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1.
J Infect Chemother ; 26(2): 242-251, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31575499

RESUMO

Pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) is associated with poor clinical outcomes. We surveyed clinical outcomes of MRSA pneumonia in daily practice to identify risk factors for the clinical failure and mortality in patients with MRSA pneumonia. This multicenter prospective observational study was performed across 48 Japanese medical institutions. Adult patients with culture-positive MRSA pneumonia were recruited and treated with anti-MRSA antibiotics. The relationships between clinical and microbiological characteristics and clinical outcomes at test of cure (TOC) or 30-day all-cause mortality were analyzed. In total, 199 eligible patients, including nursing and healthcare-associated pneumonia (n = 95), hospital-acquired pneumonia (n = 76), and community-acquired pneumonia (n = 25), received initial treatment with anti-MRSA agents such as vancomycin (n = 135), linezolid (n = 36), or teicoplanin (n = 22). Overall clinical failure rate at TOC and the 30-day mortality rate were 51.1% (48/94 patients) and 33.7% (66/196 patients), respectively. Multivariable logistic regression analyses for vancomycin-treated populations revealed that abnormal white blood cell count (odds ratio [OR] 4.34, 95% confidence interval [CI] 1.31-14.39) was a risk factor for clinical failure and that no therapeutic drug monitoring (OR 3.10, 95% CI 1.35-7.12) and abnormally high C-reactive protein level (OR 3.54, 95% CI 1.26-9.92) were risk factors for mortality. In conclusion, this study provides evidence that majority of MRSA pneumonia patients are initially treated with vancomycin in Japan, and the absence of therapeutic drug monitoring for vancomycin is significantly associated with the mortality in patients with MRSA pneumonia.


Assuntos
Linezolida/uso terapêutico , Staphylococcus aureus Resistente à Meticilina , Pneumonia Estafilocócica/tratamento farmacológico , Teicoplanina/uso terapêutico , Vancomicina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Estudos de Coortes , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/mortalidade , Monitoramento de Medicamentos , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Pneumonia Estafilocócica/mortalidade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Resultado do Tratamento
2.
Am J Respir Crit Care Med ; 200(7): e45-e67, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31573350

RESUMO

Background: This document provides evidence-based clinical practice guidelines on the management of adult patients with community-acquired pneumonia.Methods: A multidisciplinary panel conducted pragmatic systematic reviews of the relevant research and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations.Results: The panel addressed 16 specific areas for recommendations spanning questions of diagnostic testing, determination of site of care, selection of initial empiric antibiotic therapy, and subsequent management decisions. Although some recommendations remain unchanged from the 2007 guideline, the availability of results from new therapeutic trials and epidemiological investigations led to revised recommendations for empiric treatment strategies and additional management decisions.Conclusions: The panel formulated and provided the rationale for recommendations on selected diagnostic and treatment strategies for adult patients with community-acquired pneumonia.


Assuntos
Antibacterianos/uso terapêutico , Infecções Comunitárias Adquiridas/diagnóstico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Pneumonia Bacteriana/diagnóstico , Pneumonia Bacteriana/tratamento farmacológico , Adulto , Assistência Ambulatorial , Antígenos de Bactérias/urina , Hemocultura , Infecções por Chlamydophila/diagnóstico , Infecções por Chlamydophila/tratamento farmacológico , Infecções por Chlamydophila/metabolismo , Técnicas de Cultura , Quimioterapia Combinada , Infecções por Haemophilus/diagnóstico , Infecções por Haemophilus/tratamento farmacológico , Infecções por Haemophilus/metabolismo , Hospitalização , Humanos , Legionelose/diagnóstico , Legionelose/tratamento farmacológico , Legionelose/metabolismo , Macrolídeos/uso terapêutico , Infecções por Moraxellaceae/diagnóstico , Infecções por Moraxellaceae/tratamento farmacológico , Infecções por Moraxellaceae/metabolismo , Pneumonia por Mycoplasma/diagnóstico , Pneumonia por Mycoplasma/tratamento farmacológico , Pneumonia por Mycoplasma/metabolismo , Pneumonia Pneumocócica/diagnóstico , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Pneumocócica/metabolismo , Pneumonia Estafilocócica/diagnóstico , Pneumonia Estafilocócica/tratamento farmacológico , Pneumonia Estafilocócica/metabolismo , Radiografia Torácica , Índice de Gravidade de Doença , Escarro , Estados Unidos , beta-Lactamas/uso terapêutico
3.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31383747

