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Bai L, Xu T, Zhang W, Jiang Y, Gu W, Zhao W, Luan Y, Xiong Y, Zou N, Zhang Y, Luo M, Lu J, Zhang B, Wu Y. Abundant geographical divergence of Clostridioides difficile infection in China: a prospective multicenter cross-sectional study. BMC Infect Dis 2025; 25:185. [PMID: 39920584 PMCID: PMC11806848 DOI: 10.1186/s12879-025-10552-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 01/23/2025] [Indexed: 02/09/2025] Open
Abstract
Clostridioides difficile is the predominant pathogen in hospital-acquired infections and antibiotic-associated diarrhea. Dedicated networks and annual reports for C. difficile surveillance have been established in Europe and North America, however the extensive investigation on the prevalence of C. difficile infection (CDI) in China is limited. In this study, 1528 patients with diarrhea were recruited from seven geographically representative regions of China between July 2021 and July 2022. The positivity rate of toxigenic C. difficile using real-time fluorescence quantitative PCR test of feces was 10.2% (156/1528), and 125 (8.2%, 125/1528) strains were successfully isolated. The isolates from different geographical areas had divergent characteristics after multilocus sequence typing, toxin gene profiling, and antimicrobial susceptibility testing. No isolate from clade 2 were found, and clade 1 was still the main clade for these clinical isolates. Interestingly, clade 4, especially ST37, previously known as the characteristic type of China, showed a strong geographical divergence. Clade 3, although rare in China, has been detected in Hainan and Sichuan provinces. Most C. difficile isolates (76.8%, 96/125) were toxigenic. Clindamycin, erythromycin, and moxifloxacin were the top three antibiotics to which resistance was observed, with resistance rates of 81.3%, 63.6%, and 24.0%, respectively. Furthermore, 34 (27.2%, 34/125) multidrug-resistant (MDR) strains were identified. All the strains were sensitive to metronidazole, vancomycin, and meropenem. The genotype of C. difficile varies greatly among the different geographical regions in China, and new types are constantly emerging. Therefore, comprehensive, longitudinal, and standardized surveillance of C. difficile infections is needed in China, covering typical geographical areas.
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Affiliation(s)
- Lulu Bai
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China
| | - Telong Xu
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China
| | - Wenzhu Zhang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China
| | - Yajun Jiang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China
| | - Wenpeng Gu
- Institute of Acute Infectious Disease Control and Prevention, Yunnan Provincial Center for Disease Control and Prevention, Kunming, Yunnan, 650500, China
| | - Wei Zhao
- Jilin Provincial Center for Disease Control and Prevention, Changchun, Jilin, 132001, China
| | - Yang Luan
- Xi'an Municipal Center for Disease Control and Prevention, Xi'an, Shaanxi, 710061, China
| | - Yanfeng Xiong
- Ganzhou Center for Disease Control and Prevention, Ganzhou, Jiangxi, 341001, China
| | - Nianli Zou
- Zigong Center for Disease Control and Prevention, Zigong, Sichuan, 643002, China
| | - Yalin Zhang
- Hainan Provincial Center for Disease Control and Prevention, Haikou, Hainan, 570203, China
| | - Ming Luo
- Yulin Center for Disease Control and Prevention, Yulin, Guangxi, 537006, China
| | - Jinxing Lu
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China
| | - Bike Zhang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China
| | - Yuan Wu
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
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Abstract
Severe colitis is a well-defined condition encompassing several etiologies but is most often caused by severe ulcerative colitis or Clostridioides difficile infection. Severe colitis can evolve into toxic colitis, or toxic megacolon when associated with bowel dilation and systemic manifestations, resulting in a life-threatening scenario where multidisciplinary management is often required. Medical management continues to play an important role in the initial treatment of toxic megacolon. However, timely surgical intervention can be lifesaving.
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Affiliation(s)
- Marjorie R. Liggett
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Hasan B. Alam
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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Li Y, Wang Z, Bai LL, Li YZ, Jiang YJ, Xu TL, Wu Y, Zhao X. Positive Intervention of Distinct Peptides in Clostridioides difficile Infection in a Mouse Model. Commun Biol 2024; 7:1172. [PMID: 39294333 PMCID: PMC11410834 DOI: 10.1038/s42003-024-06850-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 09/05/2024] [Indexed: 09/20/2024] Open
Abstract
Clostridioides difficile infection (CDI) is a common healthcare-associated infection and the leading cause of gastroenteritis-related deaths worldwide. To investigate the effects of peptide composition of different protein products on CDI, we analyzed and compared the peptide sequences and compositions from Engraulis japonicus and Glycine max using Ultra High Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). An animal model of CDI was also established to investigate the potential therapeutic effects of these peptides in vivo. The peptide compositions of E. japonicus and G. max differed, with only 11% of the peptide sequences being identical. Oral administration of the tested peptides could reduce intestinal inflammation, repair the intestinal barrier, increase the proportion of beneficial bacteria, and reduce the proportion of harmful bacteria, providing a therapeutic effect against CDI. However, the peptides may differ considerably in some aspects. E. japonicus peptides were superior to G. max peptides in promoting colon epithelial cell proliferation and repairing tight intestinal cell junctions. Interestingly, the two sources of peptides have different effects on the cecal microbiome. E. japonicus peptides can effectively restore the diversity and richness of intestinal microbiota, while G. max peptides have poor regulatory effects on the intestinal microbiota structure. Overall, E. japonicus peptides showed better results than G. max peptides in treating CDI. This study supports the potential treatment of CDI with natural peptides and promotes the development of specialty foods for CDI enteritis. Clostridioides difficile infection (CDI) is a common healthcare-associated infection and the leading cause of gastroenteritis-related deaths worldwide. To investigate the effects of peptide composition of different protein products on CDI, we analyzed and compared the peptide sequences and compositions from Engraulis japonicus and Glycine max using Ultra High Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). An animal model of CDI was also established to investigate the potential therapeutic effects of these peptides in vivo. The peptide compositions of E. japonicus and G. max differed, with only 11% of the peptide sequences being identical. Oral administration of the tested peptides could reduce intestinal inflammation, repair the intestinal barrier, increase the proportion of beneficial bacteria, and reduce the proportion of harmful bacteria, providing a therapeutic effect against CDI. However, the peptides may differ considerably in some aspects. E. japonicus peptides were superior to G. max peptides in promoting colon epithelial cell proliferation and repairing tight intestinal cell junctions. Interestingly, the two sources of peptides have different effects on the cecal microbiome. E. japonicus peptides can effectively restore the diversity and richness of intestinal microbiota, while G. max peptides have poor regulatory effects on the intestinal microbiota structure.
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Affiliation(s)
- Ying Li
- College of Food Science and Technology, Ocean University China, Qingdao, China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Zhan Wang
- Endoscopy Center, Qingdao Central Medical Group, Qingdao, China
| | - Lu Lu Bai
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Yan Zhe Li
- College of Food Science and Technology, Ocean University China, Qingdao, China
| | - Ya Jun Jiang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Te Long Xu
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Yuan Wu
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
| | - Xue Zhao
- College of Food Science and Technology, Ocean University China, Qingdao, China.
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Kochanowsky R, Carothers K, Roxas BAP, Anwar F, Viswanathan VK, Vedantam G. Clostridioides difficile superoxide reductase mitigates oxygen sensitivity. J Bacteriol 2024; 206:e0017524. [PMID: 38953644 PMCID: PMC11270899 DOI: 10.1128/jb.00175-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 06/12/2024] [Indexed: 07/04/2024] Open
Abstract
Clostridioides difficile causes a serious diarrheal disease and is a common healthcare-associated bacterial pathogen. Although it has a major impact on human health, the mechanistic details of C. difficile intestinal colonization remain undefined. C. difficile is highly sensitive to oxygen and requires anaerobic conditions for in vitro growth. However, the mammalian gut is not devoid of oxygen, and C. difficile tolerates moderate oxidative stress in vivo. The C. difficile genome encodes several antioxidant proteins, including a predicted superoxide reductase (SOR) that is upregulated upon exposure to antimicrobial peptides. The goal of this study was to establish SOR enzymatic activity and assess its role in protecting C. difficile against oxygen exposure. Insertional inactivation of sor rendered C. difficile more sensitive to superoxide, indicating that SOR contributes to antioxidant defense. Heterologous C. difficile sor expression in Escherichia coli conferred protection against superoxide-dependent growth inhibition, and the corresponding cell lysates showed superoxide scavenging activity. Finally, a C. difficile SOR mutant exhibited global proteome changes under oxygen stress when compared to the parent strain. Collectively, our data establish the enzymatic activity of C. difficile SOR, confirm its role in protection against oxidative stress, and demonstrate SOR's broader impacts on the C. difficile vegetative cell proteome.IMPORTANCEClostridioides difficile is an important pathogen strongly associated with healthcare settings and capable of causing severe diarrheal disease. While considered a strict anaerobe in vitro, C. difficile has been shown to tolerate low levels of oxygen in the mammalian host. Among other well-characterized antioxidant proteins, the C. difficile genome encodes a predicted superoxide reductase (SOR), an understudied component of antioxidant defense in pathogens. The significance of the research reported herein is the characterization of SOR's enzymatic activity, including confirmation of its role in protecting C. difficile against oxidative stress. This furthers our understanding of C. difficile pathogenesis and presents a potential new avenue for targeted therapies.
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Affiliation(s)
- Rebecca Kochanowsky
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, Arizona, USA
| | - Katelyn Carothers
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, Arizona, USA
| | - Bryan Angelo P. Roxas
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, Arizona, USA
| | - Farhan Anwar
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, Arizona, USA
| | - V. K. Viswanathan
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, Arizona, USA
- BIO5 Institute for Collaborative Research, The University of Arizona, Tucson, Arizona, USA
| | - Gayatri Vedantam
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, Arizona, USA
- BIO5 Institute for Collaborative Research, The University of Arizona, Tucson, Arizona, USA
- Southern Arizona VA Healthcare System, Tucson, Arizona, USA
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Deshpande A, O'Brien J, Hamilton B, Pappas M. Clinical Characteristics and Risk Factors for Clostridioides difficile Infection in the Hematopoietic Cell Transplantation Population. RESEARCH SQUARE 2024:rs.3.rs-4531064. [PMID: 39041031 PMCID: PMC11261972 DOI: 10.21203/rs.3.rs-4531064/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/24/2024]
Abstract
Background Hematopoietic cell transplantation (HCT) recipients are at increased risk of developing primary and recurrent Clostridioides difficile infection (CDI). The objective of our study was to characterize the risk factors for primary and recurrent CDI in a large cohort of patients hospitalized for HCT. Methods We conducted a retrospective cohort study of adults who underwent HCT from 2010-2023 to analyze the epidemiology, timing, and risk factors for CDI. We compared patients who developed CDI with those who did not, controlling for patient demographics, comorbidities, transplant factors, medications, and laboratory values. Results Of the 2,725 adults who underwent HCT, 252 (9.3%) developed primary CDI within one-year of transplantation. The incidence was higher among allogenic HCT recipients (17.8%) compared to autologous recipients (4.1%). Independent risk factors for primary CDI included receipt of penicillin antibiotics, prior chemotherapy, and umbilical cord stem cells. Receipt of macrolide antibiotics was an independent risk factor for recurrent CDI, while receipt of autologous HCT was associated with a reduced risk of both primary and recurrent CDI. Conclusions CDI presents an early complication after HCT, particularly in allogenic recipients who experience higher incidence rates and severe complications. Early recognition and management of these risk factors are essential to prevent these adverse outcomes.
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Crone AS, Wright LM, Cheknis A, Johnson S, Pacheco SM, Skinner AM. Characteristics and outcomes of Clostridioides difficile infection after a change in the diagnostic testing algorithm. Infect Control Hosp Epidemiol 2024; 45:57-62. [PMID: 37462099 DOI: 10.1017/ice.2023.145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2023]
Abstract
BACKGROUND Polymerase chain reaction (PCR) testing for the detection of C. difficile is a highly sensitive test. Some clinical laboratories have included a 2-step testing algorithm utilizing PCR plus toxin enzyme immunoassays (EIAs) to increase specificity. OBJECTIVE To determine the risk factors and outcomes of C. difficile PCR-positive/toxin-positive encounters compared to PCR-positive/toxin-negative encounters. DESIGN Retrospective study. SETTING A Veterans' Affairs hospital. METHODS A retrospective case-control study of patient encounters with a positive C. difficile test by PCR and either a toxin EIA-positive assay (ie, cases) or toxin EIA-negative assay (ie, controls). Clinically relevant exposures and risk factors were determined to assess CDI recurrence at 30 days. Available encounter stool specimens were cultured for C. difficile and were subjected to restriction endonuclease analysis (REA) strain typing. RESULTS Among 130 C. difficile PCR-positive patient encounters, 80 (61.5%) were toxin EIA negative and 50 (38.5%) were toxin EIA positive. Encounters that were toxin positive were more frequently treated (96.0%) compared to toxin-negative encounters (71.3%; P < .01). A multivariable logistic regression model revealed that toxin-negative encounters were less likely to suffer a recurrent CDI episode within 30 days (odds ratio [OR], 0.20, 95% confidence interval [CI], 0.05-0.83). Additionally, a higher C. difficile PCR cycle threshold predicted a lower risk of CDI recurrence at 30 days. (OR, 0.82; 95% CI, 0.68-0.98). During the study period, the REA group Y strain accounted for most toxin-negative encounters (32.5%; P = .05), whereas REA group BI strain accounted for most toxin-positive encounters (24.3%; P = .02). CONCLUSIONS A testing strategy of PCR plus toxin EIA helped predict recurrent CDI.
