A species-wide genetic atlas of antimicrobial resistance in Clostridioides difficile.
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ABSTRACT:
SUBMITTER: Imwattana K
PROVIDER: S-EPMC8743556 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Clostridioides difficile infection (CDI) remains an urgent global One Health threat. The genetic heterogeneity seen across C. difficile underscores its wide ecological versatility and has driven the significant changes in CDI epidemiology seen in the last 20 years. We analysed an international collection of over 12,000 C. difficile genomes spanning the eight currently defined phylogenetic clades. Through whole-genome average nucleotide identity, and pangenomic and Bayesian analyses, we identified major taxonomic incoherence with clear species boundaries for each of the recently described cryptic clades CI-III. The emergence of these three novel genomospecies predates clades C1-5 by millions of years, rewriting the global population structure of C. difficile specifically and taxonomy of the Peptostreptococcaceae in general. These genomospecies all show unique and highly divergent toxin gene architecture, advancing our understanding of the evolution of C. difficile and close relatives. Beyond the taxonomic ramifications, this work may impact the diagnosis of CDI.
| S-EPMC8241443 | biostudies-literature
Project description:Objectives:Clostridioides (Clostridium) difficile infection as a healthcare-associated infection can cause life-threatening infectious diarrhea in hospitalized patients. The aim of this study was to investigate the toxin profiles and antimicrobial resistance patterns of C. difficile isolates obtained from hospitalized patients in Shiraz, Iran. Materials and Methods:This study was performed on 45 toxigenic C. difficile isolates. Determination of toxin profiles was done using polymerase chain reaction method. Antimicrobial susceptibility to vancomycin, metronidazole, clindamycin, tetracycline, moxifloxacin, and chloramphenicol was determined by the agar dilution method. The genes encoding antibiotic resistance were detected by the standard procedures. Results:The most frequent toxin profile was tcdA+, tcdB+, cdtA-, cdtB- (82.2%), and only one isolate harboured all toxin associated genes (tcdA+, tcdB+, cdtA+, cdtB+) (2.2%). The genes encoding CDT (binary toxin) were also found in six (13.3%) isolates. Resistance to tetracycline, clindamycin and moxifloxacin was observed in 66.7%, 60% and 42.2% of the isolates, respectively. None of the strains showed resistance to other antibiotics. The distribution of the ermB gene (the gene encoding resistance to clindamycin) was 57.8% and the tetM and tetW genes (the genes encoding resistance to tetracycline) were found in 62.2% and 13.3% of the isolates, respectively. The substitutions Thr82 to Ile in GyrA and Asp426 to Asn in GyrB were seen in moxifloxacin resistant isolates. Conclusion:Our data contributes to the present understanding of virulence and resistance traits amongst the isolates. Infection control strategies should be implemented carefully in order to curb the dissemination of C. difficile strains in hospital.
| S-EPMC7196352 | biostudies-literature
Project description:Little is known about zoonotic pathogens and their antimicrobial resistance in South American camelids (SAC) in Germany including Clostridioides (C.) difficile. The aim of this study was to investigate prevalence, molecular characteristics and antimicrobial resistance of C. difficile in SAC. Composite SAC faecal samples were collected in 43 husbandries in Central Germany and cultured for C. difficile. Toxinotyping and ribotyping was done by PCR. Whole genome sequencing was performed with Illumina® Miseq™. The genomes were screened for antimicrobial resistance determinants. Genetic relatedness of the isolates was investigated using core genome multi locus sequence typing (cgMLST) and single nucleotide polymorphism analysis. Antimicrobial susceptibility testing was done using the Etest® method. Eight C. difficile isolates were recovered from seven farms. The isolates belonged to different PCR ribotypes. All isolates were toxinogenic. cgMLST revealed a cluster containing isolates recovered from different farms. Seven isolates showed similar resistance gene patterns. Different phenotypic resistance patterns were found. Agreement between phenotypic and genotypic resistance was identified only in some cases. Consequently, SAC may act as a reservoir for C. difficile. Thus, SAC may pose a risk regarding zoonotic transmission of toxinogenic, potentially human-pathogenic and resistant C. difficile isolates.
