levels, and immunofluorescent staining were compared with controls. Nucleosomes were significantly elevated in both human and mouse NEC plasma, whereas NET staining was only present in NEC tissue in both species. Chloramidine treatment increased systemic inflammation, bacterial load, organ injury and mortality in murine NEC. Taken together, our findings suggest that NETs are critical in the innate immune defence during NEC in preventing systemic bacteraemia.
Asunto(s)
Bacteriemia/patología , Enterocolitis Necrotizante/patología , Trampas Extracelulares/fisiología , Inflamación/patología , Animales , Animales Recién Nacidos , Bacteriemia/metabolismo , Estudios de Casos y Controles , Citocinas/metabolismo , Modelos Animales de Enfermedad , Enterocolitis Necrotizante/metabolismo , Trampas Extracelulares/metabolismo , Femenino , Humanos , Inflamación/metabolismo , Intestinos/metabolismo , Intestinos/patología , Masculino , RatonesRESUMEN
The obligate intracellular bacterium Chlamydia trachomatis causes the most prevalent bacterial sexually transmitted infection worldwide. CD4 T cells play a central role in the protective immunity against Chlamydia female reproductive tract (FRT) infection, while B cells are thought to be dispensable for resolution of primary Chlamydia infection in mouse models. We recently reported an unexpected requirement of B cells in local Chlamydia-specific CD4 T-cell priming and bacterial containment within the FRT. Here, we sought to tackle the precise effector function of B cells during Chlamydia primary infection. Using mixed bone marrow chimeras that lack B-cell-dependent Ag presentation (MHCIIB-/- ) or devoid of circulating antibodies (AID-/- × µS-/- ), we show that Chlamydia-specific CD4 T-cell expansion does not rely on Ag presentation by B cells. Importantly, we demonstrate that antibody, but not B-cell-dependent Ag presentation, is required for preventing systemic bacterial dissemination following Chlamydia FRT infection.
Asunto(s)
Anticuerpos Antibacterianos/biosíntesis , Linfocitos B/inmunología , Bacteriemia/inmunología , Células de la Médula Ósea/inmunología , Linfocitos T CD4-Positivos/inmunología , Infecciones por Chlamydia/inmunología , Chlamydia trachomatis/inmunología , Animales , Presentación de Antígeno , Linfocitos B/microbiología , Bacteriemia/microbiología , Bacteriemia/patología , Células de la Médula Ósea/microbiología , Linfocitos T CD4-Positivos/microbiología , Infecciones por Chlamydia/microbiología , Infecciones por Chlamydia/patología , Chlamydia trachomatis/crecimiento & desarrollo , Chlamydia trachomatis/patogenicidad , Modelos Animales de Enfermedad , Femenino , Inmunidad Humoral , Isotipos de Inmunoglobulinas , Ratones , Quimera por Trasplante , Vagina/inmunología , Vagina/microbiología , Irradiación Corporal TotalRESUMEN
Inhalational anthrax, a disease caused by inhaling Bacillus anthracis spores, leads to respiratory distress, vascular leakage, high-level bacteremia, and often death within days. Anthrax lethal toxin and edema toxin, which are composed of protective antigen (PA) plus either lethal factor (LF) or edema factor (EF), respectively, play an important yet incompletely defined role in the pulmonary pathophysiology. To better understand their contribution, we examined the structural integrity of the alveolar-capillary barrier in archival formalin-fixed lungs of cynomolgus monkeys challenged with the fully virulent B. anthracis Ames wild-type strain or the isogenic toxin-deficient mutants ΔEF, ΔLF, and ΔPA. Pulmonary spore challenge with the wild-type strain caused high mortality, intra-alveolar hemorrhages, extensive alveolar septal sequestration of bacteria and neutrophils, diffuse destabilization of epithelial and endothelial junctions, increased markers of coagulation and complement activation (including tissue factor and C5a), and multifocal intra-alveolar fibrin deposition. ΔEF challenge was lethal and showed similar alveolar-capillary alterations; however, intra-alveolar hemorrhages, bacterial deposition, and markers of coagulation or complement were absent or markedly lower. In contrast, ΔLF or ΔPA challenges were nonlethal and showed no signs of alveolar bacterial deposition or alveolar-capillary changes. These findings provide evidence that lethal toxin plays a determinative role in bacterial dissemination and alveolar-capillary barrier dysfunction, and edema toxin may significantly exacerbate pulmonary pathologies in a systemic infection.