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Affiliation(s)
- Andrew S Crone
- Research Service and Infectious Diseases Section, Edward Hines, Jr. VA Hospital, Hines, Illinois
- Department of Medicine, Loyola University Medical Center, Maywood, Illinois
| | - Lorinda M Wright
- Research Service and Infectious Diseases Section, Edward Hines, Jr. VA Hospital, Hines, Illinois
| | - Adam Cheknis
- Research Service and Infectious Diseases Section, Edward Hines, Jr. VA Hospital, Hines, Illinois
| | - Stuart Johnson
- Research Service and Infectious Diseases Section, Edward Hines, Jr. VA Hospital, Hines, Illinois
- Department of Medicine, Loyola University Medical Center, Maywood, Illinois
| | - Susan M Pacheco
- Research Service and Infectious Diseases Section, Edward Hines, Jr. VA Hospital, Hines, Illinois
- Department of Medicine, Loyola University Medical Center, Maywood, Illinois
| | - Andrew M Skinner
- Research Service and Infectious Diseases Section, Edward Hines, Jr. VA Hospital, Hines, Illinois
- Department of Medicine, Loyola University Medical Center, Maywood, Illinois
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Ferar K, Hall TO, Crawford DC, Rowley R, Satterfield BA, Li R, Gragert L, Karlson EW, de Andrade M, Kullo IJ, McCarty CA, Kho A, Hayes MG, Ritchie MD, Crane PK, Mirel DB, Carlson C, Connolly JJ, Hakonarson H, Crenshaw AT, Carrell D, Luo Y, Dikilitas O, Denny JC, Jarvik GP, Crosslin DR. Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection. Sci Rep 2023; 13:18532. [PMID: 37898691 PMCID: PMC10613277 DOI: 10.1038/s41598-023-45649-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 10/22/2023] [Indexed: 10/30/2023] Open
Abstract
Clostridioides difficile (C. diff.) infection (CDI) is a leading cause of hospital acquired diarrhea in North America and Europe and a major cause of morbidity and mortality. Known risk factors do not fully explain CDI susceptibility, and genetic susceptibility is suggested by the fact that some patients with colons that are colonized with C. diff. do not develop any infection while others develop severe or recurrent infections. To identify common genetic variants associated with CDI, we performed a genome-wide association analysis in 19,861 participants (1349 cases; 18,512 controls) from the Electronic Medical Records and Genomics (eMERGE) Network. Using logistic regression, we found strong evidence for genetic variation in the DRB locus of the MHC (HLA) II region that predisposes individuals to CDI (P > 1.0 × 10-14; OR 1.56). Altered transcriptional regulation in the HLA region may play a role in conferring susceptibility to this opportunistic enteric pathogen.
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Affiliation(s)
- Kathleen Ferar
- Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA, USA.
| | - Taryn O Hall
- Optum Genomics, UnitedHealth Group, Minnetonka, MN, USA
| | - Dana C Crawford
- Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
- Department of Genetics and Genome Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
| | - Robb Rowley
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | | | - Rongling Li
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Loren Gragert
- Division of Biomedical Informatics and Genomics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | | | - Mariza de Andrade
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Iftikhar J Kullo
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Catherine A McCarty
- University of Minnesota Medical School, Duluth, MN, USA
- Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA
| | - Abel Kho
- Divisions of General Internal Medicine and Preventive Medicine, Northwestern University, Chicago, IL, USA
| | - M Geoffrey Hayes
- Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Marylyn D Ritchie
- Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, PA, USA
| | - Paul K Crane
- Division of General Internal Medicine, University of Washington, Seattle, WA, USA
| | | | - Christopher Carlson
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - John J Connolly
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Hakon Hakonarson
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | | | - David Carrell
- Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
| | - Yuan Luo
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ozan Dikilitas
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Joshua C Denny
- Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA
| | - Gail P Jarvik
- Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA, USA
| | - David R Crosslin
- Division of Biomedical Informatics and Genomics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
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Blau K, Berger FK, Mellmann A, Gallert C. Clostridioides difficile from Fecally Contaminated Environmental Sources: Resistance and Genetic Relatedness from a Molecular Epidemiological Perspective. Microorganisms 2023; 11:2497. [PMID: 37894155 PMCID: PMC10608975 DOI: 10.3390/microorganisms11102497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 09/28/2023] [Accepted: 09/28/2023] [Indexed: 10/29/2023] Open
Abstract
Clostridioides difficile is the most important pathogen causing antimicrobial-associated diarrhea and has recently been recognized as a cause of community-associated C. difficile infection (CA-CDI). This study aimed to characterize virulence factors, antimicrobial resistance (AMR), ribotype (RT) distribution and genetic relationship of C. difficile isolates from diverse fecally contaminated environmental sources. C. difficile isolates were recovered from different environmental samples in Northern Germany. Antimicrobial susceptibility testing was determined by E-test or disk diffusion method. Toxin genes (tcdA and tcdB), genes coding for binary toxins (cdtAB) and ribotyping were determined by PCR. Furthermore, 166 isolates were subjected to whole genome sequencing (WGS) for core genome multi-locus sequence typing (cgMLST) and extraction of AMR and virulence-encoding genes. Eighty-nine percent (148/166) of isolates were toxigenic, and 51% (76/148) were positive for cdtAB. Eighteen isolates (11%) were non-toxigenic. Thirty distinct RTs were identified. The most common RTs were RT127, RT126, RT001, RT078, and RT014. MLST identified 32 different sequence types (ST). The dominant STs were ST11, followed by ST2, ST3, and ST109. All isolates were susceptible to vancomycin and metronidazole and displayed a variable rate of resistance to moxifloxacin (14%), clarithromycin (26%) and rifampicin (2%). AMR genes, such as gyrA/B, blaCDD-1/2, aph(3')-llla-sat-4-ant(6)-la cassette, ermB, tet(M), tet(40), and tetA/B(P), conferring resistance toward fluoroquinolone, beta-lactam, aminoglycoside, macrolide and tetracycline antimicrobials, were found in 166, 137, 29, 32, 21, 72, 17, and 9 isolates, respectively. Eleven "hypervirulent" RT078 strains were detected, and several isolates belonged to RTs (i.e., RT127, RT126, RT023, RT017, RT001, RT014, RT020, and RT106) associated with CA-CDI, indicating possible transmission between humans and environmental sources pointing out to a zoonotic potential.
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Affiliation(s)
- Khald Blau
- Department of Microbiology–Biotechnology, Faculty of Technology, University of Applied Sciences Emden/Leer, 26723 Emden, Germany;
| | - Fabian K. Berger
- Institute of Medical Microbiology and Hygiene, Saarland University Medical Center, 66421 Homburg, Germany;
- German National Reference Center for Clostridioides Difficile, 66421 Homburg, Germany;
| | - Alexander Mellmann
- German National Reference Center for Clostridioides Difficile, 66421 Homburg, Germany;
- Institute of Hygiene, University of Münster, 48149 Münster, Germany
| | - Claudia Gallert
- Department of Microbiology–Biotechnology, Faculty of Technology, University of Applied Sciences Emden/Leer, 26723 Emden, Germany;
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Genomic epidemiology of Clostridioides difficile in individuals admitted to an intensive care unit. Nat Med 2023; 29:2418-2419. [PMID: 37783971 DOI: 10.1038/s41591-023-02550-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2023]
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10
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Jiang T, Hu X, Shen J. Establishment of a Novel Detection Platform for Clostridioides difficile Toxin Genes Based on Orthogonal CRISPR. Microbiol Spectr 2023; 11:e0188623. [PMID: 37378559 PMCID: PMC10434169 DOI: 10.1128/spectrum.01886-23] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Clostridioides difficile is one of the leading pathogens causing nosocomial infection. The infection can range from mild to severe, and rapid identification is pivotal for early clinical diagnosis and appropriate treatment. Here, a genetic testing platform for toxins, referred to as OC-MAB (orthogonal CRISPR system combined with multiple recombinase polymerase amplification [RPA]), was developed to detect the C. difficile toxin genes tcdA and tcdB. While recognizing the amplified products of the tcdA gene and the tcdB gene, Cas13a and Cas12a could activate their cleavage activities to cut labeled RNA and DNA probes, respectively. The cleaved products were subsequently identified by dual-channel fluorescence using a quantitative PCR (qPCR) instrument. Finally, they could also be combined with labeled antibodies on immunochromatographic test strips to achieve visual detection. The OC-MAB platform exhibited ultrahigh sensitivity in detecting the tcdA and tcdB genes at levels of as low as 102 to 101 copies/mL. When testing 72 clinical stool samples, the sensitivity (95% confidence interval [CI], 0.90, 1) and specificity (95% CI, 0.84, 1) of the single-tube method based on the fluorescence readout was 100%, with a positive predictive value (PPA) value of 100% (95% CI, 0.90, 1) and a negative predictive value (NPA) value of 100% (95% CI, 0.84, 1), compared to the results of qPCR. Likewise, the sensitivity of the 2-step method based on the test strip readout was 100% (95% CI, 0.90, 1), while the specificity was 96.3% (95% CI, 0.79, 0.99), with a PPA of 98% (95% CI, 0.87, 0.99) and an NPA of 100% (95% CI, 0.90, 1). In short, orthogonal CRISPR technology is a promising tool for the detection of C. difficile toxin genes. IMPORTANCE C. difficile is currently the primary causative agent of hospital-acquired antibiotic-induced diarrhea, and timely and accurate diagnosis is crucial for hospital-acquired infection control and epidemiological investigation. Here, a new method for the identification of C. difficile was developed based on the recently popular CRISPR technology, and an orthogonal CRISPR dual system was utilized for the simultaneous detection of toxin genes A and B. It also uses a currently rare CRISPR dual-target lateral flow strip with powerful color-changing capabilities, which is appropriate for point-of-care testing (POCT).
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Affiliation(s)
- Tong Jiang
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Public Health Clinical Center, Hefei, Anhui, China
| | - Xinyi Hu
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Public Health Clinical Center, Hefei, Anhui, China
| | - Jilu Shen
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Public Health Clinical Center, Hefei, Anhui, China
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Jiang T, Hu X, Lin C, Xia Z, Yang W, Zhu Y, Xu H, Tang H, Shen J. Rapid visualization of Clostridioides difficile toxins A and B by multiplex RPA combined with CRISPR-Cas12a. Front Microbiol 2023; 14:1119395. [PMID: 36970685 PMCID: PMC10030577 DOI: 10.3389/fmicb.2023.1119395] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/17/2023] [Indexed: 03/29/2023] Open
Abstract
Purpose Clostridioides difficile (C. difficile) infection is the most common cause of nosocomial infection, which is a severe challenge in modern medical care. Currently, many laboratory diagnostic methods for C. difficile are available, such as PCR, culture-based tests, and antigen-based tests. However, these methods are not suitable for rapid point-of-care testing (POCT). Therefore, it is of great significance to develop a rapid, sensitive, and cost-effective method to detect C. difficile toxin genes. Methods Recently, the development of clustered regularly interspaced short palindromic repeats (CRISPR) technology has emerged as a promising tool for rapid POCT. In this study, we developed a rapid and specific detection platform for dual C. difficile toxins by combining recombinase polymerase amplification (RPA) and CRISPR/Cas12a. Results The platform includes multiplex RPA-cas12a-fluorescence assay and multiplex RPA-cas12a-LFS (Lateral flow strip) assay, through which the detection limit for tcdA and tcdB was 10 copies/μL and 1 copy/μL, respectively. The results can be more clearly distinguished using a violet flashlight, which realized a portable visual readout. The platform can be tested within 50 min. Furthermore, our method did not cross-react with other pathogens that cause intestinal diarrhea. The results of 10 clinical samples using our method was 100% consistent with those from real-time PCR detection. Conclusion In conclusion, the CRISPR-based double toxin gene detection platform for C. difficile is an effective, specific, and sensitive detection method, which can be used as a powerful on-site detection tool for POCT in the future.
