RESUMEN
PURPOSE: Diverting Loop Ileostomy (DLI) with intraoperative colonic lavage has emerged as a potential alternative to Total Abdominal Colectomy (TAC) for treating Fulminant Clostridium Difficile Colitis (FCDC). This study aims to provide an updated review comparing DLI with TAC in managing FCDC. METHODS: A systematic literature search was conducted using PubMed, Scopus, and Embase to identify retrospective and prospective studies comparing DLI with TAC for fulminant CDC treatment. A meta-analysis was performed to evaluate postoperative mortality rates and complications using R Studio version 4.4.1, calculating odds ratios (ORs) with 95% confidence intervals via the Mantel-Haenszel method. Heterogeneity was assessed using the Cochrane Q test and I2 statistics. RESULTS: Our search yielded 228 relevant citations, of which 7 studies with a total of 7,048 patients were included. Of these, 1,728 underwent DLI. The mean age was 63.33 years in the DLI group and 65.74 years in the TAC group. Compared to TAC, DLI had significantly lower postoperative mortality (OR 0.75; 95% CI 0.62-0.90; P = 0.002; I2 = 34%). Trial sequential analysis for postoperative mortality rates showed the benefit of DLI with a sufficiently powered sample. The DLI group also had a significantly higher rate of ostomy reversal (OR 5.68; 95% CI 2.35-13.72; P < 0.001; I2 = 36%). Postoperative complications, such as thromboembolic events, surgical site infections, urinary tract infections, renal failure, and pneumonia, were not significantly different. CONCLUSION: DLI shows a lower postoperative mortality rate and higher ostomy reversal rate than TAC, suggesting it as a potential organ-preserving, minimally invasive alternative. Further high-quality studies and trials are needed to confirm these findings.
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Colectomía , Enterocolitis Seudomembranosa , Ileostomía , Irrigación Terapéutica , Humanos , Ileostomía/métodos , Ileostomía/efectos adversos , Colectomía/métodos , Colectomía/efectos adversos , Enterocolitis Seudomembranosa/cirugía , Enterocolitis Seudomembranosa/mortalidad , Irrigación Terapéutica/métodos , Clostridioides difficile , Complicaciones Posoperatorias , Resultado del Tratamiento , Infecciones por Clostridium/cirugíaRESUMEN
Background: The tcdA gene codes for an important toxin produced by Clostridioides difficile (C. difficile), but there is currently no simple and cost-effective method of detecting it. This article establishes and validates a rapid and visual loop-mediated isothermal amplification (LAMP) assay for the detection of the tcdA gene. Methods: Three sets of primers were designed and optimized to amplify the tcdA gene in C. difficile using a LAMP assay. To evaluate the specificity of the LAMP assay, C. difficile VPI10463 was used as a positive control, while 26 pathogenic bacterial strains lacking the tcdA gene and distilled water were utilized as negative controls. For sensitivity analysis, the LAMP assay was compared to PCR using ten-fold serial dilutions of DNA from C. difficile VPI10463, ranging from 207 ng/µl to 0.000207 pg/µl. The tcdA gene of C.difficile was detected in 164 stool specimens using both LAMP and polymerase chain reaction (PCR). Positive and negative results were distinguished using real-time monitoring of turbidity and chromogenic reaction. Results: At a temperature of 66 °C, the target DNA was successfully amplified with a set of primers designated, and visualized within 60 min. Under the same conditions, the target DNA was not amplified with the tcdA12 primers for 26 pathogenic bacterial strains that do not carry the tcdA gene. The detection limit of LAMP was 20.700 pg/µl, which was 10 times more sensitive than that of conventional PCR. The detection rate of tcdA in 164 stool specimens using the LAMP method was 17% (28/164), significantly higher than the 10% (16/164) detection rate of the PCR method (X2 = 47, p < 0.01). Conclusion: LAMP method is an effective technique for the rapid and visual detection of the tcdA gene of C. difficile, and shows potential advantages over PCR in terms of speed, simplicity, and sensitivity. The tcdA-LAMP assay is particularly suitable for medical diagnostic environments with limited resources and is a promising diagnostic strategy for the screening and detection of C. difficile infection in populations at high risk.
