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1
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Bednárik DS, Földvári-Nagy KC, Simon V, Rancz A, Gede N, Veres DS, Paraskevopoulos P, Schnabel T, Erőss B, Hegyi P, Lenti K, Földvári-Nagy L. Comparative effectiveness of different therapies for Clostridioides difficile infection in adults: a systematic review and network meta-analysis of randomized controlled trials. THE LANCET REGIONAL HEALTH. EUROPE 2025; 49:101151. [PMID: 39989875 PMCID: PMC11846439 DOI: 10.1016/j.lanepe.2024.101151] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 02/25/2025]
Abstract
Background Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated diarrhea, with substantial morbidity and mortality. CDI is a severe and growing problem with numerous treatment options. We evaluated the effectiveness of all therapies in recurrent and non-recurrent infections and their prevention. Methods This network meta-analysis and systematic review of randomized controlled trials (RCTs) compared all CDI therapies and preventions. We included RCTs published until 19 August 2024 and focused on adult population. We performed a systematic search in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. Inclusion criteria were patients: adults (>16) treated against CDI; study type: randomized controlled trial; outcome: cure rate, recurrence or effectiveness of prevention. Any publication not meeting all criteria was considered to be ineligible and excluded. We applied random-effects meta-analysis using frequentist methods. We reported our main results as odds ratios (as a symmetric effect size measure, OR) with 95% confidence interval (95% CI). We used the Cochrane risk-of-bias tool to assess the risk of bias. Our study protocol was preregistered in PROSPERO (CRD42022371210). Findings We assessed 73 RCTs with 28 interventions, involving 27,959 patients (49.2% female) in five networks. Fecal microbiota transplantation (FMT) was the most effective treatment in terms of the cure rate overall (P-score: 0.9952) and in recurrent cases (P-score: 0.9836). In recurrent cases, fidaxomicin (P-score: 0.6734) showed significantly greater effectiveness than vancomycin (P-score: 0.3677) and tolevamer (P-score: 0.0365). For non-recurrent CDI treatments ridinilazole, fidaxomicin, FMT and nitazoxanide were equally effective. Ridinilazole (P-score: 0.7671) and fidaxomicin (P-score: 0.7627) emerged as the most effective in preventing recurrence. Probiotics were not effective in preventing CDI, since network meta-analyses did not show significant differences between probiotics and placebo. In probiotics' subgroups pairwise meta-analyses Lactobacillaceae proved to be significantly more effective in prevention than placebo. Oral and colonoscopic FMT administration methods were equally effective. The study-level aggregated risk of bias of the publications included ranged from low to high. We observed relevant heterogeneity among studies in therapeutic doses, treatment durations, and follow-up times. Interpretation The superiority of FMT in the treatment of CDI highlights the potential for increased use of FMT in clinical settings. Further research on optimizing FMT protocols and exploring its long-term safety and efficacy in larger samples is needed. Our findings suggest that the preventive use of probiotics might be questioned. Funding None.
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Affiliation(s)
- Dániel Steve Bednárik
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Heim Pál National Pediatric Institute, Budapest, Hungary
| | - Kincső Csepke Földvári-Nagy
- School of Life Sciences, University of Warwick, Coventry, United Kingdom
- Faculty of Health Sciences, Semmelweis University, Budapest, Hungary
| | - Viktor Simon
- Faculty of Health Sciences, Semmelweis University, Budapest, Hungary
| | - Anett Rancz
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Noémi Gede
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Dániel Sándor Veres
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | | | - Tamás Schnabel
- Department of Gastroenterology, Skien Hospital, Telemark Hospital Trust, Skien, Norway
| | - Bálint Erőss
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary
- Institute for Translational Medicine, University of Pécs, Medical School, Pécs, Hungary
| | - Péter Hegyi
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary
- Institute for Translational Medicine, University of Pécs, Medical School, Pécs, Hungary
| | - Katalin Lenti
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary
| | - László Földvári-Nagy
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary
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2
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Conrad J, Giesbrecht K, Aguilar RC, Gräfe SK, Ullah A, Hunfeld KP, Lübbert C, Pützfeld S, Reuken PA, Schmitz-Rode M, Schalk E, Schmidt-Wilcke T, Schmiedel S, Solbach P, Vehreschild MJGT. Comparative effectiveness of vancomycin and metronidazole on event-free survival after initial infection in patients with Clostridioides difficile-a German multicentre cohort study. Clin Microbiol Infect 2024; 30:1433-1438. [PMID: 39127107 DOI: 10.1016/j.cmi.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 08/01/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024]
Abstract
OBJECTIVES The objective of this study is to examine the comparative effectiveness of vancomycin and metronidazole in a confirmatory analysis of event-free survival (EFS) after initial infection in patients with Clostridioides difficile from a German multicentre cohort study. METHODS The IBIS multicentre cohort enrolled patients with an index episode of C. difficile infection between August 2017 and September 2020. The primary endpoint was EFS, defined as response to treatment with metronidazole or vancomycin within 10 days of initiation, absence of recurrence and death from any cause up to 90 days post-treatment. A Cox proportional hazards model with inverse probability of treatment weighting was used to investigate the comparative effectiveness of this outcome. Additionally, subgroup analyses were performed based on severe and non-severe infections. RESULTS Of the 489 patients included, 118 (24%) received initial treatment with metronidazole and 371 (76%) with vancomycin. Of these, 78/118 (66.1%) and 247/371 (66.6%), respectively, responded to treatment within 10 days, neither developed a recurrence nor died within 90 days and thus achieved the outcome of EFS. In the subgroup of non-severe infections, 74/293 patients (25.3%) received metronidazole, and 219/293 (74.7%) received vancomycin. Of these, 33/74 (44.6%) metronidazole patients and 150/219 (68.5%) vancomycin patients survived event free. The Cox proportional hazards model revealed differences in EFS for the overall population and both subgroups (reference metronidazole: all severity levels: hazard ratio [HR] 0.46, [95% CI, 0.33-0.65]; non-severe: HR 0.39; [95% CI, 0.24-0.60]; severe: HR 0.52; [95% CI, 0.28-0.95]). DISCUSSION Our analysis confirms current changes in guidelines, as it supports the superiority of vancomycin compared with metronidazole across all severity levels.
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Affiliation(s)
- Jana Conrad
- Institute of Medical Biometry, Epidemiology and Informatics, University Medicine of the Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Katharina Giesbrecht
- Department of Internal Medicine, Infectious Diseases, Goethe University Frankfurt, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Rebeca Cruz Aguilar
- Department I of Internal Medicine, Division of Infectious Diseases, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Stefanie K Gräfe
- Department I of Internal Medicine, Faculty of Medicine, ECMM Excellence Centre for Medical Mycology, University Hospital of Cologne, Cologne, Germany
| | - Arhamhabib Ullah
- Department I of Internal Medicine, Division of Infectious Diseases, Medical Faculty and University Hospital Cologne, Cologne, Germany; Department I of Internal Medicine, Division of Kardiology und Internistic Intensive Care, Klinikum Leverkusen, Leverkusen, Germany
| | - Klaus-Peter Hunfeld
- Institute for Laboratory Medicine, Microbiology and Infection Control, Northwest Medical Centre, Frankfurt/Main, Germany
| | - Christoph Lübbert
- Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, University of Leipzig Medical Centre, Leipzig, Germany
| | - Stefan Pützfeld
- Division of Gastroenterology and Internal Medicine, Hospital Porz am Rhein, Cologne, Germany
| | - Philipp A Reuken
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
| | | | - Enrico Schalk
- Department of Hematology, Oncology and Cell Therapy, Medical Faculty, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Tobias Schmidt-Wilcke
- Centre of Neurology, District Hospital Mainkofen, Deggendorf, Germany; St Mauritius Therapieklinik, Meerbusch, Germany
| | - Stefan Schmiedel
- I. Department of Internal Medicine, Section Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Philipp Solbach
- Department of Medicine I, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Maria J G T Vehreschild
- Department of Internal Medicine, Infectious Diseases, Goethe University Frankfurt, University Hospital Frankfurt, Frankfurt/Main, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany.
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3
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Montgomery G, Patel A, Pfeil S. Treatment and Management of Gastrointestinal Disorders. Med Clin North Am 2024; 108:777-794. [PMID: 39084834 DOI: 10.1016/j.mcna.2024.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2024]
Abstract
This article reviews the evaluation and management of several gastrointestinal disorders that are commonly encountered by gastroenterologists and primary care physicians. With a focus on newer therapies, we discuss the management of chronic constipation, irritable bowel syndrome, Clostridioides difficile infection, gastroparesis, steatotic liver disease, and diverticulitis.
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Affiliation(s)
- Garren Montgomery
- Division of Gastroenterology, Hepatology, and Nutrition, Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - Arsheya Patel
- Division of Gastroenterology, Hepatology, and Nutrition, Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Sheryl Pfeil
- Division of Gastroenterology, Hepatology, and Nutrition, Ohio State University Medical Center, Columbus, OH, USA
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4
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Bernabè G, Castagliuolo I, Porzionato A, Casarotto G, Monte RD, Carpi A, Brun P. Insoluble polysaccharides produced in plant cell cultures protect from Clostridioides difficile colitis. Microbiol Res 2024; 286:127812. [PMID: 38954992 DOI: 10.1016/j.micres.2024.127812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 05/18/2024] [Accepted: 06/16/2024] [Indexed: 07/04/2024]
Abstract
Clostridioides difficile infection (CDI) poses a significant health threat due to high recurrence rates. Antimicrobial agents are commonly used to manage CDI-related diarrhoea; however, by aggravating intestinal dysbiosis, antibiotics enable C. difficile spores germination and production of toxins, the main virulence factors. Therefore, the binding of exotoxins using adsorbents represents an attractive alternative medication for the prevention and treatment of relapses. In this study, we provided evidence that the natural insoluble polysaccharides, named ABR119, extracted by plant cell cultures, effectively trap C. difficile toxins. In our experiments, ABR119 exhibited no cytotoxicity in vitro and was safely administered in vivo. In the animal model of C. difficile-associated colitis, ABR119 (50 mg/kg body weight) significantly reduced the colonic myeloperoxidase activity and severity of inflammation, preventing body weight loss. These effects were not evident when we treated animals with wheat bran polysaccharides. We did not detect bacterial killing effects of ABR119 against C. difficile nor against bacterial species of the normal gut microbiota. Moreover, ABR119 did not interfere in vitro with the antimicrobial activities of most clinically used antibiotics. In summary, ABR119 holds promise for treating and preventing C. difficile colitis by trapping the bacterial toxins, warranting further studies to assess the ABR119 potential in human infections caused by C. difficile.
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Affiliation(s)
- Giulia Bernabè
- University of Padova, Department of Molecular Medicine via A. Gabelli, 63, Padova 35121, Italy
| | - Ignazio Castagliuolo
- University of Padova, Department of Molecular Medicine via A. Gabelli, 63, Padova 35121, Italy; Microbiology Unit of Padua University Hospital, via N. Giustiniani, 2, Padova 35128, Italy
| | - Andrea Porzionato
- University of Padova, Department of Neurosciences, via A. Gabelli, 65, Padova 35121, Italy
| | - Gino Casarotto
- Active Botanicals Research, Via dell'Impresa, 1, Brendola, Vicenza 36040, Italy
| | - Renzo Dal Monte
- Active Botanicals Research, Via dell'Impresa, 1, Brendola, Vicenza 36040, Italy
| | - Andrea Carpi
- Active Botanicals Research, Via dell'Impresa, 1, Brendola, Vicenza 36040, Italy
| | - Paola Brun
- University of Padova, Department of Molecular Medicine via A. Gabelli, 63, Padova 35121, Italy.
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5
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Buddle JE, Thompson LM, Williams AS, Wright RCT, Durham WM, Turner CE, Chaudhuri RR, Brockhurst MA, Fagan RP. Identification of pathways to high-level vancomycin resistance in Clostridioides difficile that incur high fitness costs in key pathogenicity traits. PLoS Biol 2024; 22:e3002741. [PMID: 39146240 PMCID: PMC11326576 DOI: 10.1371/journal.pbio.3002741] [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: 10/13/2023] [Accepted: 07/09/2024] [Indexed: 08/17/2024] Open
Abstract
Clostridioides difficile is an important human pathogen, for which there are very limited treatment options, primarily the glycopeptide antibiotic vancomycin. In recent years, vancomycin resistance has emerged as a serious problem in several gram-positive pathogens, but high-level resistance has yet to be reported for C. difficile, although it is not known if this is due to constraints upon resistance evolution in this species. Here, we show that resistance to vancomycin can evolve rapidly under ramping selection but is accompanied by fitness costs and pleiotropic trade-offs, including sporulation defects that would be expected to severely impact transmission. We identified 2 distinct pathways to resistance, both of which are predicted to result in changes to the muropeptide terminal D-Ala-D-Ala that is the primary target of vancomycin. One of these pathways involves a previously uncharacterised D,D-carboxypeptidase, expression of which is controlled by a dedicated two-component signal transduction system. Our findings suggest that while C. difficile is capable of evolving high-level vancomycin resistance, this outcome may be limited clinically due to pleiotropic effects on key pathogenicity traits. Moreover, our data identify potential mutational routes to resistance that should be considered in genomic surveillance.