Asunto(s)
Carbunco/patología , Bacillus anthracis/patogenicidad , Bacteriemia/patología , Pulmón/patología , Infecciones del Sistema Respiratorio/patología , Animales , Anticuerpos Antibacterianos/inmunología , Antígenos Bacterianos/farmacología , Toxinas Bacterianas/farmacología , Pulmón/efectos de los fármacos , Macaca fascicularis/inmunología , Neutrófilos/inmunología , Esporas Bacterianas/inmunología , Esporas Bacterianas/patogenicidad , Virulencia/inmunologíaRESUMEN
BACKGROUND: Cytarabine is a nucleoside analog used in chemotherapy regimens for the treatment of multiple hematologic malignancies. One of the known adverse effects of cytarabine, particularly in patients receiving high-dose cytarabine (HDAC), is drug-induced fever. Multiple studies have demonstrated an increased risk of viridans group streptococcal bacteremia in patients who have received HDAC. For this reason, our institution and several other institutions across the country routinely include vancomycin as empiric coverage for patients who develop fever during HDAC, due to concern for resistance to cephalosporin monotherapy. MATERIALS AND METHODS: Patient demographic, diagnosis, treatment, and outcome information was collected by electronic chart review for each HDAC infusion from 2007 to August 2018 at the University of Iowa Stead Family Children's Hospital. If fever was documented during or within 24 hours of HDAC, additional information was collected regarding patient outcome and diagnostic testing. RESULTS: Of 208 HDAC administrations documented, patients developed fevers during the course on 82 occasions (39.4%). A median of 3 blood cultures per febrile period were obtained from time of fever onset during HDAC administration through >24 hours afebrile. One blood culture was positive for an oral flora organism determined by the microbiology lab report to be a likely contaminant. There were no other positive blood cultures in non-neutropenic or neutropenic patients. CONCLUSION: Fever due to HDAC is relatively common but appears to frequently lack association with bacteremia during the time of HDAC administration. Broad-spectrum empiric antibiotic regimens including vancomycin may be unnecessary for these patients, particularly before they become neutropenic.
Asunto(s)
Bacteriemia/tratamiento farmacológico , Linfoma de Burkitt/tratamiento farmacológico , Citarabina/efectos adversos , Fiebre/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Vancomicina/uso terapéutico , Adolescente , Adulto , Antibacterianos/uso terapéutico , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Bacteriemia/inducido químicamente , Bacteriemia/microbiología , Bacteriemia/patología , Linfoma de Burkitt/patología , Niño , Preescolar , Citarabina/administración & dosificación , Femenino , Fiebre/inducido químicamente , Fiebre/microbiología , Fiebre/patología , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/patología , Linfoma de Células B Grandes Difuso/patología , Masculino , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Infections caused by multidrug-resistant Pseudomonas aeruginosa (MDRPA) have been on the rise worldwide, and delayed active antimicrobial therapy is associated with high mortality. However, few studies have evaluated increases in P. aeruginosa infections with antimicrobial resistance and risk factors for such antimicrobial resistance in Korea. Here, we analyzed changes in antimicrobial susceptibility associated with P. aeruginosa bacteremia and identified risk factors of antimicrobial resistance. METHODS: The medical records of patients with P. aeruginosa bacteremia who were admitted to a tertiary hospital between January 2009 and October 2020 were retrospectively reviewed. Antibiotic resistance rates were compared among the time periods of 2009-2012, 2013-2016, and 2017-2020 and between the intensive care unit (ICU) and non-ICU setting. Empirical antimicrobial therapy was considered concordant, if the organism was susceptible to antibiotics in vitro, and discordant, if resistant. RESULTS: During the study period, 295 patients with P. aeruginosa bacteremia were identified. The hepatobiliary tract (26.8%) was the most common primary site of infection. The rates of carbapenem-resistant P. aeruginosa (CRPA), MDRPA, and extensively drug-resistant P. aeruginosa (XDRPA) were 24.7%, 35.9%, and 15.9%, respectively. XDRPA showed an increasing trend, and CRPA, MDRPA, and XDRPA were also gradually increasing in non-ICU setting. Previous exposure to fluoroquinolones and glycopeptides and urinary tract infection were independent risk factors associated with CRPA, MDRPA, and XDRPA. Previous exposure to carbapenems was an independent risk factor of CRPA. CRPA, MDRPA, and XDRPA were associated with discordant empirical antimicrobial therapy. CONCLUSION: The identification of risk factors for antimicrobial resistance and analysis of antimicrobial susceptibility might be important for concordant empirical antimicrobial therapy in patients with P. aeruginosa bacteremia.