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Affiliation(s)
- Tong Jiang
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Public Health Clinical Center, Hefei, Anhui, China
| | - Xinyi Hu
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Public Health Clinical Center, Hefei, Anhui, China
| | - Chunhui Lin
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Public Health Clinical Center, Hefei, Anhui, China
| | - Zhaoxin Xia
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Public Health Clinical Center, Hefei, Anhui, China
| | - Wensu Yang
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Public Health Clinical Center, Hefei, Anhui, China
| | - Yi Zhu
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Public Health Clinical Center, Hefei, Anhui, China
| | - Huaming Xu
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Public Health Clinical Center, Hefei, Anhui, China
| | - Hao Tang
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Public Health Clinical Center, Hefei, Anhui, China
| | - Jilu Shen
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Public Health Clinical Center, Hefei, Anhui, China
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12
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Li Y, Liao J, Jian Z, Li H, Chen X, Liu Q, Liu P, Wang Z, Liu X, Yan Q, Liu W. Molecular epidemiology and clinical characteristics of
Clostridioides difficile
infection in patients with inflammatory bowel disease from a teaching hospital. J Clin Lab Anal 2022; 36:e24773. [DOI: 10.1002/jcla.24773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 11/03/2022] [Accepted: 11/04/2022] [Indexed: 11/21/2022] Open
Affiliation(s)
- Yan‐ming Li
- Department of Clinical Laboratory, Xiangya Hospital Central South University Changsha China
| | - Jing‐zhong Liao
- Department of Clinical Laboratory, Xiangya Hospital Central South University Changsha China
| | - Zi‐juan Jian
- Department of Clinical Laboratory, Xiangya Hospital Central South University Changsha China
| | - Hong‐ling Li
- Department of Clinical Laboratory, Xiangya Hospital Central South University Changsha China
| | - Xia Chen
- Department of Clinical Laboratory, Xiangya Hospital Central South University Changsha China
| | - Qing‐xia Liu
- Department of Clinical Laboratory, Xiangya Hospital Central South University Changsha China
| | - Pei‐lin Liu
- Department of Clinical Laboratory, Xiangya Hospital Central South University Changsha China
| | - Zhi‐qian Wang
- Department of Clinical Laboratory, Xiangya Hospital Central South University Changsha China
| | - Xuan Liu
- Department of Clinical Laboratory, Xiangya Hospital Central South University Changsha China
| | - Qun Yan
- Department of Clinical Laboratory, Xiangya Hospital Central South University Changsha China
- National Clinical Research Center for Geriatric Disorders Xiangya Hospital Changsha China
| | - Wen‐en Liu
- Department of Clinical Laboratory, Xiangya Hospital Central South University Changsha China
- National Clinical Research Center for Geriatric Disorders Xiangya Hospital Changsha China
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13
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Plakoglobin and High-Mobility Group Box 1 Mediate Intestinal Epithelial Cell Apoptosis Induced by Clostridioides difficile TcdB. mBio 2022; 13:e0184922. [PMID: 36043787 DOI: 10.1128/mbio.01849-22] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated intestinal disease, resulting in severe diarrhea and fatal pseudomembranous colitis. TcdB, one of the essential virulence factors secreted by this bacterium, induces host cell apoptosis through a poorly understood mechanism. Here, we performed an RNA interference (RNAi) screen customized to Caco-2 cells, a cell line model of the intestinal epithelium, to discover host factors involved in TcdB-induced apoptosis. We identified plakoglobin, also known as junction plakoglobin (JUP) or γ-catenin, a member of the catenin family, as a novel host factor and a previously known cell death-related chromatin factor, high-mobility group box 1 (HMGB1). Disruption of those host factors by RNAi and CRISPR resulted in resistance of cells to TcdB-mediated and mitochondrion-dependent apoptosis. JUP was redistributed from adherens junctions to the mitochondria and colocalized with the antiapoptotic factor Bcl-XL. JUP proteins could permeabilize the mitochondrial membrane, resulting in the release of cytochrome c. Our results reveal a novel role of JUP in targeting the mitochondria to promote the mitochondrial apoptotic pathway. Treatment with glycyrrhizin, an HMGB1 inhibitor, resulted in significantly increased resistance to TcdB-induced epithelial damage in cultured cells and a mouse ligated colon loop model. These findings demonstrate the critical roles of JUP and HMGB1 in TcdB-induced epithelial cell apoptosis. IMPORTANCE Clostridioides difficile infection (CDI) is the leading cause of hospital-acquired diarrhea. Toxins, especially TcdB, cause epithelial cell apoptosis, but the underlying cell death mechanism is less clear. Through an apoptosis-focused RNAi screen using a bacterium-made small interfering (siRNA) library customized to a human colonic epithelial cell model, we found a novel host factor, plakoglobin (γ-catenin), as a key factor required for cell apoptosis induced by TcdB. Plakoglobin targets and permeabilizes mitochondria after stimulation by TcdB, demonstrating a hitherto underappreciated role of this catenin family member in the apoptosis of intestinal epithelial cells. We also found a previously known cell death-related chromatin factor, HMGB1, and explored the inhibition of HMGB1 for CDI therapy in vivo.
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14
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Abstract
The severity of Clostridioides difficile infections (CDI) has increased over the last few decades. Patient age, white blood cell count, and creatinine levels as well as C. difficile ribotype and toxin genes have been associated with disease severity. However, it is unclear whether specific members of the gut microbiota are associated with variations in disease severity. The gut microbiota is known to interact with C. difficile during infection. Perturbations to the gut microbiota are necessary for C. difficile to colonize the gut. The gut microbiota can inhibit C. difficile colonization through bile acid metabolism, nutrient consumption, and bacteriocin production. Here, we sought to demonstrate that members of the gut bacterial communities can also contribute to disease severity. We derived diverse gut communities by colonizing germfree mice with different human fecal communities. The mice were then infected with a single C. difficile ribotype 027 clinical isolate, which resulted in moribundity and histopathologic differences. The variation in severity was associated with the human fecal community that the mice received. Generally, bacterial populations with pathogenic potential, such as Enterococcus, Helicobacter, and Klebsiella, were associated with more-severe outcomes. Bacterial groups associated with fiber degradation and bile acid metabolism, such as Anaerotignum, Blautia, Lactonifactor, and Monoglobus, were associated with less-severe outcomes. These data indicate that, in addition to the host and C. difficile subtype, populations of gut bacteria can influence CDI disease severity.
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15
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Perry DA, Shirley D, Micic D, Patel PC, Putler R, Menon A, Young VB, Rao K. External Validation and Comparison of Clostridioides difficile Severity Scoring Systems. Clin Infect Dis 2022; 74:2028-2035. [PMID: 34459885 PMCID: PMC9187324 DOI: 10.1093/cid/ciab737] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Many models have been developed to predict severe outcomes from Clostridioides difficile infection (CDI). These models are usually developed at a single institution and largely are not externally validated. Our aim in this study was to validate previously published risk scores in a multicenter cohort of patients with CDI. METHODS This was a retrospective study on 4 inpatient cohorts with CDI from 3 distinct sites: the universities of Michigan (2010-2012 and 2016), Chicago (2012), and Wisconsin (2012). The primary composite outcome was admission to an intensive care unit, colectomy, and/or death attributed to CDI within 30 days of positive testing. Both within each cohort and combined across all cohorts, published CDI severity scores were assessed and compared to each other and the Infectious Diseases Society of America (IDSA) guideline definitions of severe and fulminant CDI. RESULTS A total of 3646 patients were included for analysis. Including the 2 IDSA guideline definitions, 14 scores were assessed. Performance of scores varied within each cohort and in the combined set (mean area under the receiver operator characteristic curve [AuROC], 0.61; range, 0.53-0.66). Only half of the scores had performance at or better than IDSA severe and fulminant definitions (AuROCs of 0.64 and 0.63, respectively). Most of the scoring systems had more false than true positives in the combined set (mean, 81.5%; range, 0%-91.5%). CONCLUSIONS No published CDI severity score showed stable, good predictive ability for adverse outcomes across multiple cohorts/institutions or in a combined multicenter cohort.
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Affiliation(s)
- D Alexander Perry
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
- University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Daniel Shirley
- Division of Infectious Disease, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Dejan Micic
- Department of Internal Medicine, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Medicine, Chicago, Illinois,USA
| | - Pratish C Patel
- Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Rosemary Putler
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
- University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Anitha Menon
- University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Vincent B Young
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
- University of Michigan Medical School, Ann Arbor, Michigan, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA
| | - Krishna Rao
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
- University of Michigan Medical School, Ann Arbor, Michigan, USA
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16
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Lanzas C, Jara M, Tucker R, Curtis S. A review of epidemiological models of Clostridioides difficile transmission and control (2009-2021). Anaerobe 2022; 74:102541. [PMID: 35217149 DOI: 10.1016/j.anaerobe.2022.102541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 02/09/2022] [Accepted: 02/20/2022] [Indexed: 02/08/2023]
Abstract
Clostridioides difficile is the leading cause of infectious diarrhea and one of the most common healthcare-acquired infections worldwide. We performed a systematic search and a bibliometric analysis of mathematical and computational models for Clostridioides difficile transmission. We identified 33 publications from 2009 to 2021. Models have underscored the importance of asymptomatic colonized patients in maintaining transmission in health-care settings. Infection control, antimicrobial stewardship, active testing, and vaccination have often been evaluated in models. Despite active testing and vaccination being not currently implemented, they are the most commonly evaluated interventions. Some aspects of C. difficile transmission, such community transmission and interventions in health-care settings other than in acute-care hospitals, remained less evaluated through modeling.
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Affiliation(s)
- Cristina Lanzas
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC, USA.
| | - Manuel Jara
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC, USA
| | - Rachel Tucker
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC, USA
| | - Savannah Curtis
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC, USA
| | -
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC, USA
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17
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A Novel Bacteriophage with Broad Host Range against Clostridioides difficile Ribotype 078 Supports SlpA as the Likely Phage Receptor. Microbiol Spectr 2022; 10:e0229521. [PMID: 35107319 PMCID: PMC8809339 DOI: 10.1128/spectrum.02295-21] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Bacteriophages represent a promising option for the treatment of Clostridioides difficile (formerly Clostridium difficile) infection (CDI), which at present relies on conventional antibiotic therapy. The specificity of bacteriophages should prevent dysbiosis of the colonic microbiota associated with antibiotic treatment of CDI. While numerous phages have been isolated, none have been characterized with broad host range activity toward PCR ribotype (RT) 078 strains, despite their relevance to medicine and agriculture. In this study, we isolated four novel C. difficile myoviruses: ΦCD08011, ΦCD418, ΦCD1801, and ΦCD2301. Their characterization revealed that each was comparable with other C. difficile phages described in the literature, with the exception of ΦCD1801, which exhibited broad host range activity toward RT 078, infecting 15/16 (93.8%) of the isolates tested. In order for wild-type phages to be exploited in the effective treatment of CDI, an optimal phage cocktail must be assembled that provides broad coverage against all C. difficile RTs. We conducted experiments to support previous findings suggesting that SlpA, a constituent of the C. difficile surface layer (S-layer) is the likely phage receptor. Through interpretation of phage-binding assays, our data suggested that ΦCD1801 could bind to an RT 012 strain only in the presence of a plasmid-borne S-layer cassette corresponding to the slpA allele found in RT 078. Armed with this information, efforts should be directed toward the isolation of phages with broad host range activity toward defined S-layer cassette types, which could form the basis of an effective phage cocktail for the treatment of CDI. IMPORTANCE Research into phage therapy has seen a resurgence in recent years owing to growing concerns regarding antimicrobial resistance. Phage research for potential therapy against Clostridioides difficile infection (CDI) is in its infancy, where an optimal “one size fits all” phage cocktail is yet to be derived. The pursuit thus far has aimed to find phages with the broadest possible host range. However, for C. difficile strains belonging to certain PCR ribotypes (RTs), in particular RT 078, phages with broad host range activity are yet to be discovered. In this study, we isolate four novel myoviruses, including ΦCD1801, which exerts the broadest host range activity toward RT 078 reported in the literature. Through the application of ΦCD1801 to phage-binding assays, we provide data to support the prior notion that SlpA represents the likely phage receptor on the bacterial cell surface. Our finding directs research attention toward the isolation of phages with activity toward strains possessing defined S-layer cassette types.
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18
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Simpson HL, Roberts CL, Thompson LM, Leiper CR, Gittens N, Trotter E, Duckworth CA, Papoutsopoulou S, Miyajima F, Roberts P, O’Kennedy N, Rhodes JM, Campbell BJ. Soluble Non-Starch Polysaccharides From Plantain ( Musa x paradisiaca L.) Diminish Epithelial Impact of Clostridioides difficile. Front Pharmacol 2021; 12:766293. [PMID: 34955836 PMCID: PMC8707065 DOI: 10.3389/fphar.2021.766293] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 11/25/2021] [Indexed: 11/13/2022] Open
Abstract
Clostridioides difficile infection (CDI) is a leading cause of antibiotic-associated diarrhoea. Adhesion of this Gram-positive pathogen to the intestinal epithelium is a crucial step in CDI, with recurrence and relapse of disease dependent on epithelial interaction of its endospores. Close proximity, or adhesion of, hypervirulent strains to the intestinal mucosa are also likely to be necessary for the release of C. difficile toxins, which when internalized, result in intestinal epithelial cell rounding, damage, inflammation, loss of barrier function and diarrhoea. Interrupting these C. difficile-epithelium interactions could therefore represent a promising therapeutic strategy to prevent and treat CDI. Intake of dietary fibre is widely recognised as being beneficial for intestinal health, and we have previously shown that soluble non-starch polysaccharides (NSP) from plantain banana (Musa spp.), can block epithelial adhesion and invasion of a number of gut pathogens, such as E. coli and Salmonellae. Here, we assessed the action of plantain NSP, and a range of alternative soluble plant fibres, for inhibitory action on epithelial interactions of C. difficile clinical isolates, purified endospore preparations and toxins. We found that plantain NSP possessed ability to disrupt epithelial adhesion of C. difficile vegetative cells and spores, with inhibitory activity against C. difficile found within the acidic (pectin-rich) polysaccharide component, through interaction with the intestinal epithelium. Similar activity was found with NSP purified from broccoli and leek, although seen to be less potent than NSP from plantain. Whilst plantain NSP could not block the interaction and intracellular action of purified C. difficile toxins, it significantly diminished the epithelial impact of C. difficile, reducing both bacteria and toxin induced inflammation, activation of caspase 3/7 and cytotoxicity in human intestinal cell-line and murine intestinal organoid cultures. Dietary supplementation with soluble NSP from plantain may therefore confer a protective effect in CDI patients by preventing adhesion of C. difficile to the mucosa, i.e. a "contrabiotic" effect, and diminishing its epithelial impact. This suggests that plantain soluble dietary fibre may be a therapeutically effective nutritional product for use in the prevention or treatment of CDI and antibiotic-associated diarrhoea.