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Affiliation(s)
- Jessica E Buddle
- Molecular Microbiology, School of Biosciences, University of Sheffield, Sheffield, United Kingdom
| | - Lucy M Thompson
- Molecular Microbiology, School of Biosciences, University of Sheffield, Sheffield, United Kingdom
| | - Anne S Williams
- Department of Physics and Astronomy, University of Sheffield, Sheffield, United Kingdom
| | - Rosanna C T Wright
- Division of Evolution and Genomic Sciences, University of Manchester, Manchester, United Kingdom
| | - William M Durham
- Department of Physics and Astronomy, University of Sheffield, Sheffield, United Kingdom
| | - Claire E Turner
- Molecular Microbiology, School of Biosciences, University of Sheffield, Sheffield, United Kingdom
| | - Roy R Chaudhuri
- Molecular Microbiology, School of Biosciences, University of Sheffield, Sheffield, United Kingdom
| | - Michael A Brockhurst
- Division of Evolution and Genomic Sciences, University of Manchester, Manchester, United Kingdom
| | - Robert P Fagan
- Molecular Microbiology, School of Biosciences, University of Sheffield, Sheffield, United Kingdom
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Di Bella S, Sanson G, Monticelli J, Zerbato V, Principe L, Giuffrè M, Pipitone G, Luzzati R. Clostridioides difficile infection: history, epidemiology, risk factors, prevention, clinical manifestations, treatment, and future options. Clin Microbiol Rev 2024; 37:e0013523. [PMID: 38421181 PMCID: PMC11324037 DOI: 10.1128/cmr.00135-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2024] Open
Abstract
SUMMARYClostridioides difficile infection (CDI) is one of the major issues in nosocomial infections. This bacterium is constantly evolving and poses complex challenges for clinicians, often encountered in real-life scenarios. In the face of CDI, we are increasingly equipped with new therapeutic strategies, such as monoclonal antibodies and live biotherapeutic products, which need to be thoroughly understood to fully harness their benefits. Moreover, interesting options are currently under study for the future, including bacteriophages, vaccines, and antibiotic inhibitors. Surveillance and prevention strategies continue to play a pivotal role in limiting the spread of the infection. In this review, we aim to provide the reader with a comprehensive overview of epidemiological aspects, predisposing factors, clinical manifestations, diagnostic tools, and current and future prophylactic and therapeutic options for C. difficile infection.
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Affiliation(s)
- Stefano Di Bella
- Clinical Department of
Medical, Surgical and Health Sciences, Trieste
University, Trieste,
Italy
| | - Gianfranco Sanson
- Clinical Department of
Medical, Surgical and Health Sciences, Trieste
University, Trieste,
Italy
| | - Jacopo Monticelli
- Infectious Diseases
Unit, Trieste University Hospital
(ASUGI), Trieste,
Italy
| | - Verena Zerbato
- Infectious Diseases
Unit, Trieste University Hospital
(ASUGI), Trieste,
Italy
| | - Luigi Principe
- Microbiology and
Virology Unit, Great Metropolitan Hospital
“Bianchi-Melacrino-Morelli”,
Reggio Calabria, Italy
| | - Mauro Giuffrè
- Clinical Department of
Medical, Surgical and Health Sciences, Trieste
University, Trieste,
Italy
- Department of Internal
Medicine (Digestive Diseases), Yale School of Medicine, Yale
University, New Haven,
Connecticut, USA
| | - Giuseppe Pipitone
- Infectious Diseases
Unit, ARNAS Civico-Di Cristina
Hospital, Palermo,
Italy
| | - Roberto Luzzati
- Clinical Department of
Medical, Surgical and Health Sciences, Trieste
University, Trieste,
Italy
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7
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Obaid NA. Alternative treatment of recurrent Clostridioides difficile infection in adults by fecal transplantation: an overview of phase I-IV studies from Clinicaltrials.gov. Front Microbiol 2024; 15:1374774. [PMID: 38784794 PMCID: PMC11111976 DOI: 10.3389/fmicb.2024.1374774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/18/2024] [Indexed: 05/25/2024] Open
Abstract
Background Fecal microbiota transplantation (FMT) is an interventional approach to treat chronic and recurrent Clostridioides difficile infection (CDI). However, there is insufficient evidence regarding its effectiveness and safety. Clinical trials have been conducted to inspect the safety and effectiveness of FMT with and without comparison to pharmacological treatments. Aim This review explored the treatment of CDI in adults using FMT and evaluated the safety of this intervention based on phase I-IV studies registered on Clinicaltrials.gov. Method A comprehensive search of Clinicaltrials.gov was conducted to identify relevant studies that investigated CDI in adults. Data on study type, study design, sample size, intervention details, and outcomes related to FMT were examined and evaluated. Results In total, 13 clinical trials on FMT for CDI published through 17 November 2023 were identified, all of which were interventional studies. The investigation focused on both terminated and completed studies. Basic and advanced outcome measures were examined. Conclusion Some studies were terminated during phase II, and FMT was less effective than antibiotics such as vancomycin and fidaxomicin. However, colonoscopy and oral FMT were explored in several completed studies with promising results, but the evidence remains limited and inconclusive.
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Affiliation(s)
- Najla A. Obaid
- Pharmaceutical Sciences Department, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
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8
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Zhong S, Yang J, Huang H. Efficacy Assessment of the Co-Administration of Vancomycin and Metronidazole in Clostridioides difficile-Infected Mice Based on Changes in Intestinal Ecology. J Microbiol Biotechnol 2024; 34:828-837. [PMID: 38668685 DOI: 10.4014/jmb.2312.12034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 02/16/2024] [Accepted: 02/19/2024] [Indexed: 05/16/2024]
Abstract
Vancomycin (VAN) and metronidazole (MTR) remain the current drugs of choice for the treatment of non-severe Clostridioides difficile infection (CDI); however, while their co-administration has appeared in clinical treatment, the efficacy varies greatly and the mechanism is unknown. In this study, a CDI mouse model was constructed to evaluate the therapeutic effects of VAN and MTR alone or in combination. For a perspective on the intestinal ecology, 16S rRNA amplicon sequencing and non-targeted metabolomics techniques were used to investigate changes in the fecal microbiota and metabolome of mice under the co-administration treatment. As a result, the survival rate of mice under co-administration was not dramatically different compared to that of single antibiotics, and the former caused intestinal tissue hyperplasia and edema. Co-administration also significantly enhanced the activity of amino acid metabolic pathways represented by phenylalanine, arginine, proline, and histidine, decreased the level of deoxycholic acid (DCA), and downregulated the abundance of beneficial microbes, such as Bifidobacterium and Akkermansia. VAN plays a dominant role in microbiota regulation in co-administration. In addition, co-administration reduced or increased the relative abundance of antibiotic-sensitive bacteria, including beneficial and harmful microbes, without a difference. Taken together, there are some risks associated with the co-administration of VAN and MTR, and this combination mode should be used with caution in CDI treatment.
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Affiliation(s)
- Saiwei Zhong
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, P.R. China
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, P.R. China
| | - Jingpeng Yang
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, P.R. China
| | - He Huang
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, P.R. China
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9
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Yang J, Rui W, Zhong S, Li X, Liu W, Meng L, Li Y, Huang H. Symbiotic biofilms formed by Clostridioides difficile and bacteroides thetaiotaomicron in the presence of vancomycin. Gut Microbes 2024; 16:2390133. [PMID: 39132815 PMCID: PMC11321409 DOI: 10.1080/19490976.2024.2390133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/15/2024] [Accepted: 08/05/2024] [Indexed: 08/13/2024] Open
Abstract
Vancomycin (VAN) treatment in Clostridioides difficile infection (CDI) suffers from a relatively high rate of recurrence, with a variety of reasons behind this, including biofilm-induced recurrent infections. C. difficile can form monophyletic or symbiotic biofilms with other microbes in the gut, and these biofilms protect C. difficile from being killed by antibiotics. In this study, we analyzed the ecological relationship between Bacteroides thetaiotaomicron and C. difficile and their formation of symbiotic biofilm in the VAN environment. The production of symbiotic biofilm formed by C. difficile and B. thetaiotaomicron was higher than that of C. difficile and B. thetaiotaomicron alone in the VAN environment. In symbiotic biofilms, C. difficile was characterized by increased production of the toxin protein TcdA and TcdB, up-regulation of the expression levels of the virulence genes tcdA and tcdB, enhanced bacterial cell swimming motility and c-di-GMP content, and increased adhesion to Caco-2 cells. The scanning electron microscope (SEM) combined with confocal laser scanning microscopy (CLSM) results indicated that the symbiotic biofilm was elevated in thickness, dense, and had an increased amount of mixed bacteria, while the fluorescence in situ hybridization (FISH) probe and plate colony counting results further indicated that the symbiotic biofilm had a significant increase in the amount of C. difficile cells, and was able to better tolerate the killing of the simulated intestinal fluid. Taken together, C. difficile and B. thetaiotaomicron become collaborative in the VAN environment, and targeted deletion or attenuation of host gut B. thetaiotaomicron content may improve the actual efficacy of VAN in CDI treatment.
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Affiliation(s)
- Jingpeng Yang
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Qixia District, Nanjing, China
| | - Wen Rui
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Qixia District, Nanjing, China
| | - Saiwei Zhong
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Qixia District, Nanjing, China
| | - Xiaoqian Li
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Qixia District, Nanjing, China
| | - Wenzheng Liu
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Qixia District, Nanjing, China
| | - Lingtong Meng
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Qixia District, Nanjing, China
| | - Yanan Li
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Qixia District, Nanjing, China
| | - He Huang
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Qixia District, Nanjing, China
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10
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Swart N, Sinha AM, Bentley A, Smethurst H, Spencer G, Ceder S, Wilcox MH. A cost-utility analysis of two Clostridioides difficile infection guideline treatment pathways. Clin Microbiol Infect 2023; 29:1291-1297. [PMID: 37356620 DOI: 10.1016/j.cmi.2023.06.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 06/07/2023] [Accepted: 06/14/2023] [Indexed: 06/27/2023]
Abstract
OBJECTIVES Treatment guidelines are key drivers of prescribing practice in the management of Clostridioides difficile infection (CDI), but recommendations on best practice can vary. We conducted a cost-utility analysis to compare the treatment pathway recommended by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guideline with the pathway proposed by the National Institute for Health and Care Excellence (NICE) guideline, from the perspective of the UK National Health Service. METHODS A decision tree modelling approach was adopted to reflect the treatment pathway for CDI as outlined in ESCMID and NICE guidelines. Patients experiencing a CDI infection received up to three treatments per infection to achieve a response and could subsequently experience up to two recurrences. Data on patient demographics, treatment response, recurrence, utilities, CDI-related mortality, and costs were taken from published literature. RESULTS The ESCMID treatment pathway was cost-effective versus the NICE treatment pathway at a threshold of £20 000 per quality-adjusted life year gained, with an incremental cost-effectiveness ratio of £4931. Cost-effectiveness was driven by differences in index infection recommendations (ESCMID recommends fidaxomicin as first-line treatment whereas NICE recommends vancomycin). The model results were robust to variations in inputs investigated in scenarios and sensitivity analyses, and probabilistic sensitivity analysis demonstrated that the ESCMID guideline treatment strategy had a 100% likelihood of being cost-effective versus the NICE treatment strategy. DISCUSSION Compared with the NICE guideline, the ESCMID guideline recommendations for treating an index CDI represent the most cost-effective use of healthcare resources from the perspective of the UK National Health Service.
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Affiliation(s)
| | | | | | | | | | | | - Mark H Wilcox
- Department of Microbiology, Leeds Teaching Hospitals NHS Trust, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom.
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Bromilow T, Holmes H, Coote L, Woods S, Pink J. Cost-Effectiveness Analysis of Antimicrobial Prescribing in the Treatment of Clostridioides Difficile Infection in England. PHARMACOECONOMICS - OPEN 2023; 7:739-750. [PMID: 37306930 PMCID: PMC10471526 DOI: 10.1007/s41669-023-00420-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 05/03/2023] [Indexed: 06/13/2023]
Abstract
BACKGROUND An economic model was developed with guidance from the National Institute for Health and Care Excellence (NICE) 'Managing Common Infections' (MCI) Committee to evaluate the cost effectiveness of different antibiotic treatment sequences for treating Clostridioides difficile infection (CDI) in England. METHODS The model consisted of a 90-day decision tree followed by a lifetime cohort Markov model. Efficacy data were taken from a network meta-analysis and published literature, while cost, utility and mortality data were taken from published literature. A treatment sequence was defined as a first-line intervention or a different second-line intervention, and used constant third- and fourth-line interventions. The possible first- and second-line interventions were vancomycin, metronidazole, teicoplanin and fidaxomicin (standard and extended regimens). Total costs and quality-adjusted life-years (QALYs) were calculated and were used to run a fully incremental cost-effectiveness analysis. Threshold analysis was conducted around pricing. RESULTS Sequences including teicoplanin, fidaxomicin (extended regimen) and second-line metronidazole were excluded based on recommendations from the committee. The final pairwise comparison was between first-line vancomycin and second-line fidaxomicin (VAN-FID), and the reverse (FID-VAN). The incremental cost-effectiveness ratio for FID-VAN compared with VAN-FID was £156,000 per QALY gained, and FID-VAN had a 0.2% likelihood of being cost effective at a £20,000 threshold. CONCLUSION First-line vancomycin and second-line fidaxomicin was the most cost-effective treatment sequence at the NICE threshold for treating CDI in England. The main limitation of this study was that the initial cure and recurrence rates of each intervention were applied constantly across each line of treatment and each round of recurrence.
