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2.
PLoS Comput Biol ; 15(8): e1007223, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31404059

RESUMO

Antimicrobial resistance is one of the major public health threats of the 21st century. There is a pressing need to adopt more efficient treatment strategies in order to prevent the emergence and spread of resistant strains. The common approach is to treat patients with high drug doses, both to clear the infection quickly and to reduce the risk of de novo resistance. Recently, several studies have argued that, at least in some cases, low-dose treatments could be more suitable to reduce the within-host emergence of antimicrobial resistance. However, the choice of a drug dose may have consequences at the population level, which has received little attention so far. Here, we study the influence of the drug dose on resistance and disease management at the host and population levels. We develop a nested two-strain model and unravel trade-offs in treatment benefits between an individual and the community. We use several measures to evaluate the benefits of any dose choice. Two measures focus on the emergence of resistance, at the host level and at the population level. The other two focus on the overall treatment success: the outbreak probability and the disease burden. We find that different measures can suggest different dosing strategies. In particular, we identify situations where low doses minimize the risk of emergence of resistance at the individual level, while high or intermediate doses prove most beneficial to improve the treatment efficiency or even to reduce the risk of resistance in the population.


Assuntos
Doenças Transmissíveis/tratamento farmacológico , Anti-Infecciosos/administração & dosagem , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/transmissão , Biologia Computacional , Simulação por Computador , Surtos de Doenças/estatística & dados numéricos , Relação Dose-Resposta a Droga , Resistência Microbiana a Medicamentos/genética , Epidemias/estatística & dados numéricos , Metas , Interações entre Hospedeiro e Microrganismos , Humanos , Modelos Biológicos , Mutação , Medicina de Precisão , Probabilidade , Análise de Sistemas , Resultado do Tratamento
3.
Nat Commun ; 10(1): 3313, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346170

RESUMO

FDA proactively invests in tools to support innovation of emerging technologies, such as infectious disease next generation sequencing (ID-NGS). Here, we introduce FDA-ARGOS quality-controlled reference genomes as a public database for diagnostic purposes and demonstrate its utility on the example of two use cases. We provide quality control metrics for the FDA-ARGOS genomic database resource and outline the need for genome quality gap filling in the public domain. In the first use case, we show more accurate microbial identification of Enterococcus avium from metagenomic samples with FDA-ARGOS reference genomes compared to non-curated GenBank genomes. In the second use case, we demonstrate the utility of FDA-ARGOS reference genomes for Ebola virus target sequence comparison as part of a composite validation strategy for ID-NGS diagnostic tests. The use of FDA-ARGOS as an in silico target sequence comparator tool combined with representative clinical testing could reduce the burden for completing ID-NGS clinical trials.


Assuntos
Doenças Transmissíveis/diagnóstico , Bases de Dados de Ácidos Nucleicos/normas , Genoma , Acesso à Informação , Doenças Transmissíveis/microbiologia , Bases de Dados de Ácidos Nucleicos/organização & administração , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estados Unidos , United States Food and Drug Administration
5.
BMC Infect Dis ; 19(1): 577, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272417

RESUMO

BACKGROUND: Acute undifferentiated febrile illness (AUFI) is caused by a multitude of diverse pathogens, with significant morbidity and mortality in the developing world. The objective of this review was to characterise the diversity and relative importance of common infectious aetiologies of AUFI in South and Southeast Asia. METHODS: We conducted a comprehensive literature review to identify common aetiologies of AUFI in Asian countries. Four medical and life sciences databases including PubMed, Medline, Embase and Cochrane Central, and Google Scholar were searched for articles published from January 1998 to March 2019. RESULTS: Forty-three studies met the inclusion criteria. Among AUFI cases, viral aetiologies at 18.5% (14888) were more common than bacterial aetiologies (12.9% [10384]). From 80,554 cases, dengue fever was the most common aetiology (11.8%, 9511), followed by leptospirosis (4.4%, 3549), typhoid (4.0%, 3258), scrub typhus (4.0%, 3243) and influenza other than H1N1 (3.1%, 2514). In both adults and children: dengue fever was the leading cause of AUFI with 16.6% (1928) and 18.7% (1281) of the total cases. In admitted patients, dengue fever was the main cause of AUFI at 16.4% (2377), however leptospirosis at 13.9% (2090) was the main cause of AUFI for outpatients. In South Asia, dengue fever was the main cause of AUFI, causing 12.0% (6821) of cases, whereas in Southeast Asia, leptospirosis was the main diagnosis, causing 12.1% (2861) of cases. CONCLUSIONS: In this study the most common causes of AUFI were viral, followed by bacterial and protozoal (malaria) infections. Dengue was the commonest virus that caused AUFI while leptospirosis and typhoid were important bacterial infectious causes. Therefore, it is imperative to maintain a sound epidemiological knowledge of AUFI so that evidence-based diagnostic criteria and treatment guidelines can be developed.


