Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 12.213
Filtrar
2.
Gut Microbes ; 16(1): 2342583, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38722061

RESUMO

Vancomycin and metronidazole are commonly used treatments for Clostridioides difficile infection (CDI). However, these antibiotics have been associated with high levels of relapse in patients. Fidaxomicin is a new treatment for CDI that is described as a narrow spectrum antibiotic that is minimally active on the commensal bacteria of the gut microbiome. The aim of this study was to compare the effect of fidaxomicin on the human gut microbiome with a number of narrow (thuricin CD) and broad spectrum (vancomycin and nisin) antimicrobials. The spectrum of activity of each antimicrobial was tested against 47 bacterial strains by well-diffusion assay. Minimum inhibitory concentrations (MICs) were calculated against a select number of these strains. Further, a pooled fecal slurry of 6 donors was prepared and incubated for 24 h with 100 µM of each antimicrobial in a mini-fermentation system together with a no-treatment control. Fidaxomicin, vancomycin, and nisin were active against most gram positive bacteria tested in vitro, although fidaxomicin and vancomycin produced larger zones of inhibition compared to nisin. In contrast, the antimicrobial activity of thuricin CD was specific to C. difficile and some Bacillus spp. The MICs showed similar results. Thuricin CD exhibited low MICs (<3.1 µg/mL) for C. difficile and Bacillus firmus, whereas fidaxomicin, vancomycin, and nisin demonstrated lower MICs for all other strains tested when compared to thuricin CD. The narrow spectrum of thuricin CD was also observed in the gut model system. We conclude that the spectrum of activity of fidaxomicin is comparable to that of the broad-spectrum antibiotic vancomycin in vitro and the broad spectrum bacteriocin nisin in a complex community.


Assuntos
Antibacterianos , Fezes , Fidaxomicina , Microbioma Gastrointestinal , Testes de Sensibilidade Microbiana , Nisina , Vancomicina , Nisina/farmacologia , Antibacterianos/farmacologia , Humanos , Fidaxomicina/farmacologia , Vancomicina/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Fezes/microbiologia , Bactérias/efeitos dos fármacos , Bactérias/classificação , Clostridioides difficile/efeitos dos fármacos , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/microbiologia , Bacteriocinas/farmacologia
3.
Microb Genom ; 10(5)2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38717815

RESUMO

Clostridioides difficile infection (CDI) remains a significant public health threat globally. New interventions to treat CDI rely on an understanding of the evolution and epidemiology of circulating strains. Here we provide longitudinal genomic data on strain diversity, transmission dynamics and antimicrobial resistance (AMR) of C. difficile ribotypes (RTs) 014/020 (n=169), 002 (n=77) and 056 (n=36), the three most prominent C. difficile strains causing CDI in Australia. Genome scrutiny showed that AMR was uncommon in these lineages, with resistance-conferring alleles present in only 15/169 RT014/020 strains (8.9 %), 1/36 RT056 strains (2.78 %) and none of 77 RT002 strains. Notably, ~90 % of strains were resistant to MLSB agents in vitro, but only ~5.9 % harboured known resistance alleles, highlighting an incongruence between AMR genotype and phenotype. Core genome analyses revealed all three RTs contained genetically heterogeneous strain populations with limited evidence of clonal transmission between CDI cases. The average number of pairwise core genome SNP (cgSNP) differences within each RT group ranged from 23.3 (RT056, ST34, n=36) to 115.6 (RT002, ST8, n=77) and 315.9 (RT014/020, STs 2, 13, 14, 49, n=169). Just 19 clonal groups (encompassing 40 isolates), defined as isolates differing by ≤2 cgSNPs, were identified across all three RTs (RT014/020, n=14; RT002, n=3; RT056, n=2). Of these clonal groups, 63 % (12/19) comprised isolates from the same Australian State and 37 % (7/19) comprised isolates from different States. The low number of plausible transmission events found for these major RTs (and previously documented populations in animal and environmental sources/reservoirs) points to widespread and persistent community sources of diverse C. difficile strains as opposed to ongoing nationwide healthcare outbreaks dominated by a single clone. Together, these data provide new insights into the evolution of major lineages causing CDI in Australia and highlight the urgent need for enhanced surveillance, and for public health interventions to move beyond the healthcare setting and into a One Health paradigm to effectively combat this complex pathogen.