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Affiliation(s)
- Tom Bromilow
- York Health Economics Consortium, University of York, Enterprise House, Innovation Way, Heslington, YO10 5NQ, York, UK.
| | - Hayden Holmes
- York Health Economics Consortium, University of York, Enterprise House, Innovation Way, Heslington, YO10 5NQ, York, UK
| | - Laura Coote
- York Health Economics Consortium, University of York, Enterprise House, Innovation Way, Heslington, YO10 5NQ, York, UK
| | - Sam Woods
- York Health Economics Consortium, University of York, Enterprise House, Innovation Way, Heslington, YO10 5NQ, York, UK
| | - Joshua Pink
- National Institute of Health and Care Excellence (NICE), Centre for Guidelines, London, UK
- School of Health and Society, University of Salford, Salford, UK
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12
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Stewart AG, Chen SCA, Hamilton K, Harris-Brown T, Korman TM, Figtree M, Worth LJ, Kok J, Van der Poorten D, Byth K, Slavin MA, Paterson DL. Clostridioides difficile Infection: Clinical Practice and Health Outcomes in 6 Large Tertiary Hospitals in Eastern Australia. Open Forum Infect Dis 2023; 10:ofad232. [PMID: 37274181 PMCID: PMC10237225 DOI: 10.1093/ofid/ofad232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 04/26/2023] [Indexed: 06/06/2023] Open
Abstract
Background Clostridioides difficile infection (CDI) is associated with significant morbidity and mortality in both healthcare and community settings. We aimed to define the predisposing factors, risks for severe disease, and mortality determinants of CDI in eastern Australia over a 1-year period. Methods This is an observational retrospective study of CDI in hospitalized patients aged ≥18 years in 6 tertiary institutions from 1 January 2016 to 31 December 2016. Patients were identified through laboratory databases and medical records of participating institutions. Clinical, imaging, and laboratory data were input into an electronic database hosted at a central site. Results A total of 578 patients (578 CDI episodes) were included. Median age was 65 (range, 18-99) years and 48.2% were male. Hospital-onset CDI occurred in 64.0%. Recent antimicrobial use (41.9%) and proton pump inhibitor use (35.8%) were common. Significant risk factors for severe CDI were age <65 years (P < .001), malignancy within the last 5 years (P < .001), and surgery within the previous 30 days (P < .001). Significant risk factors for first recurrence included severe CDI (P = .03) and inflammatory bowel disease (P = .04). Metronidazole was the most common regimen for first episodes of CDI with 65.2% being concordant with Australian treatment guidelines overall. Determinants for death at 60 days included age ≥65 years (P = .01), severe CDI (P < .001), and antibiotic use within the prior 30 days (P = .02). Of those who received metronidazole as first-line therapy, 10.1% died in the 60-day follow-up period, compared to 9.8% of those who received vancomycin (P = .86). Conclusions Patients who experience CDI are vulnerable and require early diagnosis, clinical surveillance, and effective therapy to prevent complications and improve outcomes.
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Affiliation(s)
- Adam G Stewart
- Correspondence: Adam Stewart, BBiomedSci, MBBS(Hons), MPHTM, Centre for Clinical Research, University of Queensland, Bldg 71/918 RBWH Herston, Brisbane, QLD 4029, Australia (); David Paterson, Saw Swee Hock School of Public Health, National University of Singapore, 12 Science Drive 2, #10-01, Singapore 117549 ()
| | - Sharon C A Chen
- Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, Australia
- Department of Infectious Diseases, Westmead Hospital, University of Sydney, Sydney, Australia
| | - Kate Hamilton
- Department of Infectious Diseases, Westmead Hospital, University of Sydney, Sydney, Australia
| | - Tiffany Harris-Brown
- Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Royal Brisbane and Women's Hospital Campus, Brisbane, Australia
| | - Tony M Korman
- Monash Infectious Diseases, Monash University and Monash Health, Melbourne, Australia
| | - Melanie Figtree
- Department of Infectious Diseases, Royal North Shore Hospital, Sydney, Australia
| | - Leon J Worth
- Department of Infectious Diseases, Peter MacCallum Centre, Melbourne, Australia
- National Centre for Infections in Cancer, Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Jen Kok
- Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, Australia
| | | | - Karen Byth
- Research and Education Network, Western Sydney Local Health District, Sydney, Australia
- National Health and Medical Research Council Clinical Trials Centre, Sydney University, Sydney, Australia
| | - Monica A Slavin
- Department of Infectious Diseases, Peter MacCallum Centre, Melbourne, Australia
- Department of Infectious Diseases, Royal Melbourne Hospital, Melbourne, Australia
| | - David L Paterson
- Correspondence: Adam Stewart, BBiomedSci, MBBS(Hons), MPHTM, Centre for Clinical Research, University of Queensland, Bldg 71/918 RBWH Herston, Brisbane, QLD 4029, Australia (); David Paterson, Saw Swee Hock School of Public Health, National University of Singapore, 12 Science Drive 2, #10-01, Singapore 117549 ()
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13
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Drapkina OM, Lazebnik LB, Bakulin IG, Zhuravleva MS, Bakulina NV, Skazyvaeva EV, Sitkin SI, Skalinskaya MI, Solovyeva OI, Eremina EY, Tikhonov SV, Fil' TS, Pilat TL, Kuznetsova YG, Khanferyan RA, Livzan MA, Osipenko MF, Abdulganieva DI, Tarasova LV, Khavkin AI. <i>Clostridioides difficile</i> infection: diagnosis, treatment, and prevention Clinical guidelines of the Russian Scientific Medical Society of Internal Medicine, the Gastroenterological Scientific Society of Russia, and the North- West Society of Gastroenterologists and Hepatologists. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2023:4-32. [DOI: 10.31146/1682-8658-ecg-210-2-4-32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Clostridioides difficile infection (CDI) is the most common cause of antibiotic-associated diarrhea, and an important cause of nosocomial infection. Since the publication of the National Guidelines (2016, 2017), new data have been accumulated on the genetic structure and pathogenic properties of the most common causative agent of severe forms of antibiotic- associated diarrhea, which has led to the reclassifi cation of the pathogen, formerly known as Clostridium diffi cile, to Clostridioides difficile. Laboratory algorithms have been developed to diagnose CDI and determine the toxigenicity of strains reliably. New data on the effectiveness of antibacterials have been published, monoclonal antibodies to toxin B (bezlotoxumab) have been introduced into clinical practice to prevent CDI recurrence, and fecal microbiota transplantation has been proposed. Over the past 5 years, many international guidelines on the management of adult patients with CDI have also been updated (USA, EU). In the last decade, including due to the COVID-19 pandemic, there has been an increase in CDI incidence. Considering therelevance of CDI, new data on the pathogen, and domestic features, the Russian Scientific Medical Society of Internal Medicine, the Gastroenterological Scientific Society of Russia, and the North-West Society of Gastroenterologists and Hepatologists developed these clinical guidelines.
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Affiliation(s)
- O. M. Drapkina
- National Medical Research Center for Therapy and Preventive Medicine
| | - L. B. Lazebnik
- A. I. Yevdokimov Moscow State University of Medicine and Dentistry
| | - I. G. Bakulin
- North-Western state medical University named after I. I. Mechnikov
| | - M. S. Zhuravleva
- North-Western state medical University named after I. I. Mechnikov
| | - N. V. Bakulina
- North-Western state medical University named after I. I. Mechnikov
| | - E. V. Skazyvaeva
- North-Western state medical University named after I. I. Mechnikov
| | - S. I. Sitkin
- North-Western state medical University named after I. I. Mechnikov; Almazov National Medical Research Centre
| | | | - O. I. Solovyeva
- North-Western state medical University named after I. I. Mechnikov
| | | | - S. V. Tikhonov
- North-Western state medical University named after I. I. Mechnikov
| | - T. S. Fil'
- North-Western state medical University named after I. I. Mechnikov
| | - T. L. Pilat
- Izmerov Research Institute of Occupational Health
| | | | | | | | | | | | | | - A. I. Khavkin
- Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery, Pirogov Russian National Research Medical University
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14
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Emerging Options for the Prevention and Management of Clostridioides difficile Infection. Drugs 2023; 83:105-116. [PMID: 36645620 PMCID: PMC9841950 DOI: 10.1007/s40265-022-01832-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2022] [Indexed: 01/17/2023]
Abstract
Agents in development for the prevention or treatment of Clostridioides difficile infection can be split into three broad categories: antibiotics, microbiome restoration, and vaccines. Given the extensive list of agents currently in development, this narrative review will focus on agents that have progressed into late-stage clinical trials, defined as having a Phase III clinical trial registered on ClinicalTrials.gov. These agents include one antibiotic (ridinilazole), three live biotherapeutic products (LBPs) (CP101, RBX2660, and SER109), and two toxoid vaccines (PF06425090 and a second toxoid vaccine). As new prevention and treatment strategies enter the market, clinicians and administrators will need knowledge of these products to make rational decisions on how best to adopt them into clinical practice.
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15
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Real-World Budget Impact of Fidaxomicin versus Vancomycin or Metronidazole for In-Hospital Treatment of Clostridioides difficile Infection. Antibiotics (Basel) 2023; 12:antibiotics12010106. [PMID: 36671306 PMCID: PMC9854770 DOI: 10.3390/antibiotics12010106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/18/2022] [Accepted: 12/27/2022] [Indexed: 01/10/2023] Open
Abstract
Fidaxomicin, a macrocyclic antibiotic, selectively kills Clostridioides difficile and reduces C. difficile infection (CDI) recurrence compared with vancomycin, but some studies and guidelines report fidaxomicin as being less cost-effective. The aim of this study was to compare the cost-effectiveness and budget impact of fidaxomicin versus vancomycin or metronidazole for treating CDI in a real-world UK setting. Data were retrospectively collected from medical records of 86 patients with CDI treated with vancomycin or metronidazole at a single UK hospital between April 2011 and March 2012, and prospectively from 62 patients with CDI treated with fidaxomicin between August 2012 and July 2013. CDI cases were matched by age, financial year, and healthcare resource use to control cases. CDI recurrence rates were lower with fidaxomicin (6.5%) than vancomycin/metronidazole (19.8%). An estimated 12 additional recurrent CDIs were prevented with fidaxomicin treatment. Patients with CDI had significantly higher healthcare costs than those without CDI, with a mean excess spend of GBP 10,748 and GBP 17,451 per patient in the fidaxomicin (p = 0.015) and vancomycin/metronidazole cohorts (p < 0.001), respectively. A second CDI was associated with mean excess costs of GBP 8373 and GBP 20,249 per patient in the fidaxomicin and vancomycin/metronidazole cohorts, respectively. Despite higher fidaxomicin drug costs, overall cost savings were estimated at GBP 140,292 (GBP 2125 per CDI). In this real-world study, first-line CDI treatment with fidaxomicin reduced healthcare costs versus vancomycin/metronidazole, consistent with previous studies.
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16
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Deshpande A, Chen Y, Boye-Codjoe E, Obi EN. Adoption and Trends in Uptake of Updated ICD-10 Codes for Clostridioides difficile-A Retrospective Observational Study. Open Forum Infect Dis 2022; 9:ofac622. [PMID: 36519119 PMCID: PMC9745779 DOI: 10.1093/ofid/ofac622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 11/12/2022] [Indexed: 08/30/2023] Open
Abstract
BACKGROUND In October 2017, the single International Classification of Diseases, Tenth Revision (ICD-10), code for Clostridioides difficile infection (CDI), A04.7, was replaced with 2 codes delineating "recurrent CDI" (rCDI; A04.71) and "nonrecurrent CDI" (nrCDI; A04.72). METHODS To evaluate and validate use of the updated codes, this retrospective study included inpatient encounters with a CDI-related ICD-10 code from October 2016 to May 2019 in the PINC AITM Healthcare Database (PHD). Encounters after the October 2017 code update were characterized by clinical, facility, and provider variables and whether coding was concordant or discordant to the 8-week recurrence period. Multivariable regression analysis assessed variables associated with concordant coding. RESULTS Widespread adoption of the updated CDI codes across PHD hospitals occurred in October 2017. After October 2017, 21 446 CDI-related encounters met sample selection criteria (concordance in 67% of rCDI and 25% of nrCDI encounters). Higher proportions of rCDI- vs nrCDI-coded encounters (P < .05) had emergency room admission, admission by a gastroenterologist or infectious disease specialist, and were prescribed fidaxomicin, bezlotoxumab, or fecal microbiota transfer (FMT), with no significant difference by coding concordance status. Encounters coded concordantly were significantly more likely to be for rCDI (odds ratio [OR], 5.67; 95% CI, 5.32-6.03), a nonelective admission (OR, 1.35-1.69), or prescribed fidaxomicin (OR, 1.11; 95% CI, 1.01-1.23) or FMT (OR, 1.29; 95% CI, 1.17-1.42). CONCLUSIONS Our study findings suggest no delay in transition to the updated CDI-related codes. Treatment patterns for rCDI vs nrCDI encounters were consistent with Infectious Diseases Society of America guidelines, regardless of concordance status.
