|
1
|
Hirsch W, Fischer M, Khoruts A, Allegretti JR, Kelly CR, Vaughn B. Risk Factors for Antibiotic Exposure Post-Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection: A Prospective Multicenter Observational Study. Open Forum Infect Dis 2025; 12:ofaf130. [PMID: 40103733 PMCID: PMC11913780 DOI: 10.1093/ofid/ofaf130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 03/05/2025] [Indexed: 03/20/2025] Open
Abstract
Background Recurrent Clostridioides difficile infection (CDI) is primarily driven by antibiotic-induced disruption of the indigenous intestinal microbiota. Restoration of microbiota through fecal microbiota transplantation (FMT) is effective in preventing subsequent CDI, although this effect is attenuated with additional antibiotic exposure. The aim of this study was to identify the risk factors for recurrent antibiotic administration after FMT. Methods This is a prospective cohort of patients who were administered FMT for recurrent CDI from 1 July 2019 through 23 November 2023 across 6 institutions in the United States. Providers collected de-identified data at the time of FMT administration and in the months post-FMT administration. Results The analysis included 448 patients. Risk factors for non-CDI antibiotic administration within 2 months of FMT included immunocompromised status (odds ratio [OR], 2.2 [95% confidence interval {CI}, 1.1-4.4]; P = .02), >3 non-CDI antibiotic courses pre-FMT (OR, 3.1 [95% CI, 1.4-6.8]; P = .006), and prior hospitalization for CDI (OR, 2.0 [95% CI, 1.1-3.8]; P = .02). The most common indications for non-CDI antibiotic administration post-FMT were urinary tract infections, respiratory infections, and procedure prophylaxis. Conclusions Non-CDI antibiotic exposure significantly increases the risk of CDI recurrence post-FMT. Risk factors for non-CDI antibiotic administration within 2 months of FMT include immunocompromised status, multiple prior non-CDI antibiotics, and prior hospitalization for CDI. These individuals may benefit from additional or modified recurrent CDI prevention strategies.
Collapse
Affiliation(s)
- William Hirsch
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Monika Fischer
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA
| | - Alexander Khoruts
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
- Center for Immunology, University of Minnesota, Minneapolis, Minnesota, USA
- BioTechnology Institute, University of Minnesota, St Paul, Minnesota, USA
| | | | - Colleen R Kelly
- Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Byron Vaughn
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| |
Collapse
|
|
2
|
Hensen ADO, Vehreschild MJGT, Gerding DN, Krut O, Chen W, Young VB, Tzipori S, Solbach P, Gibani MM, Chiu C, de Keersmaecker SCJ, Dasyam D, Morel S, Devaster JM, Corti N, Kuijper EJ, Roestenberg M, Smits WK. How to develop a controlled human infection model for Clostridioides difficile. Clin Microbiol Infect 2025; 31:373-379. [PMID: 39214188 DOI: 10.1016/j.cmi.2024.08.025] [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: 04/19/2024] [Revised: 08/23/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Clostridioides difficile (C. difficile) remains the leading cause of healthcare-associated diarrhoea, posing treatment challenges because of antibiotic resistance and high relapse rates. Faecal microbiota transplantation is a novel treatment strategy to prevent relapses of C. difficile infection (CDI), however, the exact components conferring colonization resistance are unknown, hampering its translation to a medicinal product. The development of novel products independent of antibiotics, which increase colonization resistance or induce protective immune mechanisms is urgently needed. OBJECTIVES To establish a framework for a Controlled Human Infection Model (CHIM) of C. difficile, in which healthy volunteers are exposed to toxigenic C. difficile spores, offering the possibility to test novel approaches and identify microbiota and immunological targets. Whereas experimental exposure to non-toxigenic C. difficile has been done before, a toxigenic C. difficile CHIM faces ethical, scientific, logistical, and biosafety challenges. SOURCES Specific challenges in developing a C. difficile CHIM were discussed by a group of international experts during a workshop organized by Inno4Vac, an Innovative Health Initiative-funded consortium. CONTENT The experts agreed that the main challenges are: developing a clinically relevant CHIM that induces mild to moderate CDI symptoms but not severe CDI, determining the optimal C. difficile inoculum dose, and understanding the timing and duration of antibiotic pretreatment in inducing susceptibility to CDI in healthy volunteers. IMPLICATIONS Should these challenges be tackled, a C. difficile CHIM will not only provide a way forward for the testing of novel products but also offer a framework for a better understanding of the pathophysiology, pathogenesis, and immunology of C. difficile colonization and infection.
Collapse
Affiliation(s)
- Annefleur D O Hensen
- Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Maria J G T Vehreschild
- Department of Internal Medicine, Division of Infectious Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; German Center for Infection Research (DZIF), Cologne, Germany
| | - Dale N Gerding
- Department of Veterans Affairs, Edward Hines Jr VA Hospital, Hines, IL, United States
| | - Oleg Krut
- Paul-Ehrlich-Institut (PEI), Langen, Germany
| | - Wilbur Chen
- Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Vincent B Young
- Department of Internal Medicine/Infectious Diseases Division and the Department of Microbiology & Immunology, The University of Michigan, Ann Arbor, MI, United States
| | - Saul Tzipori
- Division of Infectious Disease and Global Health, Tufts University, Medford, MA, United States
| | - Philipp Solbach
- First Department of Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Malick Mahdi Gibani
- Department of Infectious Disease, Imperial College London (ICL), London, United Kingdom
| | - Christopher Chiu
- Department of Infectious Disease, Imperial College London (ICL), London, United Kingdom
| | | | | | | | | | | | - Ed J Kuijper
- Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Meta Roestenberg
- Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center (LUMC), Leiden, The Netherlands.
| | - Wiep Klaas Smits
- Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center (LUMC), Leiden, The Netherlands
| |
Collapse
|
|
3
|
Moore SE, Song M, Swingler EA, Furmanek S, Chandler T, Smith D, Brenneman MT, Wilde AM. Comparing rates of recurrent infection for first occurrence of Clostridioides difficile between tapered oral vancomycin and standard vancomycin: a retrospective, propensity matched cohort study. Infect Control Hosp Epidemiol 2024:1-7. [PMID: 39400010 DOI: 10.1017/ice.2024.117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
OBJECTIVE To compare rates of Clostridioides difficile infection (CDI) recurrence following initial occurrence treated with tapered enteral vancomycin compared to standard vancomycin. DESIGN Retrospective cohort study. SETTING Community health system. PATIENTS Adults ≥18 years of age hospitalized with positive C. difficile polymerase chain reaction or toxin enzyme immunoassay who were prescribed either standard 10-14 days of enteral vancomycin four times daily or a 12-week tapered vancomycin regimen. METHODS Retrospective propensity score pair matched cohort study. Groups were matched based on age < or ≥ 65 years and receipt of non-C. difficile antibiotics during hospitalization or within 6 months post-discharge. Recurrence rates were analyzed via logistic regression conditioned on matched pairs and reported as conditional odds ratios. The primary outcome was recurrence rates compared between standard vancomycin versus tapered vancomycin for treatment of initial CDI. RESULTS The CDI recurrence rate at 6 months was 5.3% (4/75) in the taper cohort versus 28% (21/75) in the standard vancomycin cohort. The median time to CDI recurrence was 115 days versus 20 days in the taper and standard vancomycin cohorts, respectively. When adjusted for matching, patients in the taper arm were less likely to experience CDI recurrence at 6 months when compared to standard vancomycin (cOR = 0.19, 95% CI 0.07-0.56, p < 0.002). CONCLUSIONS Larger prospective trials are needed to elucidate the clinical utility of tapered oral vancomycin as a treatment option to achieve sustained clinical cure in first occurrences of CDI.
Collapse
Affiliation(s)
- Sarah E Moore
- Norton Healthcare, Norton Infectious Diseases Institute, Louisville, KY, USA
| | - Matthew Song
- Norton Healthcare, Norton Infectious Diseases Institute, Louisville, KY, USA
| | - Elena A Swingler
- Norton Healthcare, Norton Infectious Diseases Institute, Louisville, KY, USA
| | - Stephen Furmanek
- Norton Healthcare, Norton Infectious Diseases Institute, Louisville, KY, USA
| | - Thomas Chandler
- Norton Healthcare, Norton Infectious Diseases Institute, Louisville, KY, USA
| | - Dakota Smith
- Norton Healthcare, Department of Pharmacy, Louisville, KY, USA
| | | | - Ashley M Wilde
- Norton Healthcare, Norton Infectious Diseases Institute, Louisville, KY, USA
| |
Collapse
|
|
4
|
Vehreschild MJGT, Schreiber S, von Müller L, Epple HJ, Manthey C, Oh J, Weinke T, Wahler S, Stallmach A. [Need for improvement in the care of patients with Clostridioides difficile infections (CDI) - expert opinion in international comparison]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1032-1041. [PMID: 38976982 DOI: 10.1055/a-2293-7760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
INTRODUCTION Clostridioides difficile infection (CDI), as a nosocomial disease, is associated with high morbidity and mortality. Even though the incidence of CDI has been declining in Germany in recent years, the individual infection may pose a medical challenge despite therapeutic advances. The aim here is to clarify which gaps practitioners consider to be particularly serious in care and in the existing evidence base. METHODS In a moderated workshop of German CDI experts the topics considered as relevant were identified. A survey already conducted in five other countries (Australia, France, Great Britain, Canada, and Italy) was adapted and processed by 27 practitioners. During the evaluation, the topics perceived as particularly important were identified, the statements of the specialist groups were compared and changes in opinion were considered. RESULTS 27 fully completed questionnaires were evaluated. The need for improvement was primarily seen in the prevention of CDI recurrences (74.1%) and the treatment of recurrences (55.6%). Evidence deficits were noted in the treatment of recurrences (55.6%) and identification of risk factors for recurrences (48.1%). Improving care via fecal microbiota transfer (FMT) was named by 70.4%. For guidelines, more clarity (48.1%) and more regular updates (40.7%) were desired. For patients, better education on appropriate antibiotic use (52.0%) and choice of FMT were desired (48.1%). SUMMARY The German expert view and the international assessment is similar, when asked about the need for improvement in care and evidence gaps in the treatment of patients with CDI: The focus is on prevention and therapy of recurrent CDI. The problem of access to FMT is a German peculiarity that seems to need improvement.
Collapse
Affiliation(s)
- Maria J G T Vehreschild
- Universitätsklinikum Frankfurt, Medizinische Klinik 2, Infektiologie, Klinische Mikrobiomforschung, Frankfurt am Main, Germany
| | | | | | - Hans-Jörg Epple
- Gastroenterology, Charité-Campus Benjamin Franklin, Berlin, Germany
| | | | - Jun Oh
- Pediatrics, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | | | | | - Andreas Stallmach
- Gastroenterology, Hepatology and Infectology, Friedrich Schiller University, Jena, Germany
| |
Collapse
|
|
5
|
Rigo I, Young MK, Abhyankar MM, Xu F, Ramakrishnan G, Naz F, Madden GR, Petri WA. The impact of existing total anti-toxin B IgG immunity in outcomes of recurrent Clostridioides difficile infection. Anaerobe 2024; 87:102842. [PMID: 38552897 PMCID: PMC11180572 DOI: 10.1016/j.anaerobe.2024.102842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/22/2024] [Accepted: 03/19/2024] [Indexed: 04/15/2024]
Abstract
Late anti-toxin-B humoral immunity acquired after treatment is important for preventing recurrent Clostridioides difficile infection. We prospectively-measured anti-toxin-B IgG and neutralization titers at diagnosis as potential early predictors of recurrence. High anti-toxin-B-IgG/neutralizing antibodies were associated with short-lasting protection within 6-weeks, however, no difference in recurrence risk was observed by 90-days post-infection.
Collapse
Affiliation(s)
- Isaura Rigo
- University of Virginia, Department of Medicine/ Infectious Disease and International Health, USA
| | - Mary K Young
- University of Virginia, Department of Medicine/ Infectious Disease and International Health, USA
| | - Mayuresh M Abhyankar
- University of Virginia, Department of Medicine/ Infectious Disease and International Health, USA
| | - Feifan Xu
- University of Virginia, Department of Medicine/ Infectious Disease and International Health, USA
| | - Girija Ramakrishnan
- University of Virginia, Department of Medicine/ Infectious Disease and International Health, USA
| | - Farha Naz
- University of Virginia, Department of Medicine/ Infectious Disease and International Health, USA
| | - Gregory R Madden
- University of Virginia, Department of Medicine/ Infectious Disease and International Health, USA
| | - William A Petri
- University of Virginia, Department of Medicine/ Infectious Disease and International Health, USA.
| |
Collapse
|
|
6
|
Karnchanapandh K, Sanachai K, Poo-Arporn RP, Rungrotmongkol T. Enhancing bezlotoxumab binding to C. difficile toxin B2: insights from computational simulations and mutational analyses for antibody design. J Biomol Struct Dyn 2024:1-11. [PMID: 38511411 DOI: 10.1080/07391102.2024.2329785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 03/06/2024] [Indexed: 03/22/2024]
Abstract
Clostridioides difficile infection (CDI) is a significant concern caused by widespread antibiotic use, resulting in diarrhea and inflammation from the gram-positive anaerobic bacterium C. difficile. Although bezlotoxumab (Bez), a monoclonal antibody (mAb), was developed to address CDI recurrences, the recurrence rate remains high, partly due to reduced neutralization efficiency against toxin B2. In this study, we aimed to enhance the binding of Bez to C. difficile toxin B2 by combining computational simulations and mutational analyses. We identified specific mutations in Bez, including S28R, S31W/K, Y32R, S56W and G103D/S in the heavy chain (Hc), and S32F/H/R/W/Y in the light chain (Lc), which significantly improved binding to toxin B2 and formed critical protein-protein interactions. Through molecular dynamics simulations, several single mutations, such as HcS28R, LcS32H, LcS32R, LcS32W and LcS32Y, exhibited superior binding affinities to toxin B2 compared to Bez wild-type (WT), primarily attributed to Coulombic interactions. Combining the HcS28R mutation with four different mutations at residue LcS32 led to even greater binding affinities in double mutants (MTs), particularly HcS28R/LcS32H, HcS28R/LcS32R and HcS28R/LcS32Y, reinforcing protein-protein binding. Analysis of per-residue decomposition free energy highlighted key residues contributing significantly to enhanced binding interactions, emphasizing the role of electrostatic interactions. These findings offer insights into rational Bez MT design for improved toxin B2 binding, providing a foundation for developing more effective antibodies to neutralize toxin B2 and combat-related infections.