Assuntos
Clostridioides difficile , Infecções por Clostridium , Filogenia , Ribotipagem , Clostridioides difficile/genética , Clostridioides difficile/classificação , Clostridioides difficile/efeitos dos fármacos , Clostridioides difficile/isolamento & purificação , Austrália/epidemiologia , Humanos , Infecções por Clostridium/microbiologia , Infecções por Clostridium/epidemiologia , Infecções por Clostridium/transmissão , Genoma Bacteriano , Farmacorresistência Bacteriana/genética , Antibacterianos/farmacologia , Polimorfismo de Nucleotídeo Único , Genótipo
4.
BMC Microbiol ; 24(1): 177, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38783194

RESUMO

BACKGROUND: Clostridioides difficile is the main pathogen of antimicrobial-associated diarrhoea and health care facility-associated infectious diarrhoea. This study aimed to investigate the prevalence, toxin genotypes, and antibiotic resistance of C. difficile among hospitalized patients in Xi'an, China. RESULTS: We isolated and cultured 156 strains of C. difficile, representing 12.67% of the 1231 inpatient stool samples collected. Among the isolates, tcdA + B + strains were predominant, accounting for 78.2% (122/156), followed by 27 tcdA-B + strains (27/156, 17.3%) and 6 binary toxin gene-positive strains. The positive rates of three regulatory genes, tcdC, tcdR, and tcdE, were 89.1% (139/156), 96.8% (151/156), and 100%, respectively. All isolates were sensitive to metronidazole, and the resistance rates to clindamycin and cephalosporins were also high. Six strains were found to be resistant to vancomycin. CONCLUSION: Currently, the prevalence rate of C. difficile infection (CDI) in Xi'an is 12.67% (156/1231), with the major toxin genotype of the isolates being tcdA + tcdB + cdtA-/B-. Metronidazole and vancomycin were still effective drugs for the treatment of CDI, but we should pay attention to antibiotic management and epidemiological surveillance of CDI.


Assuntos
Antibacterianos , Toxinas Bacterianas , Clostridioides difficile , Infecções por Clostridium , Fezes , Genótipo , Hospitais , Clostridioides difficile/genética , Clostridioides difficile/efeitos dos fármacos , Clostridioides difficile/isolamento & purificação , Clostridioides difficile/classificação , Humanos , China/epidemiologia , Antibacterianos/farmacologia , Infecções por Clostridium/microbiologia , Infecções por Clostridium/epidemiologia , Toxinas Bacterianas/genética , Hospitais/estatística & dados numéricos , Fezes/microbiologia , Farmacorresistência Bacteriana/genética , Prevalência , Testes de Sensibilidade Microbiana , Feminino , Pessoa de Meia-Idade , Masculino , Idoso , Adulto , Proteínas de Bactérias/genética , Diarreia/microbiologia , Diarreia/epidemiologia , Metronidazol/farmacologia , Adulto Jovem , Enterotoxinas/genética , Adolescente , Vancomicina/farmacologia , Clindamicina/farmacologia , Idoso de 80 Anos ou mais
5.
PLoS Pathog ; 20(5): e1012224, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38739653