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Affiliation(s)
- Abhishek Deshpande
- Center for Value-Based Care Research, Cleveland Clinic Community Care, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Infectious Disease, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Yiyun Chen
- Merck & Co., Inc., Rahway, New Jersey, USA
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17
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Liao JX, Appaneal HJ, Vicent ML, Vyas A, LaPlante KL. Path of least recurrence: A systematic review and
meta‐analysis
of fidaxomicin versus vancomycin for
Clostridioides difficile
infection. Pharmacotherapy 2022; 42:810-827. [DOI: 10.1002/phar.2734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/19/2022] [Accepted: 09/21/2022] [Indexed: 11/06/2022]
Affiliation(s)
- J. Xin Liao
- Infectious Diseases Research Program Providence Veterans Affairs Medical Center Providence Rhode Island USA
- College of Pharmacy University of Rhode Island Kingston Rhode Island USA
| | - Haley J. Appaneal
- Infectious Diseases Research Program Providence Veterans Affairs Medical Center Providence Rhode Island USA
- College of Pharmacy University of Rhode Island Kingston Rhode Island USA
- Center of Innovation in Long‐Term Support Services Providence Veterans Affairs Medical Center Providence Rhode Island USA
| | - Martie L. Vicent
- Infectious Diseases Research Program Providence Veterans Affairs Medical Center Providence Rhode Island USA
- College of Pharmacy University of Rhode Island Kingston Rhode Island USA
| | - Ami Vyas
- College of Pharmacy University of Rhode Island Kingston Rhode Island USA
| | - Kerry L. LaPlante
- Infectious Diseases Research Program Providence Veterans Affairs Medical Center Providence Rhode Island USA
- College of Pharmacy University of Rhode Island Kingston Rhode Island USA
- Center of Innovation in Long‐Term Support Services Providence Veterans Affairs Medical Center Providence Rhode Island USA
- Warren Alpert Medical School of Brown University Providence Rhode Island USA
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18
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Pike CM, Tam J, Melnyk RA, Theriot CM. Tauroursodeoxycholic Acid Inhibits Clostridioides difficile Toxin-Induced Apoptosis. Infect Immun 2022; 90:e0015322. [PMID: 35862710 PMCID: PMC9387233 DOI: 10.1128/iai.00153-22] [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: 04/11/2022] [Accepted: 06/19/2022] [Indexed: 11/20/2022] Open
Abstract
C. difficile infection (CDI) is a highly inflammatory disease mediated by the production of two large toxins that weaken the intestinal epithelium and cause extensive colonic tissue damage. Antibiotic alternative therapies for CDI are urgently needed as current antibiotic regimens prolong the perturbation of the microbiota and lead to high disease recurrence rates. Inflammation is more closely correlated with CDI severity than bacterial burden, thus therapies that target the host response represent a promising yet unexplored strategy for treating CDI. Intestinal bile acids are key regulators of gut physiology that exert cytoprotective roles in cellular stress, inflammation, and barrier integrity, yet the dynamics between bile acids and host cellular processes during CDI have not been investigated. Here we show that several bile acids are protective against apoptosis caused by C. difficile toxins in Caco-2 cells and that protection is dependent on conjugation of bile acids. Out of 20 tested bile acids, taurine conjugated ursodeoxycholic acid (TUDCA) was the most potent inhibitor, yet unconjugated UDCA did not alter toxin-induced apoptosis. TUDCA treatment decreased expression of genes in lysosome associated and cytokine signaling pathways. TUDCA did not affect C. difficile growth or toxin activity in vitro whereas UDCA significantly reduced toxin activity in a Vero cell cytotoxicity assay and decreased tcdA gene expression. These results demonstrate that bile acid conjugation can have profound effects on C. difficile as well as the host and that conjugated and unconjugated bile acids may exert different therapeutic mechanisms against CDI.
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Affiliation(s)
- Colleen M. Pike
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
| | - John Tam
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Roman A. Melnyk
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
- SickKids Proteomics Analytics Robotics Chemical Biology Drug Discovery Facility, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Casey M. Theriot
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
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19
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Zyoud SH. Global research on Clostridium difficile-associated diarrhoea: A visualized study. World J Gastroenterol 2022; 28:3720-3731. [PMID: 36161039 PMCID: PMC9372798 DOI: 10.3748/wjg.v28.i28.3720] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/12/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Clostridioides (Clostridium) difficile (C. difficile) is still the most common cause of healthcare-associated diarrhoea and is increasing in prevalence as a community-acquired infection. In addition, the emergence of antibiotic resistance in C. difficile can increase the likelihood of the disease developing and/or spreading.
AIM To provide an up-to-date picture of the trends in publications related to C. difficile infection, together with specific insights into hot-button issues in this field.
METHODS Publications on C. difficile infections in the field of microbiology between 2001 and 2020 were identified from the Scopus database and Reference Citation Analysis. Bibliometric indicators were determined, including the number and type of publications, countries, affiliations, funding agencies, journals and citation patterns. VOSviewer was used to determine research areas and hot-button issues by identifying recurring terms with a high relative occurrence in the title and abstract.
RESULTS A total of 8127 documents on ‘C. difficile-associated diarrhoea’ published between 2001 and 2020 were retrieved from the Scopus database. In the last decade, there has been a significant almost fourfold increase in the number of published papers on this topic. The United States was among the countries (44.11%) with the most publications, and the most involved institution was the University of Leeds in the United Kingdom (2.50%). Three clusters of research were identified and included ‘illness spectrum and severity, as well as the signs, symptoms and clinical pathogenesis of C. difficile’; ‘laboratory diagnosis and characterization of C. difficile’ and ‘risk factors for C. difficile infection’.
CONCLUSION This study contains the most up-to-date and comprehensive data ever compiled in this field. More international research and cross-institutional collaborations are needed to address more global C. difficile concerns and to benefit from greater sharing of expertise, which will result in higher quality or more effective studies in the future. Promising research avenues in the near future may draw the attention of relevant scientists and funding organizations and open up novel C. difficile infection–based diagnosis and treatment approaches.
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Affiliation(s)
- Sa'ed H Zyoud
- Department of Clinical and Community Pharmacy, College of Medicine and Health Sciences, An-Najah National University, Nablus 44839, Palestine
- Poison Control and Drug Information Center, College of Medicine and Health Sciences, An-Najah National University, Nablus 44839, Palestine
- Clinical Research Centre, An-Najah National University Hospital, Nablus 44839, Palestine
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20
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Xu B, Wu X, Gong Y, Cao J. IL-27 induces LL-37/CRAMP expression from intestinal epithelial cells: implications for immunotherapy of Clostridioides difficile infection. Gut Microbes 2022; 13:1968258. [PMID: 34432564 PMCID: PMC8405154 DOI: 10.1080/19490976.2021.1968258] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Clostridioides difficile infection is currently the leading cause of nosocomial antibiotic-associated diarrhea and pseudomembranous colitis worldwide. Cathelicidins, a major group of natural antimicrobial peptides, have antimicrobial and immunomodulatory activities in Clostridioides difficile infection. Here, we have shown that cytokine IL-27 induced human cathelicidin antimicrobial peptide (LL-37) expression in primary human colonic epithelial cells. IL-27 receptor-deficient mice had impaired expression of cathelicidin-related antimicrobial peptide (CRAMP, mouse homolog for human LL-37) after Clostridioides difficile infection, and restoration of CRAMP improved Clostridium difficile clearance and reduced mortality in IL-27 receptor-deficient mice after Clostridioides difficile challenge. In clinical samples from 119 patients with Clostridioides difficile infection, elevated levels of IL-27 were positively correlated with LL-37 in the sera and stools. These findings suggest that IL-27 may be involved in host immunity against Clostridioides difficile infection via induction of LL-37/CRAMP. Therefore, IL-27-LL-37 axis may be a valuable pathway in the development of immune-based therapy.
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Affiliation(s)
- Banglao Xu
- Department of Laboratory Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Xianan Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Gong
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ju Cao
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China,CONTACT Ju Cao Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Youyi Road 1#, Yu Zhong District, Chongqing, China
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21
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van Rossen TM, Ooijevaar RE, Vandenbroucke-Grauls CMJE, Dekkers OM, Kuijper EJ, Keller JJ, van Prehn J. Prognostic factors for severe and recurrent Clostridioides difficile infection: a systematic review. Clin Microbiol Infect 2021; 28:321-331. [PMID: 34655745 DOI: 10.1016/j.cmi.2021.09.026] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Clostridioides difficile infection (CDI), its subsequent recurrences (rCDIs), and severe CDI (sCDI) provide a significant burden for both patients and the healthcare system. Identifying patients diagnosed with initial CDI who are at increased risk of developing sCDI/rCDI could lead to more cost-effective therapeutic choices. In this systematic review we aimed to identify clinical prognostic factors associated with an increased risk of developing sCDI or rCDI. METHODS PubMed, Embase, Emcare, Web of Science and COCHRANE Library databases were searched from database inception through March, 2021. The study eligibility criteria were cohort and case-control studies. Participants were patients ≥18 years old diagnosed with CDI, in which clinical or laboratory factors were analysed to predict sCDI/rCDI. Risk of bias was assessed by using the Quality in Prognostic Research (QUIPS) tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool modified for prognostic studies. Study selection was performed by two independent reviewers. Overview tables of prognostic factors were constructed to assess the number of studies and the respective effect direction and statistical significance of an association. RESULTS 136 studies were included for final analysis. Greater age and the presence of multiple comorbidities were prognostic factors for sCDI. Identified risk factors for rCDI were greater age, healthcare-associated CDI, prior hospitalization, proton pump inhibitors (PPIs) started during or after CDI diagnosis, and previous rCDI. CONCLUSIONS Prognostic factors for sCDI and rCDI could aid clinicians to make treatment decisions based on risk stratification. We suggest that future studies use standardized definitions for sCDI/rCDI and systematically collect and report the risk factors assessed in this review, to allow for meaningful meta-analysis of risk factors using data of high-quality trials.
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Affiliation(s)
- Tessel M van Rossen
- Amsterdam UMC, VU University Medical Center, Medical Microbiology & Infection Control, Amsterdam Infection & Immunity, Amsterdam, the Netherlands.
| | - Rogier E Ooijevaar
- Amsterdam UMC, VU University Medical Center, Gastroenterology & Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands.
| | - Christina M J E Vandenbroucke-Grauls
- Amsterdam UMC, VU University Medical Center, Medical Microbiology & Infection Control, Amsterdam Infection & Immunity, Amsterdam, the Netherlands; Aarhus University, Clinical Epidemiology, Aarhus, Denmark
| | - Olaf M Dekkers
- Leiden University Medical Center, Clinical Epidemiology, Leiden, the Netherlands
| | - Ed J Kuijper
- Leiden University Medical Center, Center for Infectious Diseases, Medical Microbiology, Leiden, the Netherlands
| | - Josbert J Keller
- Haaglanden Medical Center, Gastroenterology & Hepatology, The Hague, the Netherlands; Leiden University Medical Center, Gastroenterology & Hepatology, Leiden, the Netherlands
| | - Joffrey van Prehn
- Leiden University Medical Center, Center for Infectious Diseases, Medical Microbiology, Leiden, the Netherlands
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22
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Gan BH, Gaynord J, Rowe SM, Deingruber T, Spring DR. The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions. Chem Soc Rev 2021; 50:7820-7880. [PMID: 34042120 PMCID: PMC8689412 DOI: 10.1039/d0cs00729c] [Citation(s) in RCA: 223] [Impact Index Per Article: 55.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Indexed: 12/13/2022]
Abstract
Bacterial infections caused by 'superbugs' are increasing globally, and conventional antibiotics are becoming less effective against these bacteria, such that we risk entering a post-antibiotic era. In recent years, antimicrobial peptides (AMPs) have gained significant attention for their clinical potential as a new class of antibiotics to combat antimicrobial resistance. In this review, we discuss several facets of AMPs including their diversity, physicochemical properties, mechanisms of action, and effects of environmental factors on these features. This review outlines various chemical synthetic strategies that have been applied to develop novel AMPs, including chemical modifications of existing peptides, semi-synthesis, and computer-aided design. We will also highlight novel AMP structures, including hybrids, antimicrobial dendrimers and polypeptides, peptidomimetics, and AMP-drug conjugates and consider recent developments in their chemical synthesis.