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Toxinas Bacterianas , Clostridioides difficile , Infecciones por Clostridium , Enterotoxinas , Heces , Técnicas de Amplificación de Ácido Nucleico , Sensibilidad y Especificidad , Clostridioides difficile/genética , Clostridioides difficile/aislamiento & purificación , Técnicas de Amplificación de Ácido Nucleico/métodos , Humanos , Toxinas Bacterianas/genética , Infecciones por Clostridium/diagnóstico , Infecciones por Clostridium/microbiología , Heces/microbiología , Heces/química , Enterotoxinas/genética , Cartilla de ADN/genética , Técnicas de Diagnóstico Molecular/métodos , Reacción en Cadena de la Polimerasa/métodos , Adulto , Persona de Mediana EdadRESUMEN
Auranofin (AF), a former rheumatoid polyarthritis treatment, gained renewed interest for its use as an antimicrobial. AF is an inhibitor of thioredoxin reductase (TrxB), a thiol and protein repair enzyme, with an antibacterial activity against several bacteria including C. difficile, an enteropathogen causing post-antibiotic diarrhea. Several studies demonstrated the effect of AF on C. difficile physiology, but the crucial questions of resistance mechanisms and impact on microbiota remain unaddressed. We explored potential resistance mechanisms by studying the impact of TrxB multiplicity and by generating and characterizing adaptive mutations. We showed that if mutants inactivated for trxB genes have a lower MIC of AF, the number of TrxBs naturally present in clinical strains does not impact the MIC. All stable mutations isolated after AF long-term exposure were in the anti-sigma factor of σB and strongly affect physiology. Finally, we showed that AF has less impact on human gut microbiota than vancomycin.
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Antibacterianos , Auranofina , Clostridioides difficile , Microbioma Gastrointestinal , Pruebas de Sensibilidad Microbiana , Humanos , Auranofina/farmacología , Clostridioides difficile/efectos de los fármacos , Clostridioides difficile/genética , Microbioma Gastrointestinal/efectos de los fármacos , Antibacterianos/farmacología , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Reductasa de Tiorredoxina-Disulfuro/genética , Mutación , Farmacorresistencia Bacteriana , Adaptación Fisiológica , Factor sigma/genética , Factor sigma/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Vancomicina/farmacologíaRESUMEN
Clostridioides difficile, a cause of healthcare-associated infections, poses a significant global health threat. This multi-institutional retrospective study focuses on epidemic dynamics, emphasizing minor and toxin-negative clinical isolates through high-resolution genotyping. The genotype of the C. difficile clinical isolates during 2005 to 2022 was gathered from 14 hospitals across Japan (N = 982). The total number of unique genotypes was 294. Some genotypes were identified in every hospital (cross-regional genotypes), while others were unique to a specific hospital or those in close geographic proximity (region-specific genotypes). Notably, a hospital located in a sparsely populated prefecture exhibited the highest prevalence of region-specific genotypes. The isolation rate of cross-regional genotypes positively correlated with the human mobility flow. A 6-month interval analysis at a university hospital from 2019 to 2021 revealed a temporal transition of the genotype dominance. The frequent isolation of identical genotypes over a brief timeframe did not always align with the current criteria for defining nosocomial outbreaks. This study highlights the presence of diverse indigenous C. difficile strains in regional environments. The cross-regional strains may have a higher competency to spread in the human community. The longitudinal analysis underscores the need for further investigation into potential nosocomial spread.
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Clostridioides difficile , Infecciones por Clostridium , Infección Hospitalaria , Genotipo , Clostridioides difficile/genética , Clostridioides difficile/aislamiento & purificación , Clostridioides difficile/clasificación , Humanos , Japón/epidemiología , Infecciones por Clostridium/epidemiología , Infecciones por Clostridium/microbiología , Infección Hospitalaria/microbiología , Infección Hospitalaria/epidemiología , Estudios Retrospectivos , Masculino , Femenino , HospitalesRESUMEN
Clostridium difficile infection (CDI) is a major cause of hospital-acquired gastrointestinal infections in children. Current treatment for pediatric CDI primarily involves antibiotics; however, some children experience recurrence after antibiotic treatment, and those with initial recurrence remain at risk for further recurrences following subsequent antibiotic therapy. In such cases, careful consideration of treatment options is necessary. Fecal microbiota transplantation has been shown to be effective for recurrent CDI and has a high safety profile. This article reviews the latest research on the pathogenesis, risk factors, diagnosis, and treatment of pediatric CDI domestically and internationally, with a particular focus on fecal microbiota transplantation therapy.