RESUMO

Spore formation is required for environmental survival and transmission of the human enteropathogenic Clostridioides difficile. In all bacterial spore formers, sporulation is regulated through activation of the master response regulator, Spo0A. However, the factors and mechanisms that directly regulate C. difficile Spo0A activity are not defined. In the well-studied Bacillus species, Spo0A is directly inactivated by Spo0E, a small phosphatase. To understand Spo0E function in C. difficile, we created a null mutation of the spo0E ortholog and assessed sporulation and physiology. The spo0E mutant produced significantly more spores, demonstrating Spo0E represses C. difficile sporulation. Unexpectedly, the spo0E mutant also exhibited increased motility and toxin production, and enhanced virulence in animal infections. We uncovered that Spo0E interacts with both Spo0A and the toxin and motility regulator, RstA. Direct interactions between Spo0A, Spo0E, and RstA constitute a previously unknown molecular switch that coordinates sporulation with motility and toxin production. Reinvestigation of Spo0E function in B. subtilis revealed that Spo0E induced motility, demonstrating Spo0E regulation of motility and sporulation among divergent species. Further, 3D structural analyses of Spo0E revealed specific and exclusive interactions between Spo0E and binding partners in C. difficile and B. subtilis that provide insight into the conservation of this regulatory mechanism among different species.


Assuntos
Proteínas de Bactérias , Clostridioides difficile , Regulação Bacteriana da Expressão Gênica , Esporos Bacterianos , Clostridioides difficile/patogenicidade , Clostridioides difficile/genética , Clostridioides difficile/metabolismo , Esporos Bacterianos/genética , Virulência , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Animais , Camundongos , Infecções por Clostridium/microbiologia
6.
Sci Rep ; 14(1): 10665, 2024 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-38724540

RESUMO

Bioaerosols generated during toilet flushing can contribute to the spread of airborne pathogens and cross-contamination in indoor environments. This presents an increased risk of fomite-mediated or aerosol disease transmission. This study systematically investigated the factors contributing to increased bioaerosol exposure following toilet flushing and developed an empirical model for predicting the exposure-relevant bioaerosol concentration. Air in a toilet cubicle was sampled by impaction after seeding with Clostridium difficile spores. Design of Experiments (DoE) main effects screening and full factorial design approaches were then employed to investigate the significant factors that heighten the risk of exposure to bioaerosols post-flush. Our findings reveal that the inoculated bacterial concentration (C), time elapsed after flushing (t), lateral distance (d), and mechanical ventilation (v) are significant predictors of bioaerosol concentration, with p-values < 0.05. The interaction term, C × d showed a marked increase in bioaerosol concentration up to 232 CFU/m3 at the closest proximity and highest pathogen load. The interplay of C and t (C × t) demonstrated a time-dependent attenuation of bioaerosol viability, with concentrations peaking at 241 CFU/m3 immediately post-flush and notably diminishing over time. The lateral distance and time post-flush (d × t) interaction also revealed a gradual decrease in bioaerosol concentration, highlighting the effectiveness of spatial and temporal dilution in mitigating bioaerosol exposure risks. Furthermore, there is an immediate rise in relative humidity levels post-flush, impacting the air quality in the toilet environment. This study not only advances our understanding of exposure pathways in determining bioaerosol exposure, but also offers pivotal insights for designing targeted interventions to reduce bioaerosol exposure. Recommendations include designing public toilets with antimicrobial surfaces, optimizing ventilation, and initiating timely disinfection protocols to prioritise surfaces closest to the toilet bowl during peak exposure periods, thereby promoting healthier indoor environments and safeguarding public health in high-traffic toilet settings.


Assuntos
Aerossóis , Microbiologia do Ar , Clostridioides difficile , Banheiros , Aerossóis/análise , Humanos , Poluição do Ar em Ambientes Fechados/análise , Aparelho Sanitário/microbiologia
10.
J Prim Care Community Health ; 15: 21501319241249645, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38726585

RESUMO

Clostridioides difficile infection (CDI) is one of the most common and severe nosocomial infections worldwide. It can also affect healthy individuals in the community. The incidence of CDI has been on the rise globally for the past decade, necessitating a proactive approach to combat its spread; new strategies are being developed to enhance diagnostic accuracy and optimize treatment outcomes. Implementing the 2-step testing has increased diagnostic specificity, reducing the usage of CD-specific antibiotics with no concomitant increase in surgical complication rates. In 2021, the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) shifted its preference for initial treatment to fidaxomicin over vancomycin and metronidazole due to its lower recurrence rate. It also prioritized fidaxomicin for the treatment of recurrent CDI. There are new developments on the frontiers of fecal microbiota therapies, with RBX2660 and SER-109 approved recently by the FDA for prevention, with other microbiome-based therapies in various development and clinical trials. This review offers providers an updated and practical guide for CDI management.