Collapse
Affiliation(s)
- Kun Karnchanapandh
- Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, Thailand
| | - Kamonpan Sanachai
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen, Thailand
| | - Rungtiva P Poo-Arporn
- Biological Engineering Program, Faculty of Engineering, King Mongkut's University of Technology Thonburi, Bangkok, Thailand
| | - Thanyada Rungrotmongkol
- Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| |
Collapse
|
|
7
|
Warraich F, Sohail SH, Knee A, Smith J, Schlecht H, Skiest D. Factors Associated With Fecal Microbiota Transplant Failure in the Treatment of Recurrent Clostridioides difficile Infection: A Single-Center Retrospective Study. Cureus 2023; 15:e45118. [PMID: 37842346 PMCID: PMC10569438 DOI: 10.7759/cureus.45118] [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] [Accepted: 09/12/2023] [Indexed: 10/17/2023] Open
Abstract
Background Clostridioides difficile infection (CDI) is a major cause of hospital-acquired diarrhea and is associated with substantial morbidity and mortality. Recurrences following treatment are common. Fecal microbiota transplantation (FMT) is a therapeutic intervention in which stool from a healthy donor is administered to a patient with recurrent CDI. Studies to date of predictors of FMT failure have primarily included inpatients. In this study, we aimed to describe FMT failure rates within one year of FMT and evaluate factors associated with FMT failure. Methodology We conducted an exploratory retrospective study of consecutive patients who underwent outpatient FMT at a single tertiary care center in Western Massachusetts from December 2014 through September 2018. We collected patient data including demographics, CDI-related factors, and FMT-related factors. FMT failure was defined as non-response or recurrence of diarrhea, associated with positive stool C. difficile toxin or polymerase chain reaction. Unadjusted relative risk (RR) and 95% confidence intervals for factors associated with FMT failure were estimated using log-binomial regression. Results A total of 92 patients were included with a mean age of 64 years. CDI severity was mild or moderate in 73% and severe or fulminant in 27%. The most common FMT indication was recurrent CDI in 76% of patients. FMT failure occurred in 25 of 92 (27%) patients, with half occurring within 11 days. Factors associated with FMT failure were active malignancy (RR = 2.56), prior hospitalizations (RR = 2.42), and receipt of non-CDI antibiotics within six months of FMT (RR = 2.80). We did not observe strong associations for risk of FMT failure with age ≥65, sex, use of proton pump inhibitors or H2 receptor agonists, history of colectomy, immunosuppression, history of malignancy, diabetes, appendectomy, CDI severity, or probiotic use. Conclusions Active malignancy, prior CDI hospitalizations, and non-CDI antibiotics within six months before FMT were associated with FMT failure in the outpatient setting. Knowledge of the above factors may help inform shared decision-making with patients at risk for FMT failure.
Collapse
Affiliation(s)
- Fatima Warraich
- Internal Medicine, University of Massachusetts Chan Baystate Medical Center, Springfield, USA
| | - Syed H Sohail
- Internal Medicine, University of Massachusetts Chan Baystate Medical Center, Springfield, USA
| | - Alexander Knee
- Office of Research/Epidemiology/Biostatistics Research Core, University of Massachusetts Chan Baystate Medical Center, Springfield, USA
| | - Jacob Smith
- Infectious Disease, University of Massachusetts Chan Baystate Medical Center, Springfield, USA
| | - Hans Schlecht
- Infectious Disease, University of Massachusetts Chan Baystate Medical Center, Springfield, USA
| | - Daniel Skiest
- Infectious Disease, University of Massachusetts Chan Baystate Medical Center, Springfield, USA
| |
Collapse
|
|
8
|
Carvalho FAC, Silva ROS, Santos BMRTD, Diniz AN, Vilela EG. CLINICAL OUTCOME AND SEVERITY OF CLOSTRIDIOIDES (CLOSTRIDIUM) DIFFICILE INFECTION AT A TERTIARY REFERRAL HOSPITAL IN BRAZIL. ARQUIVOS DE GASTROENTEROLOGIA 2023; 60:330-338. [PMID: 37792762 DOI: 10.1590/s0004-2803.230302023-36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 06/21/2023] [Indexed: 10/06/2023]
Abstract
•The outcomes of CDI were evaluated in 65 patients with CDI in a Brazilian tertiary hospital. •Lack of clinical improvement after treatment and the severity score (ATLAS) increased the risk of death. •The use of multiple antimicrobial agents was associated with longer hospital stays. •Patients with high Charlson comorbidity index (>7) were more likely to recur. Background - Clostridioides difficile infection (CDI) is a potentially severe disease that can present with refractoriness, recurrence, and evolution to death. In Brazil, the epidemiology of CDI seems to differ from that of the United States and most European countries, with only one ribotype (RT) 027-related case and a high prevalence of RT106. Objective - The aim of this study was to evaluate the outcomes of CDI and its possible association with ribotypes at a university hospital in Brazil. Methods - A total of 65 patients with CDI were included and stool samples were submitted to A/B toxin detection and toxigenic culture, and toxigenic isolates (n=44) were also PCR ribotyped. Results - Patients' median age was 59 (20-87) years and there were 16 (24.6%) deaths. The median Charlson comorbidity index (CCI) was 4 (0-15) and 16.9% of the patients had CCI ≥8. The ATLAS score and non-improvement of diarrhea were related to higher mortality. A longer length of hospitalization was related to the enteral nutrition and use of multiple antibiotics. The period between CDI diagnosis and hospital discharge was longer in those who received new antibiotics after diagnosis, multiple antibiotics, and required intensive care treatment. Recurrence was associated with CCI >7. Twenty ribotypes were identified and RT106 was the most frequently detected strain (43.2%). No relationship was observed between the ribotypes and outcomes. CDI was present in patients with more comorbidities. Conclusion - Risk factors for higher mortality, longer hospital stay and recurrence were identified. A diversity of ribotypes was observed and C. difficile strains were not related to the outcomes.
Collapse
Affiliation(s)
| | | | | | - Amanda Nádia Diniz
- Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
| | - Eduardo Garcia Vilela
- Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
| |
Collapse
|
|
9
|
Yadegar A, Pakpoor S, Ibrahim FF, Nabavi-Rad A, Cook L, Walter J, Seekatz AM, Wong K, Monaghan TM, Kao D. Beneficial effects of fecal microbiota transplantation in recurrent Clostridioides difficile infection. Cell Host Microbe 2023; 31:695-711. [PMID: 37167952 PMCID: PMC10966711 DOI: 10.1016/j.chom.2023.03.019] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
Fecal microbiota transplantation (FMT) is highly effective in preventing recurrent Clostridioides difficile infection (rCDI). However, the mechanisms underpinning its clinical efficacy are incompletely understood. Herein, we provide an overview of rCDI pathogenesis followed by a discussion of potential mechanisms of action focusing on the current understanding of trans-kingdom microbial, metabolic, immunological, and epigenetic mechanisms. We then outline the current research gaps and offer methodological recommendations for future studies to elevate the quality of research and advance knowledge translation. By combining interventional trials with multiomics technology and host and environmental factors, analyzing longitudinally collected biospecimens will generate results that can be validated with animal and other models. Collectively, this will confirm causality and improve translation, ultimately to develop targeted therapies to replace FMT.
Collapse
Affiliation(s)
- Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sepideh Pakpoor
- School of Engineering, University of British Columbia, Kelowna, BC, Canada
| | - Fathima F Ibrahim
- National Institute for Health Research Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Ali Nabavi-Rad
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Laura Cook
- Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia
| | - Jens Walter
- School of Microbiology, Department of Medicine and APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Anna M Seekatz
- Department of Biological Sciences, Clemson University, Clemson, SC, USA
| | - Karen Wong
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Tanya M Monaghan
- National Institute for Health Research Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.
| | - Dina Kao
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
| |
Collapse
|
|
10
|
Minkoff NZ, Aslam S, Medina M, Tanner-Smith EE, Zackular JP, Acra S, Nicholson MR, Imdad A. Fecal microbiota transplantation for the treatment of recurrent Clostridioides difficile (Clostridium difficile). Cochrane Database Syst Rev 2023; 4:CD013871. [PMID: 37096495 PMCID: PMC10125800 DOI: 10.1002/14651858.cd013871.pub2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
Abstract
BACKGROUND Clostridioides difficile (formerly known as Clostridium difficile) is a bacterium that can cause potentially life-threatening diarrheal illness in individuals with an unhealthy mixture of gut bacteria, known as dysbiosis, and can cause recurrent infections in nearly a third of infected individuals. The traditional treatment of recurrent C difficile infection (rCDI) includes antibiotics, which may further exacerbate dysbiosis. There is growing interest in correcting the underlying dysbiosis in rCDI using of fecal microbiota transplantation (FMT); and there is a need to establish the benefits and harms of FMT for the treatment of rCDI based on data from randomized controlled trials. OBJECTIVES To evaluate the benefits and harms of donor-based fecal microbiota transplantation for the treatment of recurrent Clostridioides difficile infection in immunocompetent people. SEARCH METHODS We used standard, extensive Cochrane search methods. The latest search date was 31 March 2022. SELECTION CRITERIA We considered randomized trials of adults or children with rCDI for inclusion. Eligible interventions must have met the definition of FMT, which is the administration of fecal material containing distal gut microbiota from a healthy donor to the gastrointestinal tract of a person with rCDI. The comparison group included participants who did not receive FMT and were given placebo, autologous FMT, no intervention, or antibiotics with activity against C difficile. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcomes were 1. proportion of participants with resolution of rCDI and 2. serious adverse events. Our secondary outcomes were 3. treatment failure, 4. all-cause mortality, 5. withdrawal from study, 6. rate of new CDI infection after a successful FMT, 7. any adverse event, 8. quality of life, and 9. colectomy. We used the GRADE criteria to assess certainty of evidence for each outcome. MAIN RESULTS We included six studies with 320 participants. Two studies were conducted in Denmark, and one each in the Netherlands, Canada, Italy, and the US. Four were single-center and two were multicenter studies. All studies included only adults. Five studies excluded people who were severely immunocompromised, with only one study including 10 participants who were receiving immunosuppressive therapy out of the 64 enrolled; these were similarly distributed between the FMT arm (4/24 or 17%) and comparison arms (6/40 or 15%). The route of administration was the upper gastrointestinal tract via a nasoduodenal tube in one study, two studies used enema only, two used colonoscopic only delivery, and one used either nasojejunal or colonoscopic delivery, depending on a clinical determination of whether the recipient could tolerate a colonoscopy. Five studies had at least one comparison group that received vancomycin. The risk of bias (RoB 2) assessments did not find an overall high risk of bias for any outcome. All six studies assessed the efficacy and safety of FMT for the treatment of rCDI. Pooled results from six studies showed that the use of FMT in immunocompetent participants with rCDI likely leads to a large increase in resolution of rCDI in the FMT group compared to control (risk ratio (RR) 1.92, 95% confidence interval (CI) 1.36 to 2.71; P = 0.02, I2 = 63%; 6 studies, 320 participants; number needed to treat for an additional beneficial outcome (NNTB) 3; moderate-certainty evidence). Fecal microbiota transplantation probably results in a slight reduction in serious adverse events; however, the CIs around the summary estimate were wide (RR 0.73, 95% CI 0.38 to 1.41; P = 0.24, I² = 26%; 6 studies, 320 participants; NNTB 12; moderate-certainty evidence). Fecal microbiota transplantation may result in a reduction in all-cause mortality; however, the number of events was small, and the CIs of the summary estimate were wide (RR 0.57, 95% CI 0.22 to 1.45; P = 0.48, I2 = 0%; 6 studies, 320 participants; NNTB 20; low-certainty evidence). None of the included studies reported colectomy rates. AUTHORS' CONCLUSIONS In immunocompetent adults with rCDI, FMT likely leads to a large increase in the resolution of recurrent Clostridioides difficile infection compared to alternative treatments such as antibiotics. There was no conclusive evidence regarding the safety of FMT for the treatment of rCDI as the number of events was small for serious adverse events and all-cause mortality. Additional data from large national registry databases might be required to assess any short-term or long-term risks with using FMT for the treatment of rCDI. Elimination of the single study that included some immunocompromised people did not alter these conclusions. Due to the low number of immunocompromised participants enrolled, conclusions cannot be drawn about the risks or benefits of FMT for rCDI in the immunocompromised population.