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Affiliation(s)
- Bee Ha Gan
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
| | - Josephine Gaynord
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
| | - Sam M Rowe
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
| | - Tomas Deingruber
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
| | - David R Spring
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
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23
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Boekhoud IM, Sidorov I, Nooij S, Harmanus C, Bos-Sanders IMJG, Viprey V, Spittal W, Clark E, Davies K, Freeman J, Kuijper EJ, Smits WK. Haem is crucial for medium-dependent metronidazole resistance in clinical isolates of Clostridioides difficile. J Antimicrob Chemother 2021; 76:1731-1740. [PMID: 33876817 PMCID: PMC8212768 DOI: 10.1093/jac/dkab097] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 03/02/2021] [Indexed: 01/05/2023] Open
Abstract
Background Until recently, metronidazole was the first-line treatment for Clostridioides difficile infection and it is still commonly used. Though resistance has been reported due to the plasmid pCD-METRO, this does not explain all cases. Objectives To identify factors that contribute to plasmid-independent metronidazole resistance of C. difficile. Methods Here, we investigate resistance to metronidazole in a collection of clinical isolates of C. difficile using a combination of antimicrobial susceptibility testing on different solid agar media and WGS of selected isolates. Results We find that nearly all isolates demonstrate a haem-dependent increase in the MIC of metronidazole, which in some cases leads to isolates qualifying as resistant (MIC >2 mg/L). Moreover, we find an SNP in the haem-responsive gene hsmA, which defines a metronidazole-resistant lineage of PCR ribotype 010/MLST ST15 isolates that also includes pCD-METRO-containing strains. Conclusions Our data demonstrate that haem is crucial for medium-dependent metronidazole resistance in C. difficile.
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Affiliation(s)
- Ilse M Boekhoud
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Igor Sidorov
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Sam Nooij
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.,Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands
| | - Céline Harmanus
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Virginie Viprey
- Healthcare Associated Infection Research Group, School of Medicine, University of Leeds, Leeds, UK
| | - William Spittal
- Healthcare Associated Infection Research Group, School of Medicine, University of Leeds, Leeds, UK
| | - Emma Clark
- Healthcare Associated Infection Research Group, School of Medicine, University of Leeds, Leeds, UK
| | - Kerrie Davies
- Healthcare Associated Infection Research Group, School of Medicine, University of Leeds, Leeds, UK.,European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Study Group for Clostridioides difficile (ESGCD), Basel, Switzerland
| | - Jane Freeman
- Healthcare Associated Infection Research Group, School of Medicine, University of Leeds, Leeds, UK.,European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Study Group for Clostridioides difficile (ESGCD), Basel, Switzerland
| | - Ed J Kuijper
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.,European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Study Group for Clostridioides difficile (ESGCD), Basel, Switzerland.,National Institute for Public Health and the Environment, Bilthoven, The Netherlands
| | - Wiep Klaas Smits
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.,Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands.,European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Study Group for Clostridioides difficile (ESGCD), Basel, Switzerland
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24
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Guery B, Berger P, Gauzit R, Gourdon M, Barbut F, Dafne Study Group, Bémer P, Bessède E, Camou F, Cattoir V, Couzigou C, Descamps D, Dinh A, Laurans C, Lavigne JP, Lechiche C, Leflon-Guibout V, Le Monnier A, Levast M, Mootien JY, N'Guyen Y, Piroth L, Prazuck T, Rogeaux O, Roux AL, Vachée A, Vernet Garnier V, Wallet F. A prospective, observational study of fidaxomicin use for Clostridioides difficile infection in France. J Int Med Res 2021; 49:3000605211021278. [PMID: 34162264 PMCID: PMC8236878 DOI: 10.1177/03000605211021278] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE To describe the characteristics, management and outcomes of hospitalised patients with Clostridioides difficile infection (CDI) treated with and without fidaxomicin. METHODS This prospective, multicentre, observational study (DAFNE) enrolled hospitalised patients with CDI, including 294 patients treated with fidaxomicin (outcomes recorded over a 3-month period) and 150 patients treated with other CDI therapies during three 1-month periods. The primary endpoint was baseline and CDI characteristics of fidaxomicin-treated patients. RESULTS At baseline, the fidaxomicin-treated population included immunocompromised patients (39.1%) and patients with severe (59.2%) and recurrent (36.4%) CDI. Fidaxomicin was associated with a high rate of clinical cure (92.2%) and low CDI recurrence (16.3% within 3 months). Clinical cure rates were ≥90% in patients aged ≥65 years, those receiving concomitant antibiotics and those with prior or severe CDI. There were 121/296 (40.9%) patients with adverse events (AEs), 5.4% with fidaxomicin-related AEs and 1.0% with serious fidaxomicin-related AEs. No fidaxomicin-related deaths were reported. CONCLUSIONS Fidaxomicin is an effective and well-tolerated CDI treatment in a real-world setting in France, which included patients at high risk of adverse outcomes.Trial registration: Description of the use of fidaxomicin in hospitalised patients with documented Clostridium difficile infection and the management of these patients (DAFNE), NCT02214771, www.ClinicalTrials.gov.
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Affiliation(s)
- Benoit Guery
- University Hospital and University of Lausanne, Lausanne, Switzerland
| | | | | | | | - Frédéric Barbut
- National Reference Laboratory for C. difficile, Saint-Antoine Hospital, Paris, France.,INSERM S-1139, Faculty of Pharmacy, University of Paris, Paris, France
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25
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Kelly CR, Fischer M, Allegretti JR, LaPlante K, Stewart DB, Limketkai BN, Stollman NH. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. Am J Gastroenterol 2021; 116:1124-1147. [PMID: 34003176 DOI: 10.14309/ajg.0000000000001278] [Citation(s) in RCA: 273] [Impact Index Per Article: 68.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 03/25/2021] [Indexed: 02/06/2023]
Abstract
Clostridioides difficile infection occurs when the bacterium produces toxin that causes diarrhea and inflammation of the colon. These guidelines indicate the preferred approach to the management of adults with C. difficile infection and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation process. In instances where the evidence was not appropriate for Grading of Recommendations Assessment, Development, and Evaluation but there was consensus of significant clinical merit, key concept statements were developed using expert consensus. These guidelines are meant to be broadly applicable and should be viewed as the preferred, but not the only, approach to clinical scenarios.
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Affiliation(s)
- Colleen R Kelly
- Division of Gastroenterology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Monika Fischer
- Division of Gastroenterology, Indiana University, Indianapolis, Indiana, USA
| | - Jessica R Allegretti
- Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kerry LaPlante
- Department of Pharmacy Practice, University of Rhode Island College of Pharmacy, Kingston, Rhode Island, USA
| | - David B Stewart
- Department of Surgery, University of Arizona Health Sciences, Tucson, Arizona, USA
| | - Berkeley N Limketkai
- Division of Digestive Diseases, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Neil H Stollman
- Division of Gastroenterology, Alta Bates Summit Medical Center, East Bay Center for Digestive Health, Oakland, California, USA
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26
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Turner NA, Warren BG, Gergen-Teague MF, Addison RM, Addison B, Rutala WA, Weber DJ, Sexton DJ, Anderson DJ. Impact of Oral Metronidazole, Vancomycin, and Fidaxomicin on Host Shedding and Environmental Contamination with Clostridioides difficile. Clin Infect Dis 2021; 74:648-656. [PMID: 34017999 DOI: 10.1093/cid/ciab473] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES Shedding of Clostridioides difficile spores from infected individuals contaminates the hospital environment and contributes to infection transmission. We assessed whether antibiotic selection impacts C. difficile shedding and contamination of the hospital environment. METHODS In this prospective, unblinded, randomized controlled trial of hospitalized adults with C. difficile infection, subjects were randomized 1:1:1 to receive fidaxomicin, oral vancomycin, or metronidazole. The primary outcome was change in environmental contamination rate while on treatment. Secondary outcomes included stool shedding, total burden of contamination, and molecular relatedness of stool versus environmental C. difficile isolates. RESULTS 33 patients were enrolled and 31 (94%) completed the study. Fidaxomicin (-0.36 log10 CFU/day, 95% CI -0.52 to -0.19, p<0.01) and vancomycin (-0.17 log10 CFU/day, 95% CI -0.34 to -0.01, p=0.05) were associated with more rapid decline in C. difficile shedding compared to metronidazole (-0.01 log10 CFU/day, 95% CI -0.10 to +0.08). Both vancomycin (6.3%, 95% CI 4.7-8.3%) and fidaxomicin (13.1%, 95% CI 10.7-15.9%) were associated with lower rates of environmental contamination than metronidazole (21.4%, 95% CI 18.0-25.2%). When specifically modeling within-subject change over time, fidaxomicin (aOR 0.83, 95% CI 0.70-0.99, p=0.04) was associated with more rapid decline in environmental contamination than vancomycin or metronidazole. Overall, 207 of 233 (88.8%) of environmental C. difficile isolates matched subject stool isolates by ribotyping, without significant difference by treatment. CONCLUSIONS Fidaxomicin, and to a lesser extent vancomycin, reduces C. difficile shedding and contamination of the hospital environment relative to metronidazole. Treatment choice may play a role in reducing healthcare-associated C. difficile transmission.
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Affiliation(s)
- Nicholas A Turner
- Duke University School of Medicine, Division of Infectious Diseases, Durham, North Carolina, USA.,Duke Infection Control Outreach Network, Durham, North Carolina, USA
| | - Bobby G Warren
- Duke University School of Medicine, Division of Infectious Diseases, Durham, North Carolina, USA.,Duke Infection Control Outreach Network, Durham, North Carolina, USA
| | - Maria F Gergen-Teague
- Division of Infectious Diseases, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Rachel M Addison
- Duke University School of Medicine, Division of Infectious Diseases, Durham, North Carolina, USA.,Duke Infection Control Outreach Network, Durham, North Carolina, USA
| | - Bechtler Addison
- Duke University School of Medicine, Division of Infectious Diseases, Durham, North Carolina, USA.,Duke Infection Control Outreach Network, Durham, North Carolina, USA
| | - William A Rutala
- Division of Infectious Diseases, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - David J Weber
- Division of Infectious Diseases, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Daniel J Sexton
- Duke University School of Medicine, Division of Infectious Diseases, Durham, North Carolina, USA.,Duke Infection Control Outreach Network, Durham, North Carolina, USA
| | - Deverick J Anderson
- Duke University School of Medicine, Division of Infectious Diseases, Durham, North Carolina, USA.,Duke Infection Control Outreach Network, Durham, North Carolina, USA
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27
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Diagnostic and therapy of severe Clostridioides difficile infections in the ICU. Curr Opin Crit Care 2021; 26:450-458. [PMID: 32739967 DOI: 10.1097/mcc.0000000000000753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW The purpose of the review is to provide all the recent data focusing on the diagnostic and treatment of Clostridioides difficile infection in patients admitted in the ICU. RECENT FINDINGS In the ICU, diagnosis remains complicated with a large number of alternative diagnosis. The treatment classically relies on vancomycin but fidaxomicin and fecal microbiota transplantation are now potential solutions in selected indications. SUMMARY Data on ICU-related CDI remain limited and conflicting. To date, there is no unique and simple way to obtain a diagnosis for CDI, the combination of clinical signs and a two-step testing algorithm remains the recommended gold-standard. Two molecules can be proposed for first line treatment: vancomycin and fidaxomicin. Although metronidazole may still be discussed as a treatment option for mild CDI in low-risk patients, its use for ICU-patients does not seem reasonable. Several reports suggest that fecal microbiota transplantation could be discussed, as it is well tolerated and associated with a high rate of clinical cure. CDI is a dynamic and active area of research with new diagnostic techniques, molecules, and management concepts likely changing our approach to this old disease in the near future.
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28
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Pike CM, Theriot CM. Mechanisms of Colonization Resistance Against Clostridioides difficile. J Infect Dis 2020; 223:S194-S200. [PMID: 33326565 DOI: 10.1093/infdis/jiaa408] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Clostridioides difficile is an urgent antimicrobial-resistant bacterium, causing mild to moderate and sometimes life-threatening disease. Commensal gut microbes are critical for providing colonization resistance against C difficile and can be leveraged as non-antibiotic alternative therapeutics for the prevention and treatment of C difficile infection.