Assuntos
Antibacterianos , Clostridioides difficile , Infecções por Clostridium , Humanos , Infecções por Clostridium/prevenção & controle , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/terapia , Antibacterianos/uso terapêutico , Transplante de Microbiota Fecal , Infecção Hospitalar/prevenção & controle , Guias de Prática Clínica como Assunto , Fidaxomicina/uso terapêutico , Metronidazol/uso terapêutico
11.
BMC Infect Dis ; 24(1): 468, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702635

RESUMO

BACKGROUND: Clostridioides difficile infection (CDI) causes a major burden to individuals and society, yet the impact may vary depending on age, sex, underlying comorbidities and where CDI was acquired (hospital or community). METHODS: This Swedish nationwide population-based cohort study (2006-2019) compared all 43,150 individuals with CDI to their 355,172 matched controls (first year and entire follow-up). Negative binomial regression models compared the cumulated length of stay, number of in-hospital admissions, outpatient visits and prescriptions after the first CDI episode expressed as incidence rate ratios (IRR) and 95% confidence intervals for the entire follow-up. RESULTS: Overall, 91.6% of CDI cases were hospital acquired, and 16.8% presented with recurrence(s); 74.8%of cases were ≥ 65 years and 54.2% were women. Compared to individuals without CDI, in-hospital stay rates were 18.01 times higher after CDI (95% CI 17.40-18.63, first-year: 27.4 versus 1.6 days), 9.45 times higher in-hospital admission (95% CI 9.16-9.76, first-year: 2.6 versus 1.3 hospitalisations), 3.94 times higher outpatient visit (95% CI 3.84-4.05, first-year: 4.0 versus 1.9 visits) and 3.39 times higher dispensed prescriptions rates (95% CI 3.31-3.48, first-year: 25.5 versus 13.7 prescriptions). For all outcomes, relative risks were higher among the younger (< 65 years) than the older (≥ 65 years), and in those with fewer comorbidities, but similar between sexes. Compared to those without recurrence, individuals with recurrence particularly showed a higher rate of hospital admissions (IRR = 1.18, 95% 1.12-1.24). Compared to community-acquired CDI, those with hospital-acquired CDI presented with a higher rate of hospital admissions (IRR = 7.29, 95% CI 6.68-7.96) and a longer length of stay (IRR = 7.64, 95% CI 7.07-8.26). CONCLUSION: CDI was associated with increased health consumption in all affected patient groups. The majority of the CDI burden could be contributed to hospital-acquired CDI (~ 9/10), older patients (~ 3/4) and those with multiple comorbidities (~ 6/10 Charlson score ≥ 3), with 1/5 of the total CDI burden contributed to individuals with recurrence. Yet, relatively speaking the burden was higher among the younger and those with fewer comorbidities, compared to their peers without CDI.


Assuntos
Infecções por Clostridium , Recidiva , Humanos , Feminino , Masculino , Infecções por Clostridium/epidemiologia , Suécia/epidemiologia , Pessoa de Meia-Idade , Idoso , Adulto , Estudos de Coortes , Adulto Jovem , Adolescente , Idoso de 80 Anos ou mais , Clostridioides difficile , Hospitalização/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Infecção Hospitalar/epidemiologia , Incidência , Criança , Pré-Escolar , Lactente , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos
12.
Sci Rep ; 14(1): 11227, 2024 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-38755214

RESUMO

In this study, we sought to evaluate the influence of positive pathogens in stool (PPS) on clinical outcomes in critical ill patients with Sepsis-associated acute kidney injury (S-AKI) from intensive care unit. Our sample consisted of 7338 patients, of whom 752 (10.25%) had PPS. We found that the presence of Clostridium difficile (C. difficile) and protists in stool samples was correlated with survival during hospitalization, as well as 30-day and 90-day survival. Interestingly, there was no significant difference in overall survival and 30-day in-hospital survival between the PPS group and the negative pathogens in stool (NPS) control group. However, the cumulative incidence of 90-day infection-related mortality was significantly higher in the PPS group (53 vs. 48%, P = 0.022), particularly in patients with C. difficile in their stool specimens. After adjusting for propensity scores, the results also have statistical significance. These findings suggest that PPS may affect the 90-days survival outcomes of S-AKI, particularly in patients with C. difficile and protists in their stool samples. Further research is warranted to further explore these associations.