Collapse
Affiliation(s)
- Nathan Zev Minkoff
- Pediatric Gastroenterology, Hepatology and Nutrition, Valley Children's Hospital, Madera, California, USA
| | - Scheherzade Aslam
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Melissa Medina
- Department of Public Health and Preventative Medicine, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Emily E Tanner-Smith
- Counseling Psychology and Human Services, University of Oregon, Eugene, Oregon, USA
| | - Joseph P Zackular
- Department of Pathology and Laboratory Medicine, University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Sari Acra
- Department of Pediatrics, D. Brent Polk Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Maribeth R Nicholson
- Department of Pediatrics, D. Brent Polk Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Aamer Imdad
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, SUNY Upstate Medical University, Syracuse, New York, USA
| |
Collapse
|
|
11
|
Siraw BB, Reingold AL, Meyahnwi D. Association between epidemiologic case definition categories and adverse clinical outcome in patients with Clostridiodes difficile infection in San Francisco County, California: a five-year retrospective cohort study. BMC Infect Dis 2023; 23:68. [PMID: 36737685 PMCID: PMC9897617 DOI: 10.1186/s12879-023-08030-4] [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: 06/13/2022] [Accepted: 01/24/2023] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Understanding the predictors of adverse clinical outcomes following incident Clostridiodes difficile infection (CDI) can help clinicians identify which patients are at risk of complications and help prioritize the provision of their care. In this study, we assessed the associations between epidemiologic case definition categories and adverse clinical outcomes in patients with CDI in San Francisco County, California. METHODS We conducted a retrospective cohort study using CDI surveillance data (n = 3274) from the California Emerging Infections Program for the time period 2016 to 2020. After independent associations were established, two multivariable logistic and log-binomial regression models were constructed for the final statistical analysis. RESULT The mean cumulative incidence of CDI cases was 78.8 cases per 100,000 population. The overall recurrence rate and the 30-day all-cause mortality rate were 11.1% and 4.5%, respectively. After adjusting for potential confounders, compared to the community associated CDI cases, healthcare facility onset (AOR = 3.1; 95% CI [1.3-7]) and community-onset-healthcare facility associated (AOR = 2.4; 95% CI [1.4-4.3]) CDI cases were found to have higher odds of all-cause 30-day mortality. Community onset-healthcare facility-associated CDI case definition category was found to be significantly associated with an increased risk of recurrence of CDI (ARR = 1.7; 95% CI [1.2-2.4]). CONCLUSION Although the incidence of community-associated CDI cases has been rising, the odds of all-cause 30-day mortality and the risk of recurrent CDI associated with these infections are lower than healthcare facility onset and community-onset healthcare facility-associated CDI cases.
Collapse
Affiliation(s)
- Bekure B. Siraw
- grid.47840.3f0000 0001 2181 7878School of Public Health, University of California, 1279 Webster St. San Francisco, Berkeley, CA 94115 USA
| | - Arthur L. Reingold
- grid.47840.3f0000 0001 2181 7878Division of Epidemiology, School of Public Health, University of California, Berkeley, CA USA
| | - Didien Meyahnwi
- grid.47840.3f0000 0001 2181 7878School of Public Health, University of California, 1279 Webster St. San Francisco, Berkeley, CA 94115 USA
| |
Collapse
|
|
12
|
Braga DS, Oliveira DF, Lourenço NV, Carvalho GM, Rezende VMLR, Lourenço TV, Silva ROS, Kuijper EJ, Vilela EG. Incidence of healthcare-associated Clostridioides difficile infection in a quaternary referral university hospital in Brazil. Anaerobe 2023; 79:102672. [PMID: 36471553 DOI: 10.1016/j.anaerobe.2022.102672] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/21/2022] [Accepted: 11/25/2022] [Indexed: 11/27/2022]
Abstract
Clostridioides difficile infection (CDI) is an important cause of diarrhea in hospitals worldwide. The incidence of CDI in Latin America has not yet been standardized. To fill this gap, the present study performed a daily active surveillance, for three months, between April to July of 2021, at a quaternary referral university hospital in Brazil. The incidence density was 9.2 cases per 10,000 patient-days. Cases were associated mostly with ribotypes 014 and 106 (44% and 22%, respectively). Ribotype 027 was not identified. The findings strongly reinforce the need for broad epidemiological studies on the incidence of CDI in Brazilian hospitals to increase the understanding, prevention, and treatment of this infection.
Collapse
Affiliation(s)
- Daniela S Braga
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Brazil; Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Brazil
| | - Daniela F Oliveira
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Brazil; Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Brazil
| | - Natane V Lourenço
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Brazil; Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Brazil
| | - Gabriela M Carvalho
- Veterinary School, Universidade Federal de Minas Gerais, Antônio Carlos Avenue, 6627. Belo Horizonte, MG, 31.270-901, Brazil
| | - Vitória M L R Rezende
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Brazil; Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Brazil
| | - Tainá V Lourenço
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Brazil; Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Brazil
| | - Rodrigo O S Silva
- Veterinary School, Universidade Federal de Minas Gerais, Antônio Carlos Avenue, 6627. Belo Horizonte, MG, 31.270-901, Brazil.
| | - Ed J Kuijper
- Expertise Center for Clostridioides difficile infections, at Department of Medical Microbiology, Leiden University Medical Center, Leiden, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
| | - Eduardo G Vilela
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Brazil; Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Brazil
| |
Collapse
|
|
13
|
De-la-Rosa-Martinez D, Rivera-Buendía F, Cornejo-Juárez P, García-Pineda B, Nevárez-Luján C, Vilar-Compte D. Risk factors and clinical outcomes for Clostridioides difficile infections in a case control study at a large cancer referral center in Mexico. Am J Infect Control 2022; 50:1220-1225. [PMID: 35172185 DOI: 10.1016/j.ajic.2022.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 02/03/2022] [Accepted: 02/07/2022] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Clostridioides difficile infection (CDI) is recognized as the leading cause of nosocomial diarrhea. This study describes CDI's clinical characteristics, risk factors, and outcomes in the cancer population. METHODS We conducted a case-control study on cancer patients from 2015-2018 at the Instituto Nacional de Cancerologia in Mexico. CDI case was defined as diarrhea episode and positive polymerase chain reaction (PCR) for toxigenic strains. Controls were cancer diagnosis-matched patients with diarrhea and negative PCR. Healthcare Facility-Onset (HO-CDI) and Community-Onset, Healthcare Facility-Associated (CO-HCFA-CDI) rates were calculated. For assessing associations, univariate and multivariate logistic regression analyses were conducted. RESULTS We included 148 CDI cases and 148 controls. The CDI rate was 4.1 per 10,000 patient-days and 2.1 per 1,000 patient admissions for HO-CDI and CO-HCFA-CDI episodes, respectively. Clinical characteristics associated with CDI were fever, abdominal pain, and ≥4 episodes of diarrhea/24h. Previous use of proton pump inhibitors (P=.003), fluoroquinolones (P=.016), and cephalosporins (P=.026) increased the risk for CDI acquisition, while higher age (P=.022) and male gender (P=.015) were related to severe episodes. Thirty-day all-cause mortality was higher among CDI patients (18%) than controls (9%). CONCLUSION The CDI rate was lower compared to other series. The incidence of CO-HCFA-CDI episodes increased, and HO-CDI cases decreased from 2016 to 2018. Risk factors for acquisition and severe infection were similar to those reported in non-cancer populations.
Collapse
Affiliation(s)
| | - Frida Rivera-Buendía
- Instituto Nacional de Cancerologia, Department of Infectious Diseases, Mexico City, Mexico
| | | | - Bertha García-Pineda
- Instituto Nacional de Cancerologia, Department of Infectious Diseases, Mexico City, Mexico
| | - Carolina Nevárez-Luján
- Instituto Nacional de Cancerologia, Department of Infectious Diseases, Mexico City, Mexico
| | - Diana Vilar-Compte
- Instituto Nacional de Cancerologia, Department of Infectious Diseases, Mexico City, Mexico.
| |
Collapse
|
|
14
|
Granata G, Schiavone F, Pipitone G. Bezlotoxumab in Patients with a Primary Clostridioides difficile Infection: A Literature Review. Antibiotics (Basel) 2022; 11:1495. [PMID: 36358149 PMCID: PMC9687042 DOI: 10.3390/antibiotics11111495] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 10/21/2022] [Accepted: 10/25/2022] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Nowadays, one of the main issues in the management of Clostridioides difficile infection (CDI) is the high rate of recurrences (rCDI), causing increased mortality and higher health care costs. OBJECTIVES To assess the available evidence on the use of bezlotoxumab for the prevention of rCDI during a first CDI episode. METHODS Published articles on bezlotoxumab during a primary CDI episode were identified through computerized literature searches with the search terms [(bezlotoxumab) AND (CDI) OR (Clostridioides difficile infection)] using PubMed and by reviewing the references of retrieved articles. PubMed was searched until 31 August 2022. RESULTS Eighty-eight studies were identified as published from December 2014 to June 2022. Five studies were included in this study, one was a phase III clinical trial and four were sub-analyses or extensions of the previous phase III clinical trial. In the phase III clinical trial, the subgroup analysis on the included primary CDI patients showed that 13.5% of patients receiving bezlotoxumab had an rCDI, whilst 20.9% of patients in the placebo group had an rCDI at the twelve weeks follow-up (absolute difference: -7.4). CONCLUSIONS Bezlotoxumab administration during the standard of care antibiotic therapy is effective and safe in reducing the rate of rCDI. Despite its high cost, evidence suggests considering bezlotoxumab in patients with a primary CDI episode. Further studies are needed to assess the benefit in specific subgroups of primary CDI patients and to define the risk factors to guide bezlotoxumab use.
Collapse
Affiliation(s)
- Guido Granata
- Clinical and Research Department for Infectious Diseases, National Institute for Infectious Diseases L. Spallanzani, IRCCS, 00149 Rome, Italy
| | - Francesco Schiavone
- Divers and Raiders Group Command “Teseo Tesei” COMSUBIN, Medical Service, Italian Navy, 19025 Portovenere, Italy
| | - Giuseppe Pipitone
- Infectious Disease Unit, ARNAS Civico-Di Cristina, Piazza Leotta, 5, 90100 Palermo, Italy
| |
Collapse
|
|
15
|
Abstract
There is a growing awareness of the importance of sex and gender in medicine and research. Women typically have stronger immune responses to self and foreign antigens than men, resulting in sex-based differences in autoimmunity and infectious diseases. In both animals and humans, males are generally more susceptible than females to bacterial infections. At the same time, gender differences in health-seeking behavior, quality of health care, and adherence to treatment recommendations have been reported. This review explores our current understanding of differences between males and females in bacterial diseases. We describe how genetic, immunological, hormonal, and anatomical factors interact to influence sex-based differences in pathophysiology, epidemiology, clinical presentation, disease severity, and prognosis, and how gender roles affect the behavior of patients and providers in the health care system.
Collapse
|
|
16
|
Kunishima H, Ohge H, Suzuki H, Nakamura A, Matsumoto K, Mikamo H, Mori N, Morinaga Y, Yanagihara K, Yamagishi Y, Yoshizawa S. Japanese Clinical Practice Guidelines for Management of Clostridioides (Clostridium) difficile infection. J Infect Chemother 2022; 28:1045-1083. [PMID: 35618618 DOI: 10.1016/j.jiac.2021.12.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 11/16/2021] [Accepted: 12/13/2021] [Indexed: 12/19/2022]
Affiliation(s)
- Hiroyuki Kunishima
- Department of Infectious Diseases, St. Marianna University School of Medicine, Japan.
| | - Hiroki Ohge
- Department of Infectious Diseases, Hiroshima University Hospital, Japan
| | - Hiromichi Suzuki
- Division of Infectious Diseases, Department of Medicine, Tsukuba Medical Center Hospital, Japan
| | - Atsushi Nakamura
- Division of Infection Control and Prevention, Nagoya City University Hospital, Japan
| | - Kazuaki Matsumoto
- Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Japan
| | - Hiroshige Mikamo
- Clinical Infectious Diseases, Graduate School of Medicine, Aichi Medical University, Japan
| | - Nobuaki Mori
- Division of General Internal Medicine and Infectious Diseases, National Hospital Organization Tokyo Medical Center, Japan
| | - Yoshitomo Morinaga
- Department of Microbiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Katsunori Yanagihara
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Yuka Yamagishi
- Clinical Infectious Diseases, Graduate School of Medicine, Aichi Medical University, Japan
| | - Sadako Yoshizawa
- Department of Clinical Laboratory/Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Japan
| |
Collapse
|
|
17
|
Treatment and Outcomes of Clostridioides difficile Infection in Switzerland: A Two-Center Retrospective Cohort Study. J Clin Med 2022; 11:jcm11133805. [PMID: 35807087 PMCID: PMC9267637 DOI: 10.3390/jcm11133805] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 02/01/2023] Open
Abstract
Objectives: Clostridioides difficile infection (CDI) is the leading cause of healthcare-associated diarrhea, often complicated by severe infection and recurrence with increased morbidity and mortality. Data from large cohorts in Switzerland are scarce. We aimed to describe diagnostic assays, treatment, outcomes, and risk factors for CDI in a large cohort of patients in Switzerland. Methods: We conducted a retrospective cohort study of CDI episodes diagnosed in patients from two tertiary care hospitals in Switzerland. During a 3-month follow-up, we used a composite outcome combining clinical cure at day 10, recurrence at week 8, or death, to evaluate a patient’s response. Unfavorable outcomes consisted in the occurrence of any of these events. Results: From January 2014 to December 2018, we included 826 hospitalized patients with documented CDI. Overall, 299 patients (36.2%) had a severe infection. Metronidazole was used in 566 patients (83.7%), compared to 82 patients (12.1%) treated with vancomycin and 28 patients (4.1%) treated with fidaxomicin. Overall mortality at week 8 was at 15.3% (112/733). Eighty-six patients (12.7%) presented with clinical failure at day 10, and 78 (14.9%) presented with recurrence within 8 weeks; 269 (39.8%) met the composite outcome of death, clinical failure, or recurrence. The Charlson Comorbidity Index score (p < 0.001), leukocytes > 15 G/L (p = 0.008), and the use of metronidazole (p = 0.012) or vancomycin (p = 0.049) were factors associated with the composite outcome. Conclusions: Our study provides valuable insights on CDI treatment and outcomes in Switzerland, highlights the heterogeneity in practices among centers, and underlines the need for the active monitoring of clinical practices and their impact on clinical outcomes through large multicentric cohorts.