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Affiliation(s)
- Colleen M Pike
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
| | - Casey M Theriot
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
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29
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Song J, Shen X, Huang Z, Liu Y, Cui L, Cui X, Liu CY. Clostridium difficile toxin A and toxin B inhibit YAP in the colonic epithelial cells. J Biochem Mol Toxicol 2020; 35:e22652. [PMID: 33251692 DOI: 10.1002/jbt.22652] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 04/14/2020] [Accepted: 09/29/2020] [Indexed: 11/08/2022]
Abstract
Toxin A (TcdA) and toxin B (TcdB), the two exotoxins of Clostridium difficile, are main causal agents for the colonic epithelium damage in Clostridium difficile infection (CDI). The Hippo pathway is crucial for the control of tissue homeostasis and regeneration of intestines. However, the dysregulation of Hippo pathway in CDI is unclear. Here we show that YAP and TAZ, the transcriptional coactivators downstream of the Hippo pathway, are sequestered in the cytoplasm, degraded, and inactivated by treatment with TcdA and TcdB in colonic epithelial cells. The overexpression of YAP restores the messenger RNA expressions of YAP target genes, attenuates the disruption of cytoskeleton and cell rounding, and rescues the cell proliferation of colonic epithelial cells under exposure of the two toxins. Our results demonstrate that inhibition of YAP and TAZ is involved in the pathogenesis of CDI, implicating that increasing YAP activity could be a potential therapeutic strategy for the CDI treatment.
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Affiliation(s)
- Jinglue Song
- Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Colorectal Cancer Research Center, Shanghai, China
| | - Xia Shen
- Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Colorectal Cancer Research Center, Shanghai, China
| | - Zhenyu Huang
- Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Colorectal Cancer Research Center, Shanghai, China
| | - Yun Liu
- Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Colorectal Cancer Research Center, Shanghai, China
| | - Long Cui
- Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Colorectal Cancer Research Center, Shanghai, China
| | - Xuewei Cui
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen-Ying Liu
- Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Colorectal Cancer Research Center, Shanghai, China
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30
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Fidaxomicin versus metronidazole, vancomycin and their combination for initial episode, first recurrence and severe Clostridioides difficile infection - An observational cohort study. Int J Infect Dis 2020; 103:226-233. [PMID: 33188906 DOI: 10.1016/j.ijid.2020.11.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 12/11/2022] Open
Abstract
PURPOSE We aimed to evaluate the efficacy of different antibiotic regimens for the treatment of Clostridioides difficile infection (CDI) with regard to the CDI episode number and disease severity. METHODS An observation cohort study included 271 CDI patients hospitalised between 2013-2016. Univariate logistic regression was used to evaluate the association between patients' clinical outcome (sustained clinical cure or recurrence) in a 60-day follow-up and the antibiotic regimen used (oral metronidazole, oral vancomycin, combination of oral vancomycin and metronidazole, oral fidaxomicin). Subgroup analyses, based on CDI episode number and severity, were performed. RESULTS In the overall population, fidaxomicin was superior to metronidazole, vancomycin or their combination, for a sustained clinical response and in the prevention of recurrent CDI (rCDI). In the subgroup analyses, fidaxomicin was superior to vancomycin or metronidazole for a sustained clinical response and in the prevention of rCDI in the initial episode, first recurrence and non-severe cases. In the oral treatment of severe CDI, fidaxomicin had a similar treatment outcome to vancomycin and none of the antibiotic treatments were superior in the prevention of rCDI. Fidaxomicin, vancomycin, or a combination of metronidazole and vancomycin, had similar outcomes for sustained clinical response and prevention of rCDI in patients with multiple rCDI. CONCLUSION Fidaxomicin was superior to metronidazole or vancomycin for the treatment of the initial episode, first recurrence, and non-severe CDI.
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31
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Dembrovszky F, Gede N, Szakács Z, Hegyi P, Kiss S, Farkas N, Molnár Z, Imrei M, Dohos D, Péterfi Z. Fecal Microbiota Transplantation May Be the Best Option in Treating Multiple Clostridioides difficile Infection: A Network Meta-Analysis. Infect Dis Ther 2020; 10:201-211. [PMID: 33106983 PMCID: PMC7954965 DOI: 10.1007/s40121-020-00356-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 10/08/2020] [Indexed: 02/08/2023] Open
Abstract
Introduction Clostridioides difficile (formerly Clostridium) infection (CDI) is the most common cause of healthcare-associated diarrhea with high mortality and recurrence rate; furthermore, the treatment of recurrent cases is a challenge. In this network meta-analysis, we aimed to compare all available therapies against multiple recurrent CDI (mrCDI) and rank them by efficacy. Methods After a systematic search, randomized controlled trials (RCT) with any interventions against mrCDI were included. Data were extracted to the study database using Excel. Risk of bias assessment was performed with the Cochrane RoB 2 tool. The primary outcome was the clinical cure of CDI and the secondary outcome was the recurrence of CDI. A Bayesian method was performed to investigate the efficacy rank order of therapies. We registered our protocol with the Prospero Center for Reviews and Dissemination (registration no. CRD42020160365). Results Six RCTs with seven interventions were included in the quantitative synthesis. According to the surface under the cumulative ranking curve values, fecal microbiota transplantation (FMT) after a short course of vancomycin therapy (83%) shows the highest efficacy for clinical cure. Tolevamer and vancomycin + FMT seemed to be the most effective in preventing recurrence (87% and 75%, respectively). Conclusion Vancomycin + FMT is perhaps the most effective option for the treatment and prevention of mrCDI, while tolevamer is also effective in preventing recurrence. Electronic Supplementary Material The online version of this article (10.1007/s40121-020-00356-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Fanni Dembrovszky
- Medical School, Institute for Translational Medicine, University of Pécs, Pécs, Hungary
| | - Noémi Gede
- Medical School, Institute for Translational Medicine, University of Pécs, Pécs, Hungary
| | - Zsolt Szakács
- Medical School, Institute for Translational Medicine, University of Pécs, Pécs, Hungary
- János Szentágothai Research Center, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Medical School, Institute for Translational Medicine, University of Pécs, Pécs, Hungary
- János Szentágothai Research Center, University of Pécs, Pécs, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
| | - Szabolcs Kiss
- Medical School, Institute for Translational Medicine, University of Pécs, Pécs, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
| | - Nelli Farkas
- Medical School, Institute for Translational Medicine, University of Pécs, Pécs, Hungary
| | - Zsolt Molnár
- Medical School, Institute for Translational Medicine, University of Pécs, Pécs, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
- Department of Anesthesiology and Intensive Therapy, Medical Faculty, Poznan University for Medical Sciences, Poznań, Poland
| | - Marcell Imrei
- Medical School, Institute for Translational Medicine, University of Pécs, Pécs, Hungary
| | - Dóra Dohos
- Medical School, Institute for Translational Medicine, University of Pécs, Pécs, Hungary
| | - Zoltán Péterfi
- Division of Infectious Diseases, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary.
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32
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Appaneal HJ, Caffrey AR, LaPlante KL. What Is the Role for Metronidazole in the Treatment of Clostridium difficile Infection? Results From a National Cohort Study of Veterans With Initial Mild Disease. Clin Infect Dis 2020; 69:1288-1295. [PMID: 30561531 DOI: 10.1093/cid/ciy1077] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 12/12/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Metronidazole may still be an appropriate therapeutic option for mild Clostridium difficile infection (CDI) in select patients, but data are limited to guide clinicians in identifying these patients. METHODS Our 2-stage study included a national cohort of Veterans with a first episode of mild CDI (2010-2014). First, among those treated with metronidazole, we identified predictors of success, defined as absence of all-cause mortality or recurrence 30 days posttreatment, using multivariable unconditional logistic regression. Second, among a subgroup of patients with characteristics predictive of success identified in the first stage, we compared clinical outcomes among those treated with metronidazole compared with vancomycin, using Cox proportional hazards models for time to 30-day all-cause mortality, CDI recurrence, and failure. RESULTS Among 3656 patients treated with metronidazole, we identified 3282 patients with success and 374 patients without success (failure). Younger age was the only independent predictor of success. Age ≤65 years was associated with an odds of success 1.63 times higher (95% confidence interval [CI], 1.29-2.06) than age >65 years. Among 115 propensity score-matched pairs ≤65 years of age, no significant differences were observed between metronidazole and vancomycin (reference) for all-cause mortality (hazard ratio [HR], 0.29 [95% CI, .06-1.38]), CDI recurrence (HR, 0.62 [95% CI, .26-1.49]), or failure (HR, 0.50 [95% CI, .23-1.07]). CONCLUSIONS Among patients ≤65 years of age with initial mild CDI, clinical outcomes were similar with metronidazole and vancomycin. These data suggest that metronidazole may be considered for the treatment of initial mild CDI among patients 65 years of age or younger.
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Affiliation(s)
- Haley J Appaneal
- Infectious Diseases Research Program, Providence Veterans Affairs Medical Center, Kingston.,College of Pharmacy, University of Rhode Island, Kingston.,Center of Innovation in Long-Term Support Services, Providence Veterans Affairs Medical Center, Providence, Rhode Island
| | - Aisling R Caffrey
- Infectious Diseases Research Program, Providence Veterans Affairs Medical Center, Kingston.,College of Pharmacy, University of Rhode Island, Kingston.,Center of Innovation in Long-Term Support Services, Providence Veterans Affairs Medical Center, Providence, Rhode Island.,Brown University School of Public Health, Providence, Rhode Island
| | - Kerry L LaPlante
- Infectious Diseases Research Program, Providence Veterans Affairs Medical Center, Kingston.,College of Pharmacy, University of Rhode Island, Kingston.,Center of Innovation in Long-Term Support Services, Providence Veterans Affairs Medical Center, Providence, Rhode Island.,Division of Infectious Diseases, Warren Alpert Medical School, Brown University, Providence, Rhode Island
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33
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Foschetti DA, Braga-Neto MB, Bolick D, Moore J, Alves LA, Martins CS, Bomfin LE, Santos A, Leitão R, Brito G, Warren CA. Clostridium difficile toxins or infection induce upregulation of adenosine receptors and IL-6 with early pro-inflammatory and late anti-inflammatory pattern. ACTA ACUST UNITED AC 2020; 53:e9877. [PMID: 32725081 PMCID: PMC7405017 DOI: 10.1590/1414-431x20209877] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023]
Abstract
Clostridium difficile causes intestinal inflammation, which increases adenosine. We compared the expression of adenosine receptors (AR) subtypes A1, A2A, A2B, and A3 in HCT-8, IEC-6 cells, and isolated intestinal epithelial cells, challenged or not with Clostridium difficile toxin A and B (TcdA and TcdB) or infection (CDI). In HCT-8, TcdB induced an early A2BR expression at 6 h and a late A2AR expression at 6 and 24 h. In addition, both TcdA and TcdB increased IL-6 expression at all time-points (peak at 6 h) and PSB603, an A2BR antagonist, decreased IL-6 expression and production. In isolated cecum epithelial cells, TcdA induced an early expression of A2BR at 2s and 6 h, followed by a late expression of A2AR at 6 and 24 h and of A1R at 24 h. In CDI, A2AR and A2BR expressions were increased at day 3, but not at day 7. ARs play a role in regulating inflammation during CDI by inducing an early pro-inflammatory and a late anti-inflammatory response. The timing of interventions with AR antagonist or agonists may be of relevance in treatment of CDI.
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Affiliation(s)
- D A Foschetti
- Departamento de Morfologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - M B Braga-Neto
- Departamento de Morfologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - D Bolick
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA
| | - J Moore
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA
| | - L A Alves
- Departamento de Ciências Médicas, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - C S Martins
- Departamento de Morfologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - L E Bomfin
- Departamento de Ciências Médicas, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - Aaqa Santos
- Departamento de Morfologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - Rfc Leitão
- Departamento de Morfologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - Gac Brito
- Departamento de Morfologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brasil
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Magana M, Pushpanathan M, Santos AL, Leanse L, Fernandez M, Ioannidis A, Giulianotti MA, Apidianakis Y, Bradfute S, Ferguson AL, Cherkasov A, Seleem MN, Pinilla C, de la Fuente-Nunez C, Lazaridis T, Dai T, Houghten RA, Hancock REW, Tegos GP. The value of antimicrobial peptides in the age of resistance. THE LANCET. INFECTIOUS DISEASES 2020; 20:e216-e230. [PMID: 32653070 DOI: 10.1016/s1473-3099(20)30327-3] [Citation(s) in RCA: 615] [Impact Index Per Article: 123.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 03/29/2020] [Accepted: 04/16/2020] [Indexed: 12/20/2022]
Abstract
Accelerating growth and global expansion of antimicrobial resistance has deepened the need for discovery of novel antimicrobial agents. Antimicrobial peptides have clear advantages over conventional antibiotics which include slower emergence of resistance, broad-spectrum antibiofilm activity, and the ability to favourably modulate the host immune response. Broad bacterial susceptibility to antimicrobial peptides offers an additional tool to expand knowledge about the evolution of antimicrobial resistance. Structural and functional limitations, combined with a stricter regulatory environment, have hampered the clinical translation of antimicrobial peptides as potential therapeutic agents. Existing computational and experimental tools attempt to ease the preclinical and clinical development of antimicrobial peptides as novel therapeutics. This Review identifies the benefits, challenges, and opportunities of using antimicrobial peptides against multidrug-resistant pathogens, highlights advances in the deployment of novel promising antimicrobial peptides, and underlines the needs and priorities in designing focused development strategies taking into account the most advanced tools available.
