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2.
PLoS Biol ; 17(10): e3000379, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658249

RESUMO

Recent work has revealed that Clostridioides difficile, a major cause of nosocomial diarrheal disease, exhibits phenotypic heterogeneity within a clonal population as a result of phase variation. Many C. difficile strains representing multiple ribotypes develop two colony morphotypes, termed rough and smooth, but the biological implications of this phenomenon have not been explored. Here, we examine the molecular basis and physiological relevance of the distinct colony morphotypes produced by this bacterium. We show that C. difficile reversibly differentiates into rough and smooth colony morphologies and that bacteria derived from the isolates display discrete motility behaviors. We identified an atypical phase-variable signal transduction system consisting of a histidine kinase and two response regulators, named herein colony morphology regulators RST (CmrRST), which mediates the switch in colony morphology and motility behaviors. The CmrRST-regulated surface motility is independent of flagella and type IV pili, suggesting a novel mechanism of cell migration in C. difficile. Microscopic analysis of cell and colony structure indicates that CmrRST promotes the formation of elongated bacteria arranged in bundled chains, which may contribute to bacterial migration on surfaces. In a hamster model of acute C. difficile disease, the CmrRST system is required for disease development. Furthermore, we provide evidence that CmrRST phase varies during infection, suggesting that the intestinal environment impacts the proportion of CmrRST-expressing C. difficile. Our findings indicate that C. difficile employs phase variation of the CmrRST signal transduction system to generate phenotypic heterogeneity during infection, with concomitant effects on bacterial physiology and pathogenesis.


Assuntos
Proteínas de Bactérias/genética , Clostridium difficile/metabolismo , Regulação Bacteriana da Expressão Gênica , Histidina Quinase/genética , Transdução de Sinais/genética , Animais , Proteínas de Bactérias/metabolismo , Células Clonais , Infecções por Clostridium/microbiologia , Infecções por Clostridium/patologia , Clostridium difficile/genética , Clostridium difficile/patogenicidade , Clostridium difficile/ultraestrutura , Cricetulus , Modelos Animais de Doenças , Fímbrias Bacterianas/metabolismo , Fímbrias Bacterianas/ultraestrutura , Flagelos/metabolismo , Flagelos/ultraestrutura , Histidina Quinase/metabolismo , Humanos , Movimento , Fenótipo , Ribotipagem
3.
Isr Med Assoc J ; 21(10): 658-661, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31599506

RESUMO

BACKGROUND: The incidence of Clostridium difficile-associated diarrhea (CDAD) is increasing and is associated with significant morbidity and mortality. Therefore, there is a need to find new tools to determine the severity of the disease. OBJECTIVES: To investigate the prognostic values of inflammatory markers such as mean platelet volume (MPV), neutrophil-lymphocyte ratio (NLR), and C-reactive protein (CRP) in patients with CDAD. METHODS: The study comprised of 100 patients diagnosed with CDAD. The study included an additional control group of 69 patients with diarrhea who were negative for C. difficile toxin. The control group was age- and sex-matched and hospitalized at the same time period. NLR and MPV were obtained from complete blood count results. Serum CRP levels were measured by the latex particle enhanced immunoturbidimetric assay. Blood samples for all inflammatory markers were collected at time of diagnosis and prior to initiating the antibiotic therapy. Demographic, clinical, laboratory, and prognostic data were collected from medical records for a period of 90 days from the initial diagnosis of CDAD. RESULTS: The mean age of the CDAD group was 68.6 ± 21.5 years compared to 65.6 ± 24.5 in the control group (P = 0.29). Our findings show that patients with CDAD had significantly higher NLR, MPV and serum CRP levels compared to the control group (P < 0.001)). Moreover, significantly higher levels were observed when CDAD was fatal (P < 0.001). CONCLUSIONS: Elevated NLR, MPV, and serum CRP levels may serve as biomarkers for prediction of recurrence and mortality in patients with CDAD.