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Infecciones por Clostridium , Trasplante de Microbiota Fecal , Humanos , Infecciones por Clostridium/terapia , Niño , Clostridioides difficile , Factores de Riesgo , Antibacterianos/uso terapéuticoRESUMEN
Clostridioides difficile is a major nosocomial pathogen, causing significant morbidity and mortality worldwide. Antibiotic usage, a major risk factor for Clostridioides difficile infection (CDI), disrupts the gut microbiota, allowing C. difficile to proliferate and cause infection, and can often lead to recurrent CDI (rCDI). Fecal microbiota transplantation (FMT) and live biotherapeutic products (LBPs) have emerged as effective treatments for rCDI and aim to restore colonization resistance provided by a healthy gut microbiota. However, much is still unknown about the mechanisms mediating their success. Bile acids, extensively modified by gut microbes, affect C. difficile's germination, growth, and toxin production while also shaping the gut microbiota and influencing host immune responses. Additionally, microbial interactions, such as nutrient competition and cross-feeding, contribute to colonization resistance against C. difficile and may contribute to the success of microbiota-focused therapeutics. Bile acids as well as other microbial mediated interactions could have implications for other diseases being treated with microbiota-focused therapeutics. This review focuses on the intricate interplay between bile acid modifications, microbial ecology, and host responses with a focus on C. difficile, hoping to shed light on how to move forward with the development of new microbiota mediated therapeutic strategies to combat rCDI and other intestinal diseases.
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Ácidos y Sales Biliares , Clostridioides difficile , Infecciones por Clostridium , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Ácidos y Sales Biliares/metabolismo , Humanos , Clostridioides difficile/fisiología , Infecciones por Clostridium/terapia , Infecciones por Clostridium/microbiología , AnimalesRESUMEN
INTRODUCTION: Clostridioides difficile (C.diff) infection (CDI) causes significant morbidity and mortality among older adults. Vaccines to prevent CDI are in development; however, data on the target population's preferences are needed to inform vaccination recommendations in the United States (US). This study assessed US adults' willingness to receive a C.diff vaccine and examined how vaccine attributes influence their choices. METHODS: A cross-sectional online survey with a discrete choice experiment (DCE) was conducted among US adults aged ≥50 years. DCE attributes included effectiveness, duration of protection, reduction in symptom severity, out-of-pocket (OOP) costs, number of doses, and side effects. The DCE included 11 choice tasks, each with two hypothetical vaccine profiles and an opt-out (i.e., no vaccine). Attribute-level preference weights were estimated using hierarchical Bayesian modeling. Attribute relative importance (RI) was compared between select subgroups. RESULTS: Of 1216 adults in the analyses, 29.9% reported they knew either 'a little' (20.7%) or 'a lot' (9.2%) about C.diff before the study. A C.diff vaccine was chosen 58.0% of the time (vs. opt-out) across choice tasks. It was estimated that up to 75.0% would choose a vaccine when OOP was $0. Those who were immunocompromised/high-risk for CDI (vs. not) more frequently chose a C.diff vaccine. Decreases in OOP costs (RI = 56.1), improvements in vaccine effectiveness (RI = 17.7), and reduction in symptom severity (RI = 10.3) were most important to vaccine choice. The rank ordering of attributes by importance was consistent across subgroups. CONCLUSION: OOP cost, improvements in vaccine effectiveness, and reduction in CDI severity were highly influential to vaccine selection. Most adults aged ≥50 years were receptive to a C.diff vaccine, especially with little-to-no OOP cost, suggesting that mandating insurance coverage of vaccination with no copayment may increase uptake. The limited awareness about C.diff among adults presents an opportunity for healthcare providers to educate their patients about CDI prevention.
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Vacunas Bacterianas , Clostridioides difficile , Infecciones por Clostridium , Humanos , Persona de Mediana Edad , Femenino , Estados Unidos , Masculino , Infecciones por Clostridium/prevención & control , Estudios Transversales , Anciano , Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/inmunología , Vacunas Bacterianas/economía , Clostridioides difficile/inmunología , Vacunación/psicología , Prioridad del Paciente/estadística & datos numéricos , Encuestas y Cuestionarios , Anciano de 80 o más Años , Teorema de BayesRESUMEN
Steroid usage poses a risk of Clostridioides difficile infection (CDI), but high-dose corticosteroid treatment can lead to false-negative CD toxin test results. Moreover, CDI-induced nausea can complicate administration of oral antibiotics, which are typically the primary therapy for CDI. In the present case, a 43-year-old woman diagnosed with EBV-associated T-cell post-transplant lymphoproliferative disorder developed CDI during treatment with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). Following five cycles of CHOP, the patient presented with nausea and diarrhea. CT scans revealed swelling in the ileocecal to transverse area of the colon. While the glutamate dehydrogenase (GDH) antigen test result was positive, the CD toxin test result was negative. However, the nucleic amplification test (NAAT) result was positive, confirming the diagnosis of CDI. Oral treatment with fidaxomicin was initially impractical due to persistent nausea. Instead, treatment began with intravenous metronidazole, and was later switched to fidaxomicin pills. Symptoms improved notably within 10 days, and the patient ultimately made a complete recovery. This case underscores the significance of exploring alternative approaches to CDI management, particularly in immunosuppressed patients.
