|
1
|
Markantonis JE, Fallon JT, Madan R, Alam MZ. Clostridioides difficile Infection: Diagnosis and Treatment Challenges. Pathogens 2024; 13:118. [PMID: 38392856 PMCID: PMC10891949 DOI: 10.3390/pathogens13020118] [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: 01/05/2024] [Revised: 01/24/2024] [Accepted: 01/25/2024] [Indexed: 02/25/2024] Open
Abstract
Clostridioides difficile is the most important cause of healthcare-associated diarrhea in the United States. The high incidence and recurrence rates of C. difficile infection (CDI), associated with high morbidity and mortality, pose a public health challenge. Although antibiotics targeting C. difficile bacteria are the first treatment choice, antibiotics also disrupt the indigenous gut flora and, therefore, create an environment that is favorable for recurrent CDI. The challenge of treating CDI is further exacerbated by the rise of antibiotic-resistant strains of C. difficile, placing it among the top five most urgent antibiotic resistance threats in the USA. The evolution of antibiotic resistance in C. difficile involves the acquisition of new resistance mechanisms, which can be shared among various bacterial species and different C. difficile strains within clinical and community settings. This review provides a summary of commonly used diagnostic tests and antibiotic treatment strategies for CDI. In addition, it discusses antibiotic treatment and its resistance mechanisms. This review aims to enhance our current understanding and pinpoint knowledge gaps in antimicrobial resistance mechanisms in C. difficile, with an emphasis on CDI therapies.
Collapse
Affiliation(s)
- John E. Markantonis
- Department of Pathology and Laboratory Medicine, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834, USA; (J.E.M.); (J.T.F.)
| | - John T. Fallon
- Department of Pathology and Laboratory Medicine, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834, USA; (J.E.M.); (J.T.F.)
| | - Rajat Madan
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA;
- Veterans Affairs Medical Center, Cincinnati, OH 45220, USA
| | - Md Zahidul Alam
- Department of Pathology and Laboratory Medicine, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834, USA; (J.E.M.); (J.T.F.)
| |
Collapse
|
|
2
|
Ray MJ, Lacanilao KL, Lazaro MR, Strnad LC, Furuno JP, Royster K, McGregor JC. Use of electronic health record data to identify hospital-associated Clostridioides difficile infections: a validation study. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.01.10.24301118. [PMID: 38260609 PMCID: PMC10802632 DOI: 10.1101/2024.01.10.24301118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Background Clinical research focused on the burden and impact of Clostridioides difficile infection (CDI) often relies upon accurate identification of cases using existing health record data. Use of diagnosis codes alone can lead to misclassification of cases. Our goal was to develop and validate a multi-component algorithm to identify hospital-associated CDI (HA-CDI) cases using electronic health record (EHR) data. Methods We performed a validation study using a random sample of adult inpatients at a large academic hospital setting in Portland, Oregon from January 2018 to March 2020. We excluded patients with CDI on admission and those with short lengths of stay (< 4 days). We tested a multi-component algorithm to identify HA-CDI; case patients were required to have received an inpatient course of metronidazole, oral vancomycin, or fidaxomicin and have at least one of the following: a positive C. difficile laboratory test or the International Classification of Diseases, Tenth Revision (ICD-10) code for non-recurrent CDI. For a random sample of 80 algorithm-identified HA-CDI cases and 80 non-cases, we performed manual EHR review to identify gold standard of HA-CDI diagnosis. We then calculated overall percent accuracy, sensitivity, specificity, and positive and negative predictive value for the algorithm overall and for the individual components. Results Our case definition algorithm identified HA-CDI cases with 94% accuracy (95% Confidence Interval (CI): 88% to 97%). We achieved 100% sensitivity (94% to 100%), 89% specificity (81% to 95%), 88% positive predictive value (78% to 94%), and 100% negative predictive value (95% to 100%). Requiring a positive C. difficile test as our gold standard further improved diagnostic performance (97% accuracy [93% to 99%], 93% PPV [85% to 98%]). Conclusions Our algorithm accurately detected true HA-CDI cases from EHR data in our patient population. A multi-component algorithm performs better than any isolated component. Requiring a positive laboratory test for C. difficile strengthens diagnostic performance even further. Accurate detection could have important implications for CDI tracking and research.
Collapse
Affiliation(s)
- Michael J. Ray
- Oregon State University College of Pharmacy, Department of Pharmacy Practice, Portland, Oregon
- Oregon Health & Science University-Portland State University School of Public Health, Portland, Oregon
| | - Kathleen L. Lacanilao
- Oregon State University College of Pharmacy, Department of Pharmacy Practice, Portland, Oregon
| | - Maela Robyne Lazaro
- Oregon State University College of Pharmacy, Department of Pharmacy Practice, Portland, Oregon
| | - Luke C. Strnad
- Oregon Health & Science University-Portland State University School of Public Health, Portland, Oregon
- Oregon Health & Science University School of Medicine, Division of Infectious Diseases, Portland, Oregon
| | - Jon P. Furuno
- Oregon State University College of Pharmacy, Department of Pharmacy Practice, Portland, Oregon
| | - Kelly Royster
- Oregon State University College of Pharmacy, Department of Pharmacy Practice, Portland, Oregon
| | - Jessina C. McGregor
- Oregon State University College of Pharmacy, Department of Pharmacy Practice, Portland, Oregon
- Oregon Health & Science University-Portland State University School of Public Health, Portland, Oregon
| |
Collapse
|
|
3
|
Abstract
Clostridioides difficile is a common cause of community-associated and health care-associated infections. Older adults are disproportionately affected, and long-term care facilities (LTCFs) have borne a substantial proportion of the burden of C difficile infection (CDI). Recurrences of CDI are common in older adults and have substantial adverse effects on quality of life. Appropriate diagnostic testing and management is essential for older adults in the community and in LTCFs. This review focuses on current concepts related to the epidemiology, diagnosis, and management of CDI in older adults.
Collapse
Affiliation(s)
- Curtis J Donskey
- Geriatric Research Education and Clinical Center, Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA; Case Western Reserve University School of Medicine, Cleveland, OH, USA.