Assuntos
Injúria Renal Aguda , Clostridioides difficile , Estado Terminal , Fezes , Sepse , Humanos , Fezes/microbiologia , Masculino , Sepse/complicações , Sepse/microbiologia , Sepse/mortalidade , Feminino , Injúria Renal Aguda/microbiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/mortalidade , Idoso , Pessoa de Meia-Idade , Clostridioides difficile/isolamento & purificação , Unidades de Terapia Intensiva , Prognóstico
13.
World J Gastroenterol ; 30(16): 2179-2183, 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38690018

RESUMO

In this editorial we comment on the article published in the recent issue of the World journal of Gastroenterology. We focus specifically on the mechanisms un-derlying the effects of fecal microbiota transplantation (FMT) for irritable bowel syndrome (IBS), the factors which affect the outcomes of FMT in IBS patients, and challenges. FMT has emerged as a efficacious intervention for clostridium difficile infection and holds promise as a therapeutic modality for IBS. The utilization of FMT in the treatment of IBS has undergone scrutiny in numerous randomized controlled trials, yielding divergent outcomes. The current frontier in this field seeks to elucidate these variations, underscore the existing knowledge gaps that necessitate exploration, and provide a guideline for successful FMT imple-mentation in IBS patients. At the same time, the application of FMT as a treatment for IBS confronts several challenges.


Assuntos
Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Síndrome do Intestino Irritável , Síndrome do Intestino Irritável/terapia , Síndrome do Intestino Irritável/microbiologia , Transplante de Microbiota Fecal/métodos , Humanos , Resultado do Tratamento , Fezes/microbiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Clostridioides difficile/patogenicidade , Infecções por Clostridium/terapia , Infecções por Clostridium/microbiologia
14.
BMC Infect Dis ; 24(1): 512, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38778271

RESUMO

AIM: Diarrhea is a common disease in immunocompromised patients and can be associated with greater morbidity and even mortality. Therefore, the present study was designed to determine the prevalence of Aeromonas spp., Campylobacter spp., and C. difficile among immunocompromised children. METHODS: This study was conducted on 130 stool samples from patients with diarrhea who had defects in the immune system and were referred to Hazrat Masoumeh Children's Hospital in Qom. Demographic information, clinical symptoms, immune status, and duration of chemotherapy were also recorded for each child. DNAs were extracted from the stool, and then direct PCR assays were done by specific primers for the detection of Aeromonas spp., Campylobacter spp., and toxigenic C. difficile, including tcdA/B and cdtA/B genes. Co-infection in patients was also evaluated. RESULTS: 60.8% and 39.2% were male and female, respectively, with a m ± SD age of 56.72 ± 40.49 months. Most cases of immunocompromised states were related to Acute Lymphocytic Leukemia (77.7%) and Non-Hodgkin Lymphoma (14.6%). 93.1% of patients were undergoing chemotherapy during the study. Among patients, most clinical symptoms were related to bloody diarrhea (98.5%) and fever (92.3%). Based on PCR, 14.6, 9.2, and 1.5% were positive for Aeromonas spp., C. difficile, and C. jejuni, respectively. Among the C. difficile-positive cases, the tcdA gene was only detected in one patient. In total, three co-infections were identified, which included Aeromonas spp./C. difficile (tcdA+), C. jejuni/C. difficile, and C. jejuni/Aeromonas spp. CONCLUSIONS: This is the first study in Iran to investigate the simultaneous prevalence of some pathogens in immunocompromised children with diarrhea. Because Aeromonas spp., Campylobacter spp., and C. difficile are not routinely detected in some laboratories, infections caused by them are underappreciated in the clinic. Our results showed that these pathogens are present in our region and can cause gastroenteritis in children, especially those with underlying diseases. Therefore, increasing the level of hygiene in some areas and controlling bacterial diarrheal diseases should be given more attention by health officials.