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Infecciones por Clostridium , Infecciones por Virus de Epstein-Barr , Trastornos Linfoproliferativos , Técnicas de Amplificación de Ácido Nucleico , Humanos , Femenino , Adulto , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Clostridium/diagnóstico , Infecciones por Clostridium/tratamiento farmacológico , Clostridioides difficile , Herpesvirus Humano 4 , Linfocitos TRESUMEN
Biofilm formation and toxin production are some of the virulence factors of Clostridioides difficile (C. difficile), which causes hospital-acquired C. difficile infection (HA-CDI). This work investigated the prevalence and distribution of different strains recovered from HA-CDI patients hospitalized in 4 medical centres across Israel, and characterized strains' virulence factors and antibiotic susceptibility. One-hundred and eighty-eight faecal samples were collected. C. difficile 's toxins were detected by the CerTest Clostridium difficile GDH + Toxin A + B combo card test kit. Toxin loci PaLoc and PaCdt were detected by whole-genome sequencing (WGS). Multi-locus sequence typing (MLST) was performed to classify strains. Biofilm production was assessed by crystal violet. Antibiotic susceptibility was determined using Etest. Fidaxomicin susceptibility was tested via agar dilution. Sequence type (ST) 42 was the most (13.8%) common strain. All strains harboured the 2 toxins genes; 6.9% had the binary toxin. Most isolates were susceptible to metronidazole (98.9%) and vancomycin (99.5%). Eleven (5.85%) isolates were fidaxomicin-resistant. Biofilm production capacity was associated with ST (p < 0.001). In conclusion, a broad variety of C. difficile strains circulate in Israel's medical centres. Further studies are needed to explore the differences and their contribution to HA-CDI epidemiology.
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Antibacterianos , Biopelículas , Clostridioides difficile , Infecciones por Clostridium , Infección Hospitalaria , Pruebas de Sensibilidad Microbiana , Factores de Virulencia , Clostridioides difficile/genética , Clostridioides difficile/efectos de los fármacos , Clostridioides difficile/aislamiento & purificación , Clostridioides difficile/patogenicidad , Humanos , Israel/epidemiología , Infecciones por Clostridium/microbiología , Infecciones por Clostridium/epidemiología , Antibacterianos/farmacología , Factores de Virulencia/genética , Masculino , Femenino , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Infección Hospitalaria/microbiología , Infección Hospitalaria/epidemiología , Anciano , Persona de Mediana Edad , Tipificación de Secuencias Multilocus , Adulto , Anciano de 80 o más Años , Secuenciación Completa del Genoma , Heces/microbiologíaRESUMEN
The human gut pathogen Clostridioides difficile displays substantial inter-strain genetic variability and confronts a changeable nutrient landscape in the gut. We examined how human gut microbiota inter-species interactions influence the growth and toxin production of various C. difficile strains across different nutrient environments. Negative interactions influencing C. difficile growth are prevalent in an environment containing a single highly accessible resource and sparse in an environment containing C. difficile-preferred carbohydrates. C. difficile toxin production displays significant community-context dependent variation and does not trend with growth-mediated inter-species interactions. C. difficile strains exhibit differences in interactions with Clostridium scindens and the ability to compete for proline. Further, C. difficile shows substantial differences in transcriptional profiles in co-culture with C. scindens or Clostridium hiranonis. C. difficile exhibits massive alterations in metabolism and other cellular processes in co-culture with C. hiranonis, reflecting their similar metabolic niches. C. hiranonis uniquely inhibits the growth and toxin production of diverse C. difficile strains across different nutrient environments and robustly ameliorates disease severity in mice. In sum, understanding the impact of C. difficile strain variability and nutrient environments on inter-species interactions could help improve the effectiveness of anti-C. difficile strategies.