Assuntos
Infecções por Clostridium/sangue , Infecções por Clostridium/complicações , Clostridium difficile/patogenicidade , Diarreia/microbiologia , Inflamação/sangue , Inflamação/microbiologia , Idoso , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Infecções por Clostridium/diagnóstico , Diarreia/sangue , Feminino , Humanos , Linfócitos/metabolismo , Masculino , Volume Plaquetário Médio/estatística & dados numéricos , Neutrófilos/metabolismo , Prognóstico , Fatores de Risco , Índice de Gravidade de Doença
6.
Biomed Res Int ; 2019: 3469754, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467881

RESUMO

Intestinal microbial dysbiosis is associated with various intestinal and extraintestinal disorders. Fecal microbiota transplantation (FMT), a type of fecal bacteriotherapy, is considered an effective therapeutic option for recurrent Clostridium difficile infection (rCDI) and also has important value in other intestinal diseases including irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). The purpose of this review is to discuss promising therapeutic value in extraintestinal diseases associated with gut microbial dysbiosis, including liver, metabolic, chronic kidney, neuropsychiatric, allergic, autoimmune, and hematological diseases as well as tumors.


Assuntos
Transplante de Microbiota Fecal/tendências , Doenças Inflamatórias Intestinais/terapia , Enteropatias/terapia , Síndrome do Intestino Irritável/terapia , Infecções por Clostridium/microbiologia , Infecções por Clostridium/patologia , Infecções por Clostridium/terapia , Clostridium difficile/patogenicidade , Fezes/microbiologia , Microbioma Gastrointestinal , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Enteropatias/microbiologia , Enteropatias/patologia , Intestinos/microbiologia , Síndrome do Intestino Irritável/microbiologia
7.
Nat Commun ; 10(1): 2712, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221971

RESUMO

Clostridium difficile (C. difficile) incidence has tripled over the past 15 years and is attributed to the emergence of hypervirulent strains. While it is clear that C. difficile toxins cause damaging colonic inflammation, the immune mechanisms protecting from tissue damage require further investigation. Through a transcriptome analysis, we identify IL-33 as an immune target upregulated in response to hypervirulent C. difficile. We demonstrate that IL-33 prevents C. difficile-associated mortality and epithelial disruption independently of bacterial burden or toxin expression. IL-33 drives colonic group 2 innate lymphoid cell (ILC2) activation during infection and IL-33 activated ILC2s are sufficient to prevent disease. Furthermore, intestinal IL-33 expression is regulated by the microbiota as fecal microbiota transplantation (FMT) rescues antibiotic-associated depletion of IL-33. Lastly, dysregulated IL-33 signaling via the decoy receptor, sST2, predicts C. difficile-associated mortality in human patients. Thus, IL-33 signaling to ILC2s is an important mechanism of defense from C. difficile colitis.


Assuntos
Clostridium difficile/imunologia , Enterocolite Pseudomembranosa/imunologia , Imunidade Inata , Interleucina-33/metabolismo , Linfócitos/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antibacterianos/efeitos adversos , Toxinas Bacterianas/imunologia , Toxinas Bacterianas/metabolismo , Clostridium difficile/patogenicidade , Colo/citologia , Colo/imunologia , Colo/microbiologia , Colo/patologia , Modelos Animais de Doenças , Enterocolite Pseudomembranosa/microbiologia , Enterocolite Pseudomembranosa/mortalidade , Enterocolite Pseudomembranosa/terapia , Transplante de Microbiota Fecal , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Perfilação da Expressão Gênica , Humanos , Interleucina-33/imunologia , Linfócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia , Virulência/imunologia , Adulto Jovem
8.
PLoS Biol ; 17(6): e3000311, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31233493