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Affiliation(s)
- Hannah L. Simpson
- The Henry Wellcome Laboratories of Molecular & Cellular Gastroenterology, Faculty of Health & Life Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Carol L. Roberts
- The Henry Wellcome Laboratories of Molecular & Cellular Gastroenterology, Faculty of Health & Life Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Louise M. Thompson
- The Henry Wellcome Laboratories of Molecular & Cellular Gastroenterology, Faculty of Health & Life Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Cameron R. Leiper
- The Henry Wellcome Laboratories of Molecular & Cellular Gastroenterology, Faculty of Health & Life Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Nehana Gittens
- The Henry Wellcome Laboratories of Molecular & Cellular Gastroenterology, Faculty of Health & Life Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Ellie Trotter
- The Henry Wellcome Laboratories of Molecular & Cellular Gastroenterology, Faculty of Health & Life Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Carrie A. Duckworth
- The Henry Wellcome Laboratories of Molecular & Cellular Gastroenterology, Faculty of Health & Life Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Stamatia Papoutsopoulou
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection Veterinary and Ecological Sciences, Faculty of Health & Life Sciences, University of Liverpool, Liverpool, United Kingdom
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Fabio Miyajima
- Wolfson Centre for Personalised Medicine, Department of Molecular & Clinical Pharmacology, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool, United Kingdom
- Oswaldo Cruz Foundation (Fiocruz), Eusébio, Brazil
| | - Paul Roberts
- Department of Microbiology, Liverpool Clinical Laboratories, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, United Kingdom
- School for Medicine and Clinical Practice, University of Wolverhampton, Wolverhampton, United Kingdom
| | - Niamh O’Kennedy
- Provexis PLC, c/o The University of Aberdeen, Aberdeen, United Kingdom
| | - Jonathan M. Rhodes
- The Henry Wellcome Laboratories of Molecular & Cellular Gastroenterology, Faculty of Health & Life Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Barry J. Campbell
- The Henry Wellcome Laboratories of Molecular & Cellular Gastroenterology, Faculty of Health & Life Sciences, University of Liverpool, Liverpool, United Kingdom
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Krishna A, Chopra T. Prevention of Infection due to Clostridium (Clostridioides) difficile. Infect Dis Clin North Am 2021; 35:995-1011. [PMID: 34752229 DOI: 10.1016/j.idc.2021.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Clostridium (Clostridioides) difficile infection (CDI) causes significant morbidity and mortality in the United States every year. Prevention of CDI is difficult because of spore durability and requires implementation of multipronged strategies. Two categories of prevention strategies are infection control and prevention and risk factor reduction. Hand hygiene, contact precautions, patient isolation, and environmental decontamination are cornerstones of infection control and prevention. Risk factor reduction should focus on antibiotic stewardship to reduce unnecessary antibiotic use. If CDI incidence remains higher than the institution's goal despite these measures, then special measures should be considered.
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Affiliation(s)
- Amar Krishna
- Internal Medicine, Norther Light AR Gould Hospital, 140 Academy Street, Presque Isle, ME 04769, USA.
| | - Teena Chopra
- Infectious Diseases, Wayne State University/Detroit Medical Center, UHC-2B, 4201 St Antoine, Detroit, MI 48201, USA
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20
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Pakhomovskaia NL, Tatyanina OF, Lazareva ТY. Approaches to prevention of antibiotic-associated diarrhea in children. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2021:283-292. [DOI: 10.21518/2079-701x-2021-17-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The incidence of antibiotic-associated diarrhea, according to various authors, ranges from 5 to 39% and depends on the patient’s age and other contributing factors. Antibiotic-associated diarrhea can be caused by any antibiotic, regardless of dosage form or route of administration. In the pediatric population, the prevalence of antibiotic-associated diarrhea ranges from 6 to 70%. An urgent problem is the development of this disease against the background of a course of H. pylori eradication therapy, which significantly complicates tolerance and adherence to therapy. This article presents current data on the pathogenesis and risk factors of antibiotic-associated diarrhea in children. The clinical picture ranges from idiopathic enteritis to antibiotic-associated diarrhea caused by Cl. difficile - pseudomembranous colitis.The main principle of antibiotic-associated diarrhea treatment is cancellation of the antibacterial medicine that caused the diarrhea, or reducing its dose (if the course of the disease allows it). In complex treatment sorbents are used, correction of water-electrolyte balance is carried out. The use of probiotics seems quite logical for the treatment and prevention of antibiotic-associated diarrhea in terms of the pathogenesis of this condition. To correct dysbiosis, drugs are used to maintain and restore the quantitative and qualitative composition of the intestinal microbiota.Taking into account modern recommendations the main groups of drugs (probiotics, prebiotics, synbiotics) used for correction of intestinal microbiocenosis are presented. The mechanism of action of probiotics and mechanisms of their effect on intestinal microflora are considered. The basic requirements for bacterial strains that are part of the probiotic drugs are presented.The results of various randomized clinical trials and meta-analyses confirming the necessity of including probiotic complexes in antibiotic-associated diarrhea treatment regimens are presented from an evidence-based medicine perspective. The clinical effects of strains of Lactobacillusspp., Bifidobacterium spp.,Streptococcusspp. and Lactococcusspp. on the digestive tract microbiota are considered. The role of a synbiotic containing 9 probiotic strains of 4.5 * 109 CFU in one capsule and the prebiotic component fructooligosac-charides in the prevention of antibiotic-associated diarrhea in children is discussed separately. The results of microbiological studies confirmed the presence of microorganisms of genera Bifidobacterium, Lactobacillus, Streptococcus in the product, and the content of bacteria in one dose of the product was not less than 2 x 1010 CFU.
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21
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Safety and immunogenicity of different Clostridioides (Clostridium) difficile vaccine formulations in two early phase randomized studies of healthy adults aged 50-85 years. Vaccine 2021; 39:5991-6003. [PMID: 34483022 DOI: 10.1016/j.vaccine.2021.05.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 01/04/2021] [Accepted: 05/08/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Two phase 1/phase 2 studies assessed 2 formulations of investigational bivalent Clostridioides (Clostridium) difficile vaccine (QS-21 adjuvanted toxoid and toxoid-alone) in healthy adults 50-85 years of age. METHODS The QS-21 adjuvanted toxoid vaccine study randomized subjects 3:1 to 100 μg QS-21-containing C difficile vaccine or placebo administered in a shortened-month (Months 0, 1, 3) or day (Days 1, 8, 30) regimen. The toxoid-alone vaccine study randomized subjects 3:3:1 to receive 100 or 200 μg unadjuvanted C difficile vaccine formulation or placebo in Stages 1 and 2 (sentinel cohorts of different age groups), and 3:1 to receive the selected dose of unadjuvanted C difficile vaccine formulation or placebo in Stage 3 (Days 1, 8, 30). Safety was the primary outcome for both studies. Immunogenicity was determined by measuring serum toxin A- and B-specific neutralizing antibodies. RESULTS In the day regimen, 10 reports across both studies of grade 3 injection site redness postdose 2 triggered predefined stopping rules. Local reactions in both studies were more common among vaccine versus placebo recipients. Injection site pain predominated and was generally mild in severity. Systemic events were infrequent and generally mild-to-moderate in severity. Adverse events were reported by 50.0%-75.0% and 16.7%-50.0% of subjects in the QS-21 and toxoid-alone studies, respectively. Immune responses peaked around Day 37 (shortened-month regimen) or between Day 15 and Month 2 (day regimen) and remained above baseline throughout follow-up. CONCLUSIONS Both formulations demonstrated robust immunogenicity. Both studies stopped early due to grade 3 injection site redness postdose 2 of the day regimen; neither formulation progressed to later stage development. Instead, an aluminum hydroxide-containing formulation of the vaccine candidate administered at 0, 1, and 6 months, which was safe and immunogenic in phase 1 and 2 studies, advanced to phase 3 studies.
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22
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Wickramage I, Spigaglia P, Sun X. Mechanisms of antibiotic resistance of Clostridioides difficile. J Antimicrob Chemother 2021; 76:3077-3090. [PMID: 34297842 DOI: 10.1093/jac/dkab231] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
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.
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Affiliation(s)
- Ishani Wickramage
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Down Blvd, Tampa, FL 33612, USA
| | - Patrizia Spigaglia
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Xingmin Sun
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Down Blvd, Tampa, FL 33612, USA
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23
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Hassanain WA, Spoors J, Johnson CL, Faulds K, Keegan N, Graham D. Rapid ultra-sensitive diagnosis of clostridium difficile infection using a SERS-based lateral flow assay. Analyst 2021; 146:4495-4505. [PMID: 34184680 DOI: 10.1039/d1an00726b] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Clostridium difficile (C. diff) infection is one of the most contagious diseases associated with high morbidity and mortality rates in hospitalised patients. Accurate diagnosis can slow its spread by determining the most effective treatment. Herein, we report a novel testing platform as a proof-of-concept for the selective, sensitive, rapid and cost-effective diagnosis of C. diff infection (CDI) based on a duplex measurement. This was achieved by detecting two specific biomarkers, surface layer protein A (SlpA) and toxin B (ToxB), using a surface enhanced Raman scattering-based lateral flow assay (SERS-based LFA). The simultaneous duplex detection of SlpA with ToxB has not been described for the clinical diagnosis of CDI previously. The SlpA biomarker "AKDGSTKEDQLVDALA" was first reported by our group in 2018 as a species-specific identification tool. The second biomarker, ToxB, is the essential virulence biomarker of C. diff pathogenic strains and is required to confirm true infection pathogenicity. The proposed SERS-based LFA platform enabled rapid duplex detection of SlpA and ToxB on separate test lines using a duplex LF test strip within 20 minutes. The use of a handheld Raman spectrometer to scan test lines allowed for the highly sensitive quantitative detection of both biomarkers with a lowest observable concentration of 0.01 pg μL-1. The use of a handheld device in this SERS-based LFA instead of benchtop machine paves the way for rapid, selective, sensitive and cheap clinical evaluation of CDI at the point of care (POC) with minimal sample backlog.
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Affiliation(s)
- Waleed A Hassanain
- Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, Glasgow, G1 1RD, UK.
| | - Julia Spoors
- Diagnostic and Therapeutic Technologies, Translational and Clinical Research Institute, Newcastle University, Newcastle-Upon-Tyne, NE2 4HH, UK.
| | - Christopher L Johnson
- Diagnostic and Therapeutic Technologies, Translational and Clinical Research Institute, Newcastle University, Newcastle-Upon-Tyne, NE2 4HH, UK.
| | - Karen Faulds
- Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, Glasgow, G1 1RD, UK.
| | - Neil Keegan
- Diagnostic and Therapeutic Technologies, Translational and Clinical Research Institute, Newcastle University, Newcastle-Upon-Tyne, NE2 4HH, UK.
| | - Duncan Graham
- Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, Glasgow, G1 1RD, UK.
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24
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Kabała M, Gofron Z, Aptekorz M, Burdynowski K, Harmanus C, Kuijper E, Martirosian G. Detection of Clostridioides difficile in hospital environment by using C diff Banana Broth™. Anaerobe 2021; 73:102408. [PMID: 34174400 DOI: 10.1016/j.anaerobe.2021.102408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 05/06/2021] [Accepted: 06/21/2021] [Indexed: 12/31/2022]
Abstract
116 environmental samples from a 504 bed clinical hospital obtained in 2017/19 were inoculated into C diff Banana Broth™. Six C. difficile and 12 C. pefringens strains were isolated. Antibiotic-resistant Clostridium spp. dominated in hospital environment. To determine Clostridium spp. in hospital environment suitable medium like C diff Banana Broth™ should be used.
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Affiliation(s)
- Monika Kabała
- Department of Medical Microbiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Zygmunt Gofron
- Department of Medical Microbiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Małgorzata Aptekorz
- Department of Medical Microbiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Krzysztof Burdynowski
- Department of Medical Microbiology and Epidemiology, School of Medicine, Universitas Opoliensis, Opole, Poland
| | - Celine Harmanus
- Department of Microbiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Ed Kuijper
- Department of Microbiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Gayane Martirosian
- Department of Medical Microbiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
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25
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Speri E, Qian Y, Janardhanan J, Masitas C, Lastochkin E, De Benedetti S, Wang M, Schroeder VA, Wolter WR, Oliver AG, Fisher JF, Mobashery S, Chang M. Structure-Activity Relationship for the Picolinamide Antibacterials that Selectively Target Clostridioides difficile. ACS Med Chem Lett 2021; 12:991-995. [PMID: 34141083 DOI: 10.1021/acsmedchemlett.1c00135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 05/03/2021] [Indexed: 11/28/2022] Open
Abstract
Clostridioides difficile is a leading health threat. This pathogen initiates intestinal infections during gut microbiota dysbiosis caused by oral administration of antibiotics. C. difficile is difficult to eradicate due to its ability to form spores, which are not susceptible to antibiotics. To address the urgent need for treating recurrent C. difficile infection, antibiotics that selectively target C. difficile over common gut microbiota are needed. We herein describe the class of picolinamide antibacterials which show potent and selective activity against C. difficile. The structure-activity relationship of 108 analogues of isonicotinamide 4, a compound that is equally active against methicillin-resistant Staphylococcus aureus and C. difficile, was investigated. Introduction of the picolinamide core as exemplified by analogue 87 resulted in exquisite potency and selectivity against C. difficile. The ability of the picolinamide class to selectively target C. difficile and to prevent gut dysbiosis holds promise for the treatment of recurrent C. difficile infection.