Assuntos
Doenças Transmissíveis/complicações , Febre/etiologia , Ásia , Ásia Sudeste , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/virologia , Hospitalização , Humanos , Pacientes Ambulatoriais
6.
mBio ; 10(3)2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164465

RESUMO

This essay is written from the vantage point of the microbial world. While the focus of much thought in the microbial pathogenesis and infectious diseases fields has been on the impact of host-microbe interaction on the host, here we ask questions about what happens to the microbe. What are the costs and benefits for microbes of having the capacity for virulence? Our exploration of this topic leads us to conclude that virulence confers very few benefits for microbes, unless disease is necessary for microbial survival through host-to-host spread. In fact, the capacity for virulence is often fraught with risk for microbes, including host dependence and the threat of extinction. The costs of virulence may explain why, relative to their enormous numbers in nature, very few microbes are actually associated with human and animal disease.


Assuntos
Doenças dos Animais/microbiologia , Bactérias/patogenicidade , Doenças Transmissíveis/microbiologia , Interações Hospedeiro-Patógeno , Animais , Humanos , Virulência
7.
Emerg Infect Dis ; 25(7): 1380-1383, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31211676

RESUMO

We used metagenomic next-generation sequencing to longitudinally assess the gut microbiota and antimicrobial resistomes of international travelers to clarify global exchange of resistant organisms. Travel resulted in an increase in antimicrobial resistance genes and a greater proportion of Escherichia species within gut microbial communities without impacting diversity.


Assuntos
Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/microbiologia , Resistência Microbiana a Medicamentos , Metagenômica , Microbiota , Doença Relacionada a Viagens , Viagem , Biodiversidade , Biologia Computacional/métodos , Bases de Dados Genéticas , Transferência Genética Horizontal , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Metagenoma , Metagenômica/métodos , Microbiota/efeitos dos fármacos , Microbiota/genética
9.
PLoS One ; 14(4): e0215756, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31009510

RESUMO

Nucleic acid amplification technologies (NAATs) are high-performance tools for rapidly and accurately detecting infectious agents. They are widely used in high-income countries to diagnose disease and improve patient care. The complexities associated with test methods, reagents, equipment, quality control and assurance require dedicated laboratories with trained staff, which can exclude their use in low-resource and decentralized healthcare settings. For certain diseases, fully integrated NAAT devices and assays are available for use in environmentally-controlled clinics or emergency rooms where relatively untrained staff can perform testing. However, decentralized settings in many low- and middle-income countries with large burdens of infectious disease are challenged by extreme environments, poor infrastructure, few trained staff and limited financial resources. Therefore, there is an urgent need for low-cost, integrated NAAT tools specifically designed for use in low-resource settings (LRS). Two essential components of integrated NAAT tools are: 1) efficient nucleic acid extraction technologies for diverse and complex sample types; and 2) robust and sensitive nucleic acid amplification and detection technologies. In prior work we reported the performance and workflow capacity for the nucleic acid extraction component. In the current study we evaluated performance of eight novel nucleic acid amplification and detection technologies from seven developers using blinded panels of RNA and/or DNA from three pathogens to assess both diagnostic accuracy and suitability as an essential component for low-cost NAAT in LRS. In this exercise, we noted significant differences in performance among these technologies and identified those most promising for potential further development.