| S-EPMC9854998 | biostudies-literature
Project description:Clostridioides difficile is a global public health problem, which is a primary cause of antibiotic-associated diarrhea in humans. The emergence of hypervirulent and antibiotic-resistant strains is associated with the increased incidence and severity of the disease. There are limited studies on genomic characterization of C. difficile in Latin America. We aimed to learn about the molecular epidemiology and antimicrobial resistance in C. difficile strains from adults and children in hospitals of México. We studied 94 C. difficile isolates from seven hospitals in Mexico City from 2014 to 2018. Whole-genome sequencing (WGS) was used to determine the genotype and examine the toxigenic profiles. Susceptibility to antibiotics was determined by E-test. Multilocus sequence typing (MLST) was used to determine allelic profiles. Results identified 20 different sequence types (ST) in the 94 isolates, mostly clade 2 and clade 1. ST1 was predominant in isolates from adult and children. Toxigenic strains comprised 87.2% of the isolates that were combinations of tcdAB and cdtAB (tcdA+/tcdB+/cdtA+/cdtB+, followed by tcdA+/tcdB+/cdtA-/cdtB-, tcdA-/tcdB+/cdtA-/ cdtB-, and tcdA-/tcdB-/cdtA+/cdtB+). Toxin profiles were more diverse in isolates from children. All 94 isolates were susceptible to metronidazole and vancomycin, whereas a considerable number of isolates were resistant to clindamycin, fluroquinolones, rifampicin, meropenem, and linezolid. Multidrug-resistant isolates (≥3 antibiotics) comprised 65% of the isolates. The correlation between resistant genotypes and phenotypes was evaluated by the kappa test. Mutations in rpoB and rpoC showed moderate concordance with resistance to rifampicin and mutations in fusA substantial concordance with fusidic acid resistance. cfrE, a gene recently described in one Mexican isolate, was present in 65% of strains linezolid resistant, all ST1 organisms. WGS is a powerful tool to genotype and characterize virulence and antibiotic susceptibility patterns.
| S-EPMC8960119 | biostudies-literature
Project description:BackgroundClostridioides (Clostridium) difficile is an important pathogen of healthcare- associated diarrhea, however, an increase in the occurrence of C. difficile infection (CDI) outside hospital settings has been reported. The accumulation of antimicrobial resistance in C. difficile can increase the risk of CDI development and/or its spread. The limited number of antimicrobials for the treatment of CDI is matter of some concern.ObjectivesIn order to summarize the data on antimicrobial resistance to C. difficile derived from humans, a systematic review and meta-analysis were performed.MethodsWe searched five bibliographic databases: (MEDLINE [PubMed], Scopus, Embase, Cochrane Library and Web of Science) for studies that focused on antimicrobial susceptibility testing in C. difficile and were published between 1992 and 2019. The weighted pooled resistance (WPR) for each antimicrobial agent was calculated using a random- effects model.ResultsA total of 111 studies were included. The WPR for metronidazole and vancomycin was 1.0% (95% CI 0-3%) and 1% (95% CI 0-2%) for the breakpoint > 2 mg/L and 0% (95% CI 0%) for breakpoint ≥32 μg/ml. Rifampin and tigecycline had a WPRs of 37.0% (95% CI 18-58%) and 1% (95% CI 0-3%), respectively. The WPRs for the other antimicrobials were as follows: ciprofloxacin 95% (95% CI 85-100%), moxifloxacin 32% (95% CI 25-40%), clindamycin 59% (95% CI 53-65%), amoxicillin/clavulanate 0% (0-0%), piperacillin/tazobactam 0% (0-0%) and ceftriaxone 47% (95% CI 29-65%). Tetracycline had a WPR 20% (95% CI 14-27%) and meropenem showed 0% (95% CI 0-1%); resistance to fidaxomicin was reported in one isolate (0.08%).ConclusionResistance to metronidazole, vancomycin, fidaxomicin, meropenem and piperacillin/tazobactam is reported rarely. From the alternative CDI drug treatments, tigecycline had a lower resistance rate than rifampin. The high-risk antimicrobials for CDI development showed a high level of resistance, the highest was seen in the second generation of fluoroquinolones and clindamycin; amoxicillin/clavulanate showed almost no resistance. Tetracycline resistance was present in one fifth of human clinical C. difficile isolates.
| S-EPMC7517813 | biostudies-literature
Project description:Metronidazole was until recently used as a first-line treatment for potentially life-threatening Clostridioides difficile (CD) infection. Although cases of metronidazole resistance have been documented, no clear mechanism for metronidazole resistance or a role for plasmids in antimicrobial resistance has been described for CD. Here, we report genome sequences of seven susceptible and sixteen resistant CD isolates from human and animal sources, including isolates from a patient with recurrent CD infection by a PCR ribotype (RT) 020 strain, which developed resistance to metronidazole over the course of treatment (minimal inhibitory concentration [MIC] = 8 mg L-1). Metronidazole resistance correlates with the presence of a 7-kb plasmid, pCD-METRO. pCD-METRO is present in toxigenic and non-toxigenic resistant (n = 23), but not susceptible (n = 563), isolates from multiple countries. Introduction of a pCD-METRO-derived vector into a susceptible strain increases the MIC 25-fold. Our finding of plasmid-mediated resistance can impact diagnostics and treatment of CD infections.