Asunto(s)
Antibacterianos/farmacología , Bacteriemia/patología , Farmacorresistencia Bacteriana Múltiple , Pseudomonas aeruginosa/efectos de los fármacos , Anciano , Antibacterianos/uso terapéutico , Bacteriemia/tratamiento farmacológico , Bacteriemia/microbiología , Bacteriemia/mortalidad , Sistema Biliar/microbiología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Femenino , Fluoroquinolonas/farmacología , Fluoroquinolonas/uso terapéutico , Glicopéptidos/farmacología , Glicopéptidos/uso terapéutico , Mortalidad Hospitalaria , Humanos , Unidades de Cuidados Intensivos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Pseudomonas aeruginosa/aislamiento & purificación , República de Corea , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiologíaRESUMEN
Hypoalbuminemia is associated with the acquisition and severity of infectious diseases, and intact innate and adaptive immune responses depend on albumin. Albumin oxidation and breakdown affect interactions with bioactive lipid mediators that play important roles in antimicrobial defense and repair. There is bio-mechanistic plausibility for a causal link between hypoalbuminemia and increased risks of primary and secondary infections. Serum albumin levels have prognostic value for complications in viral, bacterial and fungal infections, and for infectious complications of non-infective chronic conditions. Hypoalbuminemia predicts the development of healthcare-associated infections, particularly with Clostridium difficile. In coronavirus disease 2019, hypoalbuminemia correlates with viral load and degree of acute lung injury and organ dysfunction. Non-oncotic properties of albumin affect the pharmacokinetics and pharmacodynamics of antimicrobials. Low serum albumin is associated with inadequate antimicrobial treatment. Infusion of human albumin solution (HAS) supplements endogenous albumin in patients with cirrhosis of the liver and effectively supported antimicrobial therapy in randomized controlled trials (RCTs). Evidence of the beneficial effects of HAS on infections in hypoalbuminemic patients without cirrhosis is largely observational. Prospective RCTs are underway and, if hypotheses are confirmed, could lead to changes in clinical practice for the management of hypoalbuminemic patients with infections or at risk of infectious complications.
Asunto(s)
Hipoalbuminemia/patología , Antiinfecciosos/uso terapéutico , Bacteriemia/tratamiento farmacológico , Bacteriemia/patología , COVID-19/complicaciones , COVID-19/patología , COVID-19/virología , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/patología , Humanos , Hipoalbuminemia/tratamiento farmacológico , Hipoalbuminemia/etiología , Inmunidad Innata , Pronóstico , SARS-CoV-2/aislamiento & purificación , Albúmina Sérica/uso terapéuticoRESUMEN
Serratia marcescens is a bacterium frequently found in the environment, but over the last several decades it has evolved into a concerning clinical pathogen, causing fatal bacteremia. To establish such infections, pathogens require specific nutrients; one very limited but essential nutrient is iron. We sought to characterize the iron acquisition systems in S. marcescens isolate UMH9, which was recovered from a clinical bloodstream infection. Using RNA sequencing (RNA-seq), we identified two predicted siderophore gene clusters (cbs and sch) that were regulated by iron. Mutants were constructed to delete each iron acquisition locus individually and in conjunction, generating both single and double mutants for the putative siderophore systems. Mutants lacking the sch gene cluster lost their iron-chelating ability as quantified by the chrome azurol S (CAS) assay, whereas the cbs mutant retained wild-type activity. Mass spectrometry-based analysis identified the chelating siderophore to be serratiochelin, a siderophore previously identified in Serratia plymuthica Serratiochelin-producing mutants also displayed a decreased growth rate under iron-limited conditions created by dipyridyl added to LB medium. Additionally, mutants lacking serratiochelin were significantly outcompeted during cochallenge with wild-type UMH9 in the kidneys and spleen after inoculation via the tail vein in a bacteremia mouse model. This result was further confirmed by an independent challenge, suggesting that serratiochelin is required for full S. marcescens pathogenesis in the bloodstream. Nine other clinical isolates have at least 90% protein identity to the UMH9 serratiochelin system; therefore, our results are broadly applicable to emerging clinical isolates of S. marcescens causing bacteremia.