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Affiliation(s)
- Enrico Speri
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Yuanyuan Qian
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Jeshina Janardhanan
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Cesar Masitas
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Elena Lastochkin
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Stefania De Benedetti
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Man Wang
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Valerie A. Schroeder
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - William R. Wolter
- Freimann Life Sciences Center, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Allen G. Oliver
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Jed F. Fisher
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Shahriar Mobashery
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Mayland Chang
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
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26
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Hiraki M, Suzuki R, Tanaka N, Fukunaga H, Kinoshita Y, Kimura H, Tsutsui S, Murata M, Morita S. Community-acquired fulminant Clostridioides (Clostridium) difficile infection by ribotype 027 isolate in Japan: a case report. Surg Case Rep 2021; 7:137. [PMID: 34101061 PMCID: PMC8187545 DOI: 10.1186/s40792-021-01220-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 05/29/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Clostridioides (Clostridium) difficile infection (CDI) has become an increasingly significant disease not only as healthcare-associated infection, but also as community-acquired (CA) infection worldwide. CDI caused by the NAP1/BI/027 strain is reported to be more severe, difficult to cure, and frequently associated with recurrences in North America and Europe. CASE PRESENTATION A 68-year-old woman was referred to our hospital for continuous lower abdominal pain 4 weeks after eradication therapy against Helicobacter pylori. While she was treated with fasting on the suspicion of ischemic colitis, she experienced septic shock. Emergent subtotal proctocolectomy revealed fulminant pseudomembranous C. difficile colitis. The C. difficile isolate recovered from the patient was identified as ribotype 027, which has been reported to be uncommon in Japan. CONCLUSION We report a rare case of CA fulminant pseudomembranous colitis caused by ribotype 027 C. difficile after H. pylori eradication therapy.
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Affiliation(s)
- Masayuki Hiraki
- Department of Surgery, Itami City Hospital, 1-100 Koyaike, Itami-shi, Hyogo, 664-8540, Japan. .,Department of Surgery, Kansai Rosai Hospital, Japan Organization of Occupational Health and Safety, 3-1-69 Inabaso, Amagasaki, Hyogo, 660-8511, Japan.
| | - Rei Suzuki
- Department of Surgery, Itami City Hospital, 1-100 Koyaike, Itami-shi, Hyogo, 664-8540, Japan
| | - Nobuo Tanaka
- Department of Surgery, Itami City Hospital, 1-100 Koyaike, Itami-shi, Hyogo, 664-8540, Japan
| | - Hiroki Fukunaga
- Department of Surgery, Itami City Hospital, 1-100 Koyaike, Itami-shi, Hyogo, 664-8540, Japan
| | - Yoshinori Kinoshita
- Department of Respiratory Medicine, Itami City Hospital, 1-100 Koyaike, Itami-shi, Hyogo, 664-8540, Japan
| | - Hayato Kimura
- Department of Diagnostic Pathology, Itami City Hospital, 1-100 Koyaike, Itami-shi, Hyogo, 664-8540, Japan
| | - Shusaku Tsutsui
- Department of Gastroenterology, Itami City Hospital, 1-100 Koyaike, Itami-shi, Hyogo, 664-8540, Japan
| | - Masaru Murata
- Department of Surgery, Itami City Hospital, 1-100 Koyaike, Itami-shi, Hyogo, 664-8540, Japan
| | - Shunji Morita
- Department of Surgery, Itami City Hospital, 1-100 Koyaike, Itami-shi, Hyogo, 664-8540, Japan
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27
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Poylin V, Hawkins AT, Bhama AR, Boutros M, Lightner AL, Khanna S, Paquette IM, Feingold DL. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Clostridioides difficile Infection. Dis Colon Rectum 2021; 64:650-668. [PMID: 33769319 DOI: 10.1097/dcr.0000000000002047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Vitaliy Poylin
- Division of Gastrointestinal Surgery, Northwestern Medicine, Chicago, Illinois
| | - Alexander T Hawkins
- Department of Surgery, Section of Colon & Rectal Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Anuradha R Bhama
- Department of Surgery, Division of Colon & Rectal Surgery, Rush University Medical Center, Chicago, Illinois
| | - Marylise Boutros
- Jewish General Hospital, McGill University, Montreal, Quebec, Canada
| | - Amy L Lightner
- Department of Colorectal Surgery, Digestive Disease Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Sahil Khanna
- Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Ian M Paquette
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
| | - Daniel L Feingold
- Section of Colorectal Surgery, Rutgers University, New Brunswick, New Jersey
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28
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Tortajada-Girbés M, Rivas A, Hernández M, González A, Ferrús MA, Pina-Pérez MC. Alimentary and Pharmaceutical Approach to Natural Antimicrobials against Clostridioides difficile Gastrointestinal Infection. Foods 2021; 10:foods10051124. [PMID: 34069413 PMCID: PMC8159093 DOI: 10.3390/foods10051124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/08/2021] [Accepted: 05/16/2021] [Indexed: 02/07/2023] Open
Abstract
Incidence of Clostridioides difficile infection (CDI) has been increasing in recent decades due to different factors, namely (i) extended use of broad-spectrum antibiotics, (ii) transmission within asymptomatic and susceptible patients, and (iii) unbalanced gastrointestinal microbiome and collateral diseases that favor C. difficile gastrointestinal domination and toxin production. Although antibiotic therapies have resulted in successful control of CDI in the last 20 years, the development of novel strategies is urged in order to combat the capability of C. difficile to generate and acquire resistance to conventional treatments and its consequent proliferation. In this regard, vegetable and marine bioactives have emerged as alternative and effective molecules to fight against this concerning pathogen. The present review examines the effectiveness of natural antimicrobials from vegetable and algae origin that have been used experimentally in in vitro and in vivo settings to prevent and combat CDI. The aim of the present work is to contribute to accurately describe the prospective use of emerging antimicrobials as future nutraceuticals and preventive therapies, namely (i) as dietary supplement to prevent CDI and reduce CDI recurrence by means of microbiota modulation and (ii) administering them complementarily to other treatments requiring antibiotics to prevent C. difficile gut invasion and infection progression.
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Affiliation(s)
- Miguel Tortajada-Girbés
- Department of Pediatrics, University Dr. Peset Hospital, Avda, de Gaspar Aguilar, 90, 46017 Valencia, Spain;
| | - Alejandro Rivas
- Departmento Tecnología de Alimentos, Escuela Técnica Superior de Ingeniería Agronómica y del Medio Natural (ETSIAMN), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain;
| | - Manuel Hernández
- Departmento Biotecnología, Escuela Técnica Superior de Ingeniería Agronómica y del Medio Natural (ETSIAMN), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain; (M.H.); (A.G.); (M.A.F.)
| | - Ana González
- Departmento Biotecnología, Escuela Técnica Superior de Ingeniería Agronómica y del Medio Natural (ETSIAMN), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain; (M.H.); (A.G.); (M.A.F.)
| | - Maria A. Ferrús
- Departmento Biotecnología, Escuela Técnica Superior de Ingeniería Agronómica y del Medio Natural (ETSIAMN), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain; (M.H.); (A.G.); (M.A.F.)
| | - Maria C. Pina-Pérez
- Departmento Microbiologia y Ecología, Facultad Ciencias Biológicas, Universitat de València, C/Dr. Moliner, 50, 46100 Burjassot, Spain
- Correspondence:
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29
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Zhang RF, Man YX, Bai YY, Shao CH, Liu CM, Wang CH, Lei YX, Wang Y, Jin Y. Molecular characterization of Clostridioides difficile ribotype 027 in a major Chinese hospital. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2021; 54:1179-1183. [PMID: 33563561 DOI: 10.1016/j.jmii.2021.01.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 01/04/2021] [Accepted: 01/08/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND The rapid spread of C. difficile 027 has become one of the leading threats of healthcare-associated infections wordwild. However, C. difficile 027 infections have rarely been reported in China. The objective of this study was to strengthen the understanding of the molecular characterizations of C. difficile 027 in China. METHODS In this study, stool specimens from 176 suspected CDI cases were collected from 1 Jan 2018 to 30 Jun 2019. These specimens were measured by GeneXpert test and C.difficile colonies were identified and analyzed. RESULTS There were five samples positive for tcdA, tcdB, binary toxin genes and had deletions in tcdC gene. These five Clostridioides difficile isolates belonged to ST1 and confirmed as Clostridioides difficile 027 strains by PCR ribotyping. Through using whole genome sequencing, , we found that these five strains were closely clustered into the same predominant evolutionary branch and were highly similar to C. difficile 027 strain R20291. Antimicrobial susceptibility testing result showed they were highly resistant to fluoroquinolones. CONCLUSIONS In Our study, five C. difficile 027 isolates were identified and characterized using MLST, PCR ribotyping and whole genome sequencing. We proposed that C. difficile 027 infections are probably neglected in China. Further epidemiological studies across the country together with the introduction of routine diagnostic testing and multi-center or national level surveillance are needed to ascertain the size of this potentially significant problem.
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Affiliation(s)
- Ren-Feng Zhang
- Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yu-Xia Man
- LiaochengDongchangfu People's Hospital, Liaocheng, China
| | - Yuan-Yuan Bai
- Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chun-Hong Shao
- Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chun-Mei Liu
- Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Cong-Hui Wang
- Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou, China
| | - Yong-Xing Lei
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China; Shanghai ZJ Bio-Tech Co.,Ltd., China.
| | - Yong Wang
- Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
| | - Yan Jin
- Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
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30
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Pan Z, Zhang Y, Luo J, Li D, Zhou Y, He L, Yang Q, Dong M, Tao L. Functional analyses of epidemic Clostridioides difficile toxin B variants reveal their divergence in utilizing receptors and inducing pathology. PLoS Pathog 2021; 17:e1009197. [PMID: 33507919 PMCID: PMC7842947 DOI: 10.1371/journal.ppat.1009197] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023] Open
Abstract
Clostridioides difficile toxin B (TcdB) is a key virulence factor that causes C. difficile associated diseases (CDAD) including diarrhea and pseudomembranous colitis. TcdB can be divided into multiple subtypes/variants based on their sequence variations, of which four (TcdB1-4) are dominant types found in major epidemic isolates. Here, we find that these variants are highly diverse in their receptor preference: TcdB1 uses two known receptors CSPG4 and Frizzled (FZD) proteins, TcdB2 selectively uses CSPG4, TcdB3 prefers to use FZDs, whereas TcdB4 uses neither CSPG4 nor FZDs. By creating chimeric toxins and systematically switching residues between TcdB1 and TcdB3, we determine that regions in the N-terminal cysteine protease domain (CPD) are involved in CSPG4-recognition. We further evaluate the pathological effects induced by TcdB1-4 with a mouse intrarectal installation model. TcdB1 leads to the most severe overall symptoms, followed by TcdB2 and TcdB3. When comparing the TcdB2 and TcdB3, TcdB2 causes stronger oedema while TcdB3 induces severer inflammatory cell infiltration. These findings together demonstrate divergence in the receptor preference and further lead to colonic pathology for predominant TcdB subtypes. Clostridioides difficile is a major cause of nosocomial and community-associated gastrointestinal infections. The bacterium produces three exotoxins including TcdA, TcdB, and CDT, of which TcdB is known as a key virulence factor causing the diseases. Since C. difficile was first linked to antibiotic-associated infections in 1978, a large number of clinically relevant strains were characterized and many of them were found to harbor some variant forms of TcdB. In this study, we examined four predominant TcdB variants from epidemic C. difficile strains. We found that these variants are highly diverse in preference to the known receptors, CSPG4 and Frizzled proteins. By conducting a systematically designed mutagenesis study, we determined that TcdB interacts with CSPG4 via regions across multiple domains. We also found that TcdB variants could induce distinguishable pathological phenotypes in a mouse model, suggesting C. difficile strains harboring divergent TcdB variants might exhibit different disease progression. Our study provides new insights into the toxicology and pathology of C. difficile toxin variants.
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Affiliation(s)
- Zhenrui Pan
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
| | - Yuanyuan Zhang
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
| | - Jianhua Luo
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
| | - Danyang Li
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
| | - Yao Zhou
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
| | - Liuqing He
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
| | - Qi Yang
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
| | - Min Dong
- Department of Urology, Boston Children’s Hospital, Boston, Massechusetts, United States of America
- Department of Surgery and Department of Microbiology, Harvard Medical School, Boston, Massechusetts, United States of America
- * E-mail: (MD); (LT)
| | - Liang Tao
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
- Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China
- * E-mail: (MD); (LT)
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31
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Characterization of Clostridioides difficile Isolates Available through the CDC & FDA Antibiotic Resistance Isolate Bank. Microbiol Resour Announc 2021; 10:10/1/e01011-20. [PMID: 33414286 PMCID: PMC8407687 DOI: 10.1128/mra.01011-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Thirty Clostridioides difficile isolates collected in 2016 through the Centers for Disease Control and Prevention Emerging Infections Program were selected for reference antimicrobial susceptibility testing and whole-genome sequencing. Here, we present the genetic characteristics of these isolates and announce their availability in the CDC & FDA Antibiotic Resistance Isolate Bank. Thirty Clostridioides difficile isolates collected in 2016 through the Centers for Disease Control and Prevention Emerging Infections Program were selected for reference antimicrobial susceptibility testing and whole-genome sequencing. Here, we present the genetic characteristics of these isolates and announce their availability in the CDC & FDA Antibiotic Resistance Isolate Bank.
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32
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Skinner AM, Petrella L, Siddiqui F, Sambol SP, Gulvik CA, Gerding DN, Donskey CJ, Johnson S. Unique Clindamycin-Resistant Clostridioides difficile Strain Related to Fluoroquinolone-Resistant Epidemic BI/RT027 Strain. Emerg Infect Dis 2021; 26:247-254. [PMID: 31961290 PMCID: PMC6986856 DOI: 10.3201/eid2602.181965] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
During a surveillance study of patients in a long-term care facility and the affiliated acute care hospital in the United States, we identified a Clostridioides difficile strain related to the epidemic PCR ribotype (RT) 027 strain associated with hospital outbreaks of severe disease. Fifteen patients were infected with this strain, characterized as restriction endonuclease analysis group DQ and RT591. Like RT027, DQ/RT591 contained genes for toxin B and binary toxin CDT and a tcdC gene of identical sequence. Whole-genome sequencing and multilocus sequence typing showed that DQ/RT591 is a member of the same multilocus sequence typing clade 2 as RT027 but in a separate cluster. DQ/RT591 produced a similar cytopathic effect as RT027 but showed delayed toxin production in vitro. DQ/RT591 was susceptible to moxifloxacin but highly resistant to clindamycin. Continued surveillance is warranted for this clindamycin-resistant strain that is related to the fluoroquinolone-resistant epidemic RT027 strain.