RESUMO

Clostridium difficile infection (CDI) is a major nosocomial disease associated with significant morbidity and mortality. The pathology of CDI stems primarily from the 2 C. difficile-secreted exotoxins-toxin A (TcdA) and toxin B (TcdB)-that disrupt the tight junctions between epithelial cells leading to the loss of colonic epithelial barrier function. Here, we report the engineering of a series of monomeric and dimeric designed ankyrin repeat proteins (DARPins) for the neutralization of TcdB. The best dimeric DARPin, DLD-4, inhibited TcdB with a half maximal effective concentration (EC50) of 4 pM in vitro, representing an approximately 330-fold higher potency than the Food and Drug Administration (FDA)-approved anti-TcdB monoclonal antibody bezlotoxumab in the same assay. DLD-4 also protected mice from a toxin challenge in vivo. Cryo-electron microscopy (cryo-EM) studies revealed that the 2 constituent DARPins of DLD-4-1.4E and U3-bind the central and C-terminal regions of the delivery domain of TcdB. Competitive enzyme-linked immunosorbent assay (ELISA) studies showed that the DARPins 1.4E and U3 interfere with the interaction between TcdB and its receptors chondroitin sulfate proteoglycan 4 (CSPG4) and frizzled class receptor 2 (FZD2), respectively. Our cryo-EM studies revealed a new conformation of TcdB (both apo- and DARPin-bound at pH 7.4) in which the combined repetitive oligopeptides (CROPS) domain points away from the delivery domain. This conformation of the CROPS domain is in stark contrast to that seen in the negative-stain electron microscopy (EM) structure of TcdA and TcdB at the same pH, in which the CROPS domain bends toward and "kisses" the delivery domain. The ultrapotent anti-TcdB molecules from this study serve as candidate starting points for CDI drug development and provide new biological tools for studying the pathogenicity of C. difficile. The structural insights regarding both the "native" conformation of TcdB and the putative sites of TcdB interaction with the FZD2 receptor, in particular, should help accelerate the development of next-generation anti-C. difficile toxin therapeutics.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/fisiologia , Toxinas Bacterianas/antagonistas & inibidores , Infecções por Clostridium/metabolismo , Animais , Repetição de Anquirina/genética , Anticorpos Monoclonais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Células CACO-2 , Clostridium difficile/metabolismo , Clostridium difficile/patogenicidade , Microscopia Crioeletrônica , Enterotoxinas/metabolismo , Humanos , Camundongos , Engenharia de Proteínas/métodos
9.
J Med Microbiol ; 68(7): 1118-1128, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31172910

RESUMO

PURPOSE: This study investigated the efficacy of the essential mineral, selenium (sodium selenite), in reducing the toxin production, spore outgrowth and antibiotic resistance of Clostridium difficile in vitro. METHODOLOGY: Two hypervirulent C. difficile isolates were cultured in brain heart infusion broth with and without a sub-minimum inhibitory concentration (sub-MIC) of sodium selenite, and the supernatant and bacterial pellet were harvested for total toxin quantitation and RT-qPCR analysis of toxin-encoding genes, respectively. Additionally, C. difficile isolates were cultured in brain heart infusion broth containing 0.5 or 1× the minimum inhibitory concentration (MIC) of either ciprofloxacin or vancomycin with or without sub-MICs of sodium selenite. Further, the effect of sodium selenite on C. difficile germination and spore outgrowth was also determined by exposing C. difficile spores to a sub-MIC of sodium selenite in a germination medium and measuring the germination and outgrowth by measuring the optical density at 600 nm. RESULTS: Sodium selenite significantly reduced C. difficile toxin synthesis, cytotoxicity and spore outgrowth. Further, the expression of the toxin production genes, tcdA and tcdB, was downregulated in the presence of sodium selenite, while sodium selenite significantly increased the sensitivity of C. difficile to ciprofloxacin , but not vancomycin, as revealed by decreased bacterial growth in samples containing ciprofloxacin+selenium compared to the antibiotic control. Although the sub-MIC of sodium selenite did not inhibit spore germination, it was capable of completely inhibiting spore outgrowth. CONCLUSION: Our results suggest that sodium selenite could potentially be used to control C. difficile and indicate that future in vivo studies are warranted.


