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Wang X, Wang WY, Yu XL, Chen JW, Yang JS, Wang MK. Comprehensive review of Clostridium difficile infection: Epidemiology, diagnosis, prevention, and treatment. World J Gastrointest Pharmacol Ther 2025; 16:100560. [PMID: 40094148 PMCID: PMC11907337 DOI: 10.4292/wjgpt.v16.i1.100560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 02/16/2025] [Accepted: 02/24/2025] [Indexed: 03/03/2025] Open
Abstract
In recent years, nosocomial infections caused by Clostridium difficile (C. difficile) have risen, becoming a leading cause of hospital-acquired diarrhea. The global prevalence of C. difficile infection (CDI) varies across regions and populations. The diagnosis relies primarily on laboratory testing, including toxin, glutamate dehydrogenase, and nucleic acid amplification tests. Treatment strategies for CDI include antimicrobial therapy (e.g., metronidazole, vancomycin, and fidamycin), fecal transplantation, and immunotherapy (e.g., belotozumab), depending on the patient's specificity and severity. This paper reviews recent research on CDI's epidemiological characteristics, risk factors, diagnosis, treatment, and prevention, aiming to support hospitals and public health initiatives in implementing effective detection, prevention, and treatment strategies.
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Affiliation(s)
- Xue Wang
- Naval Medical Center of People's Liberation Army, Naval Medical University, Shanghai 200052, China
| | - Wen-Yue Wang
- Department of Emergency, Qinhuangdao Hospital of Integrated Traditional Chinese and Western Medicine, Hebei Port Group Co., Ltd., Qinhuangdao 066002, Hebei Provence, China
| | - Xue-Lu Yu
- Naval Medical Center of People's Liberation Army, Naval Medical University, Shanghai 200052, China
| | - Jing-Wen Chen
- Naval Medical Center of People's Liberation Army, Naval Medical University, Shanghai 200052, China
- School of Pharmacy, Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Ji-Shun Yang
- Naval Medical Center of People's Liberation Army, Naval Medical University, Shanghai 200052, China
| | - Ming-Ke Wang
- Naval Medical Center of People's Liberation Army, Naval Medical University, Shanghai 200052, China
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Fornari V, Accardo G, Lupia T, De Rosa FG, Corcione S. Suppressive antibiotic treatment (SAT) in the era of MDRO infections: a narrative review. Expert Rev Anti Infect Ther 2025:1-13. [PMID: 40016121 DOI: 10.1080/14787210.2025.2473077] [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: 09/05/2024] [Revised: 02/02/2025] [Accepted: 02/20/2025] [Indexed: 03/01/2025]
Abstract
INTRODUCTION Antibiotics were originally developed to treat acute bacterial infections, and research studies focus their efforts on safety and efficacy in the short term; however, prolonged course of antibiotics has been documented in multiple clinical settings. The aim of this narrative review is to provide a new perspective on SAT and to discuss new therapeuticpossibilities. AREAS COVERED We discuss new clinical scenarios in which SAT could be considered. We provided a broad discussion about long-acting agents and new or repurposed oral agents as well as the use of OPAT with elastomeric pumps and an overview of the pipeline of new antifungals. Limitations of SAT are presented in this review and especially patients' adherence issues, possible spread of MDROs, possible rising of the incidence of Clostridioides difficile infections, drug-to-drug interactions and drug-related problems, cost-effectiveness evaluation issues. EXPERT OPINION Many research gaps are evident and further studies are needed. Above all, the efficacy and safety of SAT in the different clinical scenarios. Discovery of new molecules against MDROs and ongoing research on PK/PD variables as well as a better understanding of the relationship between SAT and the emergence of resistance could improve SAT usage and reduce the impact of DRPs.