Asunto(s)
Bacteriemia/microbiología , Proteínas Bacterianas/genética , Hierro/metabolismo , Infecciones por Serratia/microbiología , Serratia marcescens/genética , Serratia marcescens/patogenicidad , Sideróforos/genética , Animales , Bacteriemia/sangre , Bacteriemia/inmunología , Bacteriemia/patología , Proteínas Bacterianas/inmunología , Unión Competitiva , Femenino , Eliminación de Gen , Regulación de la Expresión Génica , Prueba de Complementación Genética , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Transporte Iónico , Hierro/inmunología , Ratones , Ratones Endogámicos CBA , Familia de Multigenes , Unión Proteica , Infecciones por Serratia/sangre , Infecciones por Serratia/inmunología , Infecciones por Serratia/patología , Serratia marcescens/inmunología , Sideróforos/inmunología , VirulenciaRESUMEN
Staphylococcus aureus is a major human pathogen, and the emergence of antibiotic-resistant strains is making all types of S. aureus infections more challenging to treat. With a pressing need to develop alternative control strategies to use alongside or in place of conventional antibiotics, one approach is the targeting of established virulence factors. However, attempts at this have had little success to date, suggesting that we need to better understand how this pathogen causes disease if effective targets are to be identified. To address this, using a functional genomics approach, we have identified a small membrane-bound protein that we have called MspA. Inactivation of this protein results in the loss of the ability of S. aureus to secrete cytolytic toxins, protect itself from several aspects of the human innate immune system, and control its iron homeostasis. These changes appear to be mediated through a change in the stability of the bacterial membrane as a consequence of iron toxicity. These pleiotropic effects on the ability of the pathogen to interact with its host result in significant impairment in the ability of S. aureus to cause infection in both a subcutaneous and sepsis model of infection. Given the scale of the effect the inactivation of MspA causes, it represents a unique and promising target for the development of a novel therapeutic approach.
Asunto(s)
Bacteriemia/microbiología , Evasión Inmune , Infecciones Estafilocócicas/microbiología , Infecciones Cutáneas Estafilocócicas/microbiología , Staphylococcus aureus/patogenicidad , Factores de Virulencia/genética , Células A549 , Animales , Bacteriemia/inmunología , Bacteriemia/patología , Toxinas Bacterianas/genética , Toxinas Bacterianas/inmunología , Eritrocitos/efectos de los fármacos , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Hemo/inmunología , Hemo/metabolismo , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/inmunología , Homeostasis/inmunología , Humanos , Hierro/inmunología , Hierro/metabolismo , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Mutación , Fagocitosis , Proteómica/métodos , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/patología , Infecciones Cutáneas Estafilocócicas/inmunología , Infecciones Cutáneas Estafilocócicas/patología , Toxoide Estafilocócico/genética , Toxoide Estafilocócico/inmunología , Staphylococcus aureus/genética , Staphylococcus aureus/inmunología , Células THP-1 , Virulencia , Factores de Virulencia/inmunología , Factores de Virulencia/toxicidad , alfa-Defensinas/genética , alfa-Defensinas/inmunologíaRESUMEN
Few patients with bacteremia from a nonpulmonary source develop acute respiratory distress syndrome (ARDS). However, the mechanisms that protect the lung from injury in bacteremia have not been identified. We simulated bacteremia by adding Streptococcus pneumoniae to the perfusate of the ex vivo perfused human lung model. In contrast to a pneumonia model in which bacteria were instilled into the distal air spaces of one lobe, injection of high doses of S. pneumoniae into the perfusate was not associated with alveolar epithelial injury as demonstrated by low protein permeability of the alveolar epithelium, intact alveolar fluid clearance, and the absence of alveolar edema. Unexpectedly, the ex vivo human lung rapidly cleared large quantities of S. pneumoniae even though the perfusate had very few intravascular phagocytes and lacked immunoglobulins or complement. The bacteria were cleared in part by the small number of neutrophils in the perfusate, alveolar macrophages in the airspaces, and probably by interstitial pathways. Together, these findings identify one mechanism by which the lung and the alveolar epithelium are protected from injury in bacteremia.