RESUMO

Postinfluenza methicillin-resistant Staphylococcus aureus (MRSA) infection can quickly develop into severe, necrotizing pneumonia, causing over 50% mortality despite antibiotic treatments. In this study, we investigated the efficacy of antibiotic therapies and the impact of S. aureus alpha-toxin in a model of lethal influenza virus and MRSA coinfection. We demonstrate that antibiotics primarily attenuate alpha-toxin-induced acute lethality, even though both alpha-toxin-dependent and -independent mechanisms significantly contribute to animal mortality after coinfection. Furthermore, we found that the protein synthesis-suppressing antibiotic linezolid has an advantageous therapeutic effect on alpha-toxin-induced lung damage, as measured by protein leak and lactate dehydrogenase (LDH) activity. Importantly, using a Panton-Valentine leucocidin (PVL)-negative MRSA isolate from patient sputum, we show that linezolid therapy significantly improves animal survival from postinfluenza MRSA pneumonia compared with vancomycin treatment. Rather than improved viral or bacterial control, this advantageous therapeutic effect is associated with a significantly attenuated proinflammatory cytokine response and acute lung damage in linezolid-treated mice. Together, our findings not only establish a critical role of alpha-toxin in the extreme mortality of secondary MRSA pneumonia after influenza but also provide support for the possibility that linezolid could be a more effective treatment than vancomycin to improve disease outcomes.


Assuntos
Antibacterianos/farmacologia , Toxinas Bacterianas/antagonistas & inibidores , Proteínas Hemolisinas/antagonistas & inibidores , Linezolida/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções por Orthomyxoviridae/complicações , Pneumonia Estafilocócica/tratamento farmacológico , Animais , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Feminino , Expressão Gênica , Gentamicinas/farmacologia , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/metabolismo , L-Lactato Desidrogenase/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Masculino , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/mortalidade , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Plasmídeos/química , Plasmídeos/metabolismo , Pneumonia Estafilocócica/complicações , Pneumonia Estafilocócica/microbiologia , Pneumonia Estafilocócica/mortalidade , Análise de Sobrevida , Vancomicina/farmacologia
4.
Int J Antimicrob Agents ; 54(4): 410-422, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31404620

RESUMO

Staphylococcus aureus (S. aureus), including methicillin-resistant S. aureus (MRSA), is an important aetiological cause of community-acquired pneumonia (CAP) and associated with significant morbidity and mortality. Empiric therapy for CAP frequently consists of ß-lactam monotherapy or ß-lactam/macrolide combination therapy. However, such agents are often ineffective against S. aureus and do not reflect the emergence and increasing prevalence of MRSA in the community setting. Ceftaroline fosamil is a fifth-generation parenteral cephalosporin with broad-spectrum activity against Gram-positive pathogens - such as S. aureus (including MRSA), Streptococcus pneumoniae and Streptococcus pyogenes - and typical Gram-negative pathogens, including Haemophilus influenzae and Moraxella catarrhalis. The approval of ceftaroline fosamil in the United States and Europe for the treatment of adults with moderate-to-severe CAP was based on two phase 3 trials (FOCUS 1 and 2), which demonstrated that ceftaroline fosamil was non-inferior to ceftriaxone, a standard empiric treatment for CAP, while exhibiting a comparable safety profile. Although head-to-head trials of ceftaroline fosamil versus comparators against MRSA CAP are lacking, the effectiveness of ceftaroline fosamil in subpopulations of patients not covered by phase 3 trials (e.g. those with MRSA CAP or severe renal impairment) has been demonstrated in the Clinical Assessment Program and Teflaro Utilization Registry (CAPTURE) study. As ineffective empiric therapy is associated with adverse outcomes, including mortality and increased costs, ceftaroline fosamil, with its extended spectrum of activity, is an attractive alternative to standard antibiotic CAP regimens.