Assuntos
Aeromonas , Campylobacter , Clostridioides difficile , Infecções por Clostridium , Diarreia , Fezes , Hospedeiro Imunocomprometido , Humanos , Feminino , Masculino , Pré-Escolar , Diarreia/microbiologia , Diarreia/epidemiologia , Criança , Aeromonas/isolamento & purificação , Aeromonas/genética , Prevalência , Clostridioides difficile/genética , Clostridioides difficile/isolamento & purificação , Campylobacter/isolamento & purificação , Campylobacter/genética , Lactente , Fezes/microbiologia , Infecções por Clostridium/epidemiologia , Infecções por Clostridium/microbiologia , Infecções por Bactérias Gram-Negativas/epidemiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Adolescente , Infecções por Campylobacter/epidemiologia , Infecções por Campylobacter/microbiologia , Coinfecção/microbiologia , Coinfecção/epidemiologia
15.
Clin Chim Acta ; 559: 119728, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38750779

RESUMO

BACKGROUND AND AIMS: The incidence of Clostridioides difficile infection and the prevalence of hypervirulent ST1 (BI/NAP1/027)strain are increasing, especially in developing countries. We aimed to develop a new PCR assay for the identification of hypervirulent ST1 strains and toxigenic C. difficile in stool samples. MATERIALS AND METHODS: We established a quadruplex TaqMan real-time PCR (pilW_4-plex PCR) assay targeting the pilW, a ST1-specific type Ⅳ minor pilin gene, and three C. difficile genes including cdtB, tcdB, and hsp. The sensitivity and specificity of the assay was tested using 403C. difficile isolates and 180 unformed stool sample. The results were compared with anaerobic culture-based conventional PCR method and MLST. RESULTS: The pilW_4-plex PCR identified toxigenic C. difficile in 333 (82.6%, 333/403) isolates with 100% sensitivity and specificity, and in 78 (43.3%, 78/180) stool samples with the sensitivity and specificity of 94.7% and 93.3%, respectively. Hypervirulent ST1 were detected in 21 strains and nine stool samples by the pilW_4-plex PCR. The pilW_4-plex PCR assay has no cross-reaction with non-toxigenic C. difficile or other bacteria. CONCLUSION: The pilW_4-plex PCR assay is an accurate and rapid method with high sensitivity and specificity for identification of ST1 and detection of toxigenic C. difficile in stool.


Assuntos
Clostridioides difficile , Clostridioides difficile/genética , Clostridioides difficile/isolamento & purificação , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Fezes/microbiologia , Reação em Cadeia da Polimerase/métodos , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/microbiologia , Virulência/genética , Sensibilidade e Especificidade
16.
EBioMedicine ; 103: 105130, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38653188

RESUMO

BACKGROUND: Active surveillance pharmacovigilance is an emerging approach to identify medications with unanticipated effects. We previously developed a framework called pharmacopeia-wide association studies (PharmWAS) that limits false positive medication associations through high-dimensional confounding adjustment and set enrichment. We aimed to assess the transportability and generalizability of the PharmWAS framework by using medical claims data to reproduce known medication associations with Clostridioides difficile infection (CDI) or gastrointestinal bleeding (GIB). METHODS: We conducted case-control studies using Optum's de-identified Clinformatics Data Mart Database of individuals enrolled in large commercial and Medicare Advantage health plans in the United States. Individuals with CDI (from 2010 to 2015) or GIB (from 2010 to 2021) were matched to controls by age and sex. We identified all medications utilized prior to diagnosis and analysed the association of each with CDI or GIB using conditional logistic regression adjusted for risk factors for the outcome and a high-dimensional propensity score. FINDINGS: For the CDI study, we identified 55,137 cases, 220,543 controls, and 290 medications to analyse. Antibiotics with Gram-negative spectrum, including ciprofloxacin (aOR 2.83), ceftriaxone (aOR 2.65), and levofloxacin (aOR 1.60), were strongly associated. For the GIB study, we identified 450,315 cases, 1,801,260 controls, and 354 medications to analyse. Antiplatelets, anticoagulants, and non-steroidal anti-inflammatory drugs, including ticagrelor (aOR 2.81), naproxen (aOR 1.87), and rivaroxaban (aOR 1.31), were strongly associated. INTERPRETATION: These studies demonstrate the generalizability and transportability of the PharmWAS pharmacovigilance framework. With additional validation, PharmWAS could complement traditional passive surveillance systems to identify medications that unexpectedly provoke or prevent high-impact conditions. FUNDING: U.S. National Institute of Diabetes and Digestive and Kidney Diseases.