| S-EPMC6992631 | biostudies-literature
Project description:Clostridioides difficile (CD) is one of the top five urgent antibiotic resistance threats in USA. There is a worldwide increase in MDR of CD, with emergence of novel strains which are often more virulent and MDR. Antibiotic resistance in CD is constantly evolving with acquisition of novel resistance mechanisms, which can be transferred between different species of bacteria and among different CD strains present in the clinical setting, community, and environment. Therefore, understanding the antibiotic resistance mechanisms of CD is important to guide optimal antibiotic stewardship policies and to identify novel therapeutic targets to combat CD as well as other bacteria. Epidemiology of CD is driven by the evolution of antibiotic resistance. Prevalence of different CD strains and their characteristic resistomes show distinct global geographical patterns. Understanding epidemiologically driven and strain-specific characteristics of antibiotic resistance is important for effective epidemiological surveillance of antibiotic resistance and to curb the inter-strain and -species spread of the CD resistome. CD has developed resistance to antibiotics with diverse mechanisms such as drug alteration, modification of the antibiotic target site and extrusion of drugs via efflux pumps. In this review, we summarized the most recent advancements in the understanding of mechanisms of antibiotic resistance in CD and analysed the antibiotic resistance factors present in genomes of a few representative well known, epidemic and MDR CD strains found predominantly in different regions of the world.
| S-EPMC8598299 | biostudies-literature
Project description:Bacteriophages (phages) are bacterial viruses that parasitize bacteria. They are highly prevalent in nature, with an estimated 1031 viral particles in the whole biosphere, and they outnumber bacteria by at least 10-fold. Hence, phages represent important drivers of bacterial evolution, although our knowledge of the role played by phages in the mammalian gut is still embryonic. Several pathogens owe their virulence to the integrated phages (prophages) they harbor, which encode diverse virulence factors such as toxins. Clostridioides (Clostridium) difficile is an important opportunistic pathogen and several phages infecting this species have been described over the last decade. However, their exact contribution to the biology and virulence of this pathogen remains elusive. Current data have shown that C. difficile phages can alter virulence-associated phenotypes, in particular toxin production, by interfering with bacterial regulatory circuits through crosstalk with phage proteins for example. One phage has also been found to encode a complete binary toxin locus. Multiple regulatory genes have also been identified in phage genomes, suggesting that their impact on the host can be complex and often subtle. In this minireview, the current state of knowledge, major findings, and pending questions regarding C. difficile phages will be presented. In addition, with the apparent role played by phages in the success of fecal microbiota transplantation and the perspective of phage therapy for treatment of recurrent C. difficile infection, it has become even more crucial to understand what C. difficile phages do in the gut, how they impact their host, and how they influence the epidemiology and evolution of this clinically important pathogen.
| S-EPMC6127314 | biostudies-literature
Project description:Effect on gene transcript levels upon up- or down-regulation of two component system WalRK (Wal-ON and Wal-OFF)
2022-04-09 | GSE200346 | GEO
Project description:Clostridium (Clostridioides) difficile infection (CDI) remains an urgent threat to patients in health systems worldwide. Recurrent CDI occurs in up to 30% of cases due to sustained dysbiosis of the gut microbiota which normally protects against CDI. Associated costs of initial and recurrent episodes of CDI impose heavy financial burdens on health systems. Vancomycin and metronidazole have been the mainstay of therapy for CDI for many years; however, these agents continue to cause significant disruption to the gut microbiota and thus carry a high risk of recurrence for CDI patients. Treatment regimens are now turning towards novel narrow spectrum antimicrobial agents which target C. difficile while conserving the commensal gut microbiota, thus significantly reducing risk of recurrence. One such agent, fidaxomicin, has been in therapeutic use for several years and is now recommended as a first-line treatment for CDI, as it is superior to vancomycin in reducing risk of recurrence. Another narrow spectrum agent, ridnilazole, was recently developed and is undergoing evaluation of its potential clinical utility. This review aimed to summarize experimental reports of ridinilazole and assess its potential as a first-line agent for treatment of CDI. Reported results from in vitro assessments, and from hamster models of CDI, show potent activity against C. difficile, non-inferiority to vancomycin for clinical cure and non-susceptibility among most gut commensal bacteria. Phase I and II clinical trials have been completed with ridinilazole showing high tolerability and efficacy in treatment of CDI, and superiority over vancomycin in reducing recurrence of CDI within 30 days of treatment completion. Phase III trials are currently underway, the results of which may prove its potential to reduce recurrent CDI and lessen the heavy health and financial burden C. difficile imposes on patients and healthcare systems.
| S-EPMC9541751 | biostudies-literature