Assuntos
Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Pneumonia Estafilocócica/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Ensaios Clínicos Fase III como Assunto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Humanos , Resultado do Tratamento
5.
Nat Commun ; 10(1): 3268, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332172

RESUMO

Teixobactin represents a new class of antibiotics with novel structure and excellent activity against Gram-positive pathogens and Mycobacterium tuberculosis. Herein, we report a one-pot reaction to conveniently construct the key building block L-allo-Enduracidine in 30-gram scale in just one hour and a convergent strategy (3 + 2 + 6) to accomplish a gram-scale total synthesis of teixobactin. Several analogs are described, with 20 and 26 identified as the most efficacious analogs with 3~8-fold and 2~4-fold greater potency against vancomycin resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus respectively in comparison with teixobactin. In addition, they show high efficiency in Streptococcus pneumoniae septicemia mouse model and neutropenic mouse thigh infection model using methicillin-resistant Staphylococcus aureus. We also propose that the antiparallel ß-sheet of teixobactin is important for its bioactivity and an antiparallel dimer of teixobactin is the minimal binding unit for lipid II via key amino acids variations and molecular docking.


Assuntos
Depsipeptídeos/farmacologia , Testes de Sensibilidade Microbiana/métodos , Pneumonia Estafilocócica/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Linhagem Celular Tumoral , Depsipeptídeos/síntese química , Depsipeptídeos/química , Células Hep G2 , Humanos , Camundongos , Modelos Químicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Pneumonia Estafilocócica/microbiologia , Relação Estrutura-Atividade
7.
Int J Antimicrob Agents ; 54(2): 149-153, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173864

RESUMO

Ceftriaxone is an empirical antibiotic commonly used to treat pneumonia. However, its use to treat infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) is controversial given limited evidence of its clinical efficacy. The objective of this study was to compare the clinical efficacy of ceftriaxone with either ceftaroline or ceftobiprole in the treatment of pneumonia caused by MSSA. A systematic review and meta-analysis of randomised controlled trials (RCTs) comparing clinical cure in patients with pneumonia who received ceftriaxone versus those who received either ceftaroline or ceftobiprole was conducted. Patients who received ceftriaxone plus vancomycin were excluded. The PubMed, Embase and Cochrane Library databases as well as clinical trial registries were searched up to 8 June 2018. Risk differences (RDs) with 95% confidence intervals (CIs) were estimated using a random-effects model and assessing for heterogeneity (I2). A total of five RCTs met the inclusion criteria; four used ceftaroline and one used ceftobiprole. Four studies included adults and one included paediatric patients. The adult studies included non-intensive care unit patients with mild-to-moderate community-acquired pneumonia. Clinical cure was statistically lower with ceftriaxone (RD, -28.5%, 95% CI -53.5% to -3.4%; P = 0.026; I2 = 16.321%) than with ceftaroline or ceftobiprole. In conclusion, ceftriaxone use was associated with higher clinical failure of MSSA pneumonia compared with ceftaroline or ceftobiprole. This supports the notion that ceftriaxone is not an ideal agent for the treatment of MSSA infections and adds new evidence against its use for MSSA pneumonia.


Assuntos
Antibacterianos/uso terapêutico , Ceftriaxona/uso terapêutico , Cefalosporinas/uso terapêutico , Pneumonia Estafilocócica/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Staphylococcus aureus/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem
8.
Int Immunopharmacol ; 72: 195-203, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30991161

RESUMO

The bacterial pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) is a potentially fatal disease, featured with extensive infection, inflammation, and airway dysfunction. With the increasing emerging of drug-resistant strains, new therapeutic strategies beyond canonical antibiotic treatment are pressingly needed. Daphnetin (DAPH) is a natural coumarin derivative with anti-inflammation, anti-microorganism and anti-oxidative properties. However, the protective effect of DAPH on S. aureus-caused pneumonia and the mechanism involved are never explored. Here we show that DAPH treatment conferred substantial protection against S. aureus-induced pneumonia, characterized by the reduced inflammatory responses, the augmented bacterial clearance and the alleviated tissue damage. Our study indicates that DAPH significantly enhanced mTOR-dependent autophagic pathway, leading to the boosted microphage bactericidal activity and the suppressed inflammatory responses. Inhibition of autophagic pathway therefore largely abolished DAPH-elicited repression of inflammatory response and macrophage anti-bacterial capability. Together, we herein not only identify a novel, natural agent to combat bacterial pneumonia, but also underscore the significance of autophagic pathway in orchestrating antimicrobial and anti-inflammatory responses, which may have important implication for the treatment of the infectious diseases, particularly that caused by obstinate, antibiotic-resistant pathogens such as MRSA.