Assuntos
Doenças Transmissíveis/diagnóstico , Técnicas de Amplificação de Ácido Nucleico/métodos , Ácidos Nucleicos/genética , Sistemas Automatizados de Assistência Junto ao Leito/economia , Chlamydia/genética , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/virologia , Análise Custo-Benefício , HIV-1/genética , Recursos em Saúde/economia , Humanos , Neisseria gonorrhoeae/genética , Técnicas de Amplificação de Ácido Nucleico/instrumentação , Reprodutibilidade dos Testes , Zika virus/genética
10.
Lancet ; 393(10180): 1496-1497, 2019 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-30983581
11.
Nat Biotechnol ; 37(5): 527-530, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30936561

RESUMO

Oral antibodies that interfere with gastrointestinal targets and can be manufactured at scale are needed. Here we show that a single-gene-encoded monomeric immunoglobulin A (IgA)-like antibody, composed of camelid variable single domain antibodies (VHH) fused to IgA Fc (mVHH-IgA), prevents infection by enterotoxigenic Escherichia coli (F4-ETEC) in piglets. The mVHH-IgA can be produced in soybean seeds or secreted from the yeast Pichia pastoris, freeze- or spray-dried and orally delivered within food.


Assuntos
Doenças Transmissíveis/tratamento farmacológico , Gastroenteropatias/tratamento farmacológico , Imunoglobulina A/uso terapêutico , Anticorpos de Domínio Único/uso terapêutico , Administração Oral , Animais , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/microbiologia , Escherichia coli/patogenicidade , Alimentos , Gastroenteropatias/imunologia , Gastroenteropatias/prevenção & controle , Gastroenteropatias/veterinária , Humanos , Imunoglobulina A/imunologia , Anticorpos de Domínio Único/imunologia , Suínos
12.
Nat Rev Genet ; 20(6): 323-340, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30953039

RESUMO

Over the past decade, a genomics revolution, made possible through the development of high-throughput sequencing, has triggered considerable progress in the study of ancient DNA, enabling complete genomes of past organisms to be reconstructed. A newly established branch of this field, ancient pathogen genomics, affords an in-depth view of microbial evolution by providing a molecular fossil record for a number of human-associated pathogens. Recent accomplishments include the confident identification of causative agents from past pandemics, the discovery of microbial lineages that are now extinct, the extrapolation of past emergence events on a chronological scale and the characterization of long-term evolutionary history of microorganisms that remain relevant to public health today. In this Review, we discuss methodological advancements, persistent challenges and novel revelations gained through the study of ancient pathogen genomes.


Assuntos
Doenças Transmissíveis/história , DNA Antigo/análise , Genoma , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Archaea/genética , Archaea/isolamento & purificação , Bactérias/genética , Bactérias/isolamento & purificação , Evolução Biológica , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/parasitologia , Doenças Transmissíveis/virologia , DNA Antigo/isolamento & purificação , Fósseis , Saúde Global/história , História do Século XIX , História do Século XXI , História Antiga , História Medieval , Humanos , Vigilância em Saúde Pública/métodos , Vírus/genética , Vírus/isolamento & purificação
13.
Exp Parasitol ; 200: 48-54, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30917916