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Clostridioides difficile , Infecciones por Clostridium , Técnicas de Cocultivo , Microbioma Gastrointestinal , Clostridioides difficile/genética , Clostridioides difficile/metabolismo , Clostridioides difficile/fisiología , Humanos , Animales , Ratones , Infecciones por Clostridium/microbiología , Nutrientes/metabolismo , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/genética , Interacciones Microbianas , Clostridium/metabolismo , Clostridium/genética , Femenino , Antibiosis , Ratones Endogámicos C57BLRESUMEN
Clostridioides difficile infection (CDI) is a significant public health threat, associated with antibiotic-induced disruption of the normally protective gastrointestinal microbiota. CDI is thought to occur in two stages: acquisition of asymptomatic colonization from ingesting C. difficile bacteria followed by progression to symptomatic CDI caused by toxins produced during C. difficile overgrowth. The degree to which disruptive antibiotic exposure increases susceptibility at each stage is uncertain, which might contribute to divergent published projections of the impact of hospital antibiotic stewardship interventions on CDI. Here, we model C. difficile transmission and CDI among hospital inpatients, including exposure to high-CDI-risk antibiotics and their effects on each stage of CDI epidemiology. We derive the mathematical relationship, using a deterministic model, between those parameters and observed equilibrium levels of colonization, CDI, and risk ratio of CDI among certain antibiotic-exposed patients relative to patients with no recent antibiotic exposure. We then quantify the sensitivity of projected antibiotic stewardship intervention impacts to alternate assumptions. We find that two key parameters, the antibiotic effects on susceptibility to colonization and to CDI progression, are not identifiable given the data frequently available. Furthermore, the effects of antibiotic stewardship interventions are sensitive to their assumed values. Thus, discrepancies between different projections of antibiotic stewardship interventions may be largely due to model assumptions. Data supporting improved quantification of mechanistic antibiotic effects on CDI epidemiology are needed to understand stewardship effects better.
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Antibacterianos , Clostridioides difficile , Infecciones por Clostridium , Humanos , Infecciones por Clostridium/epidemiología , Infecciones por Clostridium/microbiología , Infecciones por Clostridium/tratamiento farmacológico , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Clostridioides difficile/efectos de los fármacos , Programas de Optimización del Uso de los Antimicrobianos , Instituciones de Salud , Infección Hospitalaria/epidemiología , Infección Hospitalaria/microbiología , Infección Hospitalaria/tratamiento farmacológico , Factores de Riesgo , Modelos Teóricos , Microbioma Gastrointestinal/efectos de los fármacosRESUMEN
Clostridioides difficile is an important human pathogen, for which there are very limited treatment options, primarily the glycopeptide antibiotic vancomycin. In recent years, vancomycin resistance has emerged as a serious problem in several gram-positive pathogens, but high-level resistance has yet to be reported for C. difficile, although it is not known if this is due to constraints upon resistance evolution in this species. Here, we show that resistance to vancomycin can evolve rapidly under ramping selection but is accompanied by fitness costs and pleiotropic trade-offs, including sporulation defects that would be expected to severely impact transmission. We identified 2 distinct pathways to resistance, both of which are predicted to result in changes to the muropeptide terminal D-Ala-D-Ala that is the primary target of vancomycin. One of these pathways involves a previously uncharacterised D,D-carboxypeptidase, expression of which is controlled by a dedicated two-component signal transduction system. Our findings suggest that while C. difficile is capable of evolving high-level vancomycin resistance, this outcome may be limited clinically due to pleiotropic effects on key pathogenicity traits. Moreover, our data identify potential mutational routes to resistance that should be considered in genomic surveillance.
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Antibacterianos , Clostridioides difficile , Resistencia a la Vancomicina , Vancomicina , Clostridioides difficile/efectos de los fármacos , Clostridioides difficile/genética , Clostridioides difficile/patogenicidad , Resistencia a la Vancomicina/genética , Vancomicina/farmacología , Antibacterianos/farmacología , Aptitud Genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Humanos , Transducción de Señal , Mutación , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Esporas Bacterianas/efectos de los fármacos , Esporas Bacterianas/genéticaRESUMEN
Most bacteria are surrounded by a cell wall that contains peptidoglycan (PG), a large polymer composed of glycan strands held together by short peptide cross-links. There are two major types of cross-links, termed 4-3 and 3-3 based on the amino acids involved. 4-3 cross-links are created by penicillin-binding proteins, while 3-3 cross-links are created by L,D-transpeptidases (LDTs). In most bacteria, the predominant mode of cross-linking is 4-3, and these cross-links are essential for viability, while 3-3 cross-links comprise only a minor fraction and are not essential. However, in the opportunistic intestinal pathogen Clostridioides difficile, about 70% of the cross-links are 3-3. We show here that 3-3 cross-links and LDTs are essential for viability in C. difficile. We also show that C. difficile has five LDTs, three with a YkuD catalytic domain as in all previously known LDTs and two with a VanW catalytic domain, whose function was until now unknown. The five LDTs exhibit extensive functional redundancy. VanW domain proteins are found in many gram-positive bacteria but scarce in other lineages. We tested seven non-C. difficile VanW domain proteins and confirmed LDT activity in three cases. In summary, our findings uncover a previously unrecognized family of PG cross-linking enzymes, assign a catalytic function to VanW domains, and demonstrate that 3-3 cross-linking is essential for viability in C. difficile, the first time this has been shown in any bacterial species. The essentiality of LDTs in C. difficile makes them potential targets for antibiotics that kill C. difficile selectively.