Collapse
|
|
18
|
Nivet C, Duhalde V, Beaurain M, Delobel P, Quelven I, Alric L. Fecal Microbiota Transplantation for Refractory Clostridioides Difficile Infection Is Effective and Well Tolerated Even in Very Old Subjects: A Real-Life Study. J Nutr Health Aging 2022; 26:290-296. [PMID: 35297473 PMCID: PMC8886857 DOI: 10.1007/s12603-022-1756-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/15/2022] [Indexed: 11/28/2022]
Abstract
OBJECTIVES Fecal microbiota transplantation (FMT) is an innovative therapy indicated for the treatment of recurrent Clostridioides difficile infections. Although CDI and its complications are more common in very old patients (≥80 years) due to their comorbidities, frailty and senescence of the immune system, limited data are available for this older patient population. DESIGN This was a single-center, real-life cohort study with retrospective outcome data registration, conducted at Toulouse, France. SETTING AND PARTICIPANTS Older people group was compared to the control group aged 18-79 years. MEASUREMENTS The primary outcome was overall survival at 52 weeks for ≥80 years patients compared to the control group after FMT. Recurrence-free survival at 52 weeks and, the occurrence of adverse events in the short and long term were the secondary endpoints. RESULTS A total of 58 patients were included, 19 were aged ≥80 years and 39 were aged 18-79 years. Overall survival at 52 weeks after FMT of the very old patients was not different from the control group (78.9% versus 89.7%, p= 0.29). Recurrence-free survival of CDI was not different between groups, with 94.3% in the 18-79-group versus 86.9% in the ≥80 group (p=0.44). The occurrence of short- or long-term adverse events was not statistically different between the two groups (36.8% vs 41%, p=0.45). CONCLUSIONS FMT is effective and well-tolerated in very old frail patients. This treatment brings a rapid benefit and limits the loss of functions. It also favors their maintenance at home or in a non-medical institution dedicated to dependent subjects and improves their quality of life.
Collapse
Affiliation(s)
- C Nivet
- Laurent Alric, Internal medicine department of digestive disease, Rangueil hospital, Toulouse 3 university, 1 avenue du professeur Jean-poulhès, TSA 50032, 31000 Toulouse, France,
| | | | | | | | | | | |
Collapse
|
|
19
|
Hazleton KZ, Martin CG, Orlicky DJ, Arnolds KL, Nusbacher NM, Moreno-Huizar N, Armstrong M, Reisdorph N, Lozupone CA. Dietary fat promotes antibiotic-induced Clostridioides difficile mortality in mice. NPJ Biofilms Microbiomes 2022; 8:15. [PMID: 35365681 PMCID: PMC8975876 DOI: 10.1038/s41522-022-00276-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/21/2022] [Indexed: 11/15/2022] Open
Abstract
Clostridioides difficile infection (CDI) is the leading cause of hospital-acquired diarrhea, and emerging evidence has linked dietary components with CDI pathogenesis, suggesting that dietary modulation may be an effective strategy for prevention. Here, we show that mice fed a high-fat/low-fiber “Western-type” diet (WD) had dramatically increased mortality in a murine model of antibiotic-induced CDI compared to a low-fat/low-fiber (LF/LF) diet and standard mouse chow controls. We found that the WD had a pro- C. difficile bile acid composition that was driven in part by higher levels of primary bile acids that are produced to digest fat, and a lower level of secondary bile acids that are produced by the gut microbiome. This lack of secondary bile acids was associated with a greater disturbance to the gut microbiome with antibiotics in both the WD and LF/LF diet compared to mouse chow. Mice fed the WD also had the highest level of toxin TcdA just prior to the onset of mortality, but not of TcdB or increased inflammation. These findings indicate that dietary intervention to decrease fat may complement previously proposed dietary intervention strategies to prevent CDI in high-risk individuals.
Collapse
Affiliation(s)
- Keith Z Hazleton
- Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition. University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA.,Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, 80045, USA.,Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Arizona, Tucson, AZ, 85719, USA
| | - Casey G Martin
- Department of Immunology and Microbiology, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - David J Orlicky
- Department of Pathology, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Kathleen L Arnolds
- Department of Immunology and Microbiology, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Nichole M Nusbacher
- Department of Medicine, Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Nancy Moreno-Huizar
- Department of Medicine, Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Michael Armstrong
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Nichole Reisdorph
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Catherine A Lozupone
- Department of Medicine, Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO, 80045, USA.
| |
Collapse
|
|
20
|
The Stickland Reaction Precursor trans-4-Hydroxy-l-Proline Differentially Impacts the Metabolism of Clostridioides difficile and Commensal Clostridia. mSphere 2022; 7:e0092621. [PMID: 35350846 PMCID: PMC9044972 DOI: 10.1128/msphere.00926-21] [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] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
An intact gut microbiota confers colonization resistance against Clostridioides difficile through a variety of mechanisms, likely including competition for nutrients. Recently, proline was identified as an important environmental amino acid that C. difficile uses to support growth and cause significant disease. A posttranslationally modified form, trans-4-hydroxyproline, is highly abundant in collagen, which is degraded by host proteases in response to C. difficile toxin activity. The ability to dehydrate trans-4-hydroxyproline via the HypD glycyl radical enzyme is widespread among gut microbiota, including C. difficile and members of the commensal Clostridia, suggesting that this amino acid is an important nutrient in the host environment. Therefore, we constructed a C. difficile ΔhypD mutant and found that it was modestly impaired in fitness in a mouse model of infection, and was associated with an altered microbiota when compared to mice challenged with the wild-type strain. Changes in the microbiota between the two groups were largely driven by members of the Lachnospiraceae family and the Clostridium genus. We found that C. difficile and type strains of three commensal Clostridia had significant alterations to their metabolic gene expression in the presence of trans-4-hydroxyproline in vitro. The proline reductase (prd) genes were elevated in C. difficile, consistent with the hypothesis that trans-4-hydroxyproline is used by C. difficile to supply proline for energy metabolism. Similar transcripts were also elevated in some commensal Clostridia tested, although each strain responded differently. This suggests that the uptake and utilization of other nutrients by the commensal Clostridia may be affected by trans-4-hydroxyproline metabolism, highlighting how a common nutrient may be a signal to each organism to adapt to a unique niche. Further elucidation of the differences between them in the presence of hydroxyproline and other key nutrients will be important in determining their role in nutrient competition against C. difficile. IMPORTANCE Proline is an essential environmental amino acid that C. difficile uses to support growth and cause significant disease. A posttranslationally modified form, hydroxyproline, is highly abundant in collagen, which is degraded by host proteases in response to C. difficile toxin activity. The ability to dehydrate hydroxyproline via the HypD glycyl radical enzyme is widespread among gut microbiota, including C. difficile and members of the commensal Clostridia, suggesting that this amino acid is an important nutrient in the host environment. We found that C. difficile and three commensal Clostridia strains had significant, but different, alterations to their metabolic gene expression in the presence of hydroxyproline in vitro. This suggests that the uptake and utilization of other nutrients by the commensal Clostridia may be affected by hydroxyproline metabolism, highlighting how a common nutrient may be a signal to each organism to adapt to a unique niche. Further elucidation of the differences between them in the presence of hydroxyproline and other key nutrients will be important to determining their role in nutrient competition against C. difficile.
Collapse
|
|
21
|
Non-inferiority of metronidazole to vancomycin in the treatment of first episode non-severe Clostridioides difficile infection: a single center retrospective cohort study. Infection 2022; 50:973-980. [PMID: 35192148 DOI: 10.1007/s15010-022-01778-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 02/07/2022] [Indexed: 11/05/2022]
Abstract
OBJECTIVES We sought to assess the effectiveness of oral vancomycin compared to metronidazole on recurrence and mortality among hospitalized patients with non-severe Clostridioides difficile infection (CDI). METHODS A single center retrospective cohort study was conducted, including adult patients hospitalized between 2015 and 2020 with a first episode of non-severe CDI, treated with metronidazole or vancomycin as monotherapy for at least 10 days. We assessed recurrence of CDI requiring hospitalization (primary outcome) and all-cause mortality up to 8 weeks, post discharge. RESULTS Overall, 160 patients were treated with vancomycin and 149 treated with metronidazole. Re-hospitalization within 8 weeks due to CDI occurred in 10 (6.2%) patients in the vancomycin group, and 13 (8.7%) in the metronidazole group (P value = 0.407). Eight-week mortality occurred in 39 patients (26.2%) in the metronidazole group and 46 patients (28.8%) in the vancomycin group (P value = 0.61). After adjusting for age, gender, Ischemic heart disease, white blood cell count, neutrophile count and CRP, there was no significant difference between the two treatments (Re-hospitalization in 8 weeks due to CDI P = 0.5059; In-hospital death P = 0.7950; 4-week mortality P = 0.2988; 8-week mortality P = 0.8237). CONCLUSION There is no benefit of using vancomycin compared to metronidazole concerning recurrence rate requiring hospitalization, in-hospital and up to 4- and 8-week mortality rate in non-severe first episode of CDI.
Collapse
|
|
22
|
Kim MH, Kim YC, Kim JL, Park YS, Kim H. Description of antibiotic treatment in adults tested for Clostridioides difficile infection: a single-center case–control study. BMC Infect Dis 2022; 22:104. [PMID: 35093016 PMCID: PMC8801153 DOI: 10.1186/s12879-022-07085-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 01/17/2022] [Indexed: 11/10/2022] Open
Abstract
Background Diagnosing Clostridioides difficile infection (CDI) is complicated. There have been reports on effects of compliance with anti-C. difficile prescription guidelines on patient outcomes. However, the causes of non-adherence and their impact on outcomes have rarely been explored. Therefore, an investigation on the risk factors for non-adherence with treatment guidelines and their influence on recurrence is important. Methods This case–control study was conducted with patients with a positive C. difficile culture from March 2020 to April 2021. We conducted analysis based on treatment categories using factors associated with recurrent CDI as variables. Univariate and multivariable analyses were conducted to identify risk factors for non-adherence with treatment guidelines. Results In total, culture positive stool samples from 172 patients were analyzed. Having positive glutamate dehydrogenase antigen (GDH Ag), negative toxin enzyme immunoassay (EIA), and positive nucleic acid amplification test (NAAT) (GDH+/toxin EIA−/NAAT +) results were associated with both under- (adjusted odds ratio [aOR] 3.49 [95% CI 1.62–7.51], p = 0.001) and over-treatment (aOR 0.17 [95% CI 0.06–0.48], p = 0.001). Patients with refractory diarrhea were over treated (aOR 2.71 [95% CI 1.02–7.20], p = 0.046). Patients with an increased risk of CDI recurrence were not over treated. Conclusions Our results suggest that non-adherence with CDI treatment guidelines depends on the duration of symptoms and rapid EIA test results. Patients with an increased risk of recurrence were neglected. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-022-07085-z.
Collapse
|
|
23
|
Giles J, Roberts A. Clostridioides difficile: Current overview and future perspectives. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2022; 129:215-245. [PMID: 35305720 DOI: 10.1016/bs.apcsb.2021.11.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The most common world-wide cause of antibiotic-associated infectious diarrhea and colitis is the toxin producing bacterium, Clostridioides difficile (C. difficile). Here we review the background and characteristics of the bacterium and the toxins produced together with the epidemiology and the complex pathogenesis that leads to a broad clinical spectrum of disease. The review describes the difficulties faced in obtaining a quick and accurate diagnosis despite the range of sensitive and specific diagnostic tools available. We also discuss the problem of disease recurrence and the importance of disease prevention. The high rates of infection recurrence mean that treatment strategies are constantly under review and we outline the diverse treatment options that are currently in use and explore the emerging treatment options of pulsed antibiotic use, microbial replacement therapies and the use of monoclonal antibodies. We summarize the future direction of treatment strategies which include the development of novel antibiotics, the administration of oral polyclonal antibody formulations, the use of vaccines, the administration of competitive non-toxigenic spores and the neutralization of antibiotics at the microbiota level. Future successful treatments will likely involve a combination of therapies to provide the most effective and robust approach to C. difficile management.