| |
Collapse
|
|
4
|
Vázquez-Cuesta S, Villar L, García NL, Fernández AI, Olmedo M, Alcalá L, Marín M, Muñoz P, Bouza E, Reigadas E. Characterization of the gut microbiome of patients with Clostridioides difficile infection, patients with non- C. difficile diarrhea, and C. difficile-colonized patients. Front Cell Infect Microbiol 2023; 13:1130701. [PMID: 37124040 PMCID: PMC10130453 DOI: 10.3389/fcimb.2023.1130701] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 03/29/2023] [Indexed: 05/02/2023] Open
Abstract
Introduction Clostridioides difficile infection (CDI) is the main cause of nosocomial diarrhea in developed countries. A key challenge in CDI is the lack of objective methods to ensure more accurate diagnosis, especially when differentiating between true infection and colonization/diarrhea of other causes. The main objective of this study was to explore the role of the microbiome as a predictive biomarker of CDI. Methods Between 2018 and 2021, we prospectively included patients with CDI, recurrent CDI (R-CDI), non-CDI diarrhea (NO-CDI), colonization by C. difficile, and healthy individuals. Clinical data and fecal samples were collected. The microbiome was analyzed by sequencing the hypervariable V4 region of the 16S rRNA gene on an Illumina Miseq platform. The mothur bioinformatic pipeline was followed for pre-processing of raw data, and mothur and R were used for data analysis. Results During the study period, 753 samples from 657 patients were analyzed. Of these, 247 were from patients with CDI, 43 were from patients colonized with C. difficile, 63 were from healthy individuals, 324 were from NOCDI, and 76 were from R-CDI. We found significant differences across the groups in alpha and beta diversity and in taxonomic abundance. We identified various genera as the most significant biomarkers for CDI (Bacteroides, Proteus, Paraprevotella, Robinsoniella), R-CDI (Veillonella, Fusobacterium, Lactobacillus, Clostridium sensu stricto I), and colonization by C. difficile (Parabacteroides, Faecalicoccus, Flavonifractor, Clostridium XVIII). Discussion We observed differences in microbiome patterns between healthy individuals, colonized patients, CDI, R-CDI, and NOCDI diarrhea. We identified possible microbiome biomarkers that could prove useful in the diagnosis of true CDI infections. Further studies are warranted.
Collapse
Affiliation(s)
- Silvia Vázquez-Cuesta
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Biochemistry and Molecular Biology Department, Faculty of Biology, Universidad Complutense de Madrid (UCM), Madrid, Spain
- *Correspondence: Silvia Vázquez-Cuesta,
| | - Laura Villar
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Nuria Lozano García
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Ana I. Fernández
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - María Olmedo
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Luis Alcalá
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
| | - Mercedes Marín
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - Patricia Muñoz
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - Emilio Bouza
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Clostridioides difficile (ESGCD), Basel, Switzerland
| | - Elena Reigadas
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
- European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Clostridioides difficile (ESGCD), Basel, Switzerland
| |
Collapse
|
|
5
|
A Bioluminescent Sensor for Rapid Detection of PPEP-1, a Clostridioides difficile Biomarker. SENSORS 2021; 21:s21227485. [PMID: 34833562 PMCID: PMC8624784 DOI: 10.3390/s21227485] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 11/17/2022]
Abstract
Current assays for Clostridioides difficile in nonhospital settings are outsourced and time-intensive, resulting in both delayed diagnosis and quarantining of infected individuals. We designed a more rapid point-of-care assay featuring a “turn-on” bioluminescent readout of a C. difficile-specific protease, PPEP-1. NanoLuc, a bright and stable luciferase, was “caged” with a PPEP-1-responsive peptide tail that inhibited luminescence. Upon proteolytic cleavage, the peptide was released and NanoLuc activity was restored, providing a visible readout. The bioluminescent sensor detected PPEP-1 concentrations as low as 10 nM. Sensor uncaging was achieved within minutes, and signal was captured using a digital camera. Importantly, the sensor was also functional at ambient temperature and compatible with fecal material, suggesting that it can be readily deployed in a variety of settings.
Collapse
|
|
6
|
Elfassy A, Kalina WV, French R, Nguyen H, Tan C, Sebastian S, Wilcox MH, Davies K, Kutzler MA, Jansen KU, Anderson A, Pride MW. Development and clinical validation of an automated cell cytotoxicity neutralization assay for detecting Clostridioides difficile toxins in clinically relevant stools samples. Anaerobe 2021; 71:102415. [PMID: 34298152 DOI: 10.1016/j.anaerobe.2021.102415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 07/14/2021] [Accepted: 07/16/2021] [Indexed: 01/05/2023]
Abstract
OBJECTIVES To improve the diagnostic accuracy of Clostridioides difficile infection, current U.S. and E.U. guidelines recommend multistep testing that detects the presence of C. difficile and toxin in clinically relevant stool samples to confirm active disease. An accepted gold standard to detect C. difficile toxins is the cell cytotoxicity neutralization assay (CCNA). Although highly sensitive, the traditional CCNA has limitations. One such limitation is the subjective interpretation of an analyst to recognize cytopathic effects in cultured cells exposed to a fecal sample containing toxin. To overcome this limitation, an automated CCNA was developed that replaces most human pipetting steps with robotics and incorporates CellTiterGlo® for a semi-quantitative, non-subjective measure of cell viability instead of microscopy. METHODS To determine sample positivity and control for non-specific cytopathic effects, two thresholds were defined and validated by evaluating the sample with/without antitoxin antisera (sample-antitoxin/sample + antitoxin): 1) a >70% cell viability threshold was validated with samples containing anti-toxin, and 2) a >1.2-fold difference cut-off where sample results above the cut-off are considered positive. RESULTS Assay validation demonstrated excellent accuracy, precision, and sample linearity with an LOD of 126.9 pg/mL toxin-B in stool. The positivity cut-offs were clinically validated by comparing 322 diarrheal stool sample results with those run in a predicate, microscopic readout-based CCNA. The automated CCNA demonstrated 96% sensitivity and 100% specificity compared with the predicate CCNA. CONCLUSIONS Overall, the automated CCNA provides a specific, sensitive, and reproducible tool to support determination of CDI epidemiology or the efficacy of interventions such as vaccines.
Collapse
Affiliation(s)
- Arik Elfassy
- Pfizer Vaccines Research and Development, Pearl River, NY, USA; Current Affiliation: Elusys Therapeutics, Parsippany, NJ, USA
| | - Warren V Kalina
- Pfizer Vaccines Research and Development, Pearl River, NY, USA
| | - Roger French
- Pfizer Vaccines Research and Development, Pearl River, NY, USA
| | - Ha Nguyen
- Pfizer Vaccines Research and Development, Pearl River, NY, USA
| | - Charles Tan
- Pfizer Vaccines Research and Development, Pearl River, NY, USA
| | - Shite Sebastian
- Pfizer Vaccines Research and Development, Pearl River, NY, USA; Current Affiliation: Affinivax, Lexington, MA, USA
| | - Mark H Wilcox
- Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, United Kingdom
| | - Kerrie Davies
- Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, United Kingdom
| | | | | | | | - Michael W Pride
- Pfizer Vaccines Research and Development, Pearl River, NY, USA.