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Affiliation(s)
- Maria Magana
- Department of Biopathology and Clinical Microbiology, Aeginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Ana L Santos
- Department of Chemistry, Rice University, Houston, TX, USA; Investigación Sanitaria de las Islas Baleares, Palma, Spain
| | - Leon Leanse
- Department of Dermatology, Harvard Medical School, Boston, MA, USA; Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA
| | - Michael Fernandez
- Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada
| | | | | | | | - Steven Bradfute
- Department of Internal Medicine, Center for Global Health, University of New Mexico, Albuquerque, NM, USA
| | - Andrew L Ferguson
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
| | - Artem Cherkasov
- Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada
| | - Mohamed N Seleem
- Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA
| | - Clemencia Pinilla
- Torrey Pines Institute for Molecular Studies, Port St Lucie, FL, USA
| | - Cesar de la Fuente-Nunez
- Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Penn Institute for Computational Science, and Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Themis Lazaridis
- Department of Chemistry, The City College of New York, New York, NY, USA; Graduate Programs in Chemistry, Biochemistry, and Physics, The Graduate Center, City University of New York, NY, USA
| | - Tianhong Dai
- Department of Dermatology, Harvard Medical School, Boston, MA, USA; Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA
| | | | - Robert E W Hancock
- Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC, Canada
| | - George P Tegos
- Reading Hospital, Tower Health, West Reading, PA, USA; Micromoria, Venture X Marlborough, Marlborough, MA, USA.
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Bermejo Boixareu C, Tutor-Ureta P, Ramos Martínez A. [Updated review of Clostridium difficile infection in elderly]. Rev Esp Geriatr Gerontol 2020; 55:225-235. [PMID: 32423602 DOI: 10.1016/j.regg.2019.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 12/10/2019] [Accepted: 12/19/2019] [Indexed: 06/11/2023]
Abstract
Clostridium difficile infection is the most common cause of health care-associated diarrhoea, and its incidence increases with age. Clinical challenges, risk of resistance to treatment, risk of recurrence, and treatment responses are different in elderly. The aim of this review is to discuss the updated epidemiology, pathophysiology, diagnosis, and therapeutic management of C. difficile infection in elderly with the available data.
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Affiliation(s)
| | - Pablo Tutor-Ureta
- Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, España
| | - Antonio Ramos Martínez
- Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, España
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36
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Trejo-Avila M, Vergara-Fernandez O, Solórzano-Vicuña D, Santes O, Sainz-Hernández JC, Moctezuma-Velázquez P, Salgado-Nesme N. A systematic review and meta-analysis of diverting loop ileostomy versus total abdominal colectomy for the treatment of Clostridium difficile colitis. Langenbecks Arch Surg 2020; 405:715-723. [DOI: 10.1007/s00423-020-01910-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/12/2020] [Indexed: 01/28/2023]
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Antibiotic Treatment Pipeline for Clostridioides difficile Infection (CDI): A Wide Array of Narrow-Spectrum Agents. Curr Infect Dis Rep 2020. [DOI: 10.1007/s11908-020-00730-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Wu KS, Syue LS, Cheng A, Yen TY, Chen HM, Chiu YH, Hsu YL, Chiu CH, Su TY, Tsai WL, Chen WY, Huang CH, Hung HM, Huang LJ, Kuo HJ, Lin PC, Yang CH, Hong PL, Lee SSJ, Chen YS, Liu YC, Huang LM. Recommendations and guidelines for the treatment of Clostridioides difficile infection in Taiwan. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2020; 53:191-208. [PMID: 32169531 DOI: 10.1016/j.jmii.2020.02.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 01/19/2020] [Accepted: 02/01/2020] [Indexed: 12/13/2022]
Abstract
Clostridioides difficile infection (CDI) is a major enteric disease associated with antibiotic use and a leading cause of hospital-acquired infections worldwide. This is the first guideline for treatment of CDI in Taiwan, aiming to optimize medical care for patients with CDI. The target audience of this document includes all healthcare personnel who are involved in the medical care of patients with CDI. The 2018 Guidelines Recommendations for Evidence-based Antimicrobial agents use in Taiwan (GREAT) working group was formed, comprising of infectious disease specialists from 13 medical centers in Taiwan, to review the evidence and draft recommendations using the grading of recommendations assessment, development, and evaluation (GRADE) methodology. A nationwide expert panel reviewed the recommendations during a consensus meeting in March 2019. The recommendation is endorsed by the Infectious Diseases Society of Taiwan (IDST). This guideline describes the epidemiology and risk factors of CDI, and provides recommendations for treatment of CDI in both adults and children. Recommendations for treatment of the first episode of CDI, first recurrence, second and subsequent recurrences of CDI, severe CDI, fulminant CDI, and pediatric CDI are provided.
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Affiliation(s)
- Kuan-Sheng Wu
- Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ling-Shan Syue
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Aristine Cheng
- Division of Infectious Diseases, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ting-Yu Yen
- Departments of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsien-Meng Chen
- Division of Infectious Disease, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Yu-Hsin Chiu
- Division of Infectious Diseases, Chi-Mei Medical Center, Tainan, Taiwan
| | - Yu-Lung Hsu
- Division of Pediatric Infectious Diseases, China Medical University Children's Hospital, China Medical University, Taichung, Taiwan
| | - Chun-Hsiang Chiu
- Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Ting-Yi Su
- Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Wan-Lin Tsai
- Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Wei-Yu Chen
- Division of General Medicine, Infectious Disease, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Chung-Hao Huang
- Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Huei-Min Hung
- Department of Pediatrics, Chang Gung Children's Hospital, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ling-Ju Huang
- Division of General Medicine, Infectious Diseases, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hong-Jie Kuo
- Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Pei-Chin Lin
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Hsiang Yang
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Pi-Lien Hong
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Susan Shin-Jung Lee
- Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
| | - Yao-Shen Chen
- Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yung-Ching Liu
- Division of Infectious Diseases, Taipei Medical University Shuang Ho Hospital, Taipei, Taiwan
| | - Li-Ming Huang
- Departments of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
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Plasmid-mediated metronidazole resistance in Clostridioides difficile. Nat Commun 2020; 11:598. [PMID: 32001686 PMCID: PMC6992631 DOI: 10.1038/s41467-020-14382-1] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 12/24/2019] [Indexed: 12/17/2022] Open
Abstract
Metronidazole was until recently used as a first-line treatment for potentially life-threatening Clostridioides difficile (CD) infection. Although cases of metronidazole resistance have been documented, no clear mechanism for metronidazole resistance or a role for plasmids in antimicrobial resistance has been described for CD. Here, we report genome sequences of seven susceptible and sixteen resistant CD isolates from human and animal sources, including isolates from a patient with recurrent CD infection by a PCR ribotype (RT) 020 strain, which developed resistance to metronidazole over the course of treatment (minimal inhibitory concentration [MIC] = 8 mg L−1). Metronidazole resistance correlates with the presence of a 7-kb plasmid, pCD-METRO. pCD-METRO is present in toxigenic and non-toxigenic resistant (n = 23), but not susceptible (n = 563), isolates from multiple countries. Introduction of a pCD-METRO-derived vector into a susceptible strain increases the MIC 25-fold. Our finding of plasmid-mediated resistance can impact diagnostics and treatment of CD infections. Cases of C. difficile (CD) resistant to metronidazole have been reported but the mechanism remains enigmatic. Here the authors identify a plasmid, which correlates with metronidazole resistance status in a large international collection of CD isolates, and demonstrate that the plasmid can confer metronidazole resistance.
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40
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Appaneal HJ, Caffrey AR, Beganovic M, Avramovic S, LaPlante KL. Predictors of Clostridioides difficile recurrence across a national cohort of veterans in outpatient, acute, and long-term care settings. Am J Health Syst Pharm 2019; 76:581-590. [PMID: 31361830 DOI: 10.1093/ajhp/zxz032] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
PURPOSE The greatest challenge in treating Clostridioides difficile infection (CDI) is disease recurrence, which occurs in about 20% of patients, usually within 30 days of treatment cessation. We sought to identify independent predictors of first recurrence among a national cohort of veterans with CDI. METHODS We conducted a case-control study among acute and long-term care Veterans Affairs (VA) inpatients and outpatients with a first CDI episode (positive stool sample for C. difficile toxin[s] and receipt of at least 2 days of CDI treatment) between 2010 and 2014. Cases experienced first recurrence within 30 days from the end of treatment. Controls were those without first recurrence matched 4:1 to cases on year, facility, and severity. Multivariable conditional logistic regression was used to identify predictors of first recurrence. RESULTS We identified 32 predictors of first recurrence among 974 cases and 3,896 matched controls. Significant predictors included medication use prior to (probiotics, fluoroquinolones, laxatives, third- or fourth-generation cephalosporins), during (first- or second-generation cephalosporins, penicillin/amoxicillin/ampicillin, third- and fourth-generation cephalosporins), and after CDI treatment (probiotics, any antibiotic, proton pump inhibitors [PPIs], and immunosuppressants). Other predictors included current biliary tract disease, malaise/fatigue, cellulitis/abscess, solid organ cancer, medical history of HIV, multiple myeloma, abdominal pain, and ulcerative colitis. CONCLUSION In a large national cohort of outpatient and acute and long-term care inpatients, treatment with certain antibiotics, PPIs, immunosuppressants, and underlying disease were among the most important risk factors for first CDI recurrence.
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Affiliation(s)
- Haley J Appaneal
- Infectious Diseases Research Program, Providence Veterans Affairs Medical Center, Providence, RI, and College of Pharmacy, University of Rhode Island, Kingston, RI
| | - Aisling R Caffrey
- Diseases Research Program, Providence Veterans Affairs Medical Center, Providence, RI, and College of Pharmacy, University of Rhode Island, Kingston, RI
| | - Maya Beganovic
- Diseases Research Program, Providence Veterans Affairs Medical Center, Providence, RI, and College of Pharmacy, University of Rhode Island, Kingston, RI
| | - Sanja Avramovic
- Health Administration and Policy, George Mason University, Fairfax, VA
| | - Kerry L LaPlante
- Infectious Diseases Research Program, Providence Veterans Affairs Medical Center, Providence, RI, and College of Pharmacy, University of Rhode Island, Kingston, RI
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41
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Virulence Factors of Clostridioides ( Clostridium) difficile Linked to Recurrent Infections. CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY 2019; 2019:7127850. [PMID: 31933709 PMCID: PMC6942709 DOI: 10.1155/2019/7127850] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 12/02/2019] [Accepted: 12/07/2019] [Indexed: 12/18/2022]
Abstract
From 20 to 30% of Clostridioides (Clostridium) difficile infection (CDI), patients might develop recurrence of the infection (RCDI) and, after the first recurrence, the risk of further episodes increases up to 60%. Several bacterial virulence factors have been associated with RCDI, including the elevated production of toxins A and B, the presence of a binary toxin CDT, and mutations in the negative regulator of toxin expression, tcdC. Additional factors have shown to regulate toxin production and virulence in C. difficile in RCDI, including the accessory-gene regulator agr, which acts as a positive switch for toxin transcription. Furthermore, adhesion and motility-associated factors, such as Cwp84, SlpA, and flagella, have shown to increase the adhesion efficiency to host epithelia, cell internalization, and the formation of biofilm. Finally, biofilm confers to C. difficile protection from antibiotics and acts as a reservoir for spores that allow the persistence of the infection in the host. In this review, we describe the key virulence factors of C. difficile that have been associated with recurrent infections.
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Okumura H, Fukushima A, Taieb V, Shoji S, English M. Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis. J Infect Chemother 2019; 26:43-50. [PMID: 31624029 DOI: 10.1016/j.jiac.2019.07.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 06/17/2019] [Accepted: 07/01/2019] [Indexed: 12/17/2022]
Abstract
We conducted a systematic review of the literature and network meta-analysis (NMA) to compare the relative effectiveness of antibiotic treatments for Clostridioides (Clostridium) difficile infection (CDI) including vancomycin (VCM), metronidazole (MTZ) and fidaxomicin (FDX). Eligible studies were randomised controlled trials (RCTs) including adults with any severity of CDI that was treated with VCM, MTZ or FDX. The NMA was performed using a Bayesian framework, using a fixed-effects model. The searches identified seven publications for inclusion, which provided five RCTs for VCM versus MTZ, and three RCTs for FDX versus VCM. The NMA showed that for clinical cure rate, there was no difference for FDX versus VCM, and there was a significant difference in favour of FDX versus MTZ (odds ratio [OR]: 1.77; 95% credible interval [CrI] 1.11, 2.83]). For recurrence rate, there was a significant difference in favour of FDX versus both VCM (OR: 0.50; 95% CrI: 0.37, 0.68) and MTZ (OR: 0.44; 95% CrI: 0.27, 0.72). For sustained cure (clinical cure without recurrence), there was a significant difference in favour of FDX versus VCM (OR: 1.61; 95% CrI: 1.27, 2.05) and MTZ (OR: 2.39; 95% CrI: 1.65, 3.47). These findings suggest that FDX and VCM are effective first-line treatments for mild or moderate CDI, whereas MTZ is not, and FDX may be more effective at preventing CDI recurrence than VCM.