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Proteínas Bacterianas , Pared Celular , Clostridioides difficile , Peptidoglicano , Clostridioides difficile/enzimología , Clostridioides difficile/metabolismo , Peptidoglicano/metabolismo , Pared Celular/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Peptidoglicano Glicosiltransferasa/metabolismo , Peptidoglicano Glicosiltransferasa/química , Peptidoglicano Glicosiltransferasa/genéticaRESUMEN
PURPOSE: To compare the efficacy, recurrence rate, adverse event rate and mortality of fidaxomicin compared with vancomycin in treating different types of Clostridium difficile infection (CDI). METHODS: A systematic search was conducted on PubMed, Embase, Web of Science, Cochrane Library and clinical trial registration databases for research on fidaxomicin versus vancomycin in the treatment of CDI and the retrieval period extended from the establishment of the database to July 22, 2022. A total of 15 studies were included, including 8 RCTs and 7 retrospective cohort studies. RESULTS: Results showed that there was no significant difference in the overall efficacy of the treatment between fidaxomicin and vancomycin, and results in the subgroups of CDI hypervirulent strains and recurrent CDI were obtained, but vancomycin was more effective than fidaxomicin in the treatment of severe CDI (RRâ =â 0.94, 95% CI: 0.90-0.98, Pâ <â .01). Results showed that fidaxomicin is superior to vancomycin in terms of 40-day recurrence rate (RRâ =â 0.52, 95% CI: 0.38-0.70, Pâ <â .01), 60-day recurrence rate (RRâ =â 0.38, 95% CI: 0.21-0.69, Pâ <â .01) and 90-day recurrence rate (RRâ =â 0.62, 95% CI: 0.50-0.77, Pâ <â .01). For the recurrence rate of the treatment in CDI hypervirulent strains, severe CDI and recurrent CDI, there was no significant difference between the 2 groups. In addition, there was no significant difference in the incidence of clinical adverse reactions, and same outcomes appeared in all-cause mortality at 40-day, severe CDI and recurrent CDI, but fidaxomicin was superior to vancomycin in all-cause mortality over 60-day (RRâ =â 0.57, 95% CI: 0.34-0.96, Pâ =â .03). CONCLUSION: There were no significant differences between fidaxomicin and vancomycin in the treatment of CDI in therapeutic effectiveness and adverse reactions, while fidaxomicin was superior to vancomycin in terms of recurrence rate and long-term mortality, and vancomycin is more effective in treating severe CDI.
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Antibacterianos , Infecciones por Clostridium , Fidaxomicina , Vancomicina , Fidaxomicina/uso terapéutico , Vancomicina/uso terapéutico , Humanos , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/mortalidad , Antibacterianos/uso terapéutico , Recurrencia , Clostridioides difficile/efectos de los fármacos , Resultado del TratamientoRESUMEN
Vancomycin (VAN) treatment in Clostridioides difficile infection (CDI) suffers from a relatively high rate of recurrence, with a variety of reasons behind this, including biofilm-induced recurrent infections. C. difficile can form monophyletic or symbiotic biofilms with other microbes in the gut, and these biofilms protect C. difficile from being killed by antibiotics. In this study, we analyzed the ecological relationship between Bacteroides thetaiotaomicron and C. difficile and their formation of symbiotic biofilm in the VAN environment. The production of symbiotic biofilm formed by C. difficile and B. thetaiotaomicron was higher than that of C. difficile and B. thetaiotaomicron alone in the VAN environment. In symbiotic biofilms, C. difficile was characterized by increased production of the toxin protein TcdA and TcdB, up-regulation of the expression levels of the virulence genes tcdA and tcdB, enhanced bacterial cell swimming motility and c-di-GMP content, and increased adhesion to Caco-2 cells. The scanning electron microscope (SEM) combined with confocal laser scanning microscopy (CLSM) results indicated that the symbiotic biofilm was elevated in thickness, dense, and had an increased amount of mixed bacteria, while the fluorescence in situ hybridization (FISH) probe and plate colony counting results further indicated that the symbiotic biofilm had a significant increase in the amount of C. difficile cells, and was able to better tolerate the killing of the simulated intestinal fluid. Taken together, C. difficile and B. thetaiotaomicron become collaborative in the VAN environment, and targeted deletion or attenuation of host gut B. thetaiotaomicron content may improve the actual efficacy of VAN in CDI treatment.