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Akiyama S, Yamada A, Komaki Y, Komaki F, Micic D, Sakuraba A. Efficacy and Safety of Monoclonal Antibodies Against Clostridioides difficile Toxins for Prevention of Recurrent Clostridioides difficile Infection: A Systematic Review and Meta-Analysis. J Clin Gastroenterol 2021; 55:43-51. [PMID: 32053529 DOI: 10.1097/mcg.0000000000001330] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Clostridioides difficile infection is one of the most common health care-associated infections. To reduce the recurrent Clostridioides difficile infection (rCDI), monoclonal antibodies against Clostridioides difficile toxin A (actoxumab) and toxin B (bezlotoxumab) were developed. In the present study, we performed a systematic review and meta-analysis to assess their efficacy and safety. MATERIALS AND METHODS An electronic database was searched for relevant randomized controlled trials assessing bezlotoxumab and/or actoxumab. Outcomes included rate of rCDI and adverse events including cardiovascular and gastrointestinal events. RESULTS Four randomized controlled trials comparing antitoxin antibodies (n=1916) versus placebo (n=889) were identified. rCDI was significantly reduced by bezlotoxumab plus actoxumab (risk ratio=0.54, 95% confidence interval=0.41-0.70, P<0.001) and bezlotoxumab monotherapy (risk ratio=0.62, 95% confidence interval=0.51-0.76, P<0.001) compared with placebo. Subgroup analysis showed that bezlotoxumab plus actoxumab was remarkably preventive for patients with the following high-risk features: inpatients, vancomycin treatment, and BI/NAP/027 strain. Regarding safety, there was no difference in cardiovascular and gastrointestinal events as well as all-cause mortality between bezlotoxumab-treated patients and placebo. CONCLUSIONS The results of our meta-analysis demonstrated the effectiveness and safety of bezlotoxumab for the prevention of rCDI. Bezlotoxumab may be a good therapeutic option for severe C. difficile infection rather than mild cases.
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Affiliation(s)
- Shintaro Akiyama
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, IL
| | - Akihiro Yamada
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, IL
- Section of Gastroenterology, Department of Internal Medicine, Toho University Sakura Medical Center, Chiba
| | - Yuga Komaki
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, IL
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Fukiko Komaki
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, IL
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Dejan Micic
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, IL
| | - Atsushi Sakuraba
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, IL
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Roxas BAP, Roxas JL, Claus-Walker R, Harishankar A, Mansoor A, Anwar F, Jillella S, Williams A, Lindsey J, Elliott SP, Shehab KW, Viswanathan VK, Vedantam G. Phylogenomic analysis of Clostridioides difficile ribotype 106 strains reveals novel genetic islands and emergent phenotypes. Sci Rep 2020; 10:22135. [PMID: 33335199 PMCID: PMC7747571 DOI: 10.1038/s41598-020-79123-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 11/18/2020] [Indexed: 02/06/2023] Open
Abstract
Clostridioides difficile infection (CDI) is a major healthcare-associated diarrheal disease. Consistent with trends across the United States, C. difficile RT106 was the second-most prevalent molecular type in our surveillance in Arizona from 2015 to 2018. A representative RT106 strain displayed robust virulence and 100% lethality in the hamster model of acute CDI. We identified a unique 46 KB genomic island (GI1) in all RT106 strains sequenced to date, including those in public databases. GI1 was not found in its entirety in any other C. difficile clade, or indeed, in any other microbial genome; however, smaller segments were detected in Enterococcus faecium strains. Molecular clock analyses suggested that GI1 was horizontally acquired and sequentially assembled over time. GI1 encodes homologs of VanZ and a SrtB-anchored collagen-binding adhesin, and correspondingly, all tested RT106 strains had increased teicoplanin resistance, and a majority displayed collagen-dependent biofilm formation. Two additional genomic islands (GI2 and GI3) were also present in a subset of RT106 strains. All three islands are predicted to encode mobile genetic elements as well as virulence factors. Emergent phenotypes associated with these genetic islands may have contributed to the relatively rapid expansion of RT106 in US healthcare and community settings.
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Affiliation(s)
- Bryan Angelo P Roxas
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ, USA
| | - Jennifer Lising Roxas
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ, USA
| | - Rachel Claus-Walker
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ, USA
| | - Anusha Harishankar
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ, USA
| | - Asad Mansoor
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ, USA
| | - Farhan Anwar
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ, USA
| | - Shobitha Jillella
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ, USA
| | - Alison Williams
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ, USA
| | - Jason Lindsey
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ, USA
| | - Sean P Elliott
- Department of Pediatrics, The University of Arizona College of Medicine, Tucson, AZ, USA
| | - Kareem W Shehab
- Department of Pediatrics, The University of Arizona College of Medicine, Tucson, AZ, USA
| | - V K Viswanathan
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ, USA.,Department of Immunobiology, The University of Arizona, Tucson, AZ, USA.,Bio5 Institute for Collaborative Research, The University of Arizona, Tucson, AZ, USA
| | - Gayatri Vedantam
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ, USA. .,Department of Immunobiology, The University of Arizona, Tucson, AZ, USA. .,Bio5 Institute for Collaborative Research, The University of Arizona, Tucson, AZ, USA. .,Southern Arizona VA Health Care System, Tucson, AZ, USA. .,School of Animal and Comparative Biomedical Sciences, University of Arizona, 1117 E Lowell St, Bldg. 90, Room 227, Tucson, AZ, 85721, USA.
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Riley LW. Distinguishing Pathovars from Nonpathovars: Escherichia coli. Microbiol Spectr 2020; 8:10.1128/microbiolspec.ame-0014-2020. [PMID: 33385193 PMCID: PMC10773148 DOI: 10.1128/microbiolspec.ame-0014-2020] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Indexed: 02/07/2023] Open
Abstract
Escherichia coli is one of the most well-adapted and pathogenically versatile bacterial organisms. It causes a variety of human infections, including gastrointestinal illnesses and extraintestinal infections. It is also part of the intestinal commensal flora of humans and other mammals. Groups of E. coli that cause diarrhea are often described as intestinal pathogenic E. coli (IPEC), while those that cause infections outside of the gut are called extraintestinal pathogenic E. coli (ExPEC). IPEC can cause a variety of diarrheal illnesses as well as extraintestinal syndromes such as hemolytic-uremic syndrome. ExPEC cause urinary tract infections, bloodstream infection, sepsis, and neonatal meningitis. IPEC and ExPEC have thus come to be referred to as pathogenic variants of E. coli or pathovars. While IPEC can be distinguished from commensal E. coli based on their characteristic virulence factors responsible for their associated clinical manifestations, ExPEC cannot be so easily distinguished. IPEC most likely have reservoirs outside of the human intestine but it is unclear if ExPEC represent nothing more than commensal E. coli that breach a sterile barrier to cause extraintestinal infections. This question has become more complicated by the advent of whole genome sequencing (WGS) that has raised a new question about the taxonomic characterization of E. coli based on traditional clinical microbiologic and phylogenetic methods. This review discusses how molecular epidemiologic approaches have been used to address these questions, and how answers to these questions may contribute to our better understanding of the epidemiology of infections caused by E. coli. *This article is part of a curated collection.
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Affiliation(s)
- Lee W Riley
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA 94720
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McLean K, Balada-Llasat JM, Waalkes A, Pancholi P, Salipante SJ. Whole-genome sequencing of clinical Clostridioides difficile isolates reveals molecular epidemiology and discrepancies with conventional laboratory diagnostic testing. J Hosp Infect 2020; 108:64-71. [PMID: 33227298 DOI: 10.1016/j.jhin.2020.11.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 10/06/2020] [Accepted: 11/16/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND The high clinical burden of Clostridioides difficile infections merits rapid and sensitive identification of affected individuals. However, effective diagnosis remains challenging. Current best practice guidelines recommend molecular and/or direct toxin detection-based screening for symptomatic individuals, but previous work has called into question the concordance and performance of extant clinical assays. AIM To better correlate the genomic and phenotypic properties of clinical C. difficile isolates with laboratory testing outcomes in both C. difficile-infected patients and asymptomatic carriers. METHODS Whole-genome sequencing of clinical C. difficile isolates collected from an inpatient population at a single healthcare institution was performed, enabling examination of their molecular epidemiology and toxigenic gene content. Genomic findings were compared with clinical testing outcomes, identifying multiple diagnostic discrepancies. FINDINGS Toxigenic culture, considered a 'reference standard', provided perfect sensitivity and specificity in predicting toxigenic gene content, whereas reduced performance was observed for Simplexa C. difficile Direct Assay (100% specificity, 88% sensitivity), Gene Xpert CD/Epi Assay (86% specificity, 83% sensitivity), and Quick Check Complete Tox A/B (100% specificity, 30% sensitivity). Genomic analysis additionally revealed variability in toxin gene sequences among C. difficile strains, phylogenomic equivalency between isolates from affected patients and carriers, and patient carriage with uncommon environmentally derived C. difficile lineages, as well as presenting opportunities for tracing pathogen transmission events. CONCLUSION These results highlight the variable performance of clinical stool-based testing approaches as well as the potential diagnostic utility of whole-genome sequencing as an alternative to conventional testing algorithms.
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Affiliation(s)
- K McLean
- University of Washington Department of Laboratory Medicine, Seattle, WA, USA
| | - J-M Balada-Llasat
- Ohio State University Wexner Medical Center, Department of Pathology, Columbus, OH, USA
| | - A Waalkes
- University of Washington Department of Laboratory Medicine, Seattle, WA, USA
| | - P Pancholi
- Ohio State University Wexner Medical Center, Department of Pathology, Columbus, OH, USA.
| | - S J Salipante
- University of Washington Department of Laboratory Medicine, Seattle, WA, USA.
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Abstract
Clostridioides difficile is the leading cause of nosocomial infection and is the causative agent of antibiotic-associated diarrhea. The severity of the disease is directly associated with toxin production, and spores are responsible for the transmission and persistence of the organism. Previously, we characterized sin locus regulators SinR and SinR' (we renamed it SinI), where SinR is the regulator of toxin production and sporulation. The SinI regulator acts as its antagonist. In Bacillus subtilis, Spo0A, the master regulator of sporulation, controls SinR by regulating the expression of its antagonist, sinI However, the role of Spo0A in the expression of sinR and sinI in C. difficile had not yet been reported. In this study, we tested spo0A mutants in three different C. difficile strains, R20291, UK1, and JIR8094, to understand the role of Spo0A in sin locus expression. Western blot analysis revealed that spo0A mutants had increased SinR levels. Quantitative reverse transcription-PCR (qRT-PCR) analysis of its expression further supported these data. By carrying out genetic and biochemical assays, we show that Spo0A can bind to the upstream region of this locus to regulates its expression. This study provides vital information that Spo0A regulates the sin locus, which controls critical pathogenic traits such as sporulation, toxin production, and motility in C. difficile IMPORTANCE Clostridioides difficile is the leading cause of antibiotic-associated diarrheal disease in the United States. During infection, C. difficile spores germinate, and the vegetative bacterial cells produce toxins that damage host tissue. In C. difficile, the sin locus is known to regulate both sporulation and toxin production. In this study, we show that Spo0A, the master regulator of sporulation, controls sin locus expression. Results from our study suggest that Spo0A directly regulates the expression of this locus by binding to its upstream DNA region. This observation adds new detail to the gene regulatory network that connects sporulation and toxin production in this pathogen.
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Cheknis A, Devaris D, Chesnel L, Dale SE, Nary J, Sambol SP, Citron DM, Goering RV, Johnson S. Characterization of Clostridioides difficile isolates recovered from two Phase 3 surotomycin treatment trials by restriction endonuclease analysis, PCR ribotyping and antimicrobial susceptibilities. J Antimicrob Chemother 2020; 75:3120-3125. [PMID: 32747931 DOI: 10.1093/jac/dkaa297] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 06/05/2020] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES To investigate the molecular epidemiology and antimicrobial susceptibility of Clostridioides difficile isolates from patients with C. difficile infection (CDI) from two Phase 3 clinical trials of surotomycin. METHODS In both trials [Protocol MK-4261-005 (NCT01597505) conducted across Europe, North America and Israel; and Protocol MK-4261-006 (NCT01598311) conducted across North America, Asia-Pacific and South America], patients with CDI were randomized (1:1) to receive oral surotomycin (250 mg twice daily) or oral vancomycin (125 mg four times per day) for 10 days. Stool samples were collected at baseline and C. difficile isolates were characterized by restriction endonuclease analysis (REA) and PCR ribotyping. Susceptibility testing was performed by agar dilution, according to CLSI recommendations. RESULTS In total, 1147 patients were included in the microbiological modified ITT population. Of 992 recovered isolates, 922 (92.9%) were typed. There was a high association between REA groups and their corresponding predominant PCR ribotype (RT) for BI, DH, G and CF strains. REA group A showed more diverse PCR RTs. Overall, the most common strain was BI/RT027 (20.3%) followed by Y/RT014/020 (15.0%) and DH/RT106 (7.2%). The BI/RT027 strain was particularly prevalent in Europe (29.9%) and Canada (23.6%), with lower prevalence in the USA (16.8%) and Australia/New Zealand (3.4%). Resistance was most prevalent in the BI/RT027 strain, particularly to metronidazole, vancomycin and moxifloxacin. CONCLUSIONS A wide variation in C. difficile strains, both within and across different geographical regions, was documented by both REA and ribotyping, which showed overall good correlation.