Assuntos
Antibacterianos/farmacologia , Toxinas Bacterianas/metabolismo , Clostridium difficile/efeitos dos fármacos , Selenito de Sódio/farmacologia , Esporos Bacterianos/efeitos dos fármacos , Oligoelementos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Clostridium difficile/patogenicidade , Clostridium difficile/fisiologia , Farmacorresistência Bacteriana , Enterotoxinas/genética , Enterotoxinas/metabolismo , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Esporos Bacterianos/fisiologia , Virulência
10.
Int J Med Microbiol ; 309(5): 270-273, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31113737

RESUMO

In 2017, we identified a Clostridium difficile strain HKCD4 that caused community-acquired fulminant colitis in a previously healthy child. Phylogenetically, it belonged to clade 2, sequence type 67 and was resistant to fluoroquinolone and tetracycline. The strain was pathogenicity locus and binary toxin positive. It has a mutation in the trehalose repressor treR leading to the L172I substitution that was previously reported in the epidemic ribotype 027 lineage. HKCD4 has a tcdB sequence that shared very high identities with 3 highly virulent reference strains. It has a CpG depleted genome that is characteristic of hypervirulent C. difficile. The emergence of ST67 lineage with molecular feature of hypervirulence in the community is concerning and emphasizes the need for full characterization of strains causing severe disease in patients without classical risk factors.


Assuntos
Clostridium difficile/genética , Clostridium difficile/patogenicidade , Colite/microbiologia , Infecção Hospitalar/microbiologia , Genoma Bacteriano , Proteínas de Bactérias/genética , Criança , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/microbiologia , Colo/diagnóstico por imagem , Colo/microbiologia , Feminino , Genômica , Hong Kong , Humanos , Ribotipagem , Tomografia Computadorizada por Raios X , Virulência
11.
Microbiol Spectr ; 7(3)2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31124432

RESUMO

Clostridioides difficile is a Gram-positive, anaerobic, spore forming pathogen of both humans and animals and is the most common identifiable infectious agent of nosocomial antibiotic-associated diarrhea. Infection can occur following the ingestion and germination of spores, often concurrently with a disruption to the gastrointestinal microbiota, with the resulting disease presenting as a spectrum, ranging from mild and self-limiting diarrhea to severe diarrhea that may progress to life-threating syndromes that include toxic megacolon and pseudomembranous colitis. Disease is induced through the activity of the C. difficile toxins TcdA and TcdB, both of which disrupt the Rho family of GTPases in host cells, causing cell rounding and death and leading to fluid loss and diarrhea. These toxins, despite their functional and structural similarity, do not contribute to disease equally. C. difficile infection (CDI) is made more complex by a high level of strain diversity and the emergence of epidemic strains, including ribotype 027-strains which induce more severe disease in patients. With the changing epidemiology of CDI, our understanding of C. difficile disease, diagnosis, and pathogenesis continues to evolve. This article provides an overview of the current diagnostic tests available for CDI, strain typing, the major toxins C. difficile produces and their mode of action, the host immune response to each toxin and during infection, animal models of disease, and the current treatment and prevention strategies for CDI.


Assuntos
Toxinas Bacterianas/imunologia , Infecções por Clostridium/imunologia , Clostridium/patogenicidade , Enterotoxinas/imunologia , Animais , Antígenos de Bactérias/imunologia , Técnicas de Tipagem Bacteriana , Quimiocinas/metabolismo , Clostridium/classificação , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/epidemiologia , Infecções por Clostridium/prevenção & controle , Clostridium difficile/patogenicidade , Citocinas/metabolismo , Modelos Animais de Doenças , Enterocolite Pseudomembranosa , Microbioma Gastrointestinal , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ribotipagem
12.
EBioMedicine ; 43: 347-355, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31036529