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Antibacterianos , Proteínas Bacterianas , Bacteroides thetaiotaomicron , Biopelículas , Clostridioides difficile , Simbiosis , Vancomicina , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Clostridioides difficile/efectos de los fármacos , Clostridioides difficile/fisiología , Clostridioides difficile/genética , Humanos , Vancomicina/farmacología , Antibacterianos/farmacología , Células CACO-2 , Bacteroides thetaiotaomicron/efectos de los fármacos , Bacteroides thetaiotaomicron/metabolismo , Bacteroides thetaiotaomicron/fisiología , Bacteroides thetaiotaomicron/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/genética , Enterotoxinas/metabolismo , Enterotoxinas/genética , Adhesión Bacteriana/efectos de los fármacosRESUMEN
Fecal microbial transplantation (FMT) for inflammatory diseases or refractory immune checkpoint inhibitor therapy is less effective than for preventing recurrent Clostridioides difficile infection. This commentary outlines strategies to use biomarkers of successful FMT to guide newer approaches to restore microbial homeostasis in individuals with dysbiosis-mediated inflammation.
Asunto(s)
Disbiosis , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Medicina de Precisión , Humanos , Trasplante de Microbiota Fecal/métodos , Disbiosis/terapia , Medicina de Precisión/métodos , Infecciones por Clostridium/terapia , Infecciones por Clostridium/microbiología , Inflamación , Clostridioides difficile , BiomarcadoresRESUMEN
Due to envelope differences between Gram-positive and Gram-negative bacteria, engineering precision bactericidal contractile nanomachines requires atomic-level understanding of their structures; however, only those killing Gram-negative bacteria are currently known. Here, we report the atomic structures of an engineered diffocin, a contractile syringe-like molecular machine that kills the Gram-positive bacterium Clostridioides difficile. Captured in one pre-contraction and two post-contraction states, each structure fashions six proteins in the bacteria-targeting baseplate, two proteins in the energy-storing trunk, and a collar linking the sheath with the membrane-penetrating tube. Compared to contractile machines targeting Gram-negative bacteria, major differences reside in the baseplate and contraction magnitude, consistent with target envelope differences. The multifunctional hub-hydrolase protein connects the tube and baseplate and is positioned to degrade peptidoglycan during penetration. The full-length tape measure protein forms a coiled-coil helix bundle homotrimer spanning the entire diffocin. Our study offers mechanical insights and principles for designing potent protein-based precision antibiotics.
Asunto(s)
Antibacterianos , Bacteriocinas , Clostridioides difficile , Bacteriocinas/química , Bacteriocinas/metabolismo , Bacteriocinas/farmacología , Clostridioides difficile/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Modelos Moleculares , Bacterias Grampositivas/efectos de los fármacos , Peptidoglicano/metabolismo , Peptidoglicano/química , Cristalografía por Rayos XRESUMEN
BACKGROUND: Antibiotic exposure is a known risk factor for Clostridioides difficile infection (CDI) and recurrence and can lead to infection with specific C. difficile strains. In this study, we sought to explore the relationship between antecedent antibiotic exposure and C. difficile antimicrobial resistance, and the impact of resistance on clinical outcomes. METHODS: This was a single center retrospective study evaluating patients with CDI between 2011 and 2021. A logistic regression model was used to evaluate the relationship between antecedent antibiotics in the 30 days prior to CDI and resistance among isolates. In addition, an exploratory analysis using a cause-specific Cox proportional hazards model evaluated the association between resistance and a composite outcome of clinical failure, relapse at 30 days or CDI-related death. RESULTS: we analyzed one isolate from 510 patients; resistance was noted in 339 (66.5 %) of the isolates. Exposure to fluoroquinolones and macrolides was associated with 2.4 (95 % CI 1.4-4.4) and 4.7 (95 % CI 1.1-20.5) increased odds of having resistance compared to other antibiotic class exposure, respectively. There were 58 (17.0 %) patients in the resistance group who developed the composite outcome and 24 (14.2 %) patients who lacked resistance who developed the composite outcome (HR 1.32, 95 % CI 0.81-2.14). CONCLUSION: These findings suggest that fluoroquinolone and macrolide exposure were significantly associated with isolating a resistant strain, but we did not find significant differences in clinical outcomes based on the presence of antimicrobial resistance.