Assuntos
Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Autofagia/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina , Pneumonia Estafilocócica/tratamento farmacológico , Umbeliferonas/uso terapêutico , Animais , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Citocinas/genética , Citocinas/imunologia , Feminino , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia Estafilocócica/imunologia , Células RAW 264.7 , Umbeliferonas/farmacologia
9.
Int Immunopharmacol ; 72: 40-47, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30959370

RESUMO

Staphylococcus aureus is a major causative microorganism in community- and healthcare-acquired pneumonia. CD5L is an important protein in the control of immune homeostasis. In this study, we found that patients with S. aureus pneumonia displayed increased levels of circulating CD5L. Likewise, mice with S. aureus pneumonia had elevated CD5L levels in the lungs. Anti-CD5L antibody protected mice from lethal pneumonia induced by methicillin-resistant S. aureus. The survival benefit obtained with antibody against CD5L was associated with an improvement of bacterial clearance and a reduction of pulmonary inflammatory cytokines and chemokines. Conversely, co-injection of recombinant CD5L and S. aureus markedly increased the lethality of S. aureus pneumonia. These findings suggest that CD5L contributed to the immunopathology of S. aureus pneumonia.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Pneumonia Estafilocócica/imunologia , Receptores Depuradores Classe B/imunologia , Animais , Anticorpos/uso terapêutico , Proteínas Reguladoras de Apoptose/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Humanos , Pulmão/imunologia , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Pneumonia Estafilocócica/sangue , Pneumonia Estafilocócica/tratamento farmacológico , Receptores Imunológicos/imunologia , Receptores Depuradores Classe B/sangue
10.
Chest ; 155(5): 999-1007, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30776365

RESUMO

BACKGROUND: Guidelines recommend empirical vancomycin or linezolid for patients with suspected pneumonia at risk for methicillin-resistant Staphylococcus aureus (MRSA). Unneeded vancomycin or linezolid use may unnecessarily alter host flora and expose patients to toxicity. We therefore sought to determine if rapid testing for MRSA in BAL can safely decrease use of vancomycin or linezolid for suspected MRSA pneumonia. METHODS: Operating characteristics of the assay were initially validated against culture on residual BAL. A prospective, unblinded, randomized clinical trial to assess the effect of antibiotic management made on the basis of rapid diagnostic testing (RDT) compared with usual care was subsequently conducted, with primary outcome of duration of vancomycin or linezolid administration. Secondary end points focused on safety. RESULTS: Sensitivity of RPCR was 95.7%, with a negative likelihood ratio of 0.04 for MRSA. The clinical trial randomized 45 patients: 22 to antibiotic management made on the basis of RDT and 23 to usual care. Duration of vancomycin or linezolid administration was significantly reduced in the intervention group (32 h [interquartile range, 22-48] vs 72 h [interquartile range, 50-113], P < .001). Proportions with complications and length of stay trended lower in the intervention group. Hospital mortality was 13.6% in the intervention group and 39.1% for usual care (95% CI of difference, -3.3 to 50.3, P = .06). Standardized mortality ratio was 0.48 for the intervention group and 1.18 for usual care. CONCLUSIONS: A highly sensitive BAL RDT for MRSA significantly reduced use of vancomycin and linezolid in ventilated patients with suspected pneumonia. Management made on the basis of RDT had no adverse effects, with a trend to lower hospital mortality. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT02660554; URL: www.clinicaltrials.gov.


Assuntos
Gestão de Antimicrobianos/métodos , Líquido da Lavagem Broncoalveolar/microbiologia , Linezolida , Staphylococcus aureus Resistente à Meticilina , Pneumonia Estafilocócica , Vancomicina , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Técnicas Bacteriológicas/métodos , Testes Diagnósticos de Rotina/métodos , Resistência Microbiana a Medicamentos , Feminino , Humanos , Linezolida/administração & dosagem , Linezolida/efeitos adversos , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Pessoa de Meia-Idade , Projetos Piloto , Pneumonia Estafilocócica/diagnóstico , Pneumonia Estafilocócica/tratamento farmacológico , Pneumonia Estafilocócica/microbiologia , Reprodutibilidade dos Testes , Vancomicina/administração & dosagem , Vancomicina/efeitos adversos
11.
Artigo em Inglês | MEDLINE | ID: mdl-30670417