| |
Collapse
|
|
7
|
Parnell JM, Fazili I, Bloch SC, Lacy DB, Garcia-Lopez VA, Bernard R, Skaar EP, Edwards KM, Nicholson MR. Two-step Testing for Clostridioides Difficile is Inadequate in Differentiating Infection From Colonization in Children. J Pediatr Gastroenterol Nutr 2021; 72:378-383. [PMID: 32925555 PMCID: PMC7870537 DOI: 10.1097/mpg.0000000000002944] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Recent Infectious Disease Society of America guidelines recommend multistep testing algorithms to diagnose Clostridioides difficile infection (CDI), including a combination of nucleic acid amplification-based testing (NAAT) and toxin enzyme immunoassay (EIA). The use of these algorithms in children, including the ability to differentiate between C. difficile colonization and CDI, however, has not been evaluated. METHODS We prospectively enrolled asymptomatic pediatric patients with cancer, cystic fibrosis (CF), or inflammatory bowel disease (IBD) and obtained a stool sample for NAAT testing. If positive by NAAT (colonized), EIA was performed. In addition, children with symptomatic CDI who tested positive by NAAT via the clinical laboratory were enrolled, and EIA was performed on residual stool. A functional cell cytotoxicity neutralization assay (CCNA) was also applied to stool samples from both the colonized and symptomatic cohorts. RESULTS Of the 225 asymptomatic children enrolled in the study, 47 (21%) were colonized with C. difficile including 9/59 (15.5%) with cancer, 30/92 (32.6%) with CF, and 8/74 (10.8%) with IBD. An additional 41 children with symptomatic CDI were enrolled. When symptomatic and colonized children were compared, neither EIA positivity (44% vs 26%, P = 0.07) nor CCNA positivity (49% vs 45%, P = 0.70) differed significantly or were able to predict disease severity in the symptomatic cohort. CONCLUSIONS Use of a multistep testing algorithm with NAAT followed by EIA failed to differentiate symptomatic CDI from asymptomatic colonization in our pediatric cohort. As multistep algorithms are moved into clinical care, the pediatric provider will need to be aware of their limitations.
Collapse
Affiliation(s)
- Jacob M. Parnell
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Irtiqa Fazili
- University of Tennessee Health Science Center, Memphis, TN
| | - Sarah C. Bloch
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - D. Borden Lacy
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Valeria A. Garcia-Lopez
- Vanderbilt Institute of Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville TN
| | - Rachel Bernard
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN
| | - Eric P. Skaar
- Vanderbilt Institute of Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville TN
| | - Kathryn M. Edwards
- Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville TN
| | - Maribeth R. Nicholson
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN
| |
Collapse
|
|
8
|
Diverse Energy-Conserving Pathways in Clostridium difficile: Growth in the Absence of Amino Acid Stickland Acceptors and the Role of the Wood-Ljungdahl Pathway. J Bacteriol 2020; 202:JB.00233-20. [PMID: 32967909 DOI: 10.1128/jb.00233-20] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 07/23/2020] [Indexed: 12/21/2022] Open
Abstract
Clostridium difficile is the leading cause of hospital-acquired antibiotic-associated diarrhea and is the only widespread human pathogen that contains a complete set of genes encoding the Wood-Ljungdahl pathway (WLP). In acetogenic bacteria, synthesis of acetate from 2 CO2 molecules by the WLP functions as a terminal electron accepting pathway; however, C. difficile contains various other reductive pathways, including a heavy reliance on Stickland reactions, which questions the role of the WLP in this bacterium. In rich medium containing high levels of electron acceptor substrates, only trace levels of key WLP enzymes were found; therefore, conditions were developed to adapt C. difficile to grow in the absence of amino acid Stickland acceptors. Growth conditions were identified that produce the highest levels of WLP activity, determined by Western blot analyses of the central component acetyl coenzyme A synthase (AcsB) and assays of other WLP enzymes. Fermentation substrate and product analyses, enzyme assays of cell extracts, and characterization of a ΔacsB mutant demonstrated that the WLP functions to dispose of metabolically generated reducing equivalents. While WLP activity in C. difficile does not reach the levels seen in classical acetogens, coupling of the WLP to butyrate formation provides a highly efficient system for regeneration of NAD+ "acetobutyrogenesis," requiring only low flux through the pathways to support efficient ATP production from glucose oxidation. Additional insights redefine the amino acid requirements in C. difficile, explore the relationship of the WLP to toxin production, and provide a rationale for colocalization of genes involved in glycine synthesis and cleavage within the WLP operon.IMPORTANCE Clostridium difficile is an anaerobic, multidrug-resistant, toxin-producing pathogen with major health impacts worldwide. It is the only widespread pathogen harboring a complete set of Wood-Ljungdahl pathway (WLP) genes; however, the role of the WLP in C. difficile is poorly understood. In other anaerobic bacteria and archaea, the WLP can operate in one direction to convert CO2 to acetic acid for biosynthesis or in either direction for energy conservation. Here, conditions are defined in which WLP levels in C. difficile increase markedly, functioning to support metabolism of carbohydrates. Amino acid nutritional requirements were better defined, with new insight into how the WLP and butyrate pathways act in concert, contributing significantly to energy metabolism by a mechanism that may have broad physiological significance within the group of nonclassical acetogens.
Collapse
|
|
9
|
Olmedo M, Valerio M, Reigadas E, Marín M, Alcalá L, Muñoz P, Bouza E. Clinical impact of a Clostridioides ( Clostridium) difficile bedside infectious disease stewardship intervention. JAC Antimicrob Resist 2020; 2:dlaa037. [PMID: 34223003 PMCID: PMC8210181 DOI: 10.1093/jacamr/dlaa037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 01/23/2020] [Accepted: 04/06/2020] [Indexed: 11/17/2022] Open
Abstract
Objectives To evaluate the clinical impact of a bedside visit to patients with a positive Clostridioides difficile test on the antimicrobial stewardship of C. difficile infection (CDI) and non-C. difficile infections. Methods All patients ≥18 years old with positive CDI laboratory tests hospitalized between January 2017 and August 2017 received an immediate bedside intervention that consisted mainly of checking protective measures and providing recommendations on infection control and the management of CDI and other infections. Results A total of 214 patients were evaluated. The infectious disease (ID) physician was the first to establish protective measures in 25.2% of the cases. In 22/29 (75.9%) cases, physicians in charge accepted ID consultant recommendations to stop CDI treatment in asymptomatic patients. Unnecessary non-CDI antibiotics were discontinued in 19.1% of the cases. ID recommendations were not accepted by physicians in charge in only 12.6% of the cases. Conclusions A bedside rapid intervention for patients with a CDI-positive faecal sample was effective in avoiding overdiagnosis and unnecessary antibiotic treatment, optimizing anti-CDI drugs, increasing compliance with infection control measures and providing educational advice.
Collapse
Affiliation(s)
- María Olmedo
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Maricela Valerio
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,CIBER de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
| | - Elena Reigadas
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Medicine Department, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - Mercedes Marín
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,CIBER de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
| | - Luis Alcalá
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.,CIBER de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
| | - Patricia Muñoz
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,CIBER de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain
| | - Emilio Bouza
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
|
10
|
Hygienemaßnahmen bei Clostridioides difficile-Infektion (CDI). Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2019; 62:906-923. [PMID: 31236653 DOI: 10.1007/s00103-019-02959-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
11
|
Mejia-Chew C, Dubberke ER. Clostridium difficile control measures: current and future methods for prevention. Expert Rev Anti Infect Ther 2018; 16:121-131. [PMID: 29353504 DOI: 10.1080/14787210.2018.1429911] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Clostridium difficile is the most common cause of healthcare associated infection, and C. difficile infection (CDI) is associated with significant costs, morbidity, and mortality. One obstacle to preventing CDI is lack of high quality data on interventions to prevent CDI. This has led some to focus on areas, such as method of hand hygiene, unlikely to impact CDI incidence as much as others, such as contact precautions. In addition, existing strategies, although effective, do have limitations. Another challenge is the ability to rapidly, and accurately, diagnose CDI. Given these obstacles, new strategies to effectively prevent CDI are imperative to improve patient outcomes. Areas covered: Evidence of the interventions recommended by international scientific societies will be reviewed, as well as ongoing research on new strategies, such as screening for asymptomatic C. difficile carriage, microbiota sparing agents, bacteriocins and vaccines. Expert commentary: Current measures to prevent CDI are effective, but have significant limitations. Contact precautions and antimicrobial stewardship are likely the most effective of current prevention recommendations. Diagnostic assay utilization plays a role as well. New strategies to prevent CDI are needed, and, fortunately, several are being studied. Most likely a combination of approaches will be necessary to optimize CDI prevention.