Asunto(s)
Antibacterianos , Clostridioides difficile , Infecciones por Clostridium , Ribotipificación , Humanos , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Infecciones por Clostridium/microbiología , Infecciones por Clostridium/epidemiología , Infecciones por Clostridium/tratamiento farmacológico , Estudios Retrospectivos , Masculino , Femenino , Anciano , Clostridioides difficile/efectos de los fármacos , Clostridioides difficile/genética , Clostridioides difficile/aislamiento & purificación , Clostridioides difficile/clasificación , Persona de Mediana Edad , Farmacorresistencia Bacteriana , Resultado del Tratamiento , Anciano de 80 o más Años , Adulto , RecurrenciaRESUMEN
INTRODUCTION: Clostridioides difficile is the main cause of antibiotic-associated diarrhea in humans and is a major enteropathogen in several animal species. In newborn piglets, colonic lesions caused by C. difficile A and B toxins (TcdA and TcdB, respectively) cause diarrhea and significant production losses. OBJECTIVE: The present study aimed to develop two recombinant vaccines from immunogenic C-terminal fragments of TcdA and TcdB and evaluate the immune response in rabbits and in breeding sows. Two vaccines were produced: bivalent (rAB), consisting of recombinant fragments of TcdA and TcdB, and chimeric (rQAB), corresponding to the synthesis of the same fragments in a single protein. Groups of rabbits were inoculated with 10 or 50 µg of proteins adjuvanted with aluminum or 0.85 % sterile saline in a final volume of 1 mL/dose. Anti-TcdA and anti-TcdB IgG antibodies were detected in rabbits and sows immunized with both rAB and rQAB vaccines by ELISA. The vaccinated sows were inoculated intramuscularly with 20 µg/dose using a prime-boost approach. RESULTS: Different antibody titers (p ≤ 0.05) were observed among the vaccinated groups of sows (rAB and rQAB) and control. Additionally, newborn piglets from vaccinated sows were also positive for anti-TcdA and anti-TcdB IgGs, in contrast to control piglets (p ≤ 0.05). Immunization of sows with the rQAB vaccine conferred higher anti-TcdA and anti-TcdB responses in piglets, suggesting the superiority of this compound over rAB. CONCLUSION: The synthesized recombinant proteins were capable of inducing antibody titers against C. difficile toxins A and B in sows, and were passively transferred to piglets through colostrum.
Asunto(s)
Animales Recién Nacidos , Anticuerpos Antibacterianos , Toxinas Bacterianas , Vacunas Bacterianas , Clostridioides difficile , Infecciones por Clostridium , Enfermedades de los Porcinos , Vacunas Sintéticas , Animales , Femenino , Porcinos , Conejos , Infecciones por Clostridium/prevención & control , Infecciones por Clostridium/veterinaria , Infecciones por Clostridium/inmunología , Vacunas Bacterianas/inmunología , Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/genética , Embarazo , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificación , Clostridioides difficile/inmunología , Clostridioides difficile/genética , Anticuerpos Antibacterianos/sangre , Toxinas Bacterianas/inmunología , Toxinas Bacterianas/genética , Enfermedades de los Porcinos/prevención & control , Enfermedades de los Porcinos/inmunología , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/genética , Enterotoxinas/inmunología , Enterotoxinas/genéticaRESUMEN
Clostridioides difficile is a pathogen whose transmission relies on the formation of dormant endospores. Spores are highly resilient forms of bacteria that resist environmental and chemical insults. In recent work, we found that C. difficile SspA and SspB, two small acid-soluble proteins (SASPs), protect spores from UV damage and, interestingly, are necessary for the formation of mature spores. Here, we build upon this finding and show that C. difficile sspA and sspB are required for the formation of the spore cortex layer. Moreover, using an EMS mutagenesis selection strategy, we identified mutations that suppressed the defect in sporulation of C. difficile SASP mutants. Many of these strains contained mutations in CDR20291_0714 (spoIVB2) revealing a connection between the SpoIVB2 protease and the SASPs in the sporulation pathway. This work builds upon the hypothesis that the small acid-soluble proteins can regulate gene expression.