Asunto(s)
Lesión Pulmonar Aguda/microbiología , Lesión Pulmonar Aguda/patología , Bacteriemia/patología , Pulmón/patología , Streptococcus pneumoniae/patogenicidad , Adulto , Bacteriemia/microbiología , Epitelio/microbiología , Epitelio/patología , Femenino , Humanos , Pulmón/microbiología , Macrófagos/microbiología , Macrófagos/patología , Masculino , Persona de Mediana Edad , Neutrófilos/microbiología , Neutrófilos/patología , Permeabilidad , Infecciones Neumocócicas/microbiología , Infecciones Neumocócicas/patología , Alveolos Pulmonares/microbiología , Alveolos Pulmonares/patología , Síndrome de Dificultad Respiratoria/microbiología , Síndrome de Dificultad Respiratoria/patología , Mucosa Respiratoria/microbiología , Mucosa Respiratoria/parasitologíaRESUMEN
BACKGROUND: Low C-reactive protein in acute bacterial infections could convey the erroneous impression of a mild infection. We focussed on gram-negative bacteraemia, a phenomenon frequently seen at the emergency room. METHODS: Of 2200 patients with gram-negative bacteraemia, 460 patients with first C-reactive protein <30 mg/L and 460 patients with C-reactive protein >187 mg/L were reviewed. Following exclusions, we finally investigated 229 and 289 patients with low and high C-reactive protein concentrations, respectively. RESULTS: The cohort was divided into low and high C-reactive protein groups. Median first C-reactive protein was 13.6 and 219.9 mg/L, respectively (interquartile range 6.4-21.6 and 195-270.1). Compared to patients with first high C-reactive protein, patients with first low C-reactive protein concentrations had a significant five-fold higher C-reactive protein level with their second test. CONCLUSIONS: Patients with gram-negative bacteraemia can present with C-reactive protein within the range of apparently healthy individuals. A second C-reactive protein might help to avoid an erroneous decision regarding the severity of the infection.
Asunto(s)
Bacteriemia/diagnóstico , Proteína C-Reactiva/genética , Medicina de Emergencia , Bacterias Gramnegativas/genética , Adulto , Antibacterianos/uso terapéutico , Bacteriemia/genética , Bacteriemia/microbiología , Bacteriemia/patología , Servicio de Urgencia en Hospital , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Infections are common and are a major cause of morbidity and mortality during treatment of childhood leukemia. We evaluated the cost effectiveness of levofloxacin antibiotic prophylaxis, compared to no prophylaxis, in children receiving chemotherapy for acute myeloid leukemia (AML) or relapsed acute lymphoblastic leukemia (ALL). PROCEDURES: A cost-utility analysis was conducted from the perspective of the single-payer health care system using a lifetime horizon. A comprehensive literature review identified available evidence for effectiveness, safety, costs of antibiotic prophylaxis in children with leukemia, and health utilities associated with the relevant health states. The effects of levofloxacin prophylaxis on health outcomes, quality-adjusted life-years (QALY), and direct health costs were derived from a combined decision tree and state-transition model. One-way deterministic and probabilistic sensitivity analyses were performed to test the sensitivity of results to parameter uncertainty. RESULTS: The literature review revealed one randomized controlled trial on levofloxacin prophylaxis in childhood AML and relapsed ALL, by Alexander et al, that showed a significant reduction in rates of fever and neutropenia (71.2% vs 82.1%) and bacteremia (21.9% vs 43.4%) with levofloxacin compared to no prophylaxis. In our cost-utility analysis, levofloxacin prophylaxis was dominant over no prophylaxis, resulting in cost savings of $542.44 and increased survival of 0.13 QALY. In probabilistic sensitivity analysis, levofloxacin prophylaxis was dominant in 98.8% of iterations. CONCLUSIONS: The present analysis suggests that levofloxacin prophylaxis, compared to no prophylaxis, is cost saving in children receiving intensive chemotherapy for AML or relapsed ALL.