RESUMO

BACKGROUND: Clostridium difficile ribotype-027, ribotype-078, and ribotype-017 are virulent and epidemic lineages. Trehalose metabolism variants in these ribotypes, combined with increased human trehalose consumption, have been hypothesised to have contributed to their emergence and virulence. METHODS: 5232 previously whole-genome sequenced C. difficile isolates were analysed. Clinical isolates were used to investigate the impact of trehalose metabolism variants on mortality. Import data were used to estimate changes in dietary trehalose. Ribotype-027 virulence was investigated in a clinically reflective gut model. FINDINGS: Trehalose metabolism variants found in ribotype-027 and ribotype-017 were widely distributed throughout C. difficile clade-2 and clade-4 in 24/29 (83%) and 10/11 (91%) of sequence types (STs), respectively. The four-gene trehalose metabolism cluster described in ribotype-078 was common in genomes from all five clinically-important C. difficile clades (40/167 [24%] STs). The four-gene cluster was variably present in 208 ribotype-015 infections (98 [47%]); 27/208 (13%) of these patients died within 30-days of diagnosis. Adjusting for age, sex, and infecting ST, there was no association between 30-day all-cause mortality and the four-gene cluster (OR 0.36 [95%CI 0.09-1.34, p = 0.13]). Synthetic trehalose imports in the USA, UK, Germany and the EU were  < 1 g/capita/year during 2000-2006, and  < 9 g/capita/year 2007-2012, compared with dietary trehalose from natural sources of ~100 g/capita/year. Trehalose supplementation did not increase ribotype-027 virulence in a clinically-validated gut model. INTERPRETATION: Trehalose metabolism variants are common in C. difficile. Increases in total dietary trehalose during the early-mid 2000s C. difficile epidemic were likely relatively minimal. Alternative explanations are required to explain why ribotype-027, ribotype-078 and ribotype-017 have been successful. FUNDING: National Institute for Health Research. Gut model experiments only: Hayashibara Co. Ltd.


Assuntos
Infecções por Clostridium/microbiologia , Clostridium difficile/classificação , Clostridium difficile/metabolismo , Trealose/metabolismo , Idoso , Idoso de 80 Anos ou mais , Metabolismo dos Carboidratos , Infecções por Clostridium/epidemiologia , Infecções por Clostridium/mortalidade , Clostridium difficile/genética , Clostridium difficile/patogenicidade , Feminino , Genoma Bacteriano , Genômica/métodos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Filogenia , Prognóstico , Vigilância em Saúde Pública
13.
Infect Immun ; 87(8)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31085703

RESUMO

Clostridium difficile is the leading cause of antibiotic-associated diarrhea in adults. During infection, C. difficile must detect the host environment and induce an appropriate survival strategy. Signal transduction networks involving serine/threonine kinases (STKs) play key roles in adaptation, as they regulate numerous physiological processes. PrkC of C. difficile is an STK with two PASTA domains. We showed that PrkC is membrane associated and is found at the septum. We observed that deletion of prkC affects cell morphology with an increase in mean size, cell length heterogeneity, and presence of abnormal septa. A ΔprkC mutant was able to sporulate and germinate but was less motile and formed more biofilm than the wild-type strain. Moreover, a ΔprkC mutant was more sensitive to antimicrobial compounds that target the cell envelope, such as the secondary bile salt deoxycholate, cephalosporins, cationic antimicrobial peptides, and lysozyme. This increased susceptibility was not associated with differences in peptidoglycan or polysaccharide II composition. However, the ΔprkC mutant had less peptidoglycan and released more polysaccharide II into the supernatant. A proteomic analysis showed that the majority of C. difficile proteins associated with the cell wall were less abundant in the ΔprkC mutant than the wild-type strain. Finally, in a hamster model of infection, the ΔprkC mutant had a colonization delay that did not significantly affect overall virulence.


Assuntos
Proteínas de Bactérias/fisiologia , Clostridium difficile/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Parede Celular/metabolismo , Clostridium difficile/metabolismo , Clostridium difficile/patogenicidade , Cricetinae , Farmacorresistência Bacteriana , Homeostase , Mesocricetus , Testes de Sensibilidade Microbiana , Peptidoglicano/metabolismo , Proteínas Serina-Treonina Quinases/genética , Virulência
14.
Dig Dis ; 37(6): 467-472, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31055584