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Affiliation(s)
| | | | | | | | - Julia Nary
- ACM Global Laboratories, Rochester, NY, USA
| | | | | | | | - Stuart Johnson
- Edward Hines, Jr. VA Hospital, Hines, IL, USA.,Loyola University Medical Center, Maywood, IL, USA
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Orozco-Aguilar J, Alfaro-Alarcón A, Acuña-Amador L, Chaves-Olarte E, Rodríguez C, Quesada-Gómez C. In vivo animal models confirm an increased virulence potential and pathogenicity of the NAP1/RT027/ST01 genotype within the Clostridium difficile MLST Clade 2. Gut Pathog 2020; 12:45. [PMID: 32983262 PMCID: PMC7510272 DOI: 10.1186/s13099-020-00383-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 09/18/2020] [Indexed: 01/05/2023] Open
Abstract
Background Based on MLST analyses the global population of C. difficile is distributed in eight clades, of which Clade 2 includes the “hypervirulent” NAP1/RT027/ST01 strain along with various unexplored sequence types (STs). Methods To clarify whether this clinically relevant phenotype is a widespread feature of C. difficile Clade 2, we used the murine ileal loop model to compare the in vivo pro-inflammatory (TNF-α, IL-1β, IL-6) and oxidative stress activities (MPO) of five Clade 2 clinical C. difficile isolates from sequence types (STs) 01, 41, 67, and 252. Besides, we infected Golden Syrian hamsters with spores from these strains to determine their lethality, and obtain a histological evaluation of tissue damage, WBC counts, and serum injury biomarkers (LDH, ALT, AST, albumin, BUN, creatinine, Na+, and Cl−). Genomic distances were calculated using Mash and FastANI to explore whether the responses were dictated by phylogeny. Results The ST01 isolate tested ranked first in all assays, as it induced the highest overall levels of pro-inflammatory cytokines, MPO activity, epithelial damage, biochemical markers, and mortality measured in both animal models. Statistically indistinguishable or rather similar outputs were obtained for a ST67 isolate in tests such as tissue damage, neutrophils count, and lethal activity. The results recorded for the two ST41 isolates tested were of intermediate magnitude and the ST252 isolate displayed the lowest pathogenic potential in all animal experiments. This ordering matched the genomic distance of the ST01 isolate to the non-ST01 isolates. Conclusions Despite their close phylogenic relatedness, our results demonstrate differences in pathogenicity and virulence levels in Clade 2 C. difficile strains, confirm the high severity of infections caused by the NAP1/RT027/ST01 strain, and highlight the importance of C. difficile typing.
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Affiliation(s)
- Josué Orozco-Aguilar
- Laboratorio de Ensayos Biológicos (LEBi), Universidad de Costa Rica, San José, Costa Rica.,Facultad de Farmacia, Universidad de Costa Rica, San José, Costa Rica.,Programa de Posgrado en Microbiología, Parasitología, Química Clínica e Inmunología, Universidad de Costa Rica, San José, Costa Rica
| | - Alejandro Alfaro-Alarcón
- Departamento de Patología, Escuela de Medicina Veterinaria, Universidad Nacional, Heredia, Costa Rica
| | - Luis Acuña-Amador
- Centro de Investigación en Enfermedades Tropicales and Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica
| | - Esteban Chaves-Olarte
- Programa de Posgrado en Microbiología, Parasitología, Química Clínica e Inmunología, Universidad de Costa Rica, San José, Costa Rica.,Centro de Investigación en Enfermedades Tropicales and Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica
| | - César Rodríguez
- Programa de Posgrado en Microbiología, Parasitología, Química Clínica e Inmunología, Universidad de Costa Rica, San José, Costa Rica.,Centro de Investigación en Enfermedades Tropicales and Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica
| | - Carlos Quesada-Gómez
- Laboratorio de Ensayos Biológicos (LEBi), Universidad de Costa Rica, San José, Costa Rica.,Programa de Posgrado en Microbiología, Parasitología, Química Clínica e Inmunología, Universidad de Costa Rica, San José, Costa Rica.,Centro de Investigación en Enfermedades Tropicales and Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica
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Johnson S, Citron DM, Gerding DN, Wilcox MH, Goldstein EJC, Sambol SP, Best EL, Eves K, Jansen E, Dorr MB. Efficacy of bezlotoxumab in trial participants infected with Clostridioides difficile strain BI associated with poor outcomes. Clin Infect Dis 2020; 73:e2616-e2624. [PMID: 32735653 DOI: 10.1093/cid/ciaa1035] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 07/30/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Bezlotoxumab reduced rates of recurrent Clostridioides difficile infection (rCDI) versus placebo in MODIFY I/II trial participants receiving antibacterial drug treatment for CDI. A secondary objective of MODIFY I/II was to assess bezlotoxumab's efficacy against C. difficile strains associated with increased rates of morbidity and mortality. METHODS In this post-hoc analysis of pooled MODIFY I/II data, efficacy endpoints were assessed in participants infected with restriction endonuclease analysis (REA) BI and non-BI strains of C. difficile at study entry. Treatment outcomes were compared between participants receiving bezlotoxumab (alone or with actoxumab: B, B+A) and those receiving no bezlotoxumab (placebo or actoxumab: P, A). RESULTS From 2559 randomized participants, C. difficile was isolated from 1588 (67.2%) baseline stool samples. Participants with BI strains (n=328) were older and had more risk factors for rCDI than non-BI strain participants (n=1260). There were no differences in initial clinical cure rate between BI and non-BI strains in either group. The rCDI rates for BI strains treated with bezlotoxumab was lower than for the no bezlotoxumab group (B, B+A vs P, A: 23.6% vs 43.9%) and was also lower for the non-BI strains (B, B+A vs P, A: 21.4% vs 36.1%). Rates of 30-day CDI-associated re-hospitalization were greater with BI versus non-BI strains in both groups. CONCLUSIONS Infection with BI strains of C. difficile predicted poor outcomes in the MODIFY I/II trials. Bezlotoxumab (B, B+A) treatment was effective both in BI and non-BI subpopulations.
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Affiliation(s)
- Stuart Johnson
- Edward Hines, Jr. VA Hospital, Hines, IL, USA.,Loyola University, Maywood, IL, USA
| | | | | | - Mark H Wilcox
- Leeds Teaching Hospital, Leeds, UK.,University of Leeds, Leeds, UK
| | | | - Susan P Sambol
- Edward Hines, Jr. VA Hospital, Hines, IL, USA.,Loyola University, Maywood, IL, USA
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Korać M, Rupnik M, Nikolić N, Jovanović M, Tošić T, Malinić J, Mitrović N, Marković M, Vujović A, Peruničić S, Bojović K, Djordjević V, Barać A, Milošević I. Clostridioides difficile ribotype distribution in a large teaching hospital in Serbia. Gut Pathog 2020; 12:26. [PMID: 32477428 PMCID: PMC7243319 DOI: 10.1186/s13099-020-00364-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 05/16/2020] [Indexed: 12/11/2022] Open
Abstract
Background The global epidemic of nosocomial diarrhea caused by Clostridioides (Clostridium) difficile started in 2000, with high mortality rates and emergence of a new hypervirulent strain NAP1/BI/027. The aim of this study was to assess the presence of ribotype 027 and other C. difficile ribotypes in a Serbian University Hospital, compare the temporal variability of ribotypes 3 years apart, as well as to compare clinical, demographic and laboratory characteristics and disease outcome among patients infected with 027 and non-027 ribotype. This was a prospective observational cohort study addressing 4-month intervals during 2014/2015 and 2017/2018. Results Ribotyping was performed in 64 non-duplicate C. difficile strains. Ribotype 027 was the most prevalent, and was detected in 53 (82.8%) patients (43/45 and 10/19 patients in 2014-2015 and 2017/2018, respectively). Other detected ribotypes were 001/072 in 4 (6.3%), 002 in 4 (6.3%), 014/020 in 2 (3.1%) and 176 in 1 (1.5%) patient. The percentage of the patients infected with ribotype 027 significantly decreased during the 3-year period, from 95.6 to 52.6% (p < 0.001). Ribotype 027 infection was associated with fluoroquinolone treatment more frequently than infection with other ribotypes [33 (62.3%) vs. 2 (18.2%), p = 0.010)]. A severe C. difficile infection was diagnosed more often in patients with the detected ribotype 027 compared to those infected with non-027 ribotypes (p = 0.006). No significant difference in the mortality and recurrence rates was found between the patients infected with ribotype 027 and those infected with other ribotypes [10/53 (18.8%) vs. 2/11 (18.2%), p = 0.708, and 10/35 (28.6%) vs. 0/2 (0%), p = 1.000, respectively]. Conclusion Clostridium difficile ribotype 027 was the most prevalent ribotype among patients in a large Serbian hospital, but there is a clear decreasing trend.
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Affiliation(s)
- Miloš Korać
- 1University of Belgrade, Faculty of Medicine, Dr Subotića 8, 11000 Belgrade, Serbia.,2University Hospital for Infectious and Tropical Diseases, Clinical Centre of Serbia, Bulevar oslobođenja 16, 11000 Belgrade, Serbia
| | - Maja Rupnik
- 4Department for Microbiological Research, Centre for Medical Microbiology, National Laboratory for Health, Environment and Food, Prvomajska 1, 2000 Maribor, Slovenia.,5University of Maribor, Faculty of Medicine, Taborska 8, 2000 Maribor, Slovenia
| | - Nataša Nikolić
- 1University of Belgrade, Faculty of Medicine, Dr Subotića 8, 11000 Belgrade, Serbia.,2University Hospital for Infectious and Tropical Diseases, Clinical Centre of Serbia, Bulevar oslobođenja 16, 11000 Belgrade, Serbia
| | - Milica Jovanović
- 3Microbiology Department, Clinical Centre of Serbia, Pasterova 4, Belgrade, Serbia
| | - Tanja Tošić
- 3Microbiology Department, Clinical Centre of Serbia, Pasterova 4, Belgrade, Serbia
| | - Jovan Malinić
- 1University of Belgrade, Faculty of Medicine, Dr Subotića 8, 11000 Belgrade, Serbia.,2University Hospital for Infectious and Tropical Diseases, Clinical Centre of Serbia, Bulevar oslobođenja 16, 11000 Belgrade, Serbia
| | - Nikola Mitrović
- 1University of Belgrade, Faculty of Medicine, Dr Subotića 8, 11000 Belgrade, Serbia.,2University Hospital for Infectious and Tropical Diseases, Clinical Centre of Serbia, Bulevar oslobođenja 16, 11000 Belgrade, Serbia
| | - Marko Marković
- 2University Hospital for Infectious and Tropical Diseases, Clinical Centre of Serbia, Bulevar oslobođenja 16, 11000 Belgrade, Serbia
| | - Ankica Vujović
- 1University of Belgrade, Faculty of Medicine, Dr Subotića 8, 11000 Belgrade, Serbia.,2University Hospital for Infectious and Tropical Diseases, Clinical Centre of Serbia, Bulevar oslobođenja 16, 11000 Belgrade, Serbia
| | - Sanja Peruničić
- 2University Hospital for Infectious and Tropical Diseases, Clinical Centre of Serbia, Bulevar oslobođenja 16, 11000 Belgrade, Serbia
| | - Ksenija Bojović
- 1University of Belgrade, Faculty of Medicine, Dr Subotića 8, 11000 Belgrade, Serbia.,2University Hospital for Infectious and Tropical Diseases, Clinical Centre of Serbia, Bulevar oslobođenja 16, 11000 Belgrade, Serbia
| | - Vladimir Djordjević
- 1University of Belgrade, Faculty of Medicine, Dr Subotića 8, 11000 Belgrade, Serbia.,6Clinic for Digestive Surgery, Clinical Centre of Serbia, Dr Koste Todorovića 6, 11000 Belgrade, Serbia
| | - Aleksandra Barać
- 1University of Belgrade, Faculty of Medicine, Dr Subotića 8, 11000 Belgrade, Serbia.,2University Hospital for Infectious and Tropical Diseases, Clinical Centre of Serbia, Bulevar oslobođenja 16, 11000 Belgrade, Serbia
| | - Ivana Milošević
- 1University of Belgrade, Faculty of Medicine, Dr Subotića 8, 11000 Belgrade, Serbia.,2University Hospital for Infectious and Tropical Diseases, Clinical Centre of Serbia, Bulevar oslobođenja 16, 11000 Belgrade, Serbia
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Pacyga K, Razim A, Martirosian G, Aptekorz M, Szuba A, Gamian A, Myc A, Górska S. The Bioinformatic and In Vitro Studies of Clostridioides Difficile Aminopeptidase M24 Revealed the Immunoreactive KKGIK Peptide. Cells 2020; 9:cells9051146. [PMID: 32392707 PMCID: PMC7291276 DOI: 10.3390/cells9051146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 05/04/2020] [Accepted: 05/05/2020] [Indexed: 01/07/2023] Open
Abstract
Clostridioides difficile (CD) is a Gram-positive pathogen responsible for CD-associated disease (CDAD), which is characterized by symptoms ranging from mild diarrhea to pseudomembranous colitis. This work is an attempt to respond to the need of novel methods for CD infection (CDI) prevention, since the number of CDI cases is still rising. A bioinformatics approach was applied to design twenty-one peptides consisting of in silico predicted linear B-cell and T-cell epitopes of aminopeptidase M24 from CD. These peptides were mapped for epitopes exploiting PEPSCAN procedure and using sera obtained from CD infected patients, umbilical cord blood, and healthy volunteers. Two new CD epitopes, 131KKGIK135 and 184KGTSTHVIT192, were identified and characterized. Immunoreactivity of the synthetic biotinylated 131KKGIK135 epitope was significantly higher compared to 184KGTSTHVIT192 epitope in Enzyme-Linked Immunosorbent Assay (ELISA) with umbilical cord blood and CDI patients' sera. Hereafter, the conjugate of bovine serum albumin and epitope 131KKGIK135 was evaluated in vitro on lung epithelial cell line. In vitro, a significant induction of IL-6 by conjugate was observed, thereby we postulate that this new 131KKGIK135 epitope possesses immunostimulating properties suggesting possibility of its use in a vaccine against Clostridioides difficile.