Collapse
Affiliation(s)
- Joanna Giles
- MicroPharm Ltd, Newcastle Emlyn, United Kingdom.
| | - April Roberts
- Toxins Group, National Infection Service, Public Health England, Porton Down, United Kingdom
| |
Collapse
|
|
24
|
El Halabi J, Palmer N, Fox K, Kohane I, Farhat MR. Fecal microbiota transplantation and Clostridioides difficile infection among privately insured patients in the United States. J Gastroenterol 2022; 57:10-18. [PMID: 34495400 DOI: 10.1007/s00535-021-01822-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/26/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Clostridioides difficile infection (CDI) may be rising in severity in the US over the past decade and its treatment landscape is changing given the recent adoption of fecal microbiota transplantation (FMT) METHODS: We built a retrospective observational cohort using a database of a national care-plan containing medical claims of over 50 million individuals between 2008 and 2019. We used International Classification of Disease (ICD) and prescription data to identify patients with CDI. We estimated trends in disease burden and FMT use, and evaluated complications post FMT using a phenome-wide association approach. RESULTS We identified 38,396 patients with CDI; the median age was 60 years (IQR 45-74) and 60% were female (n = 23,374). The rate of CDI increased from 33.4 to 69.46 cases per 100,000 person-years between 2008 and 2015, and stabilized from 2015 to 2019 (increase of 4.77 cases per 100,000 person-years per year, 95% CI 3.55-5.98 prior to 2015 vs. 2.01 95% CI - 10.16 to 14.18 after 2015). Of the 7715 patients with recurrent CDI, 407 patients (5%) underwent FMT. Gastrointestinal complications were increased within 1 month post FMT (OR 99.60, p < 0.001). Sepsis was identified in two individuals (0.49% 95% CI 0.05-1.7%) within the first month post FMT. The risk of CDI recurrence significantly decreased post FMT compared with anti-CDI antibiotics in the multivariable model (raw-recurrence rate 9.8% vs 36%, aOR = 0.21, 95% CI 0.12-0.53, p < 0.001). CONCLUSION We show that FMT is strongly associated with a decrease in CDI recurrence compared with the usual care with generally mild complications for up to 2 years.
Collapse
Affiliation(s)
- Jessica El Halabi
- Department of Biomedical Informatics, Harvard Medical School, 10 Shattuck Street #307, Boston, MA, 02115, USA
| | - Nathan Palmer
- Department of Biomedical Informatics, Harvard Medical School, 10 Shattuck Street #307, Boston, MA, 02115, USA
| | - Kathe Fox
- Department of Biomedical Informatics, Harvard Medical School, 10 Shattuck Street #307, Boston, MA, 02115, USA
| | - Isaac Kohane
- Department of Biomedical Informatics, Harvard Medical School, 10 Shattuck Street #307, Boston, MA, 02115, USA
| | - Maha R Farhat
- Department of Biomedical Informatics, Harvard Medical School, 10 Shattuck Street #307, Boston, MA, 02115, USA. .,Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA.
| |
Collapse
|
|
25
|
Alharbi AK, Ahmed MA, Tashkandi A, Alkhathaami FA, Alshehri AI. Persistent Clostridium Difficile Diarrhea, Thinking Beyond Pseudomembranous Colitis: A Case Report. Cureus 2021; 13:e20704. [PMID: 35106241 PMCID: PMC8788889 DOI: 10.7759/cureus.20704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/26/2021] [Indexed: 11/05/2022] Open
|
|
26
|
van Prehn J, Reigadas E, Vogelzang EH, Bouza E, Hristea A, Guery B, Krutova M, Norén T, Allerberger F, Coia JE, Goorhuis A, van Rossen TM, Ooijevaar RE, Burns K, Scharvik Olesen BR, Tschudin-Sutter S, Wilcox MH, Vehreschild MJGT, Fitzpatrick F, Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clin Microbiol Infect 2021; 27 Suppl 2:S1-S21. [PMID: 34678515 DOI: 10.1016/j.cmi.2021.09.038] [Citation(s) in RCA: 310] [Impact Index Per Article: 77.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 09/23/2021] [Accepted: 09/30/2021] [Indexed: 12/13/2022]
Abstract
SCOPE In 2009, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) published the first treatment guidance document for Clostridioides difficile infection (CDI). This document was updated in 2014. The growing literature on CDI antimicrobial treatment and novel treatment approaches, such as faecal microbiota transplantation (FMT) and toxin-binding monoclonal antibodies, prompted the ESCMID study group on C. difficile (ESGCD) to update the 2014 treatment guidance document for CDI in adults. METHODS AND QUESTIONS Key questions on CDI treatment were formulated by the guideline committee and included: What is the best treatment for initial, severe, severe-complicated, refractory, recurrent and multiple recurrent CDI? What is the best treatment when no oral therapy is possible? Can prognostic factors identify patients at risk for severe and recurrent CDI and is there a place for CDI prophylaxis? Outcome measures for treatment strategy were: clinical cure, recurrence and sustained cure. For studies on surgical interventions and severe-complicated CDI the outcome was mortality. Appraisal of available literature and drafting of recommendations was performed by the guideline drafting group. The total body of evidence for the recommendations on CDI treatment consists of the literature described in the previous guidelines, supplemented with a systematic literature search on randomized clinical trials and observational studies from 2012 and onwards. The Grades of Recommendation Assessment, Development and Evaluation (GRADE) system was used to grade the strength of our recommendations and the quality of the evidence. The guideline committee was invited to comment on the recommendations. The guideline draft was sent to external experts and a patients' representative for review. Full ESCMID endorsement was obtained after a public consultation procedure. RECOMMENDATIONS Important changes compared with previous guideline include but are not limited to: metronidazole is no longer recommended for treatment of CDI when fidaxomicin or vancomycin are available, fidaxomicin is the preferred agent for treatment of initial CDI and the first recurrence of CDI when available and feasible, FMT or bezlotoxumab in addition to standard of care antibiotics (SoC) are preferred for treatment of a second or further recurrence of CDI, bezlotoxumab in addition to SoC is recommended for the first recurrence of CDI when fidaxomicin was used to manage the initial CDI episode, and bezlotoxumab is considered as an ancillary treatment to vancomycin for a CDI episode with high risk of recurrence when fidaxomicin is not available. Contrary to the previous guideline, in the current guideline emphasis is placed on risk for recurrence as a factor that determines treatment strategy for the individual patient, rather than the disease severity.
Collapse
Affiliation(s)
- Joffrey van Prehn
- Department of Medical Microbiology, Centre for Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands
| | - Elena Reigadas
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Erik H Vogelzang
- Department of Medical Microbiology and Infection Control, Amsterdam University Medical Center, Location VUmc, Amsterdam, the Netherlands
| | - Emilio Bouza
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Adriana Hristea
- University of Medicine and Pharmacy Carol Davila, National Institute for Infectious Diseases Prof Dr Matei Bals, Romania
| | - Benoit Guery
- Infectious Diseases Specialist, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Marcela Krutova
- Department of Medical Microbiology, Charles University in Prague and Motol University Hospital, Czech Republic
| | - Torbjorn Norén
- Faculty of Medicine and Health, Department of Laboratory Medicine, National Reference Laboratory for Clostridioides difficile, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden
| | | | - John E Coia
- Department of Clinical Microbiology, Hospital South West Jutland and Department of Regional Health Research IRS, University of Southern Denmark, Esbjerg, Denmark
| | - Abraham Goorhuis
- Department of Infectious Diseases, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, the Netherlands
| | - Tessel M van Rossen
- Department of Medical Microbiology and Infection Control, Amsterdam University Medical Center, Location VUmc, Amsterdam, the Netherlands
| | - Rogier E Ooijevaar
- Department of Gastroenterology, Amsterdam University Medical Center, Location VUmc, Amsterdam, the Netherlands
| | - Karen Burns
- Departments of Clinical Microbiology, Beaumont Hospital & Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | - Sarah Tschudin-Sutter
- Department of Infectious Diseases and Infection Control, University Hospital Basel, University Basel, Universitatsspital, Basel, Switzerland
| | - Mark H Wilcox
- Department of Microbiology, Old Medical, School Leeds General Infirmary, Leeds Teaching Hospitals & University of Leeds, Leeds, United Kingdom
| | - Maria J G T Vehreschild
- German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany; Department of Internal Medicine, Infectious Diseases, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Fidelma Fitzpatrick
- Department of Clinical Microbiology, Beaumont Hospital, Dublin, Ireland; Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Ed J Kuijper
- Department of Medical Microbiology, Centre for Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands; National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
| | | |
Collapse
|
|
27
|
Sattler MM, Crews JD. Challenges in the Diagnosis and Management of Recurrent and Severe Clostridioides difficile Infection in Children. J Pediatric Infect Dis Soc 2021; 10:S27-S33. [PMID: 34791399 DOI: 10.1093/jpids/piab079] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Children with Clostridioides difficile infection (CDI) can experience recurrent or severe disease. Recurrent CDI occurs in 20%-30% of children with an initial CDI episode. A careful clinical evaluation is important to distinguish recurrent CDI from other disorders that cause recurring gastrointestinal symptoms. Multiple treatment options exist for recurrent CDI, but the optimal therapeutic approach remains undefined. Severe or fulminant CDI can result in poor outcomes and significant morbidity in children. Since there is not a validated definition for severe CDI in children, physicians must use their clinical judgment to identify patients with severe CDI to institute appropriate therapy. In this review, we describe the diagnostic and management challenges in caring for children with recurrent and severe CDI.
Collapse
Affiliation(s)
- Matthew M Sattler
- Department of Pediatrics, Baylor College of Medicine, Children's Hospital of San Antonio, San Antonio, Texas, USA
| | - Jonathan D Crews
- Department of Pediatric Infectious Diseases, Baylor College of Medicine, Children's Hospital of San Antonio, San Antonio, Texas, USA
| |
Collapse
|
|
28
|
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.
Collapse
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
| |
Collapse
|
|
29
|
Wang S, Deng W, Li F, Chen YE, Wang PU. Blockade of T helper 17 cell function ameliorates recurrent Clostridioides difficile infection in mice. Acta Biochim Biophys Sin (Shanghai) 2021; 53:1290-1299. [PMID: 34379099 DOI: 10.1093/abbs/gmab107] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Indexed: 11/12/2022] Open
Abstract
Clostridioides difficile infection (CDI) is a common infection of the gastrointestinal tract. Typically, 20%-30% of CDI patients experience recurrent C.difficile infection (RCDI). Although the role of Th17 in infectious and inflammatory diseases including CDI has gained attention, reports on the correlation between Th17 and RCDI are scarce. In this study, CDI and RCDI mice models were challenged with C. difficile. Serum lactic acid dehydrogenase, inflammatory factor levels, reverse transcriptase-polymerase chain reaction, western blot analysis, hematoxylin and eosin staining, immunohistochemistry, flow cytometry analysis, and enzyme-linked immunosorbent assay were performed on the CDI, RCDI, and control group mice. The results showed more serious clinical manifestations in the RCDI group compared with those in the CDI group. More severe gut barrier disruption and higher degree of microbiota translocation were observed in the RCDI group compared with those in the CDI group. Moreover, extremely severe apoptosis was observed in HCT-116 cells incubated with the serum from RCDI mice model. In addition, higher levels of Th17 and IL-17 were detected in the blood or serum from the RCDI mouse model. Treatment with RORγt small molecule inhibitor SR1001 increased the expression of occludin, decreased the apoptotic rate of HCT-116 cells, and decreased the concentrations of Th17 and IL-17. Concisely, Th17 and IL-17 are potential indicators of RCDI and may serve as therapeutic targets for RCDI treatment. This study lays the foundation for future research on RCDI diagnosis and treatment.
Collapse
Affiliation(s)
- Siqi Wang
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Wenlin Deng
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Department of Pediatrics, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China
| | - Fang Li
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Y E Chen
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - P U Wang
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| |
Collapse
|
|
30
|
Hotinger JA, Morris ST, May AE. The Case against Antibiotics and for Anti-Virulence Therapeutics. Microorganisms 2021; 9:2049. [PMID: 34683370 PMCID: PMC8537500 DOI: 10.3390/microorganisms9102049] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/22/2021] [Accepted: 09/24/2021] [Indexed: 12/14/2022] Open
Abstract
Although antibiotics have been indispensable in the advancement of modern medicine, there are downsides to their use. Growing resistance to broad-spectrum antibiotics is leading to an epidemic of infections untreatable by first-line therapies. Resistance is exacerbated by antibiotics used as growth factors in livestock, over-prescribing by doctors, and poor treatment adherence by patients. This generates populations of resistant bacteria that can then spread resistance genes horizontally to other bacterial species, including commensals. Furthermore, even when antibiotics are used appropriately, they harm commensal bacteria leading to increased secondary infection risk. Effective antibiotic treatment can induce bacterial survival tactics, such as toxin release and increasing resistance gene transfer. These problems highlight the need for new approaches to treating bacterial infection. Current solutions include combination therapies, narrow-spectrum therapeutics, and antibiotic stewardship programs. These mediate the issues but do not address their root cause. One emerging solution to these problems is anti-virulence treatment: preventing bacterial pathogenesis instead of using bactericidal agents. In this review, we discuss select examples of potential anti-virulence targets and strategies that could be developed into bacterial infection treatments: the bacterial type III secretion system, quorum sensing, and liposomes.