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Affiliation(s)
- Valentina Fornari
- Department of Medical Sciences, Infectious Diseases, University of Turin, Turin, Italy
| | - Guido Accardo
- Department of Medical Sciences, Infectious Diseases, University of Turin, Turin, Italy
| | - Tommaso Lupia
- Infectious Diseases Unit, A.O.U. Città della Salute e della Scienza di Torino, Presidio Molinette, Turin, Italy
| | | | - Silvia Corcione
- Department of Medical Sciences, Infectious Diseases, University of Turin, Turin, Italy
- Division of Geographic Medicine and Infectious Diseases, Tufts University School of Medicine, Boston, MA, USA
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3
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Redepenning DH, Maddali S, Glotfelty-Scheuering OA, Berry JB, Dicianno BE. Incidence, timing, and risk factors for development of gastrointestinal bleeding in acute traumatic spinal cord injury: A systematic review. J Spinal Cord Med 2024:1-11. [PMID: 39173126 DOI: 10.1080/10790268.2024.2391593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/24/2024] Open
Abstract
CONTEXT Current guidelines recommend four weeks of stress ulcer prophylaxis following traumatic spinal cord injury. OBJECTIVES Assess the current literature on the incidence, timing, and risk factors for gastrointestinal bleeding/clinically important gastrointestinal bleeding in the acute setting following a traumatic spinal cord injury and whether the use of stress ulcer prophylaxis has been shown to reduce the rates of gastrointestinal bleeding. METHODS A systematic review was performed in PubMed, Embase, Web of Science, and Cochrane Library following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. RESULTS A total of 24 articles met the inclusion/exclusion criteria. The average rate of gastrointestinal bleeding among all studies was 5.5% (95% CI = 5.4-5.6%; n = 26,576). The average rate of clinically important gastrointestinal bleeding was 1.8% (95% CI = 1.79-1.82%; n = 3,857). The mean time since injury to when gastrointestinal bleeding occurred ranged from 5 to 22.5 days. For clinically important gastrointestinal bleeding the average time was 16 days or less. Those with cervical injuries had a higher incidence of clinically important gastrointestinal bleeding compared to those with non-cervical injuries (2.7% vs. 0.7%). No study found any difference in the use of stress ulcer prophylaxis in participants with or without gastrointestinal bleeding. CONCLUSIONS The overall incidence of clinically important gastrointestinal bleeding among studies was found to be low. Individuals with non-cervical injury were not found to be at high risk of clinically important gastrointestinal bleeding. There was also insufficient evidence to indicate that use of stress ulcer prophylaxis reduces the rate of gastrointestinal bleeding in those with traumatic spinal cord injury.
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Affiliation(s)
- Drew H Redepenning
- Department of Physical Medicine & Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Human Engineering Research Laboratories, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
| | - Shivaali Maddali
- Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Olivia A Glotfelty-Scheuering
- Department of Physical Medicine & Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Jessica B Berry
- Department of Physical Medicine & Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Brad E Dicianno
- Department of Physical Medicine & Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Human Engineering Research Laboratories, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
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Manthey CF, Epple HJ, Keller KM, Lübbert C, Posovszky C, Ramharter M, Reuken P, Suerbaum S, Vehreschild M, Weinke T, Addo MM, Stallmach A, Lohse AW. S2k-Leitlinie Gastrointestinale Infektionen der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1090-1149. [PMID: 38976986 DOI: 10.1055/a-2240-1428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Affiliation(s)
- Carolin F Manthey
- I. Medizinische Klinik und Poliklinik - Schwerpunkt Gastroenterologie; Sektionen Infektions- und Tropenmedizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
- Gemeinschaftspraxis Innere Medizin Witten, Witten, Deutschland
| | - Hans-Jörg Epple
- Antibiotic Stewardship, Vorstand Krankenversorgung, Universitätsmedizin Berlin, Berlin, Deutschland
| | - Klaus-Michael Keller