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Affiliation(s)
- Katarzyna Pacyga
- Department of Microbiology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland;
| | - Agnieszka Razim
- Department of Microbiology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland;
- Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (A.G.); (A.M.)
- Correspondence: (A.R.); (S.G.); Tel.: +48-71-3371-172 (ext. 183) (A.R.); +48-71-3371-172 (ext. 148) (S.G.)
| | - Gayane Martirosian
- Department of Medical Microbiology, School of Medical Science in Katowice, Medical University of Silesia, 40-752 Katowice, Poland; (G.M.); (M.A.)
| | - Małgorzata Aptekorz
- Department of Medical Microbiology, School of Medical Science in Katowice, Medical University of Silesia, 40-752 Katowice, Poland; (G.M.); (M.A.)
| | - Andrzej Szuba
- Division of Angiology, Wroclaw Medical University, 51-618 Wroclaw, Poland;
- Department of Internal Medicine, 4th Military Hospital in Wroclaw, 50-981 Wroclaw, Poland
| | - Andrzej Gamian
- Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (A.G.); (A.M.)
| | - Andrzej Myc
- Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (A.G.); (A.M.)
- MNIMBS, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-5648, USA
| | - Sabina Górska
- Department of Microbiology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland;
- Correspondence: (A.R.); (S.G.); Tel.: +48-71-3371-172 (ext. 183) (A.R.); +48-71-3371-172 (ext. 148) (S.G.)
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Quesada-Gómez C, Murillo T, Arce G, Badilla-Lobo A, Castro-Peña C, Molina J, López-Ureña D, González-Camacho S, Lomonte B, Chacón-Díaz C, Rodríguez C, Chaves-Olarte E. Proteogenomic analysis of the Clostridium difficile exoproteome reveals a correlation between phylogenetic distribution and virulence potential. Anaerobe 2020; 62:102151. [DOI: 10.1016/j.anaerobe.2020.102151] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 12/28/2019] [Accepted: 01/10/2020] [Indexed: 12/16/2022]
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Abstract
Clostridium (reclassified as " Clostridioides ") difficile infection (CDI) is a healthcare-associated infection and significant source of potentially preventable morbidity, recurrence, and death, particularly among hospitalized older adults. Additional risk factors include antibiotic use and severe underlying illness. The increasing prevalence of community-associated CDI is gaining recognition as a novel source of morbidity in previously healthy patients. Even after recovery from initial infection, patients remain at risk for recurrence or reinfection with a new strain. Some pharmaco-epidemiologic studies have suggested an increased risk associated with proton pump inhibitors and protective effect from statins, but these findings have not been uniformly reproduced in all studies. Certain ribotypes of C. difficile , including the BI/NAP1/027, 106, and 018, are associated with increased antibiotic resistance and potential for higher morbidity and mortality. CDI remains a high-morbidity healthcare-associated infection, and better understanding of ribotypes and medication risk factors could help to target treatment, particularly for patients with high recurrence risk.
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Affiliation(s)
- Ana C. De Roo
- Center for Healthcare Outcomes and Policy, University of Michigan, Ann Arbor, Michigan
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Scott E. Regenbogen
- Center for Healthcare Outcomes and Policy, University of Michigan, Ann Arbor, Michigan
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
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Vitucci JC, Pulse M, Tabor-Simecka L, Simecka J. Epidemic ribotypes of Clostridium (now Clostridioides) difficile are likely to be more virulent than non-epidemic ribotypes in animal models. BMC Microbiol 2020; 20:27. [PMID: 32024477 PMCID: PMC7003423 DOI: 10.1186/s12866-020-1710-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 01/21/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Clostridioides difficile infections have become more frequently diagnosed and associated with greater disease severity, which has resulted in an increase burden on the healthcare system. These increases are attributed to the increased prevalence of hypervirulent strains encompassing select ribotypes. These epidemic ribotypes were characterized as hypervirulent due to higher in vitro spore and toxin production, as well as increased incidence, severity and mortality within patients. However, it is unclear whether epidemic ribotypes are truly more virulent than non-epidemic ribotypes in vivo. Furthermore, there is conflicting evidence about the ability of a strain's in vitro phenotype to be predictive of their in vivo virulence. The goals of the current studies were to determine if epidemic ribotypes are more virulent than other ribotypes in animal models, and whether the in vitro virulence phenotype of an isolate or ribotype predict in vivo virulence. RESULTS To determine if epidemic strains were truly more virulent than other non-epidemic strains, the in vivo virulence of 13 C. difficile isolates (7 non-epidemic and 6 epidemic ribotype isolates) were determined in murine and hamster models of CDI. The isolates of epidemic ribotype of C. difficile were found to be more virulent in both the murine and hamster models than non-epidemic isolates. In particular, the group of epidemic ribotypes of C. difficile had lower LD50 values in hamsters. The increased severity of disease was associated with higher levels of Toxin A and Toxin B production found in fecal samples, but not numbers of organisms recovered. The isolates were further characterized for their in vitro virulence phenotypes, e.g. toxin production, growth rates, spore formation and adherence of spores to intestinal epithelial cell lines. Although there were higher levels of toxins produced and greater adherence for the group of epidemic ribotypes, the in vitro profiles of individual isolates were not always predictive of their in vivo virulence. CONCLUSIONS Overall, the group of epidemic ribotypes of C. difficile were more virulent in vivo despite individual isolates having similar phenotypes to the non-epidemic isolates in vitro.
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Affiliation(s)
- John C Vitucci
- Department of Pharmaceutical Sciences and UNTHSC Preclinical Services, University of North Texas System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Mark Pulse
- Department of Pharmaceutical Sciences and UNTHSC Preclinical Services, University of North Texas System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA
| | | | - Jerry Simecka
- Department of Pharmaceutical Sciences and UNTHSC Preclinical Services, University of North Texas System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA.
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Reply to: Caution is warranted in using cephamycin antibiotics against recurrent Clostridioides difficile infection. Nat Microbiol 2020; 5:237-238. [DOI: 10.1038/s41564-019-0662-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 12/15/2019] [Indexed: 11/08/2022]
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Muhammad A, Madhav D, Rawish F, Viveksandeep TC, Albert E, Mollie J, Prateek S. Surotomycin (A Novel Cyclic Lipopeptide) vs. Vancomycin for the Treatment of Clostridioides difficile Infection: A Systematic Review and Meta-analysis. ACTA ACUST UNITED AC 2019; 14:166-174. [DOI: 10.2174/1574884714666190328162637] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 02/18/2019] [Accepted: 03/19/2019] [Indexed: 12/16/2022]
Abstract
Background:
Current guidelines recommend the use of vancomycin for the initial treatment
of moderate to severe Clostridioides difficile Infection (CDI). Surotomycin, a novel antibiotic,
has been utilized for the management of CDI with variable results.
Methods:
A systematic literature search was performed using the following electronic databases
[Medline, Embase, google scholar and Cochrane] for eligible studies. Randomized controlled trials
comparing Surotomycin with Vancomycin for the CDI treatment were included. Demographic variables
and outcomes (CDI resolution, CDI recurrence, B1/NAP1/027-specific strain treatment,
B1/NAP1/027-strain recurrence, death not related to treatment) were analyzed. The primary outcome
was clinical cure rate defined as the resolution of CDI at the end of the 10-day drug course.
Results:
Three RCTs met the inclusion criteria with a total of 1280 patients with CDI who received
either surotomycin 250 mg twice daily (642 patients) or vancomycin 125 mg four times daily (638
patients). Clinical cure rates after 10 days of treatment with either surotomycin or vancomycin were
not significantly different (pooled OR: 0.89, 95% CI 0.66-1.18, p=0.41). Sustained clinical response
at clinical follow-up and the overall recurrence of CDI were also not significantly different between
the two groups – pooled OR 1.15 (95% CI 0.89-1.50, p=0.29) and pooled OR 0.74 (95%CI 0.52-
1.04, p=0.08), respectively. With regards to the NAP1/BI/027 strain, patients in the surotomycin
group had significantly lower rates of recurrence compared to vancomycin (pooled OR 0.35, 95%
CI 0.19-0.63, p<0.01).
Conclusion:
Surotomycin is non-inferior to vancomycin and offers a promising alternative for the
treatment and prevention of C. diff infection.
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Affiliation(s)
- Aziz Muhammad
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, KS66160, United States
| | - Desai Madhav
- Department of Gastroenterology and Hepatology, Veterans Affairs Medical Center and University of Kansas Medical Center, Kansas City, Kansas, KS66160, United States
| | - Fatima Rawish
- Dow University of Health Sciences, Karachi, Pakistan
| | - Thoguluva C. Viveksandeep
- Department of Gastroenterology and Hepatology, Veterans Affairs Medical Center and University of Kansas Medical Center, Kansas City, Kansas, KS66160, United States
| | - Eid Albert
- Department of Infectious Disease, University of Kansas Medical Center, Kansas City, Kansas, KS66160, United States
| | - Jackson Mollie
- Department of Gastroenterology and Hepatology, University of Kansas Medical Center, Kansas City, Kansas, KS66160, United States
| | - Sharma Prateek
- Department of Gastroenterology and Hepatology, Veterans Affairs Medical Center and University of Kansas Medical Center, Kansas City, Kansas, KS66160, United States
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48
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Borody TJ, Eslick GD, Clancy RL. Fecal microbiota transplantation as a new therapy: from Clostridioides difficile infection to inflammatory bowel disease, irritable bowel syndrome, and colon cancer. Curr Opin Pharmacol 2019; 49:43-51. [PMID: 31173991 DOI: 10.1016/j.coph.2019.04.017] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 04/23/2019] [Indexed: 12/26/2022]
Abstract
Fecal microbiota transplantation (FMT) represents the most effective means of therapeutically manipulating the gastrointestinal microbiome. Originally employed as a treatment of last-resort in patients with life-threatening Clostridioides difficile infection (CDI), FMT gained widespread acceptance during the CDI epidemic, where it achieved resolution rates approaching 100%. Following our newfound appreciation for the role of the gut microbiome in both health and disease and owing to FMT's unique mechanism/s of action, FMT is rapidly advancing as an effective treatment for a number of conditions in which the gastrointestinal microbiome is thought to play a role. We review the role of FMT from its beginnings in CDI to its expansion into inflammatory bowel disease, irritable bowel syndrome, and colon cancer.
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Affiliation(s)
- Thomas J Borody
- Centre for Digestive Diseases, Level 1, 229 Great North Road, Five Dock, NSW, 2046, Australia.
| | - Guy D Eslick
- Department of Surgery, Nepean Hospital, The University of Sydney, NSW, Australia
| | - Robert L Clancy
- Centre for Digestive Diseases, Level 1, 229 Great North Road, Five Dock, NSW, 2046, Australia
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O'Hagan JJ, McDonald LC. The Challenges of Tracking Clostridium difficile to Its Source in Hospitalized Patients. Clin Infect Dis 2019; 68:210-212. [PMID: 29846537 DOI: 10.1093/cid/ciy461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 05/24/2018] [Indexed: 12/18/2022] Open
Affiliation(s)
- Justin J O'Hagan
- Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - L Clifford McDonald
- Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia
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50
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Mody D, Athamneh AIM, Seleem MN. Curcumin: A natural derivative with antibacterial activity against Clostridium difficile. J Glob Antimicrob Resist 2019; 21:154-161. [PMID: 31622683 DOI: 10.1016/j.jgar.2019.10.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 10/06/2019] [Accepted: 10/07/2019] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVES The rapid emergence of hypervirulent Clostridium difficile (C. difficile) isolates and the paucity of effective anti-clostridial antibiotics call for extensive research to identify new treatment options. This study aimed to test the anti-clostridial activity of bioactive extracts of turmeric, which is a natural herb widely known for its profound medicinal properties. METHODS The MICs of turmeric derivatives were determined against 27 C. difficile strains, including hypervirulent (BI/NAP1/027) and clinical toxigenic isolates. Additionally, their ability to inhibit C. difficile toxin production and spore formation was investigated. Furthermore, the safety profiles of turmeric derivatives regarding their effects on human gut microflora - such as Bacteroides, Lactobacillus and Bifidobacterium - were evaluated. RESULTS Curcuminoids, the major phytoconstituents of turmeric - including curcumin, demethoxycurcumin and bisdemethoxycurcumin - inhibited growth of C. difficile at concentrations ranging from 4 to 32μg/mL. Additionally, curcuminoids showed no negative effect on major populating species of the human gut. Curcumin was more effective than fidaxomicin in inhibiting C. difficile toxin production, but less so in inhibiting spore formation. CONCLUSION The findings suggest that curcumin has potential as an anti-clostridial agent. More work is needed to further investigate the efficacy of curcumin as a stand-alone drug or as a supplement of current drugs of choice, as it has no antagonistic activities but might overcome their drawbacks.
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Affiliation(s)
- Deepansh Mody
- Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA
| | - Ahmad I M Athamneh
- Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA
| | - Mohamed N Seleem
- Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA; Purdue Institute of Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, IN, USA.
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