RESUMO

BACKGROUND: Clostridium difficile is a gram-positive, anaerobic, and spore-forming bacillus, which is responsible for the majority of antibiotic-associated diarrhea and colitis. OBJECTIVE: Determine if fecal microbiota transplantation (FMT) is effective in a population sample from Connecticut. METHODS: We report the clinical experience of 92 consecutive patients from one gastroenterology practice in central Connecticut treated by colonoscopy with FMT for infection with Clostridium difficile from 2012 to 2017. The analyses are based on clinical follow-up up to 3 months after the FMT procedure and on medical chart review. RESULTS: Overall, complete recovery occurred in 86% of patients. As previously reported in a limited number of previous studies, community-acquired cases were more common than hospital-acquired cases, and community-acquired cases were more likely to be female. CONCLUSIONS: Consistent with some previous reports, we found the following: the source of the donor for FMT did not make a difference in recovery: material from nonrelatives was as effective as from close relatives; and the presence of multiple comorbidities did not make a difference in recovery: patients with 2 or more comorbidities did as well as those with one or none.


Assuntos
Infecções por Clostridium/microbiologia , Infecções por Clostridium/terapia , Clostridium difficile/patogenicidade , Transplante de Microbiota Fecal , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Probabilidade , Doadores de Tecidos , Resultado do Tratamento
15.
Eur J Clin Microbiol Infect Dis ; 38(7): 1211-1221, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30945014

RESUMO

Clostridium difficile (C. difficile) is a Gram-positive, spore-forming, anaerobic bacillus, which is widely distributed in the intestinal tract of humans and animals and in the environment. In the last decade, the frequency and severity of C. difficile infection has been increasing worldwide to become one of the most common hospital-acquired infections. Transmission of this pathogen occurs by the fecal-oral route and the most important risk factors include antibiotic therapy, old age, and hospital or nursing home stay. The clinical picture is diverse and ranges from asymptomatic carrier status, through various degrees of diarrhea, to the most severe, life threatening colitis resulting with death. Diagnosis is based on direct detection of C. difficile toxins in feces, most commonly with the use of EIA assay, but no single test is suitable as a stand-alone test confirming CDI. Antibiotics of choice are vancomycin, fidaxomicin, and metronidazole, though metronidazole is considered as inferior. The goal of this review is to update physicians on current scientific knowledge of C. difficile infection, focusing also on fecal microbiota transplantation which is a promising therapy.


Assuntos
Infecções por Clostridium/prevenção & controle , Infecções por Clostridium/terapia , Clostridium difficile/efeitos dos fármacos , Infecção Hospitalar/terapia , Diarreia/microbiologia , Transplante de Microbiota Fecal , Antibacterianos/uso terapêutico , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/transmissão , Clostridium difficile/patogenicidade , Colite/microbiologia , Infecção Hospitalar/microbiologia , Reservatórios de Doenças/microbiologia , Fezes/microbiologia , Humanos , Fatores de Risco , Virulência
16.
Hum Vaccin Immunother ; 15(10): 2475-2481, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30945972

RESUMO

We evaluated the applicability of a Clostridium difficile infection (CDI) risk index developed for patients at hospital discharge to identify persons at high-risk of CDI in a primary care population. This retrospective observational study used data from the UK Clinical Practice Research Datalink, linked with Hospital Episodes Statistics. The risk index was based on the following patient characteristics: age, previous hospitalizations, days in hospital, and prior antibiotics use. Individual risk scores were calculated by summing points assigned to pre-defined categories for each characteristic. We assessed the association of risk factors with CDI by multivariate logistic regression. The estimated CDI incidence rate was 4/10,000 and 2/10,000 person-years in 2008 and 2012, respectively. On an index with a maximal risk of 19, a cut-off for high risk of ≥7 had sensitivity, specificity and positive predictive values of 80%, 87% and 12%, respectively. A high-risk person had a ~ 35% higher risk of CDI than a low-risk person. Multivariate risk factor analysis indicated a need to reconsider the relative risk scores. The CDI risk index can be applied to the UK primary care population and help identify study populations for vaccine development studies. Reassessing the relative weights assigned to risk factors could improve the index performance in this setting.