- Klinik für Kinder- und Jugendmedizin, Helios Dr. Horst Schmidt Kliniken, Klinik für Kinder- und Jugendmedizin, Wiesbaden, Deutschland
| | - Christoph Lübbert
- Bereich Infektiologie und Tropenmedizin, Medizinische Klinik I (Hämatologie, Zelltherapie, Infektiologie und Hämostaseologie), Universitätsklinikum Leipzig, Leipzig, Deutschland
| | | | - Michael Ramharter
- I. Medizinische Klinik und Poliklinik - Schwerpunkt Gastroenterologie; Sektionen Infektions- und Tropenmedizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
| | - Philipp Reuken
- Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie, Infektiologie, Zentrale Endoskopie), Universitätsklinikum Jena, Jena, Deutschland
| | - Sebastian Suerbaum
- Universität München, Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, München, Deutschland
| | - Maria Vehreschild
- Medizinische Klinik II, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Weinke
- Klinik für Gastroenterologie und Infektiologie, Klinikum Ernst von Bergmann, Potsdam, Deutschland
| | - Marylyn M Addo
- I. Medizinische Klinik und Poliklinik - Schwerpunkt Gastroenterologie; Sektionen Infektions- und Tropenmedizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
- Institut für Infektionsforschung und Impfstoffentwicklung Sektion Infektiologie, I. Med. Klinik, Zentrum für Innere Medizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
| | - Andreas Stallmach
- Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie, Infektiologie, Zentrale Endoskopie), Universitätsklinikum Jena, Jena, Deutschland
| | - Ansgar W Lohse
- I. Medizinische Klinik und Poliklinik - Schwerpunkt Gastroenterologie; Sektionen Infektions- und Tropenmedizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
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Rafalko N, Webster JL, Jacob G, Kutzler MA, Goldstein ND. Generalizability of predictive models for Clostridioides difficile infection, severity and recurrence at an urban safety-net hospital. J Hosp Infect 2024; 146:10-20. [PMID: 38219834 DOI: 10.1016/j.jhin.2024.01.001] [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: 10/17/2023] [Revised: 12/21/2023] [Accepted: 01/01/2024] [Indexed: 01/16/2024]
Abstract
INTRODUCTION Predictive models for Clostridioides difficile infection can identify high-risk patients and aid clinicians in preventing infection. Issues of generalizability regarding current predictive models have been acknowledged but, to the authors' knowledge, have never been quantified. METHODS C. difficile infection, severity and recurrence predictive models were created using multi-variate logistic regression through case-control sampling from an urban safety-net hospital. Models were validated using five-fold cross-validation, and inverse probability weights (IPW) based on two different catchment area definitions were used to improve external validity. Akaike Information Criterion (AIC), area under the receiver operating characteristic curve (AUROC), and sensitivity and specificity with bootstrapped confidence intervals (CI) were used to assess and compare model fit and performance. RESULTS Changes in performance before and after weighting were small across all models, although differences were more apparent after weighting the recurrence model (AUROC values of 0.78, 0.76 and 0.71 for the unweighted and two weighted models, respectively). Overall, the infection model performed the best (AUROC 0.82, 95% CI 0.78-0.85), followed by the recurrence model (AUROC 0.78, 95% CI 0.69-0.86) and then the severity model (AUROC 0.70, 95% CI 0.63-0.78). CONCLUSIONS The performance of the models after weighting did not change drastically, suggesting that the models predicting C. difficile infection, severity and recurrence may not be impacted by patient selection factors. However, other researchers may wish to consider addressing these catchment forces using IPW.
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Affiliation(s)
- N Rafalko
- Department of Epidemiology and Biostatistics, Drexel University Dornsife School of Public Health, Philadelphia, PA, USA
| | - J L Webster
- Department of Epidemiology and Biostatistics, Drexel University Dornsife School of Public Health, Philadelphia, PA, USA
| | - G Jacob
- Department of Epidemiology and Biostatistics, Drexel University Dornsife School of Public Health, Philadelphia, PA, USA
| | - M A Kutzler
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
| | - N D Goldstein
- Department of Epidemiology and Biostatistics, Drexel University Dornsife School of Public Health, Philadelphia, PA, USA.