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Affiliation(s)
| | | | | | | | - Marci English
- Astellas Pharma Global Development, Inc., Northbrook, IL, USA
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Abstract
Clostridioides difficile (formerly Clostridium) is a major cause of healthcare associated diarrhea, and is increasingly present in the community. Historically, C difficile infection was considered easy to diagnose and treat. Over the past two decades, however, diagnostic techniques have changed in line with a greater understanding of the physiopathology of C difficile infection and the use of new therapeutic molecules. The evolution of diagnosis showed there was an important under- and misdiagnosis of C difficile infection, emphasizing the importance of algorithms recommended by European and North American infectious diseases societies to obtain a reliable diagnosis. Previously, metronidazole was considered the reference drug to treat C difficile infection, but more recently vancomycin and other newer drugs are shown to have higher cure rates. Recurrence of infection represents a key parameter in the evaluation of new drugs, and the challenge is to target the right population with the adapted therapeutic molecule. In multiple recurrences, fecal microbiota transplantation is recommended. New approaches, including antibodies, vaccines, and new molecules are already available or in the pipeline, but more data are needed to support the inclusion of these in practice guidelines. This review aims to provide a baseline for clinicians to understand and stratify their choice in the diagnosis and treatment of C difficile infection based on the most recent data available.
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Affiliation(s)
- Benoit Guery
- Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
- French Group of Faecal Microbiota Transplantation
- European Study Group on Host and Microbiota Interactions
- European Study Group on Clostridium difficile
| | - Tatiana Galperine
- Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
- French Group of Faecal Microbiota Transplantation
| | - Frédéric Barbut
- National Reference Laboratory for Clostridium difficile, Paris, France
- INSERM, Faculté de Pharmacie de Paris, Université Paris Descartes, Paris, France
- European Study Group on Clostridium difficile
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Yang J, Yang H. Non-antibiotic therapy for Clostridioides difficile infection: a review. Crit Rev Clin Lab Sci 2019; 56:493-509. [PMID: 31411909 DOI: 10.1080/10408363.2019.1648377] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Clostridioides difficile infection (CDI) is a common infectious disease that is mainly caused by antibiotics. Antibiotic therapy is still the dominant treatment for CDI, although it is accompanied by side effects. Probiotics, fecal microbiota transplantation (FMT), engineered microorganisms, bacteriophages, diet, natural active substances, nanoparticles and compounds are examples of emerging non-antibiotic therapies that have received a great amount of attention. In this review, we collected data about different non-antibiotic therapies for CDI and provided a comprehensive analysis and detailed comparison of these therapies. The mechanism of action, therapeutic efficacy, and the strengths and weaknesses of these non-antibiotic therapies have been investigated to provide a basis for the reasonable alternative of non-antibiotic therapies for CDI. In summary, probiotics and FMT are currently the best choice for non-antibiotic therapy for CDI.
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Affiliation(s)
- Jingpeng Yang
- State Key Laboratory of Microbial Metabolism, and School of Life Science & Biotechnology, Shanghai Jiao Tong University , Shanghai , China
| | - Hong Yang
- State Key Laboratory of Microbial Metabolism, and School of Life Science & Biotechnology, Shanghai Jiao Tong University , Shanghai , China
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Singh T, Bedi P, Bumrah K, Singh J, Rai M, Seelam S. Updates in Treatment of Recurrent Clostridium difficile Infection. J Clin Med Res 2019; 11:465-471. [PMID: 31236163 PMCID: PMC6575119 DOI: 10.14740/jocmr3854] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 05/31/2019] [Indexed: 12/18/2022] Open
Abstract
Recurrent Clostridium difficile infection (CDI) is a perpetual problem that leads to increased economic burden, higher healthcare cost, and significant morbidity and mortality. Its treatment remains a challenge. While various treatment approaches have been attempted with different levels of success, robust data establishing the superiority of one approach over the others is lacking. In this article, we review the current evidence pertaining to conventional pharmacological treatment as well as fecal microbiota transplantation (FMT) as a novel, rapidly emerging treatment modality for recurrent CDI.
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Affiliation(s)
- Tanveer Singh
- Department of Hospital Medicine, Rochester General Hospital, Rochester, NY 14621, USA
| | - Prabhjot Bedi
- Department of Medicine, UPMC East, Monroeville, PA 15146, USA
| | | | - Jeevandeep Singh
- Department of Medicine, Montefiore Medical Center-Wakefield, Bronx, NY 10466, USA
| | - Manoj Rai
- Department of Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Susmitha Seelam
- Department of Medicine, UPMC East, Monroeville, PA 15146, USA
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Biggs M, Iqbal T, Holden E, Clewer V, Garvey M. Effect of using fidaxomicin on recurrent Clostridium difficile infection. J Hosp Infect 2019; 102:165-167. [DOI: 10.1016/j.jhin.2018.12.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 12/26/2018] [Accepted: 12/28/2018] [Indexed: 10/27/2022]
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Comparison of antibiotics for Clostridium difficile infection. Drug Ther Bull 2019; 57:71-72. [PMID: 31018929 DOI: 10.1136/dtb.2019.000022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
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Shrestha R, Cochran AM, Sorg JA. The requirement for co-germinants during Clostridium difficile spore germination is influenced by mutations in yabG and cspA. PLoS Pathog 2019; 15:e1007681. [PMID: 30943268 PMCID: PMC6464247 DOI: 10.1371/journal.ppat.1007681] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 04/15/2019] [Accepted: 03/05/2019] [Indexed: 12/13/2022] Open
Abstract
Clostridium difficile spore germination is critical for the transmission of disease. C. difficile spores germinate in response to cholic acid derivatives, such as taurocholate (TA), and amino acids, such as glycine or alanine. Although the receptor with which bile acids are recognized (germinant receptor) is known, the amino acid co-germinant receptor has remained elusive. Here, we used EMS mutagenesis to generate mutants with altered requirements for the amino acid co-germinant, similar to the strategy we used previously to identify the bile acid germinant receptor, CspC. Surprisingly, we identified strains that do not require co-germinants, and the mutant spores germinated in response to TA alone. Upon sequencing these mutants, we identified different mutations in yabG. In C. difficile, yabG expression is required for the processing of key germination components to their mature forms (e.g., CspBA to CspB and CspA). A defined yabG mutant exacerbated the EMS mutant phenotype. Building upon this work, we found that small deletions in cspA resulted in spores that germinated in the presence of TA alone without the requirement of a co-germinant. cspA encodes a pseudoprotease that was previously shown to be important for incorporation of the CspC germinant receptor. Herein, our study builds upon the role of CspA during C. difficile spore germination by providing evidence that CspA is important for recognition of co-germinants during C. difficile spore germination. Our work suggests that two pseudoproteases (CspC and CspA) likely function as the C. difficile germinant receptors. Germination by C. difficile spores is one of the very first steps in the pathogenesis of this organism. The transition from the metabolically dormant spore form to the actively-growing, toxin-producing vegetative form is initiated by certain host-derived bile acids and amino acid signals. Despite near universal conservation in endospore-forming bacteria of the Ger-type germinant receptors, C. difficile and related organisms do not encode these proteins. In prior work, we identified the C. difficile bile acid germinant receptor as the CspC pseudoprotease. In this manuscript, we implicate the CspA pseudoprotease as the C. difficile co-germinant receptor. C. difficile cspA is encoded as a translational fusion to cspB. The resulting CspBA protein is processed post-translationally by the YabG protease. Inactivation of yabG resulted in strains whose spores no longer responded to amino acids or divalent cations as co-germinants and germinated in response to bile acid alone. Building upon this, we found that small deletions in the cspA portion of cspBA resulted in spores that could germinate in response to bile acids alone. Our results suggest that two pseudoproteases regulate C. difficile spore germination and provide further evidence that C. difficile spore germination proceeds through a novel spore germination pathway.
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Affiliation(s)
- Ritu Shrestha
- Department of Biology, Texas A&M University, College Station, United States of America
| | - Alicia M. Cochran
- Department of Biology, Texas A&M University, College Station, United States of America
| | - Joseph A. Sorg
- Department of Biology, Texas A&M University, College Station, United States of America
- * E-mail:
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Dinh A, Le Monnier A, Emery C, Alami S, Torreton É, Duburcq A, Barbier F. Predictors and burden of hospital readmission with recurrent Clostridioides difficile infection: a French nation-wide inception cohort study. Eur J Clin Microbiol Infect Dis 2019; 38:1297-1305. [PMID: 30941532 DOI: 10.1007/s10096-019-03552-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 03/26/2019] [Indexed: 12/17/2022]
Abstract
To investigate the predictors and burden of hospital readmission with recurrent Clostridioides difficile infection (rCDI) in a large European healthcare system with a low prevalence of hyper-virulent C. difficile clones. We conducted an inception cohort study based on an exhaustive health insurance database and including all survivors of a first hospital stay with CDI over a one-year period (2015) in France. Readmissions with rCDI were defined as a novel hospital stay with CDI within 12 weeks following discharge of the index hospitalization. Risk factors for readmission with rCDI were investigated through multivariate logistic regression analyses. Among the 14,739 survivors of the index hospital stay (females, 57.3%; median age, 74 [58-84] years), 2135 (14.5%) required at least one readmission with rCDI. Independent predictors of readmission were age ≥ 65 years (adjusted odds ratio (aOR), 1.34, 95% confidence interval (CI), 1.21-1.49, P < 0.0001), immunosuppression (aOR, 1.27, 95% CI, 1.15-1.41, P < 0.0001), chronic renal failure (aOR, 1.29, 95% CI, 1.14-1.46, P < 0.0001), and a previous history of CDI (aOR, 2.05, 95% CI, 1.55-2.71, P < 0.0001). The cumulative number of risk factors was independently associated with the hazard of readmission. Mean acute care costs attributable to rCDI were 5619 ± 3594 Euros for readmissions with rCDI as primary diagnosis (mean length of stay, 11.3 ± 10.2 days) and 4851 ± 445 Euros for those with rCDI as secondary diagnosis (mean length of stay, 16.8 ± 18.2 days), for an estimated annual nation-wide cost of 14,946,632 Euros. Hospital readmissions with rCDI are common after an index episode and drive major healthcare expenditures with substantial bed occupancy, strengthening the need for efficient secondary prevention strategies in high-risk patients.
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Affiliation(s)
- Aurélien Dinh
- Infectious Diseases Unit, APHP, Raymond-Poincaré University Hospital, Garches, France.,Versailles-Saint Quentin University, Versailles, France
| | - Alban Le Monnier
- Department of Clinical Microbiology, GH Paris Saint-Joseph Hospital, Paris, France.,EA4043-UBaPS, Saclay - Paris Sud University, Châtenay-Malabry, France
| | | | | | | | | | - François Barbier
- Medical Intensive Care Unit, La Source Hospital, CHR Orléans, 14, Hospital Bd, 45100, Orléans, France.
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Carlson TJ, Endres BT, Bassères E, Gonzales-Luna AJ, Garey KW. Ridinilazole for the treatment of Clostridioides difficile infection. Expert Opin Investig Drugs 2019; 28:303-310. [PMID: 30767587 DOI: 10.1080/13543784.2019.1582640] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 02/11/2019] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Ridinilazole is a novel antibiotic being developed for the treatment of Clostridioides difficile infection (CDI). Ridinilazole has completed two phase II trials and phase III trials which are denoted Ri-CoDIFy 1 and 2, are planned (ClinicalTrials.gov identifiers: NCT03595553 and NCT03595566). Areas covered: This article covers the chemistry, mechanism of action, in vitro microbiology versus C. difficile and host microbiota, pre-clinical and clinical efficacy, pharmacokinetics, pharmacodynamics and safety and tolerability of ridinilazole. Expert opinion: Ridinilazole is a novel antibiotic with ideal properties for the treatment of CDI. Given the promising results from the phase II clinical trial, ridinilazole may have the capability to lower the risk for CDI recurrence thus improving sustained clinical response rates - a current unmet medical need. Assuming a positive phase III trial, ridinilazole will enter a market with heightened awareness on the importance of prevention of CDI. This along with further research into the economic consequences and decreased patient quality of life associated with recurrent CDI, should provide clinicians with further evidence for the need for therapy that limits CDI recurrence and improves sustained clinical cure.
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Affiliation(s)
- Travis J Carlson
- a Department of Pharmacy Practice and Translational Research , University of Houston College of Pharmacy , Houston , TX , USA
| | - Bradley T Endres
- a Department of Pharmacy Practice and Translational Research , University of Houston College of Pharmacy , Houston , TX , USA
| | - Eugénie Bassères
- a Department of Pharmacy Practice and Translational Research , University of Houston College of Pharmacy , Houston , TX , USA
| | - Anne J Gonzales-Luna
- a Department of Pharmacy Practice and Translational Research , University of Houston College of Pharmacy , Houston , TX , USA
| | - Kevin W Garey
- a Department of Pharmacy Practice and Translational Research , University of Houston College of Pharmacy , Houston , TX , USA
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