Collapse
Affiliation(s)
- Carlos Mejia-Chew
- a Division of Infectious Disease , Washington University School of Medicine , St Louis , MO , USA
| | - Erik R Dubberke
- a Division of Infectious Disease , Washington University School of Medicine , St Louis , MO , USA
| |
Collapse
|
|
12
|
Pituch H, Obuch-Woszczatyński P, Lachowicz D, Kuthan R, Dzierżanowska-Fangrat K, Mikucka A, Jermakow K, Pituch-Zdanowska A, Davies K. Prevalence of Clostridium difficile infection in hospitalized patients with diarrhoea: Results of a Polish multicenter, prospective, biannual point-prevalence study. Adv Med Sci 2018; 63:290-295. [PMID: 29665558 DOI: 10.1016/j.advms.2018.03.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 02/08/2018] [Accepted: 03/15/2018] [Indexed: 12/18/2022]
Abstract
PURPOSE We aimed to measure the underdiagnosis of Clostridium difficile infection across Poland and the distribution of PCR-ribotypes of C. difficile. MATERIAL AND METHODS Twenty seven Polish healthcare facilities (HCFs) participated in this prospective study. Each HCF systematically sent all diarrhoeal stools received from inpatients at their laboratories on two days (one in January 2013 and one in July 2013), independently of CDI test request, to the National Coordinating Laboratory (NCL) for standardized testing of CDI. Positive samples (using two-stage algorithm), had CDI, confirmed by qPCR and toxigenic culture. C. difficile isolates were characterized by PCR-ribotyping. Hospitals were questioned about their methods and testing policy for CDI during the study period: September 2011 to August 2013. RESULTS During the study period, participating hospitals reported a mean of 33.2 tests for CDI per 10 000 patient-days and a mean of 8.4 cases of CDI per 10 000 patient-days. The overall prevalence of positive CDI patients at NCL was 16.5%. Due to absence of clinical suspicion, 19.1% of these patients were not diagnosed by the local diagnostic laboratory. We identified 23 different PCR-ribotypes among 87C. difficile strains isolated from patients. PCR-ribotype 027 (48%) was the most prevalent. CONCLUSIONS The incidence of CDI in Poland in study period was very high. It should be noted however, that there is a lack of clinical suspicion and underestimation of the need to perform diagnostic tests for CDI in hospitalized patients. This will have an impact on the reported epidemiological status of CDI in Poland.
Collapse
Affiliation(s)
- Hanna Pituch
- Department of Medical Microbiology, Medical University of Warsaw, Warsaw, Poland.
| | | | - Dominika Lachowicz
- Department of Medical Microbiology, Medical University of Warsaw, Warsaw, Poland
| | - Robert Kuthan
- Department of Medical Microbiology, Medical University of Warsaw, Warsaw, Poland
| | | | - Agnieszka Mikucka
- Department of Microbiology, Nicolaus Copernicus University, Ludwik Rydygier Collegium Medicum, Bydgoszcz, Poland
| | - Katarzyna Jermakow
- Department of Medical Microbiology, Wrocław Medical University, Wrocław, Poland
| | | | - Kerrie Davies
- Healthcare Associated Infections Research Group, University of Leeds, Leeds, UK
| |
Collapse
|
|
13
|
Sensitivity of Single-Molecule Array Assays for Detection of Clostridium difficile Toxins in Comparison to Conventional Laboratory Testing Algorithms. J Clin Microbiol 2018; 56:JCM.00452-18. [PMID: 29898996 PMCID: PMC6062787 DOI: 10.1128/jcm.00452-18] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 06/01/2018] [Indexed: 01/05/2023] Open
Abstract
Guidelines recommend the use of an algorithm for the laboratory diagnosis of Clostridium difficile infection (CDI). Enzyme immunoassays (EIAs) detecting C. difficile toxins cannot be used as standalone tests due to suboptimal sensitivity, and molecular tests suffer from nonspecificity by detecting colonization. Guidelines recommend the use of an algorithm for the laboratory diagnosis of Clostridium difficile infection (CDI). Enzyme immunoassays (EIAs) detecting C. difficile toxins cannot be used as standalone tests due to suboptimal sensitivity, and molecular tests suffer from nonspecificity by detecting colonization. Sensitive immunoassays have recently been developed to improve and simplify CDI diagnosis. Assays detecting CD toxins have been developed using single-molecule array (SIMOA) technology. SIMOA performance was assessed relative to a laboratory case definition of CDI defined by positive glutamate dehydrogenase (GDH) screen and cell cytotoxicity neutralizing assay (CCNA). Samples were tested with SIMOA assays and a commercial toxin EIA to compare performance, with discrepancy resolution using a commercial nucleic acid-based test and a second cell cytotoxicity assay. The SIMOA toxin A and toxin B assays showed limits of detection of 0.6 and 2.9 pg/ml, respectively, and intra-assay coefficients of variation of less than 10%. The optimal clinical thresholds for the toxin A and toxin B assays were determined to be 22.1 and 18.8 pg/ml, respectively, with resultant sensitivities of 84.8 and 95.5%. In contrast, a high-performing EIA toxin test had a sensitivity of 71.2%. Thus, the SIMOA assays detected toxins in 24% more samples with laboratory-defined CDI than the high performing toxin EIA (95% [63/66] versus 71% [47/66]). This study shows that SIMOA C. difficile toxin assays have a higher sensitivity than currently available toxin EIA and have the potential to improve CDI diagnosis.
Collapse
|
|
14
|
Rubin ZA, Martin EM, Allyn P. Primary Prevention of Clostridium difficile-Associated Diarrhea: Current Controversies and Future Tools. Curr Infect Dis Rep 2018; 20:32. [PMID: 29959605 DOI: 10.1007/s11908-018-0639-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Clostridium difficile infection (CDI) is a major cause of morbidity and mortality in hospitalized patients and rates in most places have not decreased significantly despite broad efforts by both hospitals and public health entities. This review aims to provide readers with a better understanding of the limitations of current prevention strategies. We also review potential future tools that may be available for the primary prevention of CDI in the next decade. RECENT FINDINGS Research over the last decade has expanded our appreciation of the role of asymptomatic shedding in the healthcare setting and in the community. This review demonstrates that poor quality data underlies even well-established guidance from national authorities on basic topics such as contact precautions, avoidance of alcohol-based hand hygiene products, CDI testing, supplemental cleaning modalities, and the use of bleach solutions. Additionally, we review research on novel preventative interventions such as identification of asymptomatic carriers, supplemental environmental cleaning technologies, vaccines, and the manipulation of the intestinal microbiome. While there is preliminary data that supports further research in all of these areas, the research is not yet robust enough on which to base local or national policy recommendations, though late-phase human clinical trials of CDI vaccine trials are ongoing. Over the last decade, researchers have begun to reassess the traditional infection prevention model for CDI. Data suggesting a greater role for asymptomatic shedders has increased our understanding of current vertical prevention techniques and is forcing researchers to look more at new processes and technologies to decrease disease incidence.
Collapse
Affiliation(s)
- Zachary A Rubin
- Division of Infectious Diseases, David Geffen School of Medicine at UCLA, 924 Westwood Blvd, Suite 900, Los Angeles, CA, 90095, USA.
- UCLA Clinical Epidemiology & Infection Prevention, 924 Westwood Blvd, Suite 900, Los Angeles, CA, 90095, USA.
| | - Elise M Martin
- Division of Infectious Diseases, David Geffen School of Medicine at UCLA, 924 Westwood Blvd, Suite 900, Los Angeles, CA, 90095, USA
- UCLA Clinical Epidemiology & Infection Prevention, 924 Westwood Blvd, Suite 900, Los Angeles, CA, 90095, USA
- UCLA Antibiotic Stewardship Program, Los Angeles, CA, USA
| | - Paul Allyn
- Division of Infectious Diseases, David Geffen School of Medicine at UCLA, 924 Westwood Blvd, Suite 900, Los Angeles, CA, 90095, USA
| |
Collapse
|
|
15
|
Abstract
Recent increases in the incidence of Clostridium difficile infection (CDI) have been observed in all age groups, but the elderly have been disproportionately affected and long-term care facilities (LTCFs) have borne a significant proportion of the increasing burden. Recurrences are common in older adults and may have significant adverse effects on quality of life. Ensuring appropriate diagnostic testing and management is challenging for older adults in the community and in LTCFs. This review focuses on current concepts related to the epidemiology, diagnosis, and management of CDI in older adults.
Collapse
Affiliation(s)
- Curtis J Donskey
- Geriatric Research Education and Clinical Center, Cleveland Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA; Case Western Reserve University School of Medicine, 10,000 Euclid Avenue, Cleveland, OH 44106, USA.
| |
Collapse
|
|
16
|
Peng Z, Ling L, Stratton CW, Li C, Polage CR, Wu B, Tang YW. Advances in the diagnosis and treatment of Clostridium difficile infections. Emerg Microbes Infect 2018; 7:15. [PMID: 29434201 PMCID: PMC5837143 DOI: 10.1038/s41426-017-0019-4] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 12/22/2017] [Accepted: 12/27/2017] [Indexed: 12/14/2022]
Abstract
Clostridium difficile is a leading cause of antibiotic-associated diarrhea worldwide. The diagnosis of C. difficile infection (CDI) requires both clinical manifestations and a positive laboratory test for C. difficile and/or its toxins. While antibiotic therapy is the treatment of choice for CDI, there are relatively few classes of effective antibiotics currently available. Therefore, the development of novel antibiotics and/or alternative treatment strategies for CDI has received a great deal of attention in recent years. A number of emerging agents such as cadazolid, surotomycin, ridinilazole, and bezlotoxumab have demonstrated activity against C. difficile; some of these have been approved for limited clinical use and some are in clinical trials. In addition, other approaches such as early and accurate diagnosis of CDI as well as disease prevention are important for clinical management. While the toxigenic culture and the cell cytotoxicity neutralization assay are still recognized as the gold standard for the diagnosis of CDI, new diagnostic approaches such as nucleic acid amplification methods have become available. In this review, we will discuss both current and emerging diagnostic and therapeutic modalities for CDI.
Collapse
Affiliation(s)
- Zhong Peng
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Lifen Ling
- The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, Guangdong, China
- Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Charles W Stratton
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Chunhui Li
- Infection Control Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China
| | - Christopher R Polage
- Departments of Pathology and Laboratory Medicine and Internal Medicine, University of California Davis School of Medicine, Sacramento, CA, 95817, USA
| | - Bin Wu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Yi-Wei Tang
- Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
- Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, 10065, USA.
| |
Collapse
|
|
17
|
Abstract
Clostridium difficile infection is a major health care challenge in terms of patient and economic consequences. For the patient, it is a morbid and sometimes a life-threatening iatrogenic complication of antibiotic treatment. In the United States, the provider's institution may face financial penalties, because the Centers for Disease Control and Prevention views this as an iatrogenic health care-associated complication that may not be reimbursable by the Centers for Medicare and Medicaid Services; this has resulted in substantial incentives for new approaches to prevention and treatment.
Collapse
Affiliation(s)
- John G Bartlett
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, 1830 Orleans Street, Baltimore MD, 2128, USA.
| |
Collapse
|
|
18
|
Martínez-Meléndez A, Camacho-Ortiz A, Morfin-Otero R, Maldonado-Garza HJ, Villarreal-Treviño L, Garza-González E. Current knowledge on the laboratory diagnosis of Clostridium difficile infection. World J Gastroenterol 2017; 23:1552-1567. [PMID: 28321156 PMCID: PMC5340807 DOI: 10.3748/wjg.v23.i9.1552] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 01/21/2017] [Accepted: 02/17/2017] [Indexed: 02/06/2023] Open
Abstract
Clostridium difficile (C. difficile) is a spore-forming, toxin-producing, gram-positive anaerobic bacterium that is the principal etiologic agent of antibiotic-associated diarrhea. Infection with C. difficile (CDI) is characterized by diarrhea in clinical syndromes that vary from self-limited to mild or severe. Since its initial recognition as the causative agent of pseudomembranous colitis, C. difficile has spread around the world. CDI is one of the most common healthcare-associated infections and a significant cause of morbidity and mortality among older adult hospitalized patients. Due to extensive antibiotic usage, the number of CDIs has increased. Diagnosis of CDI is often difficult and has a substantial impact on the management of patients with the disease, mainly with regards to antibiotic management. The diagnosis of CDI is primarily based on the clinical signs and symptoms and is only confirmed by laboratory testing. Despite the high burden of CDI and the increasing interest in the disease, episodes of CDI are often misdiagnosed. The reasons for misdiagnosis are the lack of clinical suspicion or the use of inappropriate tests. The proper diagnosis of CDI reduces transmission, prevents inadequate or unnecessary treatments, and assures best antibiotic treatment. We review the options for the laboratory diagnosis of CDI within the settings of the most accepted guidelines for CDI diagnosis, treatment, and prevention of CDI.
Collapse
|
|
19
|
Wong KK, Choi B, Fraser TG, Donskey CJ, Deshpande A. Diagnostic testing methods for Clostridium difficile infection: A statewide survey of Ohio acute care hospitals. Am J Infect Control 2017; 45:306-307. [PMID: 28029400 DOI: 10.1016/j.ajic.2016.09.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 09/15/2016] [Accepted: 09/16/2016] [Indexed: 01/05/2023]
Abstract
We surveyed Ohio acute care hospitals on laboratory testing used for diagnosis of Clostridium difficile infection (CDI). Of 146 hospitals surveyed, 109 (84%) used nucleic acid amplification tests (NAATs) as stand-alone diagnostic assays. Only 53 (42.4%) hospitals using NAATs had a mechanism in place to prevent repeat CDI testing.
Collapse
|
|
20
|
Chen S, Sun C, Gu H, Wang H, Li S, Ma Y, Wang J. Salubrinal protects against Clostridium difficile toxin B-induced CT26 cell death. Acta Biochim Biophys Sin (Shanghai) 2017; 49:228-237. [PMID: 28119311 DOI: 10.1093/abbs/gmw139] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Indexed: 12/18/2022] Open
Abstract
Clostridium difficile (C. difficile) is considered to be the major cause of the antibiotic-associated diarrhea and pseudomembranous colitis in animals and humans. The prevalence of C. difficile infections (CDI) has been increasing since 2000. Two exotoxins of C. difficile, Toxin A (TcdA) and Toxin B (TcdB), are the main virulence factors of CDI, which can induce glucosylation of Rho GTPases in host cytosol, leading to cell morphological changes, cell apoptosis, and cell death. The mechanism of TcdB-induced cell death has been investigated for decades, but it is still not completely understood. It has been reported that TcdB induces endoplasmic reticulum stress via PERK-eIF2α signaling pathway in CT26 cell line (BALB/C mouse colon tumor cells). In this study, we found that salubrinal, a selective inhibitor of eIF2α dephosphorylation, efficiently protects CT26 cell line against TcdB-induced cell death and tried to explore the mechanism underlying in this protective effect. Our results demonstrated that salubrinal protects CT26 cells from TcdB-mediated cytotoxic and cytopathic effect, inhibits apoptosis and death of the toxin-exposed cells via caspase-9-dependent pathway, eIF2α signaling pathway, and autophagy. These findings will be helpful for the development of CDI therapies.
Collapse
Affiliation(s)
- Shuyi Chen
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Chunli Sun
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Huawei Gu
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Haiying Wang
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Shan Li
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Yi Ma
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Jufang Wang
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| |
Collapse
|
|
21
|
Kumar S, Pollok R, Muscat I, Planche T. Diagnosis and outcome of Clostridium difficile infection by toxin enzyme immunoassay and polymerase chain reaction in an island population. J Gastroenterol Hepatol 2017; 32:415-419. [PMID: 27505006 DOI: 10.1111/jgh.13504] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIM Clostridium difficile infection (CDI) is a potentially life-threatening cause of diarrhea. Correct laboratory diagnosis is essential to differentiate CDI from other causes of diarrhea. A positive fecal C. difficile toxin (CDT) is the best indicator of CDI, but the significance of a positive fecal nucleic acid amplification test (NAAT) remains unclear. Our aim was to elucidate the significance of CDI diagnostics in patients in Jersey. METHODS A retrospective, 5-year study was conducted at an island district general hospital of patients who developed CDI. Patients were grouped according to CDT and NAAT status and their association with outcome (indicators of severity and 30-day case-fatality rate) compared. RESULTS A total of 207 specimens were toxin positive, 92 NAAT positive and toxin negative, and 39 had a stool sample negative by both toxin and NAAT testing. A positive toxin stool sample was associated with both significantly higher white cell count (14.5 × 109 /L vs 11.3 × 109 /L, P = 0.003) and C-reactive protein (114.7 mg/dL vs 82.9 mg/dL, P = 0.001), but NAAT positivity was not (P = 0.269, 0.728). A positive CDT assay was a significant independent predictor of death (odds ratio [OR]: 1.89 [95% CI: 1.04-3.43], P = 0.046), but a positive NAAT in CDT negative samples was not (OR: 1.02 [95% CI: 0.34-3.12], P = 1.0). CONCLUSIONS The findings of this study, derived from evolving clinical practice, provide greater clarity in the interpretation of CDI diagnostics. In CDT-negative disease, a positive NAAT neither predicts disease severity nor mortality. NAAT-positive and toxin-negative patients require instigation of infection control measures, but the need for specific treatment remains unclear.
Collapse
Affiliation(s)
- Shankar Kumar
- Department of Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Richard Pollok
- Department of Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Ivan Muscat
- Microbiology Department, Jersey General Hospital, Jersey, UK
| | - Timothy Planche
- Department of Medical Microbiology, St George's University Hospitals NHS Foundation Trust, London, UK
| |
Collapse
|
|
22
|
Neemann K, Freifeld A. Clostridium difficile–Associated Diarrhea in the Oncology Patient. J Oncol Pract 2017; 13:25-30. [DOI: 10.1200/jop.2016.018614] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Clostridium difficile is the most common cause of nosocomial diarrhea, resulting in significant morbidity and mortality in hospitalized patients. Oncology patients are particularly at risk of this infection secondary to frequent exposure to known risk factors. In a population in which diarrhea is a common adverse effect of chemotherapeutic regimens, diagnosis can be challenging secondary to current limitations in testing to differentiate between colonization and active infection. Although several currently available antimicrobial therapies achieve resolution of symptoms in this population, further research is needed to determine which agent least affects the host intestinal microbiota, especially in times of neutropenia and mucosal barrier injury. The purpose of this article is to review the current literature on the epidemiology, pathogenesis, and management of C difficile–associated diarrhea in the oncology population.
Collapse
Affiliation(s)
- Kari Neemann
- University of Nebraska Medical Center, Omaha, NE
| | | |
Collapse
|
|
23
|
Usacheva EA, Jin JP, Peterson LR. Host response to Clostridium difficile infection: Diagnostics and detection. J Glob Antimicrob Resist 2016; 7:93-101. [PMID: 27693863 PMCID: PMC5124533 DOI: 10.1016/j.jgar.2016.08.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 07/29/2016] [Accepted: 08/08/2016] [Indexed: 02/08/2023] Open
Abstract
Clostridium difficile infection (CDI) is a significant healthcare concern worldwide, and C. difficile is recognised as the most frequent aetiological agent of infectious healthcare-associated diarrhoea in hospitalised adult patients. The clinical manifestation of CDI varies from self-limited diarrhoea to life-threatening colitis. Such a broad disease spectrum can be explained by the impact of host factors. Currently, a complex CDI aetiology is widely accepted, acknowledging the interaction between bacteria and the host. C. difficile strains producing clostridial toxins A and B are considered toxigenic and can cause disease; those not producing the toxins are non-pathogenic. A person colonised with a toxigenic strain will not necessarily develop CDI. It is imperative to recognise patients with active disease from those only colonised with this pathogen and to implement appropriate treatment. This can be achieved by diagnostics that rely on host factors specific to CDI. This review will focus on major aspects of CDI pathogenesis and molecular mechanisms, describing host factors in disease progression and assessment of the host response in order to facilitate the development of CDI-specific diagnostics.
Collapse
Affiliation(s)
- Elena A Usacheva
- Infectious Disease Research, NorthShore University HealthSystem, 2650 Ridge Ave., Evanston, IL 60201, USA; University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
| | - Jian-P Jin
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Lance R Peterson
- Infectious Disease Research, NorthShore University HealthSystem, 2650 Ridge Ave., Evanston, IL 60201, USA; University of Chicago Pritzker School of Medicine, Chicago, IL, USA
| |
Collapse
|
|
24
|
Chung HS, Lee M. Evaluation of the performance of C. DIFF QUIK CHEK COMPLETE and its usefulness in a hospital setting with a high prevalence of Clostridium difficile infection. J Investig Med 2016; 65:88-92. [PMID: 27625418 DOI: 10.1136/jim-2016-000231] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2016] [Indexed: 02/06/2023]
Abstract
Rapid and accurate diagnosis of Clostridium difficile infection (CDI) is crucial for patient care, infection control, and efficient surveillance. We evaluated C. DIFF QUIK CHEK COMPLETE (QCC; TechLab), which detects glutamate dehydrogenase (GDH) antigen (QCC-Ag) and toxin A/B (QCC-Tox) simultaneously, and compared it to the laboratory diagnostics for CDI currently in use in a tertiary hospital setting with a high prevalence of CDI. QCC, RIDASCREEN C. difficile toxin A/B assay (Toxin EIA; R-Biopharm AG), chromID C. difficile agar (bioMérieux) culture (ChromID culture), and Xpert C. difficile PCR assay (Xpert PCR; Cepheid) were performed according to the manufacturers' instructions. Performances of the assays were compared against that of Xpert PCR as a reference. Of the 231 loose stool specimens, 83 (35.9%) were positive by Xpert PCR. The sensitivity, specificity, and positive and negative predictive values were 97.6%, 93.9%, 90.0%, and 98.6%, respectively, for QCC-Ag and 55.4%, 100%, 100%, and 80.0%, respectively, for QCC-Tox. The median threshold cycle values of the QCC-Tox(+) specimens were lower than those of the QCC-Tox(-) specimens. Results of QCC as an initial screening test were confirmed in 81.0% (187/231) of samples; these specimens did not require further testing. QCC is a rapid, easy, and cost-effective method that would be a useful first-line screening assay for laboratory diagnosis of CDI in a tertiary hospital with a high prevalence of CDI. A two-step algorithm using QCC as an initial screening tool, followed by Xpert PCR as a confirmatory test, is a practical and cost-effective approach.
Collapse
Affiliation(s)
- Hae-Sun Chung
- Department of Laboratory Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Miae Lee
- Department of Laboratory Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| |
Collapse
|
|
25
|
Chen S, Gu H, Sun C, Wang H, Wang J. Rapid detection of Clostridium difficile toxins and laboratory diagnosis of Clostridium difficile infections. Infection 2016; 45:255-262. [PMID: 27601055 DOI: 10.1007/s15010-016-0940-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 08/11/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Clostridium difficile is an anaerobic, spore-forming and Gram-positive bacillus. It is the major cause of antibiotic-associated diarrhea prevailing in hospital settings. The morbidity and mortality of C. difficile infection (CDI) has increased significantly due to the emergence of hypervirulent strains. Because of the poor clinical different between CDI and other causes of hospital-acquired diarrhea, laboratory test for C. difficile is an important intervention for diagnosis of CDI. OBJECTIVE Laboratory tests for CDI can broadly detect either the organisms or its toxins. Currently, several laboratory tests are used for diagnosis of CDI, including toxigenic culture, glutamate dehydrogenase detection, nucleic acid amplification testing, cell cytotoxicity assay, and enzyme immunoassay towards toxin A and/or B. This review focuses on the rapid testing of C. difficile toxins and currently available methods for diagnosis of CDI, giving an overview of the role that the toxins rapid detecting plays in clinical diagnosis of CDI.
Collapse
Affiliation(s)
- Shuyi Chen
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China
| | - Huawei Gu
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China
| | - Chunli Sun
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China
| | - Haiying Wang
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China
| | - Jufang Wang
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China.
| |
Collapse
|
|
26
|
Abstract
Alteration in the host microbiome at skin and mucosal surfaces plays a role in the function of the immune system, and may predispose immunocompromised patients to infection. Because obligate anaerobes are the predominant type of bacteria present in humans at skin and mucosal surfaces, immunocompromised patients are at increased risk for serious invasive infection due to anaerobes. Laboratory approaches to the diagnosis of anaerobe infections that occur due to pyogenic, polymicrobial, or toxin-producing organisms are described. The clinical interpretation and limitations of anaerobe recovery from specimens, anaerobe-identification procedures, and antibiotic-susceptibility testing are outlined. Bacteriotherapy following analysis of disruption of the host microbiome has been effective for treatment of refractory or recurrent Clostridium difficile infection, and may become feasible for other conditions in the future.
Collapse
Affiliation(s)
- Deirdre L Church
- Departments of Pathology & Laboratory Medicine and Medicine, University of Calgary, and Division of Microbiology, Calgary Laboratory Services, Calgary, Alberta, Canada T2N 1N4
| |
Collapse
|
|
27
|
Shin JH, Chaves-Olarte E, Warren CA. Clostridium difficile Infection. Microbiol Spectr 2016; 4:10.1128/microbiolspec.EI10-0007-2015. [PMID: 27337475 PMCID: PMC8118380 DOI: 10.1128/microbiolspec.ei10-0007-2015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Indexed: 02/07/2023] Open
Abstract
Clostridium difficile is an anaerobic, Gram-positive, spore-forming, toxin-secreting bacillus that has long been recognized to be the most common etiologic pathogen of antibiotic-associated diarrhea. C. difficile infection (CDI) is now the most common cause of health care-associated infections in the United States and accounts for 12% of these infections (Magill SS et al., N Engl J Med370:1198-1208, 2014). Among emerging pathogens of public health importance in the United States, CDI has the highest population-based incidence, estimated at 147 per 100,000 (Lessa FC et al., N Engl J Med372:825-834, 2015). In a report on antimicrobial resistance, C. difficile has been categorized by the Centers for Disease Control and Prevention as one of three "urgent" threats (http://www.cdc.gov/drugresistance/threat-report-2013/). Although C. difficile was first described in the late 1970s, the past decade has seen the emergence of hypertoxigenic strains that have caused increased morbidity and mortality worldwide. Pathogenic strains, host susceptibility, and other regional factors vary and may influence the clinical manifestation and approach to intervention. In this article, we describe the global epidemiology of CDI featuring the different strains in circulation outside of North America and Europe where strain NAP1/027/BI/III had originally gained prominence. The elderly population in health care settings has been disproportionately affected, but emergence of CDI in children and healthy young adults in community settings has, likewise, been reported. New approaches in management, including fecal microbiota transplantation, are discussed.