Assuntos
Infecções por Clostridium/epidemiologia , Hospitalização/estatística & dados numéricos , Hospitalização/tendências , Atenção Primária à Saúde/estatística & dados numéricos , Adolescente , Adulto , Idoso , Antibacterianos/uso terapêutico , Clostridium difficile/patogenicidade , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/microbiologia , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Reino Unido/epidemiologia , Adulto Jovem
17.
Vet Microbiol ; 231: 1-6, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30955794

RESUMO

Neonatal porcine diarrhea (NPD) is a current problem on pig farms and is caused by several enteropathogens. Among them, Clostridioides difficile stands out due to its importance in piglets and zoonotic potential. A non-toxigenic strain of C. difficile (NTCD), named Z31, was previously tested in hamster and piglet experimental models as a strategy to prevent C. difficile infection (CDI). To evaluate the capacity of the strain Z31 to prevent CDI and NPD in one-day-old piglets on a commercial farm, 90 piglets from 16 litters received 1 × 106 spores of Z31 while 84 animals from the same litters served as controls. Animals were clinically evaluated, and fecal samples were collected 24 h after administration and submitted to A/B toxin detection and isolation of C. difficile. Stool samples were also submitted to rotavirus, Escherichia coli, and Clostridium perfringens detection. Administration of Z31 reduced the incidence of CDI in treated animals (7.8%) when compared to the control group (25.0%; P = 0.003). In animals that developed CDI, the intensity of diarrhea was lower in those that received Z31 than in the control group. Neonatal porcine diarrhea was reduced in treated animals when compared to untreated animals (P < 0.001). The present study suggests that Z31 can potentially be used to prevent CDI in piglets on commercial farms.


Assuntos
Infecções por Clostridium/prevenção & controle , Clostridium difficile/fisiologia , Clostridium difficile/patogenicidade , Diarreia/veterinária , Doenças dos Suínos/microbiologia , Animais , Animais Recém-Nascidos , Derrame de Bactérias , Infecções por Clostridium/microbiologia , Clostridium perfringens/isolamento & purificação , Diarreia/microbiologia , Diarreia/prevenção & controle , Escherichia coli Enterotoxigênica/isolamento & purificação , Fazendas , Fezes/microbiologia , Suínos , Doenças dos Suínos/prevenção & controle
18.
Kaohsiung J Med Sci ; 35(6): 327-331, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017741

RESUMO

Fecal microbiota transplantation (FMT) had been an ancient remedy for severe illness several centuries ago. Under modern medical analysis and evidence-based research, it has been proved as an alternative treatment for recurrent Clostridium difficile infection and recent randomized control study also showed that FMT could be an adjuvant treatment for inflammatory bowel disease. As we get a better understanding of the relationship between gut microbiota and systemic disease, FMT became a potential treatment to explore. This article summarized procedures such as donor selection, fecal material preparation, transplantation delivery methods, and adverse events. We also review the present evidence about FMT in clinical practice.


Assuntos
Infecções por Clostridium/terapia , Transplante de Microbiota Fecal/métodos , Doenças Inflamatórias Intestinais/terapia , Administração Oral , Administração Retal , Infecções por Clostridium/microbiologia , Infecções por Clostridium/patologia , Clostridium difficile/patogenicidade , Clostridium difficile/fisiologia , Constipação Intestinal/etiologia , Constipação Intestinal/fisiopatologia , Diarreia/etiologia , Diarreia/fisiopatologia , Enema/métodos , Transplante de Microbiota Fecal/efeitos adversos , Fezes/microbiologia , Febre/etiologia , Febre/fisiopatologia , Flatulência/etiologia , Flatulência/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Vômito/etiologia , Vômito/fisiopatologia
19.
Anaerobe ; 58: 53-72, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30946985

RESUMO

Clostridioides difficile infection (CDI) is an emerging public health threat and C. difficile is the most common cause of antimicrobial-associated diarrhea worldwide and the leading cause of hospital-associated infections in the US, yet the burden of community-acquired infections (CAI) is poorly understood. Characterizing C. difficile isolated from canines is important for understanding the role that canines may play in CAI. In addition, several studies have suggested that canines carry toxigenic C. difficile asymptomatically, which may imply that there are mechanisms responsible for resistance to CDI in canines that could be exploited to help combat human CDI. To assess the virulence potential of canine-derived C. difficile, we tested whether toxins TcdA and TcdB (hereafter toxins) derived from a canine isolate were capable of causing tight junction disruptions to colonic epithelial cells. Additionally, we addressed whether major differences exist between human and canine cells regarding C. difficile pathogenicity by exposing them to identical toxins. We then examined the canine gut microbiome associated with C. difficile carriage using 16S rRNA gene sequencing and searched for deviations from homeostasis as an indicator of CDI. Finally, we queried 16S rRNA gene sequences for bacterial taxa that may be associated with resistance to CDI in canines. Clostridioides difficile isolated from a canine produced toxins that reduced tight junction integrity in both human and canine cells in vitro. However, canine guts were not dysbiotic in the presence of C. difficile. These findings support asymptomatic carriage in canines and, furthermore, suggest that there are features of the gut microbiome and/or a canine-specific immune response that may protect canines against CDI. We identified two biologically relevant bacteria that may aid in CDI resistance in canines: 1) Clostridium hiranonis, which synthesizes secondary bile acids that have been shown to provide resistance to CDI in mice; and 2) Sphingobacterium faecium, which produces sphingophospholipids that may be associated with regulating homeostasis in the canine gut. Our findings suggest that canines may be cryptic reservoirs for C. difficile and, furthermore, that mechanisms of CDI resistance in the canine gut could provide insights into targeted therapeutics for human CDI.


Assuntos
Biota , Infecções por Clostridium/veterinária , Clostridium difficile/crescimento & desenvolvimento , Doenças do Cão/microbiologia , Disbiose , Trato Gastrointestinal/microbiologia , Animais , Proteínas de Bactérias/toxicidade , Toxinas Bacterianas/toxicidade , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Infecções por Clostridium/microbiologia , Clostridium difficile/patogenicidade , Cães , Enterotoxinas/toxicidade , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/microbiologia , Células Epiteliais/fisiologia , Humanos , Camundongos , Fosfolipídeos/análise , Junções Íntimas/efeitos dos fármacos
20.
Intensive Crit Care Nurs ; 53: 73-78, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30979531

RESUMO

BACKGROUND: Clostridium difficile is one of the major causes of diarrhoea among critically ill patients and its prevalence increases exponentially in relation to the use of antibiotics and medical devices. We sought to investigate the incidence of C. difficile infection in Greek units, and identify potential risk factors related to C. difficile infection. METHODS: A prospective multicenter cohort analysis of critically ill patients (3 ICUs from 1/1/2014 to 31/12/2014). RESULTS: Among 970(100%) patients, 95(9.79%) with diarrhoea, were included. Their demographic, comorbidity and clinical characteristics were recorded on admission to the unit. The known predisposing factors for the infection were recorded and the diagnostic tests to confirm C. difficile were conducted, based on the current guidelines. The incidence of C. difficile infection was 1.3% (n = 13). All-cause mortality in patients with diarrhoea, C. difficile infection and attributable mortality in patients with C. difficile infection was 28%, 38.5% and 30.8% respectively. Sequential Organ Failure Assessment (SOFA) scores on admission were significantly lower and prior C. difficile infection was more common in patients with current C. difficile infection. Regarding other potential risk factors, no difference was found between groups. No factor was independently associated with C. difficile infection. CONCLUSIONS: C. difficile infection is low in Greek intensive care units, but remains a serious problem among the critically-ill. Mortality was similar to reports from other countries. No factor was independently associated with C. difficile infection.


Assuntos
Infecções por Clostridium/classificação , /estatística & dados numéricos , APACHE , Idoso , Idoso de 80 Anos ou mais , Infecções por Clostridium/complicações , Infecções por Clostridium/epidemiologia , Clostridium difficile/efeitos dos fármacos , Clostridium difficile/patogenicidade , Estudos de Coortes , Feminino , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença
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