RESUMO

SAL200 is derived from a phage endolysin and is a novel candidate drug for the treatment of Staphylococcus aureus infection. We investigated the efficacy of the recombinant endolysin SAL200 in a lethal murine pneumonia model. Lethal pneumonia was established by intranasally administering a methicillin-susceptible (Newman) or methicillin-resistant (LAC) S. aureus strain into BALB/c mice. The mice were treated with a single intranasal administration of SAL200 or phosphate-buffered saline at 2 h after S. aureus infection. The survival rates were recorded until 60 h after the bacterial challenge. The bacterial loads in the lungs and blood, histopathology of lung tissues, and serum cytokine levels were evaluated following the S. aureus challenge. The SAL200-treated group and control group exhibited 90% to 95% and 10% to 40% survival rates, respectively. The bacterial loads in the lungs of the SAL200-treated group were significantly lower by ∼10-fold than those of the control group as early as 1 h after treatment. Histopathologic recovery of pneumonia was observed in the SAL200-treated mice. The cytokine levels were comparable between groups. These results suggest that direct administration of SAL200 into the lungs could be a potential adjunct treatment against severe pneumonia caused by S. aureus.


Assuntos
Antibacterianos/uso terapêutico , Endopeptidases/uso terapêutico , Pneumonia Estafilocócica/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Administração Intranasal , Animais , Carga Bacteriana/efeitos dos fármacos , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia Estafilocócica/mortalidade
12.
Chest ; 155(1): 53-59, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30621854

RESUMO

BACKGROUND: In culture-positive nosocomial pneumonia, de-escalation (DE) from broad-spectrum empirical antimicrobials to narrower-spectrum agents has shown to decrease broad-spectrum antibiotic use without compromising patient outcomes. However, uncertainty exists regarding the safety of anti-methicillin-resistant Staphylococcus aureus (MRSA) agent DE in culture-negative nosocomial pneumonia. This study aimed to determine if anti-MRSA agent DE in culture-negative nosocomial pneumonia affects 28-day and hospital mortality, ICU and hospital length of stay (LOS), treatment failure, and safety. METHODS: This single-center retrospective cohort study included adult patients admitted from 2012 to 2017 with nosocomial pneumonia and a negative respiratory culture. DE was defined as anti-MRSA agent discontinuation within 4 days of initiation. Secondary outcomes included hospital mortality, hospital and ICU LOS, treatment failure, and occurrence of acute kidney injury (AKI). RESULTS: Of 279 patients included, 92 were in the DE group and 187 were in the no DE (NDE) group. Patients who were not de-escalated received 5 more days of MRSA coverage than patients who were de-escalated; however, there was no difference in 28-day mortality (NDE group, 28% vs DE group, 23%; difference, -5.5%; 95% CI, -16.1 to 6.5). Patients who were de-escalated had shorter hospital (DE group, 15 days vs NDE group, 20 days; difference, 3.2 days; 95% CI, 0.1-6.4) and ICU (DE group, 10 days vs NDE group, 13 days; difference, 2.2 days; 95% CI, -0.3 to 4.9) LOSs after the index date. The incidence of AKI was significantly higher in patients who were not de-escalated (DE group, 36% vs NDE group, 50%; difference, -13.8%; 95% CI, -26.9 to -0.4). CONCLUSIONS: Although anti-MRSA agent DE in culture-negative nosocomial pneumonia did not affect 28-day mortality, it was associated with a shorter hospital LOS and lower incidence of AKI.


Assuntos
Anti-Infecciosos/uso terapêutico , Pneumonia Associada a Assistência à Saúde/tratamento farmacológico , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Pneumonia Estafilocócica/tratamento farmacológico , Idoso , Feminino , Seguimentos , Pneumonia Associada a Assistência à Saúde/microbiologia , Pneumonia Associada a Assistência à Saúde/mortalidade , Mortalidade Hospitalar/tendências , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pessoa de Meia-Idade , Missouri/epidemiologia , Pneumonia Estafilocócica/microbiologia , Pneumonia Estafilocócica/mortalidade , Estudos Retrospectivos , Resultado do Tratamento
13.
Curr Opin Infect Dis ; 32(2): 169-175, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30640820

RESUMO

PURPOSE OF REVIEW: This review provides the rationale for the development of new antibiotics to treat community-acquired pneumonia (CAP). It also provides an overview of the new antibiotics targeting CAP that have recently received approval by the regulatory agencies, and those antibiotics that are in the development pipeline. RECENT FINDINGS: CAP is one of the most common reasons for hospitalization and carries a significant morbidity and risk of mortality. Increasing antibiotic resistance amongst the common bacterial pathogens associated with CAP, especially staphylococci and Streptococcus pneumoniae, has made the empiric treatment of this infection increasingly problematic. Moreover, failure of initial empiric therapy to cover the causative agents associated with CAP can be associated with worse clinical outcomes. There have been several antibiotics newly approved or in development for the treatment of CAP. These agents include delafloxacin, omadacycline, lefamulin, solithromycin, nemonoxacin, and ceftaroline. Their major advantages include activity against methicillin-resistant Staphylococcus aureus and macrolide-resistant Strep. pneumoniae. SUMMARY: CAP continues to be an important infection because of its impact on patient outcomes especially in the elderly and immunocompromised hosts. The availability of new antibiotics offers an opportunity for enhanced empiric treatment of the antibiotic-resistant bacterial pathogens associated with CAP.


Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/uso terapêutico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Desenvolvimento de Medicamentos/tendências , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Estafilocócica/tratamento farmacológico , Ensaios Clínicos como Assunto , Humanos , Resultado do Tratamento
14.
Acta Pharmacol Sin ; 40(8): 1040-1048, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30644422

RESUMO

Staphylococcus aureus (S. aureus) infection leads to a severe inflammatory response and causes acute lung injury (ALI), eventually threatening human life. Therefore, it is of importance to find an agent to inhibit inflammation and reduce ALI. Here, we found that costunolide, a sesquiterpene lactone, displays anti-inflammatory effects and ameliorates heat-killed S. aureus (HKSA)-induced pneumonia. Costunolide treatment attenuated HKSA-induced murine ALI in which pulmonary neutrophil infiltration was inhibited, lung edema was decreased, and the production of pro-inflammatory cytokines was significantly reduced. In addition, costunolide dose-dependently inhibited the generation of IL-6, TNF-α, IL-1ß, and keratinocyte-derived cytokine (KC), as well as the expression of iNOS, in HKSA-induced macrophages. Furthermore, costunolide attenuated the phosphorylation of p38 MAPK and cAMP response element-binding protein (CREB). Collectively, our findings suggested that costunolide is a promising agent for alleviating bacterial-induced ALI via the inhibition of the MAPK signaling pathways.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Ativação de Macrófagos/efeitos dos fármacos , Sesquiterpenos/uso terapêutico , Lesão Pulmonar Aguda/microbiologia , Animais , Citocinas/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Pneumonia Estafilocócica/tratamento farmacológico , Pneumonia Estafilocócica/microbiologia , Edema Pulmonar/tratamento farmacológico , Edema Pulmonar/microbiologia , Staphylococcus aureus
15.
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
16.
Clin Infect Dis ; 68(3): 365-372, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29893805

RESUMO

Background: Coinfection with influenza virus and methicillin-resistant Staphylococcus aureus (MRSA) causes life-threatening necrotizing pneumonia in children. Sporadic incidence precludes evaluation of antimicrobial efficacy. We assessed the clinical characteristics and outcomes of critically ill children with influenza-MRSA pneumonia and evaluated antibiotic use. Methods: We enrolled children (<18 years) with influenza infection and respiratory failure across 34 pediatric intensive care units 11/2008-5/2016. We compared baseline characteristics, clinical courses, and therapies in children with MRSA coinfection, non-MRSA bacterial coinfection, and no bacterial coinfection. Results: We enrolled 170 children (127 influenza A, 43 influenza B). Children with influenza-MRSA pneumonia (N = 30, 87% previously healthy) were older than those with non-MRSA (N = 61) or no (N = 79) bacterial coinfections. Influenza-MRSA was associated with increased leukopenia, acute lung injury, vasopressor use, extracorporeal life support, and mortality than either group (P ≤ .0001). Influenza-related mortality was 40% with MRSA compared to 4.3% without (relative risk [RR], 9.3; 95% confidence interval [CI], 3.8-22.9). Of 29/30 children with MRSA who received vancomycin within the first 24 hours of hospitalization, mortality was 12.5% (N = 2/16) if treatment also included a second anti-MRSA antibiotic compared to 69.2% (N = 9/13) with vancomycin monotherapy (RR, 5.5; 95% CI, 1.4, 21.3; P = .003). Vancomycin dosing did not influence initial trough levels; 78% were <10 µg/mL. Conclusions: Influenza-MRSA coinfection is associated with high fatality in critically ill children. These data support early addition of a second anti-MRSA antibiotic to vancomycin in suspected severe cases.