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Moreels N, Boven A, Gressani O, Andersson FL, Vlieghe E, Callens S, Engstrand L, Simin J, Brusselaers N. The combined effect of systemic antibiotics and proton pump inhibitors on Clostridioides difficile infection and recurrence. J Antimicrob Chemother 2024; 79:608-616. [PMID: 38267263 PMCID: PMC10904719 DOI: 10.1093/jac/dkae012] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 01/03/2024] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND Antibiotics and proton pump inhibitors (PPI) are recognized risk factors for acquisition and recurrence of Clostridioides difficile infection (CDI), yet combined effects remain unclear. OBJECTIVES To assess the short- and long-term effects of antibiotics and PPIs on CDI risk and recurrence. METHODS Population-based study including all 43 152 patients diagnosed with CDI in Sweden (2006-2019), and 355 172 matched population controls without CDI. The impact of antibiotics and PPIs on CDI risk and recurrence was explored for recent (0-30 days) and preceding (31-180 days) use prior to their first CDI diagnosis, using multivariable conditional logistic regression presented as odds ratios (ORs) and 95% confidence interval, adjusted for demographics, comorbidities and other drugs. RESULTS Compared to controls, the combined effect of recent PPIs and antibiotics [ORAB+PPI = 17.51 (17.48-17.53)] on CDI risk was stronger than the individual effects [ORAB = 15.37 (14.83-15.93); ORPPI = 2.65 (2.54-2.76)]. Results were less pronounced for exposure during the preceding months. Dose-response analyses showed increasing exposure correlated with CDI risk [recent use: ORAB = 6.32 (6.15-6.49); ORPPI = 1.65 (1.62-1.68) per prescription increase].Compared to individuals without recurrence (rCDI), recent [ORAB = 1.30 (1.23-1.38)] and preceding [ORAB = 1.23 (1.16-1.31); ORPPI = 1.12 (1.03-1.21)] use also affected the risk of recurrence yet without significant interaction between both. Recent macrolides/lincosamides/streptogramins; other antibacterials including nitroimidazole derivates; non-penicillin beta lactams and quinolones showed the strongest association with CDI risk and recurrence, particularly for recent use. PPI use, both recent and preceding, further increased the CDI risk associated with almost all antibiotic classes. CONCLUSION Recent and less recent use of PPIs and systemic antibiotics was associated with an increased risk of CDI, particularly in combination.
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Affiliation(s)
- Nele Moreels
- Department of Microbiology, Centre for Translational Microbiome Research, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- I-BioStat, Data Science Institute, Hasselt University, Hasselt, Belgium
| | - Annelies Boven
- Department of Microbiology, Centre for Translational Microbiome Research, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Department of Family Medicine and Population Health, Global Health Institute, Antwerp University, Antwerp, Belgium
| | - Oswaldo Gressani
- I-BioStat, Data Science Institute, Hasselt University, Hasselt, Belgium
| | | | - Erika Vlieghe
- Department of Family Medicine and Population Health, Global Health Institute, Antwerp University, Antwerp, Belgium
| | - Steven Callens
- Department of Internal Medicine and Pediatrics, General Internal Medicine, Ghent University, Ghent, Belgium
| | - Lars Engstrand
- Department of Microbiology, Centre for Translational Microbiome Research, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Johanna Simin
- Department of Microbiology, Centre for Translational Microbiome Research, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Nele Brusselaers
- Department of Microbiology, Centre for Translational Microbiome Research, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Department of Family Medicine and Population Health, Global Health Institute, Antwerp University, Antwerp, Belgium
- Department of Public Health and Primary Care, Ghent University, Ghent, Belgium
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7
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Rohde AM, Mischnik A, Behnke M, Dinkelacker A, Eisenbeis S, Falgenhauer J, Gastmeier P, Häcker G, Herold S, Imirzalioglu C, Käding N, Kramme E, Peter S, Piepenbrock E, Rupp J, Schneider C, Schwab F, Seifert H, Steib-Bauert M, Tacconelli E, Trauth J, Vehreschild MJGT, Walker SV, Kern WV, Jazmati N. Association of ward-level antibiotic consumption with healthcare-associated Clostridioides difficile infections: an ecological study in five German university hospitals, 2017-2019. J Antimicrob Chemother 2023; 78:2274-2282. [PMID: 37527398 DOI: 10.1093/jac/dkad232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 07/09/2023] [Indexed: 08/03/2023] Open
Abstract