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Profilaxis Antibiótica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Bacteriemia/economía , Análisis Costo-Beneficio , Leucemia Mieloide Aguda/economía , Levofloxacino/economía , Leucemia-Linfoma Linfoblástico de Células Precursoras/economía , Antibacterianos/economía , Antibacterianos/uso terapéutico , Profilaxis Antibiótica/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bacteriemia/tratamiento farmacológico , Bacteriemia/patología , Niño , Estudios de Seguimiento , Hospitalización , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Levofloxacino/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Años de Vida Ajustados por Calidad de VidaRESUMEN
Early changes in biomarker levels probably occur before bloodstream infection (BSI) is diagnosed. However, this issue has not been fully addressed. We aimed at evaluating the kinetics of C-reactive protein (CRP) and plasma albumin (PA) in the 30 days before community-acquired (CA) BSI diagnosis. From a population-based BSI database we identified 658 patients with at least one measurement of CRP or PA from day -30 (D-30) through day -1 (D-1) before the day of CA-BSI (D0) and a measurement of the same biomarker at D0 or D1. Amongst these, 502 had both CRP and PA measurements which fitted these criteria. CRP and PA concentrations began to change inversely some days before CA-BSI diagnosis, CRP increasing by day -3.1 and PA decreasing by day -1.3. From D-30 to D-4, CRP kinetics (expressed as slopes - rate of concentration change per day) was -1.5 mg/l/day. From D-3 to D1, the CRP slope increased to 36.3 mg/l/day. For albumin, the slope between D-30 to D-2 was 0.1 g/l/day and changed to -1.8 g/l/day between D-1 and D1. We showed that biomarker levels begin to change some days before the CA-BSI diagnosis, CRP 3.1 days and PA 1.3 days before.
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Bacteriemia/patología , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Infecciones Comunitarias Adquiridas/patología , Periodo de Incubación de Enfermedades Infecciosas , Albúmina Sérica/análisis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Dinamarca , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
AIMS: Staphylococcus aureus is one of the most common pathogens in hospital environment and community. Panton-Valentine leukocidin (PVL) production is clinically associated with skin abscesses, soft tissues infections, bacteraemia and sepsis. This study aimed to investigate the effects of the presence of genes lukF/S-PV coding for PVL, in histological and haematological features during systemic infection, using a Swiss mice experimental model. METHODS AND RESULTS: Experiments were performed using 25 mice distributed into five experimental groups, intravenously inoculated with 50 µl suspensions at density 1·0 × 107 CFU per ml of strains: methicillin-susceptible (MSSA) and pvl-negative strains isolated from nasal colonization; MSSA pvl-positive strains isolated from nasal colonization; methicillin-resistant (MRSA) and pvl-positive strains isolated from peripheral blood of a patient with severe pulmonary infection; and a MRSA pvl-positive strains isolated from a peripheral blood culture of a patient with bacteraemia. Haematological analysis was performed at 24, 48, 72 and 96 h post-infection. Morphoanatomy and histopathological analyses were performed at 96 h post-infection. For all S. aureus strains tested, the capability of intravenous dissemination and survival into mice tissues was demonstrated. Inflammatory processes at different levels were related to the presence of pvl genes, and included alterations in the format, size and colour of the organs. Staphylococcus aureus pvl-positive strains were detected in greater numbers in the organs of the infected animals. CONCLUSIONS: The pvl-positive strains isolated from blood cultures were capable to induce the greatest modifications in both haematological and histopathological profiles, and seemed to aggravate the systemic infections. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings are valuable in characterizing infections caused by S. aureus in humans and murine.
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Toxinas Bacterianas/metabolismo , Exotoxinas/metabolismo , Leucocidinas/metabolismo , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/patología , Animales , Bacteriemia/microbiología , Bacteriemia/patología , Toxinas Bacterianas/genética , Modelos Animales de Enfermedad , Exotoxinas/genética , Humanos , Leucocidinas/genética , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Staphylococcus aureus Resistente a Meticilina/metabolismo , Ratones , Staphylococcus aureus/genética , Staphylococcus aureus/crecimiento & desarrollo , Staphylococcus aureus/metabolismo , Staphylococcus aureus/patogenicidadRESUMEN
BACKGROUND: The optimal choice of initial antibiotic therapy for patients with high-risk febrile neutropenia (FN) in children is unclear and varies by the institution on the basis of local antibiograms and epidemiology of specific pathogens. The authors evaluated the appropriateness of antibiotics for the empiric treatment of FN in pediatric patients with cancer in our institution on the basis of changes in the epidemiology of organisms isolated from blood cultures (BCx). METHODS: The authors conducted a retrospective medical record review of pediatric patients who received any oncology care (including patients with cancer and patients who had stem cell transplant) at University of Chicago Medicine Comer Children's Hospitals (March 2009 to December 2016) with a diagnosis of FN who had at least 1 BCx obtained. They reviewed pathogens isolated from BCx and determined whether they were pathogens or contaminants using the Infectious Diseases Society of America (IDSA) guidelines and the team's decision to treat. They investigated the microbiologic spectrum and susceptibility patterns of pathogens causing bacteremia in pediatric FN and whether the empiric therapy chosen may have affected clinical outcomes. RESULTS: A total of 667 FN episodes were identified in 268 patients. BCx were negative in 497 (74.5%) and were determined to be contaminants in 27 (4%). In 143 episodes (21.5%), the BCx were positive for a pathogenic species. Polymicrobial bacteremia was identified in 25 episodes; a total of 176 pathogens were isolated. The majority of pathogens (95/176, 54%) were Gram-positive (GP), whereas 64 of 162 (36%) were Gram-negative (GN), 5 were fungal, and 4 were mycobacterial. The most common GP pathogens were viridans group streptococci (VGS) (n=34, 19.3%), coagulase-negative staphylococci (n=25, 14%), and methicillin-susceptible Staphylococcus aureus (n=12, 6.8%). Of aerobic GN bacilli, 15 (8.5%) were AmpC producers and 3 (1.7%) carried extended-spectrum beta-lactamases. There was no increase in the prevalence of multidrug-resistant GN isolates during the study period. Patients with VGS and multidrug-resistant GN bacteremia were more likely to be admitted to the pediatric intensive care unit [odds ratio (OR), 3.24; P=0.017; and OR, 2.8; P=0.07, respectively]. There were trends toward a higher prevalence of GP pathogens causing bacteremia and the emergence of VGS with decreased penicillin sensitivity. The prevalence of bacteremia with VGS was higher in acute myelogenous leukemia and neuroblastoma (OR, 2.3; P<0.01) than in patients with other solid tumors. CONCLUSIONS: Empiric antibiotic treatment should be tailored to patients' risk for VGS and multidrug-resistant organisms. Individual hospitals should monitor the pathogens causing FN among patients with cancer to guide choice of empiric therapy.
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Antibacterianos/uso terapéutico , Bacteriemia/tratamiento farmacológico , Bacterias/aislamiento & purificación , Cultivo de Sangre/métodos , Neutropenia Febril/tratamiento farmacológico , Neoplasias/complicaciones , Adolescente , Adulto , Bacteriemia/etiología , Bacteriemia/patología , Bacterias/efectos de los fármacos , Niño , Preescolar , Terapia Combinada , Neutropenia Febril/etiología , Neutropenia Febril/patología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Pruebas de Sensibilidad Microbiana , Neoplasias/patología , Neoplasias/terapia , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVE: Infections are a threat to frail patients as they have a higher risk of developing serious complications from bloodstream pathogens. The aim of this study was to determine which factors can predict or diagnose bloodstream infections in patients with an underlying gynecologic malignancy. MATERIALS AND METHODS: Between July 2016 and December 2017, 68 patients visiting the emergency room with an underlying gynecologic malignancy were evaluated. Variables concerning underlying disease, invasive procedures, and laboratory and clinical parameters were analyzed. Patients were divided into three groups based on their blood and urine specimens (positive blood specimens, positive urine specimens, and no positive specimens; patients who had both positive blood and urine specimens were included in the group of positive blood specimens). Risk factors for surgical site infections, recent (<30 days) surgery, and chemotherapy were studied separately. RESULTS: 68 patients were included in the analysis. Mean age was 55.6 years (standard deviation 14.1). 44% of patients had ovarian cancer, 35% cervical cancer, 12% endometrial cancer, and 9% had other cancer types. In total, 96% of all patients had undergone surgery. Patients who had been treated with chemotherapy were at a higher risk of developing bloodstream infection (P=0.04; odds ratio (OR)=7.9). C reactive protein, bilirubin, and oxygen saturation (SO2) were significantly different between patients with an underlying infection and those who had none. Only C reactive protein maintained its significance in a linear model, with a cut-off of 180 mg/L (linear regression, P=0.03; OR=4). CONCLUSIONS: Chemotherapy is a risk factor for the development of bloodstream infections in patients with an underlying gynecologic malignancy; C reactive protein could be a useful tool in making this diagnosis.