Collapse
Affiliation(s)
| | | | - Aaron E. May
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23219, USA; (J.A.H.); (S.T.M.)
| |
Collapse
|
|
31
|
Solanki D, Kichloo A, El-Amir Z, Dahiya DS, Singh J, Wani F, Solanki S. Clostridium difficile Infection Hospitalizations in the United States: Insights From the 2017 National Inpatient Sample. Gastroenterology Res 2021; 14:87-95. [PMID: 34007350 PMCID: PMC8110239 DOI: 10.14740/gr1371] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 03/25/2021] [Indexed: 12/27/2022] Open
Abstract
Background There is a paucity of contemporary national estimates for Clostridium difficile infection (CDI) hospitalizations by age group, sex, and region in the US population. Also, there is lack of contemporary national statistics on CDI hospitalizations with comorbidities. Methods We analyzed the 2017 National Inpatient Sample (NIS) to determine the population-based rates of CDI hospitalizations, characteristics of hospitalizations with CDI, and the rates of comorbidities associated with CDI hospitalizations. Results There were 329,460 CDI-related hospitalizations in 2017 (almost 1% of all hospitalizations). The average age for patients admitted with CDI as a principal or secondary diagnosis was 64.7 years (almost 20 years older when compared with all other hospitalizations). Patients 85 years and older had the highest rate of CDI hospitalizations (716 per 100,000 hospitalizations), and patients less than 18 years of age had the lowest rate (12 per 100,000 hospitalizations). There was a progressive increase in the CDI hospitalization rates with each successive age group. The hospitalization rates were higher in females (114 per 100,000 hospitalizations) than males (88 per 100,000 hospitalizations). The CDI hospitalization rate was highest in the Northeast (109 per 100,000 hospitalizations) and lowest in the West (84 per 100,000 hospitalizations). Fluid and electrolyte disturbance (63.3%) and renal failure (33.4%) were the two most common comorbidities associated with CDI hospitalizations. When CDI is a secondary diagnosis, major loss of function, extreme likelihood of dying, septicemia, and septic shock were more common in comparison to CDI as a principal diagnosis. Conclusions CDI hospitalization rates were highest in the elderly over 85 years old and declined with successive decreases in age. Women had higher CDI hospitalization rates than men, and fluid and electrolyte disturbances and renal failure were the most common comorbid conditions. The presence of CDI as a comorbid condition at the time of hospitalization for other principal diagnoses or development of CDI during a hospitalization for other principal diagnoses significantly increases the risk of in-hospital morbidity and mortality.
Collapse
Affiliation(s)
| | - Asim Kichloo
- Department of Medicine, Central Michigan University, Saginaw, MI, USA
| | - Zain El-Amir
- Department of Medicine, Central Michigan University, Saginaw, MI, USA
| | | | - Jagmeet Singh
- Department of Medicine, Geisinger Commonwealth School of Medicine, Scranton, PA, USA
| | - Farah Wani
- Department of Medicine, Samaritan Medical Center, Watertown, NY, USA
| | - Shantanu Solanki
- Department of Medicine, Geisinger Commonwealth School of Medicine, Scranton, PA, USA
| |
Collapse
|
|
32
|
Imwattana K, Knight DR, Riley TV. Can sequencing improve the diagnosis and management of Clostridioides difficile infection? Expert Rev Mol Diagn 2021; 21:429-431. [PMID: 33843381 DOI: 10.1080/14737159.2021.1915774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Korakrit Imwattana
- School of Biomedical Sciences, The University of Western Australia, Crawley, Australia.,Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Daniel R Knight
- School of Biomedical Sciences, The University of Western Australia, Crawley, Australia.,Medical, Molecular and Forensic Sciences, Murdoch University, Murdoch, Australia
| | - Thomas V Riley
- School of Biomedical Sciences, The University of Western Australia, Crawley, Australia.,Medical, Molecular and Forensic Sciences, Murdoch University, Murdoch, Australia.,School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia.,PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, Australia
| |
Collapse
|
|
33
|
The effect of a microbial ecosystem therapeutic (MET-2) on recurrent Clostridioides difficile infection: a phase 1, open-label, single-group trial. Lancet Gastroenterol Hepatol 2021; 6:282-291. [PMID: 33631102 DOI: 10.1016/s2468-1253(21)00007-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/18/2020] [Accepted: 12/21/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Faecal microbiota transplantation (FMT) is highly effective for recurrent Clostridioides difficile infection but has inherent risks. Microbial Ecosystem Therapeutic 2 (MET-2) is an oral encapsulated formulation of 40 lyophilised bacterial species initially isolated from stool of a healthy donor, but subsequently manufactured independently of donors, eliminating potential risks introduced by changes in donor health. The aim of this study was to determine MET-2 activity, safety, and tolerability. METHODS This phase 1, open-label, single-group feasibility study was done in Alberta, Canada. The main inclusion criteria were mild to moderate C difficile infection and at least one episode of C difficile infection recurrence (ie, two episodes of C difficile infection) within 12 months. Initial daily treatment was ten oral capsules for 2 days, then three capsules for 8 days. If C difficile infection recurred, a higher dose was offered: 20 capsules for 2 days, then three capsules for 8 days. Patients were followed for adverse events and C difficile infection recurrence up to day 130. The primary outcome was absence of C difficile infection recurrence (fewer than three unformed bowel movements in 24 h persisting for at least 2 days) at day 40 by intention-to-treat analysis. Secondary outcomes were mortality or hospitalisation due to C difficile infection, infections attributed to treatment, nausea, abdominal pain, vomiting, or diarrhoea during treatment, quality of life (C difficile Health Related Quality of Life Questionnaire) before and after treatment, and engrafted MET-2 bacteria in patient stool. Absence of C difficile infection recurrence at day 130 was an exploratory outcome. This study is registered with ClinicalTrials.gov, NCT02865616 FINDINGS: Between Sept 19, 2018, and Feb 28, 2020, we enrolled 19 adult patients with at least two episodes of mild to moderate C difficile infection (median age 65 years [IQR 56-67]; 12 women [63%], seven men [37%]). Recurrent C difficile infection was absent at day 40 in 15 (79%) of 19 patients after initial treatment, increasing to 18 (95%) 40 days after retreatment. No mortality associated with C difficile infection, infections associated with MET-2 treatment, or other serious adverse events were observed. The most common self-limited, mild to moderate symptoms reported during treatment were diarrhoea in 12 (63%) of 19 patients and abdominal cramps in 12 (63%). After MET-2 treatment, quality of life improved significantly, as did alpha diversity in stool microbial composition (p=1·93×10-6). MET-2 associated taxa were found in greater abundance in most patients after treatment compared with baseline. 16 (84%) of 19 patients did not have recurrence of C difficile infection by day 130. INTERPRETATION MET-2 appears to be safe, efficacious, and well tolerated among patients with recurrent C difficile infection. Results must be validated in controlled studies. FUNDING NuBiyota.
Collapse
|
|
34
|
Contribution of Inhibitory Metabolites and Competition for Nutrients to Colonization Resistance against Clostridioides difficile by Commensal Clostridium. Microorganisms 2021; 9:microorganisms9020371. [PMID: 33673352 PMCID: PMC7918557 DOI: 10.3390/microorganisms9020371] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/09/2021] [Accepted: 02/09/2021] [Indexed: 12/16/2022] Open
Abstract
Clostridioides difficile is an anaerobic pathogen that causes significant morbidity and mortality. Understanding the mechanisms of colonization resistance against C. difficile is important for elucidating the mechanisms by which C. difficile is able to colonize the gut after antibiotics. Commensal Clostridium play a key role in colonization resistance. They are able to modify bile acids which alter the C. difficile life cycle. Commensal Clostridium also produce other inhibitory metabolites including antimicrobials and short chain fatty acids. They also compete with C. difficile for vital nutrients such as proline. Understanding the mechanistic effects that these metabolites have on C. difficile and other gut pathogens is important for the development of new therapeutics against C. difficile infection (CDI), which are urgently needed.
Collapse
|
|
35
|
Elbeddini A, Gerochi R. Treatment of Clostridium difficile infection in community teaching hospital: a retrospective study. J Pharm Policy Pract 2021; 14:19. [PMID: 33568232 PMCID: PMC7877108 DOI: 10.1186/s40545-020-00289-1] [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: 08/14/2020] [Accepted: 12/28/2020] [Indexed: 11/25/2022] Open
Abstract
Objectives Clostridium difficile infection (CDI) is responsible for 15–25% cases of health-care-associated diarrhea. The CDI treatment algorithm used at our hospital is adapted from the Infectious Diseases Society of America 2010 C. difficile guideline. The primary objective of this study was to assess the treatment adherence to our algorithm; this was defined as therapy consisting of the appropriate antibiotic, dose, route, interval, and duration indicated based on the disease severity and episode within 24 h of diagnosis. Furthermore, our study also described the population and their risk factors for CDI at our hospital. Methods This was a single-centre, retrospective cohort chart review of CDI cases that were diagnosed at admission or during hospitalization from June 1st, 2017 to June 30th, 2018. Cases were identified by a positive stool test along with watery diarrhea or by colonoscopy. Results Sixty cases were included, of which adherence to our algorithm was 50%. Overall, severe CDI had the highest treatment non-adherence (83%), and the biggest contributing factor was prescribing the wrong antibiotic (72%). In severe CDI, which warrants vancomycin monotherapy, wrong antibiotic consisted of metronidazole monotherapy (55%) or dual therapy with metronidazole and vancomycin (45%). Patients were mostly older, females being treated for an initial episode of mild-to-moderate CDI. Common risk factors identified were age over 65 years (80%), use of antibiotics (83%) and proton pump inhibitors (PPI) (68%) within the previous 3 months. The use of a PPI in this study, a modifiable risk factor without a clear indication, was 35%. Conclusion An area for antimicrobial stewardship intervention in CDI treatment at our hospital is prescribing the right antibiotic based on the CDI indication. In severe CDI, an emphasis should be on prescribing vancomycin monotherapy as the drug of choice. PPI use should be reassessed for tapering when appropriate.
Collapse
Affiliation(s)
- Ali Elbeddini
- Winchester District Memorial Hospital, 566 Louise Street, Winchester, ON, KK0C2K0, Canada.
| | - Rachel Gerochi
- Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St, Toronto, M5S 3M2, Canada
| |
Collapse
|
|
36
|
Imdad A, Minkoff NZ, Tanner-Smith EE, Zackular JP, Acra S, Nicholson MR. Fecal microbiota transplantation for the treatment of recurrent Clostridioides difficile
( Clostridium difficile
). Hippokratia 2021. [DOI: 10.1002/14651858.cd013871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Aamer Imdad
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition; SUNY Upstate Medical University; Syracuse NY USA
| | - Nathan Zev Minkoff
- Pediatric Gastroenterology, Hepatology and Nutrition; University of Rochester Medical Center; Rochester NY USA
| | - Emily E Tanner-Smith
- Counseling Psychology and Human Services; University of Oregon; Eugene Oregon USA
| | - Joseph P Zackular
- Department of Pathology and Laboratory Medicine; University of Pennsylvania; Philadelphia PA USA
| | - Sari Acra
- Department of Pediatrics, D. Brent Polk Division of Gastroenterology, Hepatology and Nutrition; Vanderbilt University School of Medicine; Nashville TN USA
| | - Maribeth R Nicholson
- Department of Pediatrics, D. Brent Polk Division of Gastroenterology, Hepatology and Nutrition; Vanderbilt University School of Medicine; Nashville TN USA
| |
Collapse
|
|
37
|
Kampouri E, Croxatto A, Prod’hom G, Guery B. Clostridioides difficile Infection, Still a Long Way to Go. J Clin Med 2021; 10:jcm10030389. [PMID: 33498428 PMCID: PMC7864166 DOI: 10.3390/jcm10030389] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 12/11/2022] Open
Abstract
Clostridioides difficile is an increasingly common pathogen both within and outside the hospital and is responsible for a large clinical spectrum from asymptomatic carriage to complicated infection associated with a high mortality. While diagnostic methods have considerably progressed over the years, the optimal diagnostic algorithm is still debated and there is no single diagnostic test that can be used as a standalone test. More importantly, the heterogeneity in diagnostic practices between centers along with the lack of robust surveillance systems in all countries and an important degree of underdiagnosis due to lack of clinical suspicion in the community, hinder a more accurate evaluation of the burden of disease. Our improved understanding of the physiopathology of CDI has allowed some significant progress in the treatment of CDI, including a broader use of fidaxomicine, the use of fecal microbiota transplantation for multiples recurrences and newer approaches including antibodies, vaccines and new molecules, already developed or in the pipeline. However, the management of CDI recurrences and severe infections remain challenging and the main question remains: how to best target these often expensive treatments to the right population. In this review we discuss current diagnostic approaches, treatment and potential prevention strategies, with a special focus on recent advances in the field as well as areas of uncertainty and unmet needs and how to address them.
Collapse
Affiliation(s)
- Eleftheria Kampouri
- Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, 1011 Lausanne, Switzerland;
| | - Antony Croxatto
- Institute of Microbiology, Department of Medical Laboratory and Pathology, University Hospital and University of Lausanne, 1011 Lausanne, Switzerland; (A.C.); (G.P.)
| | - Guy Prod’hom
- Institute of Microbiology, Department of Medical Laboratory and Pathology, University Hospital and University of Lausanne, 1011 Lausanne, Switzerland; (A.C.); (G.P.)
| | - Benoit Guery
- Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, 1011 Lausanne, Switzerland;
- Correspondence: ; Tel.: +41-21-314-1643
| |
Collapse
|
|
38
|
Stewart D, Anwar F, Vedantam G. Anti-virulence strategies for Clostridioides difficile infection: advances and roadblocks. Gut Microbes 2020; 12:1802865. [PMID: 33092487 PMCID: PMC7588222 DOI: 10.1080/19490976.2020.1802865] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/21/2020] [Accepted: 07/23/2020] [Indexed: 02/03/2023] Open
Abstract
Clostridioides difficile infection (CDI) is a common healthcare- and antibiotic-associated diarrheal disease. If mis-diagnosed, or incompletely treated, CDI can have serious, indeed fatal, consequences. The clinical and economic burden imposed by CDI is great, and the US Centers for Disease Control and Prevention has named the causative agent, C. difficile (CD), as an Urgent Threat To US healthcare. CDI is also a significant problem in the agriculture industry. Currently, there are no FDA-approved preventives for this disease, and the only approved treatments for both human and veterinary CDI involve antibiotic use, which, ironically, is associated with disease relapse and the threat of burgeoning antibiotic resistance. Research efforts in multiple laboratories have demonstrated that non-toxin factors also play key roles in CDI, and that these are critical for disease. Specifically, key CD adhesins, as well as other surface-displayed factors have been shown to be major contributors to host cell attachment, and as such, represent attractive targets for anti-CD interventions. However, research on anti-virulence approaches has been more limited, primarily due to the lack of genetic tools, and an as-yet nascent (but increasingly growing) appreciation of immunological impacts on CDI. The focus of this review is the conceptualization and development of specific anti-virulence strategies to combat CDI. Multiple laboratories are focused on this effort, and the field is now at an exciting stage with numerous products in development. Herein, however, we focus only on select technologies (Figure 1) that have advanced near, or beyond, pre-clinical testing (not those that are currently in clinical trial), and discuss roadblocks associated with their development and implementation.
Collapse
Affiliation(s)
- David Stewart
- Department of Surgery, University of Arizona, Tucson, AZ, USA
| | - Farhan Anwar
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA
| | - Gayatri Vedantam
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA
- Bio5 Institute for Collaborative Research, University of Arizona, Tucson, AZ, USA
- Southern Arizona VA Healthcare System, University of Arizona, Tucson, AZ, USA
| |
Collapse
|
|
39
|
Kuon C, Wannier R, Sterken D, Fang MC, Wolf J, Prasad PA. Are Antimotility Agents Safe for Use in Clostridioides difficile Infections? Results From an Observational Study in Malignant Hematology Patients. Mayo Clin Proc Innov Qual Outcomes 2020; 4:792-800. [PMID: 33367215 PMCID: PMC7749233 DOI: 10.1016/j.mayocpiqo.2020.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Objectives To evaluate the safety of antimotility agents (AAs) in a population of patients with hematologic malignancies and concurrent Clostridioides difficile infection (CDI) and to describe the outcomes of AA use in a hospital setting. Patients and Methods We used the electronic health record to identify patients who were hospitalized in the adult malignant hematology service who had 1 or more toxin-positive C difficile stool assay between April 1, 2012, and September 21, 2017. We reviewed medical charts to obtain information on the use of AAs and any subsequent gastrointestinal complications. Results There were 339 patients who were stool toxin positive for CDI during the study period. Of those, 94 patients (27%) were prescribed AAs within 14 days of CDI diagnosis. All patients received CDI antimicrobial therapy within the first 24 hours. There were 2 adverse gastrointestinal events in the group that received AAs and 6 in the group that did not receive AAs. The risk of adverse events did not differ between patients who received AAs and those who did not (adjusted odds ratio, 0.36; 95% CI, 0.06 to 2.10). The mean age of the full cohort was 52.7±15.5 years, and the mean length of stay was 26.7±22.6 days. Early AA use (<48 hours of diagnosis) was not associated with increased adverse effects. Conclusion There was no increase in the incidence of gastrointestinal events in the arm that used AAs compared with the control arm. The evidence suggests that for patients with hematologic malignancies and CDI, the addition of AAs to appropriate antimicrobial therapy poses no additional risk.
Collapse
Key Words
- AA, antimotility agent
- CDI, Clostridioides difficile infection
- EHR, electronic health record
- HSCT, hematopoietic stem cell transplant
- ICD-10, International Statistical Classification of Diseases, Tenth Revision
- ICD-9, International Classification of Diseases, Ninth Revision
- IDSA, Infectious Disease Society of America
- RR, relative risk
- UCSF, University of California, San Francisco
Collapse
Affiliation(s)
- Carla Kuon
- Division of Hospital Medicine, University of California, San Francisco, San Francisco
| | - Rae Wannier
- Division of Hospital Medicine, University of California, San Francisco, San Francisco
| | - David Sterken
- Division of Hospital Medicine, University of California, San Francisco, San Francisco
| | - Margaret C Fang
- Division of Hospital Medicine, University of California, San Francisco, San Francisco
| | - Jeffrey Wolf
- Division of Hospital Medicine, University of California, San Francisco, San Francisco
| | - Priya A Prasad
- Division of Hospital Medicine, University of California, San Francisco, San Francisco
| |
Collapse
|
|
40
|
Analysis of predisposing factors for the development of Clostridioides difficile infection recurrence. Eur J Clin Microbiol Infect Dis 2020; 39:2161-2168. [DOI: 10.1007/s10096-020-03982-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 07/03/2020] [Indexed: 10/23/2022]
|
|
41
|
Essrani R, Saturno D, Mehershahi S, Essrani RK, Hossain MR, Ravi SJK, Berger A, Mehmood A. The Impact of Appendectomy in Clostridium difficile Infection and Length of Hospital Stay. Cureus 2020; 12:e10342. [PMID: 33062466 PMCID: PMC7549846 DOI: 10.7759/cureus.10342] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Introduction We aim to investigate Clostridium difficile infection (CDI) recurrence, severity, complications, and length of hospital stay in patients with and without prior history of appendectomy who were admitted to the hospital with CDI. Method We analyzed retrospective data for 862 patients, 18 years and older, with C. difficile inpatients diagnosed between January 1, 2017 and December 31, 2018 and sorted into two groups, with or without prior appendicectomy, to look for outcomes such as recurrence, hospital stay, complications, and related death in each group and use statistical analysis for comparison. Result There were 862 patients admitted with CDI, of which 122 (14.2%) had a prior history of appendectomy and 740 (85.8%) did not. Patients with an appendectomy prior were older (median age of 75 vs. 69, p = 0.0033) and had a higher proportion of females (68.9% vs. 53.6%, p = 0.0017). C. difficile recurrence in prior appendicectomy group vs. no appendectomy group was 12.3% and 9.3%, respectively, but no statistical difference was noted (p = 0.28). Also, there was no statistical difference in complications like ileus, colectomy, and mortality related to CDI in both groups. However, patients with appendectomies had significantly shorter hospital stays during C. difficile admission compared to patients without appendectomies (median of six days vs. seven days, p = 0.0014). Conclusion Our study shows that there is no statistical difference in the recurrence, severity, and complications of CDI in the presence or absence of the appendix but remarkably noted that people with prior appendicectomy had a shorter hospital stay.
Collapse
Affiliation(s)
- Rajesh Essrani
- Internal Medicine, Geisinger Medical Center, Danville, USA.,Internal Medicine, Lehigh Valley Health Network, Allentown, USA
| | - Dany Saturno
- General Internal Medicine, BronxCare Health System, Bronx, USA
| | | | | | | | | | - Andrea Berger
- Biostatistics, Geisinger Medical Center, Danville, USA
| | - Asif Mehmood
- Internal Medicine, Geisinger Medical Center, Danville, USA.,Internal Medicine, Abington Hospital - Jefferson Health, Abington, USA
| |
Collapse
|
|
42
|
Mild or Malign: Clinical Characteristics and Outcomes of Clostridium difficile Infection in Thailand. J Clin Microbiol 2020; 58:JCM.01217-20. [PMID: 32580954 DOI: 10.1128/jcm.01217-20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 06/22/2020] [Indexed: 01/02/2023] Open
Abstract
Little is known about the clinical characteristics of Clostridium difficile infection (CDI) in Asia in general, and Thailand specifically, with a few studies suggesting that the disease may be milder than elsewhere. This study aimed to describe CDI in Thailand, evaluate treatment options and their outcomes, and explore possible protective factors responsible for any unique disease characteristics. From 2015 to 2018, 469 patients were included in the study. All patients had their stools tested for the tcdB gene by direct PCR and detection of toxigenic C. difficile by culture. C. difficile isolates were subjected to toxin gene profiling and ribotyping, and patient medical records were reviewed retrospectively. There were 248 and 221 patients included in CDI and control groups, respectively. The CDI group had a higher overall 30-day mortality rate than the control group (21% versus 14%, P = 0.046), but only 2 deaths (1%) were directly attributable to CDI. Metronidazole treatment was not inferior to vancomycin in this population, and vancomycin was associated with a higher 30-day mortality rate (P = 0.047). The prevalence of severe CDI and disease outcomes were not different between patients infected with A-B+ C. difficile and A+B+ C. difficile strains or between patients with and without colonization by nontoxigenic C. difficile Besides C. difficile-specific tests, neither a single laboratory result nor a combination of results was predictive of CDI. In conclusion, CDI in Thailand was relatively mild, and metronidazole remained an effective treatment option for these mild infections.
Collapse
|
|
43
|
Schriever CA, Danziger LH. Recurrent Clostridioides difficile Infections: Should We Respond More to Toxin B? Clin Infect Dis 2020; 71:87-88. [DOI: 10.1093/cid/ciz814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 08/16/2019] [Indexed: 11/13/2022] Open
Affiliation(s)
| | - Larry H Danziger
- Colleges of Pharmacy and Medicine, University of Illinois at Chicago
| |
Collapse
|
|
44
|
Okumura H, Ueyama M, Shoji S, English M. Cost-effectiveness analysis of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in Japan. J Infect Chemother 2020; 26:611-618. [PMID: 32165072 DOI: 10.1016/j.jiac.2020.01.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/15/2020] [Accepted: 01/31/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND The cost of treating Clostridioides difficile infection (CDI), particularly recurrent disease, is high. In clinical trials, fidaxomicin has been associated with significantly lower recurrence rates and higher sustained cure rates versus vancomycin. The high acquisition cost of fidaxomicin has limited its acceptance into clinical practice. OBJECTIVE To evaluate the cost-effectiveness of fidaxomicin versus vancomycin in patients with CDI after failure of metronidazole in the Japanese healthcare setting. METHODS Clinical results from three phase III trials and inputs based on assumptions validated by clinical experts in Japan were used in a semi-Markov model with 1-year time horizon. Incremental cost-effectiveness ratios (ICERs) for fidaxomicin versus vancomycin were expressed as cost per quality-adjusted life year (QALY) and interpreted using willingness-to-pay thresholds of JPY 5,000,000 (primary) and JPY 7,500,000 (secondary) per QALY gained in Japan. Probabilistic sensitivity analyses and scenario analyses were performed. RESULTS Higher drug acquisition costs for fidaxomicin were partially offset by lower hospitalization costs driven by fewer recurrences, lower costs of complications, and fewer general practitioner visits versus vancomycin. The ICER for fidaxomicin versus vancomycin was estimated at JPY 5,715,183 per QALY gained. Sensitivity analyses showed a 46% probability of fidaxomicin being cost-effective versus vancomycin at a willingness-to-pay threshold of JPY 5,000,000 per QALY gained. At a threshold of JPY 7,500,000, there was a 54% probability of fidaxomicin being cost-effective. CONCLUSIONS Fidaxomicin treatment in patients with CDI following failure of metronidazole improves health outcomes with partial offset of higher drug acquisition costs versus vancomycin.
Collapse
Affiliation(s)
| | | | - Shingo Shoji
- Medical Affairs, Astellas Pharma, Inc., Tokyo, Japan.
| | - Marci English
- Astellas Pharma Global Development, Inc., Northbrook, IL, USA.
| |
Collapse
|
|
45
|
Reed AD, Nethery MA, Stewart A, Barrangou R, Theriot CM. Strain-Dependent Inhibition of Clostridioides difficile by Commensal Clostridia Carrying the Bile Acid-Inducible ( bai) Operon. J Bacteriol 2020; 202:e00039-20. [PMID: 32179626 PMCID: PMC7221253 DOI: 10.1128/jb.00039-20] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 03/06/2020] [Indexed: 12/18/2022] Open
Abstract
Clostridioides difficile is one of the leading causes of antibiotic-associated diarrhea. Gut microbiota-derived secondary bile acids and commensal Clostridia that carry the bile acid-inducible (bai) operon are associated with protection from C. difficile infection (CDI), although the mechanism is not known. In this study, we hypothesized that commensal Clostridia are important for providing colonization resistance against C. difficile due to their ability to produce secondary bile acids, as well as potentially competing against C. difficile for similar nutrients. To test this hypothesis, we examined the abilities of four commensal Clostridia carrying the bai operon (Clostridium scindens VPI 12708, C. scindens ATCC 35704, Clostridium hiranonis, and Clostridium hylemonae) to convert cholate (CA) to deoxycholate (DCA) in vitro, and we determined whether the amount of DCA produced was sufficient to inhibit the growth of a clinically relevant C. difficile strain. We also investigated the competitive relationships between these commensals and C. difficile using an in vitro coculture system. We found that inhibition of C. difficile growth by commensal Clostridia supplemented with CA was strain dependent, correlated with the production of ∼2 mM DCA, and increased the expression of bai operon genes. We also found that C. difficile was able to outcompete all four commensal Clostridia in an in vitro coculture system. These studies are instrumental in understanding the relationship between commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics. Future studies dissecting the regulation of the bai operon in vitro and in vivo and how this affects CDI will be important.IMPORTANCE Commensal Clostridia carrying the bai operon, such as C. scindens, have been associated with protection against CDI; however, the mechanism for this protection is unknown. Herein, we show four commensal Clostridia that carry the bai operon and affect C. difficile growth in a strain-dependent manner, with and without the addition of cholate. Inhibition of C. difficile by commensals correlated with the efficient conversion of cholate to deoxycholate, a secondary bile acid that inhibits C. difficile germination, growth, and toxin production. Competition studies also revealed that C. difficile was able to outcompete the commensals in an in vitro coculture system. These studies are instrumental in understanding the relationship between commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics.
Collapse
Affiliation(s)
- A D Reed
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
| | - M A Nethery
- Department of Food, Bioprocessing and Nutrition Sciences, North Carolina State University, Raleigh, North Carolina, USA
| | - A Stewart
- Molecular Education, Technology and Research Innovation Center, North Carolina State University, Raleigh, North Carolina, USA
| | - R Barrangou
- Department of Food, Bioprocessing and Nutrition Sciences, North Carolina State University, Raleigh, North Carolina, USA
| | - C M Theriot
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
| |
Collapse
|
|
46
|
Bouza E, Aguado JM, Alcalá L, Almirante B, Alonso-Fernández P, Borges M, Cobo J, Guardiola J, Horcajada JP, Maseda E, Mensa J, Merchante N, Muñoz P, Pérez Sáenz JL, Pujol M, Reigadas E, Salavert M, Barberán J. Recommendations for the diagnosis and treatment of Clostridioides difficile infection: An official clinical practice guideline of the Spanish Society of Chemotherapy (SEQ), Spanish Society of Internal Medicine (SEMI) and the working group of Postoperative Infection of the Spanish Society of Anesthesia and Reanimation (SEDAR). REVISTA ESPANOLA DE QUIMIOTERAPIA : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE QUIMIOTERAPIA 2020; 33:151-175. [PMID: 32080996 PMCID: PMC7111242 DOI: 10.37201/req/2065.2020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 01/26/2020] [Indexed: 12/12/2022]
Abstract
This document gathers the opinion of a multidisciplinary forum of experts on different aspects of the diagnosis and treatment of Clostridioides difficile infection (CDI) in Spain. It has been structured around a series of questions that the attendees considered relevant and in which a consensus opinion was reached. The main messages were as follows: CDI should be suspected in patients older than 2 years of age in the presence of diarrhea, paralytic ileus and unexplained leukocytosis, even in the absence of classical risk factors. With a few exceptions, a single stool sample is sufficient for diagnosis, which can be sent to the laboratory with or without transportation media for enteropathogenic bacteria. In the absence of diarrhoea, rectal swabs may be valid. The microbiology laboratory should include C. difficile among the pathogens routinely searched in patients with diarrhoea. Laboratory tests in different order and sequence schemes include GDH detection, presence of toxins, molecular tests and toxigenic culture. Immediate determination of sensitivity to drugs such as vancomycin, metronidazole or fidaxomycin is not required. The evolution of toxin persistence is not a suitable test for follow up. Laboratory diagnosis of CDI should be rapid and results reported and interpreted to clinicians immediately. In addition to the basic support of all diarrheic episodes, CDI treatment requires the suppression of antiperistaltic agents, proton pump inhibitors and antibiotics, where possible. Oral vancomycin and fidaxomycin are the antibacterials of choice in treatment, intravenous metronidazole being restricted for patients in whom the presence of the above drugs in the intestinal lumen cannot be assured. Fecal material transplantation is the treatment of choice for patients with multiple recurrences but uncertainties persist regarding its standardization and safety. Bezlotoxumab is a monoclonal antibody to C. difficile toxin B that should be administered to patients at high risk of recurrence. Surgery is becoming less and less necessary and prevention with vaccines is under research. Probiotics have so far not been shown to be therapeutically or preventively effective. The therapeutic strategy should be based, rather than on the number of episodes, on the severity of the episodes and on their potential to recur. Some data point to the efficacy of oral vancomycin prophylaxis in patients who reccur CDI when systemic antibiotics are required again.
Collapse
Affiliation(s)
- E Bouza
- Emilio Bouza MD, PhD, Instituto de Investigación Sanitaria Gregorio Marañón, Servicio de Microbiología Clínica y E. Infecciosas C/ Dr. Esquerdo, 46 - 28007 Madrid, Spain.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
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.
Collapse
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
| |
Collapse
|
|
48
|
Incidence of and risk factors for recurrent Clostridioidesdifficile infection in Japan using a claims database: A retrospective cohort study. Anaerobe 2019; 61:102139. [PMID: 31830597 DOI: 10.1016/j.anaerobe.2019.102139] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 11/29/2019] [Accepted: 12/05/2019] [Indexed: 12/19/2022]
Abstract
This retrospective cohort study aimed to determine the incidence rates of and risk factors for recurrent Clostridioides difficile infection (rCDI) in Japan using a claims database. Inpatients of any age with ≥1 record of C. difficile infection (CDI) during the study period (January 2012-September 2016) were analyzed. We estimated the incidence rate of health care onset, health care facility associated (HO-HCFA) primary CDI and HO-HCFA rCDI for each of the first to fifth recurrences. Risk factors for the first recurrence were investigated using a univariate, and subsequently, a multivariable Cox regression model. The incidence rates (95% confidence interval [CI]) of CDI and HO-HCFA CDI were 2.43 (2.40-2.46) and 1.26 (1.24-1.28) cases per 10,000 inpatient-days, respectively. Among the 11,287 inpatients with ≥1 HO-HCFA CDI, 1424 patients had ≥1 recurrent episode (12.6% [95% CI 12.0-13.2]). The rCDI incidence rates consistently increased, with the number of recurrences ranging from 29.2 to 181.8 cases per 10,000 inpatient-days. The multivariable analysis revealed five risk factors (hazard ratio [95% CI]): age ≥65 years (vs. <65 years; 65-74 years, 1.275 [1.048-1.551]; 75-79 years, 1.612 [1.315-1.975]; ≥80 years, 2.110 [1.776-2.507]); cephalosporin use both before (vs. without cephalosporin; 1.241 [1.098-1.402]) and during the primary CDI (vs. without cephalosporin; 1.137 [1.011-1.279]); higher number of comorbidities (vs. ≤10 comorbidities; 11-14 comorbidities: 1.336 [1.131-1.580]; 15-20 comorbidities: 1.433 [1.219-1.685]; ≥21 comorbidities: 1.310 [1.099-1.561]); and gastrointestinal surgery (vs. without surgery; 0.823 [0.701-0.965]). In conclusion, CDI recurred in some Japanese patients, and the incidence rates increased with the number of recurrences. Special care is needed in patients aged ≥65 years, those with a higher number (>10) of comorbidities, and those who have received cephalosporin before or during the primary CDI.
Collapse
|
|
49
|
A Single-Center Experience and Literature Review of Management Strategies for Clostridium difficile Infection in Hematopoietic Stem Cell Transplant Patients. ACTA ACUST UNITED AC 2019; 28:10-15. [PMID: 33424210 DOI: 10.1097/ipc.0000000000000798] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction The aim of our study is to evaluate risk factors associated with the development of C. difficile infection (CDI) in hematopoietic stem cell transplant (HSCT) patients, determine its incidence and report outcomes of CDI in our patient population. Methods We performed a retrospective review of medical records of adult HSCT recipients diagnosed between 2013 and 2016 at our center. Logistic regression models were used to determine the relationship between risk factors and the odds of CDI. Results The overall incidence of CDI in HSCT patients was 9.4%. The incidence of CDI was higher in allogeneic HSCT (20%) versus autologous HSCT (4.8%). No statistically significant differences in age, gender, cancer type, transplant type were found between those who developed CDI and those who did not. However, patients with CDI had a longer length of stay (25 days) and used more antibiotics (30 days prior to and during admission for HSCT) than non-CDI patients (19 days). Only two of 17 patients (11.8%) with CDI experienced recurrence among 180 patients after HSCT. No patient suffered from toxic megacolon or ileus and no patient underwent colectomy. There was no mortality associated with CDI at our center. Conclusion CDI has an incidence rate of 9.4% in HSCT recipients. Established risk factors including age, gender, cancer type, and transplant type were not identified as risk factors in our population. However, longer LOS and use of greater than four lines of antibiotics were observed among those with CDI compared to those without CDI.
Collapse
|
|
50
|
Hourigan SK, Ahn M, Gibson KM, Pérez-Losada M, Felix G, Weidner M, Leibowitz I, Niederhuber JE, Sears CL, Crandall KA, Oliva-Hemker M. Fecal Transplant in Children With Clostridioides difficile Gives Sustained Reduction in Antimicrobial Resistance and Potential Pathogen Burden. Open Forum Infect Dis 2019; 6:ofz379. [PMID: 31660343 PMCID: PMC6790402 DOI: 10.1093/ofid/ofz379] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 08/22/2019] [Indexed: 12/19/2022] Open
Abstract
Background Fecal microbiota transplantation (FMT) treats Clostridioides difficile infection (CDI). Little is known regarding the changes in antimicrobial resistance (AMR) genes and potential pathogen burden that occur in pediatric recipients of FMT. The aim of this study was to investigate changes in AMR genes, potential pathogens, species, and functional pathways with FMT in children. Methods Nine children with recurrent CDI underwent FMT. Stool was collected from donor and recipient pre-FMT and longitudinally post-FMT for up to 24 weeks. Shotgun metagenomic sequencing was performed. Reads were analyzed using PathoScope 2.0. Results All children had resolution of CDI. AMR genes decreased post-FMT (P < .001), with a sustained decrease in multidrug resistance genes (P < .001). Tetracycline resistance genes increased post-FMT (P < .001). Very low levels of potential pathogens were identified in donors and recipients, with an overall decrease post-FMT (P < .001). Prevotella sp. 109 expanded in all recipients post-FMT, and no recipients had any clinical infection. Alpha diversity was lower in recipients vs donors pre-FMT (P < .001), with an increase post-FMT (P ≤ .002) that was sustained. Beta diversity differed significantly in pre- vs post-FMT recipient samples (P < .001). Bacterial species Faecalibacterium prausnitzii and Bacteroides ovatus showed higher abundance in donors than recipients (P = .008 and P = .040, respectively), with expansion post-FMT. Biosynthetic pathways predominated in the donor and increased in the recipient post-FMT. Conclusions FMT for CDI in children decreases AMR genes and potential pathogens and changes microbiota composition and function. However, acquisition of certain AMR genes post-FMT combined with low levels of potential pathogens found in donors suggests that further study is warranted regarding screening donors using metagenomics sequencing before FMT.
Collapse
Affiliation(s)
- Suchitra K Hourigan
- Inova Translational Medicine Institute, Falls Church, Virginia.,Inova Children's Hospital, Falls Church, Virginia.,Pediatric Specialists of Virginia, Fairfax, Virginia.,Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michelle Ahn
- Computational Biology Institute and, Washington, DC
| | | | - Marcos Pérez-Losada
- Computational Biology Institute and, Washington, DC.,Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Washington, DC.,CIBIO-InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Universidade do Porto, Campus Agrário de Vairão, Vairão, Portugal
| | - Grace Felix
- Pediatric Specialists of Virginia, Fairfax, Virginia.,Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Melissa Weidner
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ian Leibowitz
- Pediatric Specialists of Virginia, Fairfax, Virginia
| | - John E Niederhuber
- Inova Translational Medicine Institute, Falls Church, Virginia.,Johns Hopkins University School of Medicine, Baltimore, Maryland.,Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, Virginia
| | - Cynthia L Sears
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Keith A Crandall
- Computational Biology Institute and, Washington, DC.,Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Washington, DC
| | | |
Collapse
|