Assuntos
Antibacterianos/uso terapêutico , Coinfecção/tratamento farmacológico , Estado Terminal , Influenza Humana/complicações , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Pneumonia Estafilocócica/tratamento farmacológico , Vancomicina/uso terapêutico , Adolescente , Criança , Pré-Escolar , Coinfecção/microbiologia , Coinfecção/mortalidade , Coinfecção/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Influenza Humana/mortalidade , Influenza Humana/patologia , Masculino , Pneumonia Estafilocócica/microbiologia , Pneumonia Estafilocócica/mortalidade , Pneumonia Estafilocócica/patologia , Estudos Prospectivos , Análise de Sobrevida , Resultado do Tratamento
17.
Tissue Eng Part A ; 25(3-4): 257-270, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30019635

RESUMO

IMPACT STATEMENT: Lung infection is a leading cause of human life lost to morbidity and/or mortality. This problem is exacerbated by the alarming emergence of increasingly antibiotic-resistant (AR) microorganisms worldwide and the lack of effective antimicrobials to overcome the AR bacterial infection. Urinary bladder matrix (UBM) is a biologically derived scaffold material that has been used to promote site-appropriate tissue regeneration and remodeling in a variety of body systems. Our novel findings demonstrate that the preformulated UBM effectively protects the host from methicillin-resistant Staphylococcus aureus (MRSA)- and Pseudomonas aeruginosa-induced murine pneumonia and may provide a viable alternative/supplement for protection against respiratory AR bacterial infection.


Assuntos
Matriz Extracelular/química , Staphylococcus aureus Resistente à Meticilina/metabolismo , Infecções por Pseudomonas , Pseudomonas aeruginosa/metabolismo , Infecções Estafilocócicas , Bexiga Urinária/química , Animais , Feminino , Camundongos , Pneumonia Estafilocócica/tratamento farmacológico , Pneumonia Estafilocócica/metabolismo , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/metabolismo , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/metabolismo
18.
Intern Med ; 58(5): 685-691, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30333405

RESUMO

A 66-year-old man was transferred to our hospital for pneumonia that was resistant to sulbactam/ampicillin and levofloxacin therapy. Chest computed tomography showed the rapidly progressive formation of multiple cavities. Methicillin-resistant Staphylococcus aureus (MRSA) was isolated, and the patient was diagnosed with necrotizing pneumonia caused by community-acquired MRSA (CA-MRSA). The MRSA strain had type IV staphylococcus cassette chromosome mec and genes encoding Panton-Valentine leucocidin (PVL). CA-MRSA necrotizing pneumonia with the PVL gene is rare; only three cases have been previously reported in Japan. We administered anti-MRSA antibiotics and the patient achieved complete clinical and radiological improvement.


Assuntos
Toxinas Bacterianas/genética , Exotoxinas/genética , Leucocidinas/genética , Staphylococcus aureus Resistente à Meticilina/genética , Pneumonia Necrosante/diagnóstico por imagem , Pneumonia Estafilocócica/diagnóstico por imagem , Idoso , Antibacterianos/uso terapêutico , Infecções Comunitárias Adquiridas/diagnóstico por imagem , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Humanos , Masculino , Resistência a Meticilina , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Pneumonia Necrosante/tratamento farmacológico , Pneumonia Necrosante/microbiologia , Pneumonia Estafilocócica/tratamento farmacológico , Pneumonia Estafilocócica/microbiologia , Radiografia , Tomografia Computadorizada por Raios X
19.
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
20.
J Hosp Med ; 13(12): 848-852, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30379141

RESUMO

Within a cohort of >2,000 children hospitalized with community-acquired pneumonia, staphylococcal pneumonia was rare (1%) but associated with adverse in-hospital outcomes. Despite this low prevalence, use of antistaphylococcal antibiotics was common (24%). Efforts are needed to minimize overuse of antistaphylococcal antibiotics while also ensuring adequate treatment for pathogen-specific diseases.


Assuntos
Antibacterianos/uso terapêutico , Infecções Comunitárias Adquiridas/epidemiologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pneumonia Estafilocócica/diagnóstico , Pneumonia Estafilocócica/tratamento farmacológico , Criança , Pré-Escolar , Testes Diagnósticos de Rotina/estatística & dados numéricos , Feminino , Hospitais , Humanos , Prescrição Inadequada/estatística & dados numéricos , Lactente , Masculino , Pneumonia Estafilocócica/epidemiologia , Prevalência , Estudos Retrospectivos
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