OBJECTIVES To analyse the influence of antibiotic consumption on healthcare-associated healthcare onset (HAHO) Clostridioides difficile infection (CDI) in a German university hospital setting. METHODS Monthly ward-level antibiotic consumption measured in DDD/100 patient days (pd) and CDI surveillance data from five university hospitals in the period 2017 through 2019 were analysed. Uni- and multivariable analyses were performed with generalized estimating equation models. RESULTS A total of 225 wards with 7347 surveillance months and 4 036 602 pd participated. With 1184 HAHO-CDI cases, there was a median incidence density of 0.17/1000 pd (IQR 0.03-0.43) across all specialties, with substantial differences among specialties. Haematology-oncology wards showed the highest median incidence density (0.67/1000 pd, IQR 0.44-1.01), followed by medical ICUs (0.45/1000 pd, IQR 0.27-0.73) and medical general wards (0.32/1000 pd, IQR 0.18-0.53). Multivariable analysis revealed carbapenem (mostly meropenem) consumption to be the only antibiotic class associated with increased HAHO-CDI incidence density. Each carbapenem DDD/100 pd administered increased the HAHO-CDI incidence density by 1.3% [incidence rate ratio (IRR) 1.013; 95% CI 1.006-1.019]. Specialty-specific analyses showed this influence only to be valid for haematological-oncological wards. Overall, factors like ward specialty (e.g. haematology-oncology ward IRR 2.961, 95% CI 2.203-3.980) or other CDI cases on ward had a stronger influence on HAHO-CDI incidence density (e.g. community-associated CDI or unknown association case in same month IRR 1.476, 95% CI 1.242-1.755) than antibiotic consumption. CONCLUSIONS In the German university hospital setting, monthly ward-level carbapenem consumption seems to increase the HAHO-CDI incidence density predominantly on haematological-oncological wards. Furthermore, other patient-specific factors seem to be equally important to control HAHO-CDI.
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Affiliation(s)
- Anna M Rohde
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute for Hygiene and Environmental Medicine, Charité - University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Hindenburgdamm 27, 12203 Berlin, Germany
| | - Alexander Mischnik
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Department of Infectious Diseases and Microbiology, University Hospital Schleswig-Holstein/Campus Lübeck, Lübeck, Germany
- Division of Infectious Diseases, Department of Medicine II, University Medical Centre and Faculty of Medicine, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Michael Behnke
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute for Hygiene and Environmental Medicine, Charité - University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Hindenburgdamm 27, 12203 Berlin, Germany
| | - Ariane Dinkelacker
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany
| | - Simone Eisenbeis
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Division of Infectious Diseases, Department of Internal Medicine 1, University Hospital Tübingen, Tübingen, Germany
| | - Jane Falgenhauer
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute of Medical Microbiology, Justus Liebig University Giessen, Giessen, Germany
| | - Petra Gastmeier
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute for Hygiene and Environmental Medicine, Charité - University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Hindenburgdamm 27, 12203 Berlin, Germany
| | - Georg Häcker
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute for Medical Microbiology and Hygiene, University Medical Centre Freiburg, University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Susanne Herold
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- University Hospital Giessen and Marburg, Department of Medicine V (Internal Medicine, Infectious Diseases and Infection Control), Justus-Liebig-University Giessen, Giessen, Germany, member of the German Centre for Lung Research (DZL), member of the German Centre for Infection Research (DZIF) Department of Internal Medicine (Infectiology)
| | - Can Imirzalioglu
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute of Medical Microbiology, Justus Liebig University Giessen, Giessen, Germany
| | - Nadja Käding
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Department of Infectious Diseases and Microbiology, University Hospital Schleswig-Holstein/Campus Lübeck, Lübeck, Germany
| | - Evelyn Kramme
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Department of Infectious Diseases and Microbiology, University Hospital Schleswig-Holstein/Campus Lübeck, Lübeck, Germany
| | - Silke Peter
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany
| | - Ellen Piepenbrock
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Jan Rupp
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Department of Infectious Diseases and Microbiology, University Hospital Schleswig-Holstein/Campus Lübeck, Lübeck, Germany
| | - Christian Schneider
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute for Medical Microbiology and Hygiene, University Medical Centre Freiburg, University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Frank Schwab
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute for Hygiene and Environmental Medicine, Charité - University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Hindenburgdamm 27, 12203 Berlin, