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1.
Clin Exp Rheumatol ; 38(2): 245-256, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31498077

RESUMO

OBJECTIVES: To provide evidence-based recommendations for vaccination against influenza virus and S. pneumoniae in patients with autoimmune rheumatic diseases (ARDs). METHODS: A Consensus Committee including physicians with expertise in rheumatic and infectious diseases was established by two Italian scientific societies, Società Italiana di Reumatologia (SIR) and Società Italiana di Malattie Infettive e Tropicali (SIMIT). The experts were invited to develop evidence-based recommendations concerning vaccinations in ARDs patients, based on their clinical status before and after undergoing immunosuppressive treatments. Key clinical questions were formulated for the systematic literature reviews, based on the clinical pathway. A search was made in Medline (via PubMed) according to the original MeSH strategy from October 2009 and a keyword strategy from January 2016 up to December 2017, updating existing EULAR recommendations. Specific recommendations were separately voted and scored from 0 (no agreement with) to 100 (maximal agreement) and supporting evidence graded. The mean and standard deviation of the scores were calculated to determine the level of agreement among the experts' panel for each recommendation. Total cumulative agreement ≥70 defined consensus for each statement. RESULTS: Nine recommendations, based on 6 key clinical questions addressed by the expert committee, were proposed. The aim of this work is to integrate the 2011 EULAR recommendations on vaccination against influenza and S. pneumoniae in ARDs patients. An implementation plan was proposed to improve the vaccination status of these patients and their safety during immunosuppressive treatments. CONCLUSIONS: Influenza and pneumococcus vaccinations are effective and safe in patients with ARDs. More efforts should be made to translate the accumulated evidence into practice.


Assuntos
Vacinas contra Influenza/administração & dosagem , Vacinas Pneumocócicas/administração & dosagem , Doenças Reumáticas/imunologia , Vacinação , Adulto , Doenças Autoimunes/complicações , Doenças Autoimunes/tratamento farmacológico , Consenso , Medicina Baseada em Evidências/métodos , Feminino , Humanos , Imunossupressores/efeitos adversos , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Itália , Masculino , Vacinas Pneumocócicas/imunologia , Pneumonia Estafilocócica/imunologia , Pneumonia Estafilocócica/prevenção & controle , Doenças Reumáticas/complicações , Doenças Reumáticas/tratamento farmacológico , Vacinação/normas
2.
Vet Microbiol ; 229: 72-80, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30642601

RESUMO

Staphylococcus aureus is one of the most important pathogens causing rabbit necrotizing pneumonia and brings huge economic losses to rabbit production. This study investigated the preventive effect of a phage on rabbit necrotizing pneumonia caused by S. aureus. S. aureus S6 was isolated from the lungs of rabbits suffering necrotizing pneumonia and identified. A novel phage named VB-SavM-JYL01 was isolated by using S. aureus S6 as a host and showed a broader host range than the phages GH15 and K. The genome of VB-SavM-JYL01 lacked bacterial virulence-, antibiotic resistance- and lysogenesis-related genes. A single intranasal administration of VB-SavM-JYL01 (3 × 109 PFU) could effectively improve the survival rate at 48 h to 90% (9/10) compared with the survival rate of 10% and 80% observed with the PBS or linezolid treatment, respectively. The bacterial count in the lungs of rabbits treated with the phage VB-SavM-JYL01 was 4.18 × 104 CFU/g at 24 h, which was significantly decreased compared to that of rabbits treated with PBS (7.38 × 107 CFU/g) or linezolid (3.12 × 105 CFU/g). The phage treatment significantly alleviated lung tissue damage. The levels of total proteins, Panton-Valentine leukocidin (PVL), alpha-toxin (Hla) and cytokines in the lungs of the rabbits treated with the phage were significantly lower than those of the rabbits treated with PBS and similar to those of the rabbits treated with linezolid. These data demonstrate the potential utility of phage as an alternative for preventing rabbit necrotizing pneumonia caused by S. aureus.


Assuntos
Pneumonia Necrosante/veterinária , Pneumonia Estafilocócica/veterinária , Coelhos/microbiologia , Fagos de Staphylococcus , Staphylococcus aureus/virologia , Animais , Feminino , Pneumonia Necrosante/microbiologia , Pneumonia Necrosante/prevenção & controle , Pneumonia Estafilocócica/prevenção & controle
3.
Microb Pathog ; 127: 85-90, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30468853

RESUMO

Staphylococcus aureus is an important zoonotic pathogen that causes a variety of life-threatening diseases. The increasing emergence of drug resistance further complicates the treatment of S. aureus infections. The critical role of alpha-hemolysin (Hla) in virulence renders this toxin an ideal target for the development of anti-infective agents for S. aureus. Here, We found that resveratrol, a natural compound widely found in fruits without antibacterial activity, could effectively inhibit Hla expression via down-regulating the transcription of hla, the gene that encodes Hla, and RNAIII, the effector molecule of the agr system. The addition of resveratrol to a co-culture system of S. aureus and A549 cells significantly alleviated bacteria-mediated cellular injury. Furthermore, treatment with resveratrol effectively protected mice from S. aureus pneumonia. Our results established resveratrol as an effective Hla inhibitor that reduces Hla expression without antimicrobial activity and can be further developed into novel therapeutics against S. aureus infections.


Assuntos
Toxinas Bacterianas/antagonistas & inibidores , Inibidores Enzimáticos/metabolismo , Proteínas Hemolisinas/antagonistas & inibidores , Pneumonia Estafilocócica/prevenção & controle , Resveratrol/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Células A549 , Animais , Técnicas de Cocultura , Modelos Animais de Doenças , Humanos , Camundongos , Pneumonia Estafilocócica/tratamento farmacológico , Resultado do Tratamento , Virulência/efeitos dos fármacos
4.
Acta Cir Bras ; 33(11): 983-990, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30517325

RESUMO

PURPOSE: To investigate the efficacy and mechanisms of root tuber of Polygonum ciliinerve (Nakai) ohwi (rPC) which has been used to treat bacterial infection in traditional Chinese medicine. METHODS: With the mouse model of Staphylococcus aureus (S. aureus) pneumonia, the phenotype of rPC treated mice, including body weight, mortality, lung slices and bacterial burden were evaluated. Furthermore, inflammatory factors in bronchoalveolar lavage (BAL) were determined by ELISA and the distribution of T cells in lung was assessed by immunofluorescence assay. RESULTS: rPC treatment could dose-dependently reduce weight loss and mortality in S. aureus-infected mice. Upon 10 mg/ml rPC treatment, S. aureus-infected mice showed about 8 grams increase in body weight (P<0.001) and 50% enhancement in mortality. The integrity of lung tissue and bacterial burden were also improved by rPC treatment. Moreover, rPC was found to modulate the immune response in infection. CONCLUSION: rPC has therapeutic potential for S. aureus infections and pneumonia with immunomodulatory functions.


Assuntos
Antibacterianos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Imunomodulação/efeitos dos fármacos , Pneumonia Estafilocócica/prevenção & controle , Polygonum/química , Substâncias Protetoras/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar/química , Quimiocina CCL2/análise , Contagem de Colônia Microbiana , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Interleucina-6/análise , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos Endogâmicos C57BL , Pneumonia Estafilocócica/tratamento farmacológico , Pneumonia Estafilocócica/patologia , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análise
5.
Acta cir. bras ; 33(11): 983-990, Nov. 2018. graf
Artigo em Inglês | LILACS | ID: biblio-973479

RESUMO

Abstract Purpose: To investigate the efficacy and mechanisms of root tuber of Polygonum ciliinerve (Nakai) ohwi (rPC) which has been used to treat bacterial infection in traditional Chinese medicine. Methods: With the mouse model of Staphylococcus aureus (S. aureus) pneumonia, the phenotype of rPC treated mice, including body weight, mortality, lung slices and bacterial burden were evaluated. Furthermore, inflammatory factors in bronchoalveolar lavage (BAL) were determined by ELISA and the distribution of T cells in lung was assessed by immunofluorescence assay. Results: rPC treatment could dose-dependently reduce weight loss and mortality in S. aureus-infected mice. Upon 10 mg/ml rPC treatment, S. aureus-infected mice showed about 8 grams increase in body weight (P<0.001) and 50% enhancement in mortality. The integrity of lung tissue and bacterial burden were also improved by rPC treatment. Moreover, rPC was found to modulate the immune response in infection. Conclusion: rPC has therapeutic potential for S. aureus infections and pneumonia with immunomodulatory functions.


Assuntos
Animais , Pneumonia Estafilocócica/prevenção & controle , Staphylococcus aureus/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Substâncias Protetoras/farmacologia , Polygonum/química , Imunomodulação/efeitos dos fármacos , Antibacterianos/farmacologia , Pneumonia Estafilocócica/patologia , Pneumonia Estafilocócica/tratamento farmacológico , Fatores de Tempo , Ensaio de Imunoadsorção Enzimática , Líquido da Lavagem Broncoalveolar/química , Imuno-Histoquímica , Contagem de Colônia Microbiana , Reprodutibilidade dos Testes , Interleucina-6/análise , Fator de Necrose Tumoral alfa/análise , Resultado do Tratamento , Quimiocina CCL2/análise , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos Endogâmicos C57BL
6.
World J Microbiol Biotechnol ; 34(5): 64, 2018 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-29671126

RESUMO

Staphylococcus aureus (S. aureus) is a common pathogenic bacterium that causes various diseases in both humans and animals. With the increased prevalence of methicillin-resistant S. aureus, the therapeutic effects of commonly used antibiotics are limited against S. aureus infection. Novel treatment strategies and new antibiotics are needed urgently to address this concern. Many studies have shown that virulence factors secreted from S. aureus play vital roles in their pathogenic processes. Alpha-hemolysin (Hla), an important exotoxin in S. aureus, is one such virulence factor that increases sensitivity of multiple host cells to S. aureus resulting in various diseases. Eriodictyol is a flavonoid compound that exists in many fruits and vegetables. In this study, eriodictyol was demonstrated to inhibit the expression of Hla by hemolysis assays, western blotting, and RT-qPCR at the sub-minimal inhibitory concentration. In live/dead and cytotoxicity assays, the results showed that eriodictyol protected A549 cells against Hla-induced injury in a dose-dependent manner. The minimal inhibitory concentration of eriodictyol against S. aureus was 512 µg/mL. Eriodictyol can downregulate S. aureus Hla at both the expressional and transcriptional levels without affecting S. aureus growth. In addition, cell assays had proved that eriodictyol could protect A549 cells against Hla damage. Eriodictyol could therefore have the potential to treat S. aureus infection targeting Hla.


Assuntos
Antibacterianos/farmacologia , Toxinas Bacterianas/toxicidade , Flavanonas/farmacologia , Proteínas Hemolisinas/efeitos dos fármacos , Proteínas Hemolisinas/toxicidade , Lesão Pulmonar/prevenção & controle , Staphylococcus aureus/efeitos dos fármacos , Células A549/efeitos dos fármacos , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/metabolismo , Hemólise , Humanos , Lesão Pulmonar/microbiologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/metabolismo , Testes de Sensibilidade Microbiana , Pneumonia Estafilocócica/microbiologia , Pneumonia Estafilocócica/patologia , Pneumonia Estafilocócica/prevenção & controle , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/metabolismo , Staphylococcus aureus/patogenicidade , Fatores de Virulência/metabolismo
7.
J Trauma Acute Care Surg ; 82(5): 853-860, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28431414

RESUMO

BACKGROUND: Nosocomial pneumonias are common in trauma patients and so interventions to prevent and treat nosocomial pneumonia may improve outcomes. Our prior work strongly suggests that tissue injury predisposes to infections like nosocomial pneumonia because mitochondrial debris originating from injured cells contains damage-associated molecular patterns that can reduce neutrophil (PMN) migration into the airway and diminish PMN function in response to bacterial inoculation of the airway. This suggested that putting exogenous "normal" PMN into the airway might be beneficial. METHODS: Postinjury pneumonia (PNA) commonly arises in two groups, early, community-acquired PNA (CAP) and later hospital-acquired PNA (HAP). Posttraumatic early-onset CAP and late-onset HAP were modeled in CD-1 mice using Staphylococcus aureus or Pseudomonas aeruginosa instilled intratracheal (i.t.) at clinically relevant times with or without extrapulmonary injuries mimicked by an intraperitoneal application of mitochondrial damage-associated molecular patterns. We applied bone marrow-derived PMN (BM-PMN) intratracheally to assess their effect on bacterial clearance in the lung. RESULTS: BM-PMN instillation i.t. had no untoward clinical effects on recipient animals. In both the early/CAP and late/HAP models, clearance of the bacterial inoculum from the lung was suppressed by mitochondrial debris and restored to uninjured levels by i.t. instillation of exogenous BM-PMN. Furthermore, PMN instillation cleared the inoculum of P. aeruginosa that could not be cleared by uninjured mice. Instillation of PMN into the lung, even across strains (CD-1 vs. C57BL/6) had no injurious effect. CONCLUSION: These initial studies suggest PMN instillation (i.t.) is worthy of further study as a potential adjunctive therapy aimed at decreasing the morbidity of lung infections in trauma patients. Moreover, PMN instillation (i.t.) may represent a unique means of preventing or treating pneumonia after serious injury that is completely independent of the need for antibiotic use.


Assuntos
Infecção Hospitalar/prevenção & controle , Lesão Pulmonar/complicações , Neutrófilos/transplante , Pneumonia Bacteriana/prevenção & controle , Animais , Infecção Hospitalar/etiologia , Camundongos , Pneumonia Bacteriana/etiologia , Pneumonia Estafilocócica/etiologia , Pneumonia Estafilocócica/prevenção & controle , Infecções por Pseudomonas/etiologia , Infecções por Pseudomonas/prevenção & controle , Pseudomonas aeruginosa , Staphylococcus aureus , Traqueia
8.
World J Microbiol Biotechnol ; 33(1): 11, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27878749

RESUMO

We reported the inhibition of α-Hemolysin (Hla) production in methicillin-resistant Staphylococcus aureus USA300 by osthole and further investigated the combination of osthole and baicalin in the treatment of staphylococcal pneumonia. Using cytotoxicity assays and a mouse model of intranasal lung infection, we evaluated the effect of combined therapy. Our results suggest that the combination of osthole and baicalin alleviated S. aureus-mediated A549 cell injury and protected mice from S. aureus pneumonia.


Assuntos
Toxinas Bacterianas/antagonistas & inibidores , Cumarínicos/administração & dosagem , Flavonoides/administração & dosagem , Proteínas Hemolisinas/antagonistas & inibidores , Pneumonia Estafilocócica/prevenção & controle , Células A549 , Animais , Cumarínicos/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Flavonoides/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/enzimologia , Camundongos , Testes de Sensibilidade Microbiana
9.
Antimicrob Agents Chemother ; 60(10): 6333-40, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27527081

RESUMO

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), especially the USA300 pulsotype, is a frequent cause of skin and soft tissue infections and severe pneumonia. Despite appropriate antibiotic treatment, complications are common and pneumonia is associated with high mortality. S. aureus strains express multiple cytotoxins, including alpha-hemolysin (Hla) and up to five bicomponent leukocidins that specifically target phagocytic cells for lysis. CA-MRSA USA300 strains carry the genes for all six cytotoxins. Species specificity of the leukocidins greatly contributes to the ambiguity regarding their role in S. aureus pathogenesis. We performed a comparative analysis of the leukocidin susceptibility of human, rabbit, and mouse polymorphonuclear leukocytes (PMNs) to assess the translational value of mouse and rabbit S. aureus models. We found that mouse PMNs were largely resistant to LukSF-PV, HlgAB, and HlgCB and susceptible only to LukED, whereas rabbit and human PMNs were highly sensitive to all these cytotoxins. In the rabbit pneumonia model with a USA300 CA-MRSA strain, passive immunization with a previously identified human monoclonal antibody (MAb), Hla-F#5, which cross-neutralizes Hla, LukSF-PV, HlgAB, HlgCB, and LukED, provided full protection, whereas an Hla-specific MAb was only partially protective. In the mouse USA300 CA-MRSA pneumonia model, both types of antibodies demonstrated full protection, suggesting that Hla, but not leukocidin(s), is the principal virulence determinant in mice. As the rabbit recapitulates the high susceptibility to leukocidins characteristic of humans, this species represents a valuable model for assessing novel, cytotoxin-targeting anti-S. aureus therapeutic approaches.


Assuntos
Anticorpos Neutralizantes/farmacologia , Toxinas Bacterianas/imunologia , Proteínas Hemolisinas/imunologia , Leucocidinas/imunologia , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Pneumonia Necrosante/prevenção & controle , Pneumonia Estafilocócica/prevenção & controle , Animais , Anticorpos Monoclonais/farmacologia , Infecções Comunitárias Adquiridas/microbiologia , Modelos Animais de Doenças , Feminino , Humanos , Leucocidinas/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/microbiologia , Pneumonia Necrosante/imunologia , Pneumonia Necrosante/microbiologia , Pneumonia Necrosante/mortalidade , Pneumonia Estafilocócica/imunologia , Coelhos
10.
CuidArte, Enferm ; 10(2): 188-193, jul.-dez.2016.
Artigo em Português | BDENF - Enfermagem | ID: biblio-1027704

RESUMO

Introdução: A pneumonia estafilocócica constitui apenas 1-10% de todos os casos de pneumonias adquiridas na comunidade, porémapresenta uma elevada taxa de morbimortalidade, de 30% a 40%. A sintomatologia geralmente é de instalação aguda com intensidadee frequência variáveis. Objetivo: Relatar, por meio de um caso clínico, a importância do diagnóstico e tratamento precoce, nos casos depneumonia estafilocócia, devido à gravidade da doença e possibilidade de rápida progressão do quadro clínico. Material e Método: Estudodescritivo, tipo relato de caso de um paciente com quadro clínico de pneumonia adquirida na comunidade, apresentando sinais e sintomasde descompensação rápida e exames comprovando a etiologia por Staphylococcus aureus oxacilina resistente (MRSA). Resultados: Pacienteatendido em Unidade de Emergência com quadro de pneumonia e sinais de descompensação rápida, exame radiográfico e tomográficoapresentando derrame pleural bilateral, submetido à drenagem de tórax e encaminhado para unidade de terapia intensiva já comquadro de insuficiência respiratória, foi intubado, colhido lavado broncoalveolar e enviado para cultura que confirmou o crescimento deMRSA. O quadro evoluiu de forma rápida e grave, mesmo o paciente recebendo tratamento com teicoplamina e piperacilina-tazobactam,apresentando cultura...


Introduction: Staphylococcal pneumonia accounts for only 1-10% of all cases of community-acquired pneumonias, but has a morbimortalityrate as high as 30 to 40%. The symptoms present usually an acute installation, with varying intensity and frequency. Objective:To report, through a clinical case, the relevance of early diagnosis and treatment of patients with Staphylococcal pneumonia, due tothe severity of the disease and to the possibility of fast progression of the clinical picture. Material and Method: Descriptive studythrough a reporting case of a patient with clinical picture of community-acquired pneumonia, presenting signs and symptoms of quickdecompensation and tests proving the etiology of oxacillin-resistant Staphylococcus aureus (MRSA). Results: Patient attended at anEmergency Unit with clinical picture of pneumonia, showing signs of rapid decompensation and radiographic examination and CT scanshowing bilateral pleural effusion. He underwent chest drainage and was referred to the intensive care unit already with a picture ofrespiratory failure, being intubated and having bronchoalveolar lavage collected and sent for culture, which confirmed MRSA growing.Clinical evolution was rapid and severe, despite of patient...


Introducción: La neumonía estafilocócica es solamente 1-10% de todos los casos de neumonía adquirida en la comunidad, pero tiene unaalta tasa de mortalidad del 30% al 40%. Los síntomas son generalmente de comienzo agudo con variables de intensidad y frecuencia.Objetivo: Reportar por medio de un caso, la importancia del diagnóstico precoz y el tratamiento de los casos de neumonía estafilocóciadebido a la gravedad de la enfermedad y la posibilidad de una rápida progresión del cuadro clínico. Material y Método: Se realizó unestudio descriptivo, reporte de un caso de un paciente con un cuadro clínico de la neumonía adquirida en la comunidad, que presentasignos y síntomas de descompensación rápida y pruebas que demuestran la etiología de la oxacilina-resistente Staphylococcus aureus(MRSA). Resultados: Paciente tratada en la Unidad de Emergencia con el marco de la neumonía y signos de descompensación rápida, elexamen radiográfico y TC que muestra un derrame pleural bilateral, presentado para drenar el pecho y llevado a la unidad de cuidadosintensivos ya con insuficiencia respiratoria, fue intubado, el lavado broncoalveolar recogido y enviado para cultivo confirmó el crecimientode MRSA. Los signos clínicos de incluso el paciente que recibe tratamiento rápido y grave, con teicoplanina y piperacilina-tazobactam, concultivo negativo lavado broncoalveolar en 24...


Assuntos
Humanos , Derrame Pleural , Pneumonia Estafilocócica/diagnóstico , Pneumonia Estafilocócica/prevenção & controle , Sepse , Staphylococcus aureus Resistente à Meticilina
11.
Ther Umsch ; 73(5): 231-4, 2016.
Artigo em Alemão | MEDLINE | ID: mdl-27268444

RESUMO

Influenza is an infectious disease that can be prevented by a vaccine but the readiness to vaccinate against this recurrent infection is weak in the general population. However, influenza is not always a harmless illness as illustrated in our authentic case report. Individuals with an impaired immune response, particularly pregnant women and the elderly are particularly at risk for a complicated course of influenza. But it is precisely this population, which also has an attenuated immune response to the vaccine. The limited efficacy in this target group is a potential "loss of image" for any flu vaccination campaign. This raises the question whether we should not try to motivate healthy individuals to get vaccinated, particularly if they are living or working next to vulnerable individuals. Epidemiologic data but also recent mathematical models indicate that consistent vaccination of (school-)children results in reduced mortality in elderly people.


Assuntos
Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Staphylococcus aureus Resistente à Meticilina , Pneumonia Estafilocócica/prevenção & controle , Infecções Estafilocócicas/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunocompetência/imunologia , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/mortalidade , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Influenza Humana/mortalidade , Masculino , Pessoa de Meia-Idade , Pneumonia Estafilocócica/imunologia , Pneumonia Estafilocócica/mortalidade , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/prevenção & controle , Gravidez , Fatores de Risco , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/mortalidade
12.
J Appl Microbiol ; 118(3): 753-63, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25564958

RESUMO

AIMS: To investigate the mechanism by which morin hydrate inhibits the haemolytic activity of α-hemolysin (Hla), a channel-forming toxin that is important for the pathogenesis of disease in experimental animals, and its therapeutic effect against Staphylococcus aureus pneumonia in a mouse model. METHODS AND RESULTS: The results from the in vitro (haemolysis, western blot and cytotoxicity assays) and in vivo (mouse model of intranasal lung infection) experiments indicated that morin hydrate, a natural compound with little anti-Staph. aureus activity, could effectively antagonize the cytolytic activity of Hla, alleviate human lung cell injury, and protect against mortality of Staph. aureus pneumonia in a mouse model of infection. Molecular dynamics simulations, free energy calculations and mutagenesis assays were further employed to determine the catalytic mechanism of inhibition, which indicated that a direct binding of morin to the 'Stem' domain of Hla (residues I107 and T109) and the concomitant change in conformation led to the inhibition of the self-assembly of the heptameric transmembrane pore, thus inhibiting the biological activity of Hla for cell lysis. CONCLUSIONS: Morin inhibited Staph. aureus virulence via inhibiting the haemolytic activity of α-hemolysin. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings suggested that morin is a promising candidate for the development of anti-virulence therapeutic agents for the treatment of Staph. aureus infections.


Assuntos
Antibacterianos/uso terapêutico , Toxinas Bacterianas/antagonistas & inibidores , Flavonoides/uso terapêutico , Proteínas Hemolisinas/antagonistas & inibidores , Pneumonia Estafilocócica/prevenção & controle , Staphylococcus aureus/efeitos dos fármacos , Animais , Toxinas Bacterianas/metabolismo , Proteínas Hemolisinas/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Pulmão/microbiologia , Camundongos , Staphylococcus aureus/patogenicidade , Virulência/efeitos dos fármacos
13.
Infect Control Hosp Epidemiol ; 35(10): 1263-70, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25203180

RESUMO

BACKGROUND: States have established public reporting of hospital-associated (HA) infections-including those of methicillin-resistant Staphylococcus aureus (MRSA)-but do not account for hospital case mix or postdischarge events. OBJECTIVE: Identify facility-level characteristics associated with HA-MRSA infection admissions and create adjusted hospital rankings. METHODS: A retrospective cohort study of 2009-2010 California acute care hospitals. We defined HA-MRSA admissions as involving MRSA pneumonia or septicemia events arising during hospitalization or within 30 days after discharge. We used mandatory hospitalization and US Census data sets to generate hospital population characteristics by summarizing across admissions. Facility-level factors associated with hospitals' proportions of HA-MRSA infection admissions were identified using generalized linear models. Using state methodology, hospitals were categorized into 3 tiers of HA-MRSA infection prevention performance, using raw and adjusted values. RESULTS: Among 323 hospitals, a median of 16 HA-MRSA infections (range, 0-102) per 10,000 admissions was found. Hospitals serving a greater proportion of patients who had serious comorbidities, were from low-education zip codes, and were discharged to locations other than home were associated with higher HA-MRSA infection risk. Total concordance between all raw and adjusted hospital rankings was 0.45 (95% confidence interval, 0.40-0.51). Among 53 community hospitals in the poor-performance category, more than 20% moved into the average-performance category after adjustment. Similarly, among 71 hospitals in the superior-performance category, half moved into the average-performance category after adjustment. CONCLUSIONS: When adjusting for nonmodifiable facility characteristics and case mix, hospital rankings based on HA-MRSA infections substantially changed. Quality indicators for hospitals require adequate adjustment for patient population characteristics for valid interhospital performance comparisons.


Assuntos
Infecção Hospitalar/epidemiologia , Hospitais/normas , Staphylococcus aureus Resistente à Meticilina , Pneumonia Estafilocócica/epidemiologia , Sepse/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , California/epidemiologia , Comorbidade , Infecção Hospitalar/prevenção & controle , Grupos Diagnósticos Relacionados , Feminino , Hospitais/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Estafilocócica/microbiologia , Pneumonia Estafilocócica/prevenção & controle , Estudos Retrospectivos , Fatores de Risco , Sepse/microbiologia , Sepse/prevenção & controle , Adulto Jovem
14.
Biomed Res Int ; 2014: 602185, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25136599

RESUMO

The advent of methicillin-resistant Staphylococcus aureus (MRSA) and the frequent and excessive abuse of ventilators have made MRSA pneumonia an inordinate threat to human health. Appropriate antibacterial therapies are crucial, including the use of lysostaphin as an alternative to antibiotics. To explore the potential use of lysostaphin as a therapeutic agent for MRSA pneumonia, mice were intranasally infected with MRSA and then treated with recombinant lysostaphin (rLys; 45 mg/kg in the high-dose group and 1 mg/kg in the low-dose group) (0.33 mg/mL, 15 mg/mL), vancomycin (120 mg/kg) (40 mg/mL), or phosphate-buffered saline (PBS, negative control) 4 h after infection. Therapeutic efficacy was assessed by mouse survival, lung histopathology, bacterial density in the lungs, bodyweight, lung weight, temperature, white blood cells counts, lymphocytes counts, granulocytes counts, and monocytes counts. The mice treated with rLys showed lower mortality, less lung parenchymal damage, and lower bacterial density at metastatic tissue sites than mice treated with PBS or vancomycin. The overall mortality was 100%, 60%, 40%, and 60% for the control, vancomycin, high-dose rLys, and low-dose rLys groups, respectively. These findings indicate that, as a therapeutic agent for MRSA pneumonia, lysostaphin exerts profound protective effects in mice against the morbidity and mortality associated with S. aureus pneumonia.


Assuntos
Antibacterianos/farmacologia , Lisostafina/farmacologia , Staphylococcus aureus Resistente à Meticilina , Pneumonia Estafilocócica/prevenção & controle , Animais , Contagem de Células Sanguíneas , Feminino , Humanos , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia Estafilocócica/sangue , Pneumonia Estafilocócica/microbiologia , Pneumonia Estafilocócica/patologia , Proteínas Recombinantes/farmacologia , Vancomicina/farmacologia
15.
J Infect Dis ; 209(12): 1955-62, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24357631

RESUMO

BACKGROUND: Staphylococcus aureus causes serious infections in both hospital and community settings. Attempts have been made to prevent human infection through vaccination against bacterial cell-surface antigens; thus far all have failed. Here we show that superantigens and cytolysins, when used in vaccine cocktails, provide protection from S. aureus USA100-USA400 intrapulmonary challenge. METHODS: Rabbits were actively vaccinated (wild-type toxins or toxoids) or passively immunized (hyperimmune serum) against combinations of superantigens (toxic shock syndrome toxin 1, enterotoxins B and C, and enterotoxin-like X) and cytolysins (α-, ß-, and γ-toxins) and challenged intrapulmonarily with multiple strains of S. aureus, both methicillin-sensitive and methicillin-resistant. RESULTS: Active vaccination against a cocktail containing bacterial cell-surface antigens enhanced disease severity as tested by infective endocarditis. Active vaccination against secreted superantigens and cytolysins resulted in protection of 86 of 88 rabbits when challenged intrapulmonarily with 9 different S. aureus strains, compared to only 1 of 88 nonvaccinated animals. Passive immunization studies demonstrated that production of neutralizing antibodies was an important mechanism of protection. CONCLUSIONS: The data suggest that vaccination against bacterial cell-surface antigens increases disease severity, but vaccination against secreted virulence factors provides protection against S. aureus. These results advance our understanding of S. aureus pathogenesis and have important implications in disease prevention.


Assuntos
Imunização Passiva , Pneumonia Estafilocócica/prevenção & controle , Vacinas Antiestafilocócicas/imunologia , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Neutralizantes/sangue , Toxinas Bacterianas/imunologia , Citotoxinas/imunologia , Modelos Animais de Doenças , Endocardite Bacteriana/imunologia , Endocardite Bacteriana/prevenção & controle , Enterotoxinas/imunologia , Feminino , Masculino , Staphylococcus aureus Resistente à Meticilina/imunologia , Pneumonia Estafilocócica/imunologia , Coelhos , Superantígenos/imunologia , Fatores de Virulência/imunologia
17.
Virol J ; 10: 40, 2013 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-23369570

RESUMO

Secondary pneumonia due to Staphylococcus aureus (S. aureus) causes significant morbidity and mortality. The aim of the research was designed a novel DNA vaccine encoding the Mycobacterium tuberculosis secreted antigen Ag85A fused with the influenza A virus (IAV) HA2 protein to provide protection against both influenza and secondary infection with S. aureus. The DNA vaccine vector efficiently expressed the encoded antigen in mammalian cells, as determined by RT-PCR, Western blotting and immunofluorescence analysis. Mice were immunized with the vaccine by intramuscular injection before challenge with IAV and S. aureus. The pulmonary and the splenocyte culture IFN-γ levels were significant higher in immunized mice than their respective controls. Although the antibody titer in the HI test was low, the sera of mice immunized with the novel vaccine vector were effective in neutralisation assay in vitro. The vaccine could reduce the loss of body weight in mice during IAV challenge. Both Western blotting and RT-PCR showed that the vaccine markedly enhanced toll like receptor 2 (TLR2) expression in splenocytes after the secondary infection with S. aureus. The survival rate of mice with high TLR2 expression (pEGFP/Ag85A-HA2 or iPR) was significantly increased compared with mice immunized with pEGFP/HA2 after challenge with S. aureus. However, the pulmonary IL-10 concentration and S. aureus titer were significantly decreased in immunized mice, and expression of TLR2 was increased after challenge with S. aureus. These results demonstrated that Ag85A could strengthen the immune response to IAV and S. aureus, and TLR2 was involved in the host response to S. aureus.


Assuntos
Aciltransferases/imunologia , Antígenos de Bactérias/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vacinas contra Influenza/imunologia , Vacinas Antiestafilocócicas/imunologia , Vacinas de DNA/imunologia , Aciltransferases/genética , Animais , Anticorpos Antivirais/sangue , Antígenos de Bactérias/genética , Carga Bacteriana , Modelos Animais de Doenças , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/genética , Injeções Intramusculares , Interferon gama/metabolismo , Leucócitos Mononucleares/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Testes de Neutralização , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Pneumonia Estafilocócica/imunologia , Pneumonia Estafilocócica/prevenção & controle , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Vacinas Antiestafilocócicas/administração & dosagem , Vacinas Antiestafilocócicas/genética , Análise de Sobrevida , Vacinas de DNA/administração & dosagem , Vacinas de DNA/genética
18.
J Infect Dis ; 206(2): 292-301, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22551812

RESUMO

α-Hemolysin (Hla) is a self-assembling, channel-forming toxin that is secreted by Staphylococcus aureus and is central to the pathogenesis of pulmonary, intraperitoneal, intramammary, and corneal infections in animal models. In this study, we report that baicalin (BAI), a natural compound that lacks anti-S. aureus activity, could inhibit the hemolytic activity of Hla. Using molecular dynamics simulations and mutagenesis assays, we further demonstrate that BAI binds to the binding sites of Y148, P151, and F153 in the Hla. This binding interaction inhibits heptamer formation. Furthermore, when added to S. aureus cultures, BAI prevents Hla-mediated human alveolar epithelial (A549) cell injury. In vivo studies further demonstrated that BAI protects mice from S. aureus pneumonia. These findings indicate that BAI hinders the cell lysis activity of Hla through a novel mechanism of interrupting the formation of heptamer, which may lead to the development of novel therapeutics that aim against S. aureus Hla.


Assuntos
Anti-Infecciosos/farmacologia , Toxinas Bacterianas/antagonistas & inibidores , Flavonoides/farmacologia , Proteínas Hemolisinas/antagonistas & inibidores , Pneumonia Estafilocócica/prevenção & controle , Staphylococcus aureus/efeitos dos fármacos , Animais , Anti-Infecciosos/metabolismo , Toxinas Bacterianas/metabolismo , Sítios de Ligação , Flavonoides/metabolismo , Regulação Bacteriana da Expressão Gênica/fisiologia , Proteínas Hemolisinas/metabolismo , Hemólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Staphylococcus aureus/metabolismo , Relação Estrutura-Atividade
19.
Am J Pathol ; 181(1): 196-210, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22642909

RESUMO

The importance of the priming of the lung environment by past infections is being increasingly recognized. Exposure to any given antigen can either improve or worsen the outcome of subsequent lung infections, depending on the immunological history of the host. Thus, an ability to impart transient alterations in the lung environment in anticipation of future insult could provide an important novel therapy for emerging infectious diseases. In this study, we show that nasal administration of virus-like particles (VLPs) before, or immediately after, lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA) of mice i) ensures complete recovery from lung infection and near absolute clearance of bacteria within 12 hours of challenge, ii) reduces host response-induced lung tissue damage, iii) promotes recruitment and efficient bacterial clearance by neutrophils and CD11c(+) cells, and iv) protects macrophages from MRSA-induced necrosis. VLP-mediated protection against MRSA relied on innate immunity. Complete recovery occurred in VLP-dosed mice with severe combined immunodeficiency, but not in wild-type mice depleted of either Ly6G(+) or CD11c(+) cells. Early IL-13 production associated with VLP-induced CD11c(+) cells was essential for VLP-induced protection. These results indicate that VLP-induced alteration of the lung environment protects the host from lethal MRSA pneumonia by enhancing phagocyte recruitment and killing and by reducing inflammation-induced tissue damage via IL-13-dependent mechanisms.


Assuntos
Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Fagócitos/imunologia , Pneumonia Estafilocócica/prevenção & controle , Vacinas Antiestafilocócicas/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Imunidade Adaptativa , Administração Intranasal , Animais , Carga Bacteriana , Antígeno CD11c/análise , Células Dendríticas/imunologia , Feminino , Imunofenotipagem , Interleucina-13/imunologia , Pulmão/microbiologia , Macrófagos Alveolares/imunologia , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Monócitos/imunologia , Neutrófilos/imunologia , Fagocitose/imunologia , Pneumonia Estafilocócica/imunologia , Pneumonia Estafilocócica/patologia , Vacinas Antiestafilocócicas/administração & dosagem , Fatores de Tempo , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem
20.
PLoS One ; 7(3): e33032, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22427935

RESUMO

BACKGROUND: α-toxin is one of the major virulence factors secreted by most Staphylococcus aureus strains, which played a central role in the pathogenesis of S. aureus pneumonia. The aim of this study was to investigate the impact of capsaicin on the production of α-toxin by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strain USA 300 and to further assess its performance in the treatment of CA-MRSA pneumonia in a mouse model. METHODOLOGY/PRINCIPAL FINDINGS: The in vitro effects of capsaicin on α-toxin production by S. aureus USA 300 were determined using hemolysis, western blot, and real-time RT-PCR assays. The influence of capsaicin on the α-toxin-mediated injury of human alveolar epithelial cells was determined using viability and cytotoxicity assays. Mice were infected intranasally with S. aureus USA300; the in vivo protective effects of capsaicin against S. aureus pneumonia were assessed by monitoring the mortality, histopathological changes and cytokine levels. Low concentrations of capsaicin substantially decreased the production of α-toxin by S. aureus USA 300 without affecting the bacterial viability. The addition of capsaicin prevented α-toxin-mediated human alveolar cell (A549) injury in co-culture with S. aureus. Furthermore, the in vivo experiments indicated that capsaicin protected mice from CA-MRSA pneumonia caused by strain USA 300. CONCLUSIONS/SIGNIFICANCE: Capsaicin inhibits the production of α-toxin by CA-MRSA strain USA 300 in vitro and protects mice from CA-MRSA pneumonia in vivo. However, the results need further confirmation with other CA-MRSA lineages. This study supports the views of anti-virulence as a new antibacterial approach for chemotherapy.


Assuntos
Toxinas Bacterianas/metabolismo , Capsaicina/farmacologia , Infecções Comunitárias Adquiridas/prevenção & controle , Proteínas Hemolisinas/metabolismo , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pneumonia Estafilocócica/prevenção & controle , Animais , Western Blotting , Capsaicina/farmacocinética , Linhagem Celular , Infecções Comunitárias Adquiridas/patologia , Citocinas/imunologia , Primers do DNA/genética , Hemólise , Técnicas Histológicas , Humanos , Pulmão/patologia , Staphylococcus aureus Resistente à Meticilina/metabolismo , Camundongos , Pneumonia Estafilocócica/patologia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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