Assuntos
Clostridioides difficile , Infecções por Clostridium , Hemorragia Gastrointestinal , Farmacovigilância , Humanos , Infecções por Clostridium/epidemiologia , Infecções por Clostridium/etiologia , Infecções por Clostridium/tratamento farmacológico , Estudos de Casos e Controles , Masculino , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/epidemiologia , Hemorragia Gastrointestinal/etiologia , Feminino , Idoso , Pessoa de Meia-Idade , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Estados Unidos/epidemiologia , Fatores de Risco , Adulto , Idoso de 80 Anos ou mais
17.
J Microbiol Biotechnol ; 34(4): 828-837, 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38668685

RESUMO

Vancomycin (VAN) and metronidazole (MTR) remain the current drugs of choice for the treatment of non-severe Clostridioides difficile infection (CDI); however, while their co-administration has appeared in clinical treatment, the efficacy varies greatly and the mechanism is unknown. In this study, a CDI mouse model was constructed to evaluate the therapeutic effects of VAN and MTR alone or in combination. For a perspective on the intestinal ecology, 16S rRNA amplicon sequencing and non-targeted metabolomics techniques were used to investigate changes in the fecal microbiota and metabolome of mice under the co-administration treatment. As a result, the survival rate of mice under co-administration was not dramatically different compared to that of single antibiotics, and the former caused intestinal tissue hyperplasia and edema. Co-administration also significantly enhanced the activity of amino acid metabolic pathways represented by phenylalanine, arginine, proline, and histidine, decreased the level of deoxycholic acid (DCA), and downregulated the abundance of beneficial microbes, such as Bifidobacterium and Akkermansia. VAN plays a dominant role in microbiota regulation in co-administration. In addition, co-administration reduced or increased the relative abundance of antibiotic-sensitive bacteria, including beneficial and harmful microbes, without a difference. Taken together, there are some risks associated with the co-administration of VAN and MTR, and this combination mode should be used with caution in CDI treatment.


Assuntos
Antibacterianos , Clostridioides difficile , Infecções por Clostridium , Modelos Animais de Doenças , Quimioterapia Combinada , Fezes , Microbioma Gastrointestinal , Metronidazol , RNA Ribossômico 16S , Vancomicina , Animais , Metronidazol/administração & dosagem , Vancomicina/administração & dosagem , Vancomicina/farmacologia , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Clostridioides difficile/efeitos dos fármacos , Clostridioides difficile/genética , RNA Ribossômico 16S/genética , Fezes/microbiologia , Intestinos/microbiologia , Intestinos/efeitos dos fármacos , Masculino , Bactérias/classificação , Bactérias/genética , Bactérias/efeitos dos fármacos , Metaboloma/efeitos dos fármacos
18.
Proc Natl Acad Sci U S A ; 121(19): e2321836121, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38687788