Collapse
Affiliation(s)
- Jae Hyun Shin
- Department of Medicine, Division of Infectious Disease and International Health, University of Virginia, Charlottesville, VA 22908
| | - Esteban Chaves-Olarte
- Centro de Investigación en Enfermedades Tropicales, Facultad de Microbiología, Universidad de Costa Rica, Costa Rica
| | - Cirle A Warren
- Department of Medicine, Division of Infectious Disease and International Health, University of Virginia, Charlottesville, VA 22908
| |
Collapse
|
|
28
|
Abstract
Infection of the colon with the Gram-positive bacterium Clostridium difficile is potentially life threatening, especially in elderly people and in patients who have dysbiosis of the gut microbiota following antimicrobial drug exposure. C. difficile is the leading cause of health-care-associated infective diarrhoea. The life cycle of C. difficile is influenced by antimicrobial agents, the host immune system, and the host microbiota and its associated metabolites. The primary mediators of inflammation in C. difficile infection (CDI) are large clostridial toxins, toxin A (TcdA) and toxin B (TcdB), and, in some bacterial strains, the binary toxin CDT. The toxins trigger a complex cascade of host cellular responses to cause diarrhoea, inflammation and tissue necrosis - the major symptoms of CDI. The factors responsible for the epidemic of some C. difficile strains are poorly understood. Recurrent infections are common and can be debilitating. Toxin detection for diagnosis is important for accurate epidemiological study, and for optimal management and prevention strategies. Infections are commonly treated with specific antimicrobial agents, but faecal microbiota transplants have shown promise for recurrent infections. Future biotherapies for C. difficile infections are likely to involve defined combinations of key gut microbiota.
Collapse
Affiliation(s)
- Wiep Klaas Smits
- Section Experimental Bacteriology, Department of Medical Microbiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
| | - Dena Lyras
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Department of Microbiology, Monash University, Victoria, Australia
| | - D. Borden Lacy
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, and The Veterans Affairs Tennessee Valley Healthcare System, Nashville Tennessee, USA
| | - Mark H. Wilcox
- Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK
| | - Ed J. Kuijper
- Section Experimental Bacteriology, Department of Medical Microbiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
| |
Collapse
|
|
29
|
|
|
30
|
Moure R, Cañizares Á, Muíño M, Lobato M, Fernández A, Rodríguez M, Gude MJ, Tomás M, Bou G. Use of the cobas 4800 system for the rapid detection of toxigenic Clostridium difficile and methicillin-resistant Staphylococcus aureus. J Microbiol Methods 2016; 120:50-2. [DOI: 10.1016/j.mimet.2015.11.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Revised: 11/19/2015] [Accepted: 11/19/2015] [Indexed: 02/04/2023]
|
|
31
|
Goret J, Blanchi J, Eckert C, Lacome S, Petit A, Barbut F, Bébéar C, Mégraud F. Comparison of a novel chemiluminescent based algorithm to three algorithmic approaches for the laboratory diagnosis of Clostridium difficile infection. Gut Pathog 2015; 7:33. [PMID: 26705425 PMCID: PMC4690238 DOI: 10.1186/s13099-015-0079-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 12/01/2015] [Indexed: 01/05/2023] Open
Abstract
Background Rapid commercial assays, including nucleic acid amplification tests and immunoassays for Clostridium. difficile toxins, have replaced the use of older assays. They are included in a two-step algorithm diagnosis, including first the detection of the glutamate dehydrogenase (GDH) as a screening method and second the detection of toxins as a confirmatory method. Although assays that detect the presence of free toxins in feces are known to lack sensitivity, they are preferable to confirm infection. We evaluated the accuracy of the chemiluminescence-based method detecting C.difficile GDH and free toxins A/B (DiaSorin algorithm) to an enzyme-immunoassay (EIA) for GDH with a molecular toxins test (Meridian algorithm), EIA-GDH and an EIA-toxins A/B algorithm (Alere algorithm) with and without toxigenic culture for confirmation. Findings A total of 468 diarrhoeal and loose stool samples were included in the study. A positive result was defined by a positive GDH and a positive toxin test. Discordant samples were resolved using an enriched toxigenic culture considered as the reference method. After resolution, the DiaSorin algorithm showed a high sensitivity (86.7 %) compared to that of the Alere algorithm with (60.0 %) and without (50.0 %) confirmation by culture and was as sensitive as the Meridian algorithm (90.0 %), while the specificities were similar: 99.1, 99.5, 99.5 and 98.9 %, respectively. Conclusions The DiaSorin algorithm was as sensitive as an algorithm including nucleic acid amplification test for toxins. Chemiluminescence toxin-enhanced signal assay compensates the lack of sensitivity usually observed for EIA tests for toxins.
Collapse
Affiliation(s)
- J Goret
- Laboratoire de Bactériologie, C.H.U. de Bordeaux, Hôspital Pellegrin, 33076 Bordeaux Cedex, France
| | - J Blanchi
- Laboratoire de Bactériologie, C.H.U. de Bordeaux, Hôspital Pellegrin, 33076 Bordeaux Cedex, France
| | - C Eckert
- National Reference Laboratory for Clostridium difficile, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
| | - S Lacome
- Laboratoire de Bactériologie, C.H.U. de Bordeaux, Hôspital Pellegrin, 33076 Bordeaux Cedex, France
| | - A Petit
- National Reference Laboratory for Clostridium difficile, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
| | - F Barbut
- National Reference Laboratory for Clostridium difficile, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
| | - C Bébéar
- Laboratoire de Bactériologie, C.H.U. de Bordeaux, Hôspital Pellegrin, 33076 Bordeaux Cedex, France
| | - Francis Mégraud
- Laboratoire de Bactériologie, C.H.U. de Bordeaux, Hôspital Pellegrin, 33076 Bordeaux Cedex, France
| |
Collapse
|
|
32
|
Chen S, Sun C, Wang H, Wang J. The Role of Rho GTPases in Toxicity of Clostridium difficile Toxins. Toxins (Basel) 2015; 7:5254-67. [PMID: 26633511 PMCID: PMC4690124 DOI: 10.3390/toxins7124874] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 11/18/2015] [Accepted: 11/18/2015] [Indexed: 12/18/2022] Open
Abstract
Clostridium difficile (C. difficile) is the main cause of antibiotic-associated diarrhea prevailing in hospital settings. In the past decade, the morbidity and mortality of C. difficile infection (CDI) has increased significantly due to the emergence of hypervirulent strains. Toxin A (TcdA) and toxin B (TcdB), the two exotoxins of C. difficile, are the major virulence factors of CDI. The common mode of action of TcdA and TcdB is elicited by specific glucosylation of Rho-GTPase proteins in the host cytosol using UDP-glucose as a co-substrate, resulting in the inactivation of Rho proteins. Rho proteins are the key members in many biological processes and signaling pathways, inactivation of which leads to cytopathic and cytotoxic effects and immune responses of the host cells. It is supposed that Rho GTPases play an important role in the toxicity of C. difficile toxins. This review focuses on recent progresses in the understanding of functional consequences of Rho GTPases glucosylation induced by C. difficile toxins and the role of Rho GTPases in the toxicity of TcdA and TcdB.
Collapse
Affiliation(s)
- Shuyi Chen
- School of Bioscience and Bioengineering, South China University of Technology (SCUT), Guangzhou 510006, China.
| | - Chunli Sun
- School of Bioscience and Bioengineering, South China University of Technology (SCUT), Guangzhou 510006, China.
| | - Haiying Wang
- School of Bioscience and Bioengineering, South China University of Technology (SCUT), Guangzhou 510006, China.
| | - Jufang Wang
- School of Bioscience and Bioengineering, South China University of Technology (SCUT), Guangzhou 510006, China.
| |
Collapse
|