RESUMO

Free-living amoebae belong to the genus Acanthamoeba; can feed on microbial population by phagocytosis, and with the capability to act as a reservoir and a vehicle of microorganisms to susceptible host. Therefore, the role of endosymbiosis in the pathogenesis of Acanthamoeba is complex and not fully understood. The aim of the present study was to identify bacterial, fungal, and human adenovirus (HADV) endosymbionts as well as evaluating the endosymbionts role of such organisms in the pathogenesis of Acanthamoeba in keratitis patients living in Iran. Fifteen Acanthamoeba (T4 genotype) isolates were recovered from corneal scrapes and contact lenses of patients with keratitis. Cloning and purification was performed for all isolate. Gram staining was performed to identify bacterial endosymbionts. DNA extraction, PCR, and nested PCR was set up to identify endosymbiont of amoeba. Evaluation of pathogenicity was conducted by osmo-tolerance and thermo-tolerance assays and cell culture, and then CPE (cytopathic effect) was survey. Statistical analysis was used between Acanthamoeba associated endosymbionts and Acanthamoeba without endosymbiont at 24, 48, 72, and 96 h. A p value < 0.05 was considered as significant, statistically. A total of 9 (60%) Acanthamoeba (T4 genotypes) isolates were successfully cloned for detecting microorganism endosymbionts. The only isolate negative for the presence of endosymbiont was ICS9. ICS7 (Pseudomonas aeruginosa, Aspergillus sp., and human adenovirus endosymbionts) and ICS2 (Escherichia coli endosymbiont) isolates were considered as Acanthamoeba associated endosymbionts. ICS7 and ICS2 isolates were highly pathogen whereas ICS9 isolate showed low pathogenicity in pathogenicity evaluated. Positive CPE for ICS7 and ICS2 isolates and negative CPE for ICS9 isolate were observed in cell culture. The average number of cells, trophozoites, and cysts among ICS7, ICS2, and ICS9 isolates at 24, 48, 72, and 96 h was significant. This is the first survey on microbial endosymbionts of Acanthamoeba in keratitis patients of Iran, and also the first report of Aspergillus sp, Achromobacter sp., Microbacterium sp., Brevibacillus sp, Brevundimonas sp and Mastadenovirus sp in Acanthamoeba as endosymbionts. Our study demonstrated that microbial endosymbionts can affect the pathogenicity of Acanthamoeba; however, further research is required to clarify the exact pattern of symbiosis, in order to modify treatment protocol.


Assuntos
Ceratite por Acanthamoeba/complicações , Acanthamoeba/fisiologia , Adenovírus Humanos/isolamento & purificação , Bactérias/isolamento & purificação , Fungos/isolamento & purificação , Simbiose , Acanthamoeba/isolamento & purificação , Acanthamoeba/microbiologia , Acanthamoeba/patogenicidade , Adenovírus Humanos/genética , Adenovírus Humanos/fisiologia , Animais , Bactérias/genética , Clonagem Molecular , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/transmissão , Lentes de Contato/parasitologia , Córnea/parasitologia , Reservatórios de Doenças , Fungos/genética , Humanos , Irã (Geográfico) , Reação em Cadeia da Polimerase , Células Vero , Virulência
15.
Nat Rev Genet ; 20(6): 341-355, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30918369

RESUMO

Clinical metagenomic next-generation sequencing (mNGS), the comprehensive analysis of microbial and host genetic material (DNA and RNA) in samples from patients, is rapidly moving from research to clinical laboratories. This emerging approach is changing how physicians diagnose and treat infectious disease, with applications spanning a wide range of areas, including antimicrobial resistance, the microbiome, human host gene expression (transcriptomics) and oncology. Here, we focus on the challenges of implementing mNGS in the clinical laboratory and address potential solutions for maximizing its impact on patient care and public health.


Assuntos
Doenças Transmissíveis/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Ciência de Laboratório Médico/métodos , Metagenoma , Metagenômica/métodos , Animais , Antibacterianos/uso terapêutico , Bactérias/genética , Bactérias/isolamento & purificação , Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/virologia , DNA/genética , DNA/isolamento & purificação , Farmacorresistência Bacteriana Múltipla/genética , Fungos/genética , Fungos/isolamento & purificação , Helmintos/genética , Helmintos/isolamento & purificação , Interações Hospedeiro-Patógeno , Humanos , Ciência de Laboratório Médico/instrumentação , Metagenômica/instrumentação , Saúde Pública/tendências , Vírus/genética , Vírus/isolamento & purificação
16.
Eur J Clin Microbiol Infect Dis ; 38(7): 1235-1240, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30900056