RESUMO

Interleukin 22 (IL-22) promotes intestinal barrier integrity, stimulating epithelial cells to enact defense mechanisms against enteric infections, including the production of antimicrobial peptides. IL-22 binding protein (IL-22BP) is a soluble decoy encoded by the Il22ra2 gene that decreases IL-22 bioavailability, attenuating IL-22 signaling. The impact of IL-22BP on gut microbiota composition and functioning is poorly understood. We found that Il22ra2-/- mice are better protected against Clostridioides difficile and Citrobacter rodentium infections. This protection relied on IL-22-induced antimicrobial mechanisms before the infection occurred, rather than during the infection itself. Indeed, the gut microbiota of Il22ra2-/- mice mitigated infection of wild-type (WT) mice when transferred via cohousing or by cecal microbiota transplantation. Indicator species analysis of WT and Il22ra2-/- mice with and without cohousing disclosed that IL22BP deficiency yields a gut bacterial composition distinct from that of WT mice. Manipulation of dietary fiber content, measurements of intestinal short-chain fatty acids and oral treatment with acetate disclosed that resistance to C. difficile infection is related to increased production of acetate by Il22ra2-/--associated microbiota. Together, these findings suggest that IL-22BP represents a potential therapeutic target for those at risk for or with already manifest infection with this and perhaps other enteropathogens.


Assuntos
Citrobacter rodentium , Clostridioides difficile , Infecções por Enterobacteriaceae , Microbioma Gastrointestinal , Interleucina 22 , Camundongos Knockout , Animais , Camundongos , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/prevenção & controle , Receptores de Interleucina/metabolismo , Receptores de Interleucina/genética , Interleucinas/metabolismo , Camundongos Endogâmicos C57BL , Infecções por Clostridium/imunologia , Infecções por Clostridium/microbiologia , Infecções por Clostridium/prevenção & controle
19.
Surg Clin North Am ; 104(3): 545-556, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38677819

RESUMO

Clostridioides difficile colitis is an important source of hospital-acquired diarrhea associated with antibiotic use. Symptoms are profuse watery diarrhea, typically following a course of antibiotics; however, some cases of fulminant disease may manifest with shock, ileus, or megacolon. Nonfulminant colitis is treated with oral fidaxomicin. C difficile colitis has a high potential for recurrence, and recurrent episodes are also treated with fidaxomicin. Bezlotoxumab is another medication that may be used in populations at high risk for further recurrence. Fulminant disease is treated with maximal medical therapy and early surgical consultation. Antibiotic stewardship is critical to preventing C difficile colitis.


Assuntos
Antibacterianos , Clostridioides difficile , Infecções por Clostridium , Colite , Humanos , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/terapia , Antibacterianos/uso terapêutico , Colite/microbiologia , Colite/diagnóstico , Colite/terapia , Fidaxomicina/uso terapêutico
20.
Biochem Biophys Res Commun ; 715: 149957, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38688057

RESUMO

Clostridioides difficile endolysin (Ecd09610) consists of an unknown domain at its N terminus, followed by two catalytic domains, a glucosaminidase domain and endopeptidase domain. X-ray structure and mutagenesis analyses of the Ecd09610 catalytic domain with glucosaminidase activity (Ecd09610CD53) were performed. Ecd09610CD53 was found to possess an α-bundle-like structure with nine helices, which is well conserved among GH73 family enzymes. The mutagenesis analysis based on X-ray structures showed that Glu405 and Asn470 were essential for enzymatic activity. Ecd09610CD53 may adopt a neighboring-group mechanism for a catalytic reaction in which Glu405 acted as an acid/base catalyst and Asn470 helped to stabilize the oxazolinium ion intermediate. Structural comparisons with the newly identified Clostridium perfringens autolysin catalytic domain (AcpCD) in the P1 form and a zymography analysis demonstrated that AcpCD was 15-fold more active than Ecd09610CD53. The strength of the glucosaminidase activity of the GH73 family appears to be dependent on the depth of the substrate-binding groove.


Assuntos
Domínio Catalítico , Clostridioides difficile , Endopeptidases , Clostridioides difficile/enzimologia , Clostridioides difficile/genética , Cristalografia por Raios X , Endopeptidases/química , Endopeptidases/metabolismo , Endopeptidases/genética , Modelos Moleculares , Hexosaminidases/química , Hexosaminidases/genética , Hexosaminidases/metabolismo , Mutagênese , Sequência de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Mutagênese Sítio-Dirigida , Domínios Proteicos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...