RESUMO

To identify differences in perception on multi-drug-resistant (MDR) organisms and their management at intensive care units (ICU). A cross-sectional survey was conducted. A proposal addressing a pathogen priority list (PPL) for ICU, arising from the TOTEM study, was compared with a sample of global experts in infections in critically ill patients. The survey was responded by 129 experts. Globally, ESBL Enterobacteriaceae, followed by carbapenem-resistant Acinetobacter baumannii and carbapenem-resistant Klebsiella pneumoniae, were the main concerns. Some differences in opinion were identified between 63 (49%) ICU physicians (ICU/anesthesiology) and 43 (33%) infectious disease consultants (ID physicians/microbiologists). The pathogens most concerning in the ICU for intensivists were ESBL Enterobacteriaceae (38%) versus carbapenem-resistant A. baumannii (48.3%) for ID consultants, (p < 0.05). Increasing number of ID consultants over intensivists (26% vs 14%) reported difficulty in choosing initial therapy for carbapenem-resistant A. baumannii. For intensivists, the urgent measures to limit development of antibiotic resistance were headed by cohort measures (26.3%) versus increasing nurse/patient ratio (32.5%) for ID consultants, (p < 0.05). Regarding effectiveness to prevent MDR development and spread, education programs (42.4%) were the priority for intensivists versus external consultation (35.7%) for ID consultants. Finally, both groups agreed that carbapenem resistance was the most pressing concern (> 70%) regarding emerging resistance. Differences in priorities regarding organisms, infection control practices, and educational priorities were visualized between ID/clinical microbiologists and ICU/anesthesiologists. Multi-disciplinary collaboration is required to achieve best care for ICU patients with severe infections.


Assuntos
Farmacorresistência Bacteriana Múltipla , Saúde Global , Controle de Infecções , Unidades de Terapia Intensiva/estatística & dados numéricos , Antibacterianos/uso terapêutico , Carbapenêmicos/uso terapêutico , Estudos de Coortes , Doenças Transmissíveis/tratamento farmacológico , Doenças Transmissíveis/microbiologia , Cuidados Críticos/normas , Estudos Transversais , Enterobacteriaceae/efeitos dos fármacos , Humanos , Unidades de Terapia Intensiva/normas , Testes de Sensibilidade Microbiana , Médicos/classificação
17.
PLoS Pathog ; 15(3): e1007585, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30897154

RESUMO

Nuclear receptors (NRs) are ligand-activated transcription factors that are expressed in a variety of cells, including macrophages. For decades, NRs have been therapeutic targets because their activity can be pharmacologically modulated by specific ligands and small molecule inhibitors. NRs regulate a variety of processes, including those intersecting metabolic and immune functions, and have been studied in regard to various autoimmune diseases. However, the complex roles of NRs in host response to infection are only recently being investigated. The NRs peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptors (LXRs) have been most studied in the context of infectious diseases; however, recent work has also linked xenobiotic pregnane X receptors (PXRs), vitamin D receptor (VDR), REV-ERBα, the nuclear receptor 4A (NR4A) family, farnesoid X receptors (FXRs), and estrogen-related receptors (ERRs) to macrophage responses to pathogens. Pharmacological inhibition or antagonism of certain NRs can greatly influence overall disease outcome, and NRs that are protective against some diseases can lead to susceptibility to others. Targeting NRs as a novel host-directed treatment approach to infectious diseases appears to be a viable option, considering that these transcription factors play a pivotal role in macrophage lipid metabolism, cholesterol efflux, inflammatory responses, apoptosis, and production of antimicrobial byproducts. In the current review, we discuss recent findings concerning the role of NRs in infectious diseases with an emphasis on PPARγ and LXR, the two most studied. We also highlight newer work on the activity of emerging NRs during infection.


Assuntos
Macrófagos/metabolismo , Receptores Citoplasmáticos e Nucleares/fisiologia , Animais , Bactérias , Doenças Transmissíveis/metabolismo , Doenças Transmissíveis/microbiologia , Fungos , Regulação da Expressão Gênica/genética , Humanos , Ligantes , Receptores X do Fígado/metabolismo , PPAR gama/metabolismo , Receptores de Calcitriol , Receptores Citoplasmáticos e Nucleares/metabolismo , Relação Estrutura-Atividade , Fatores de Transcrição , Vírus
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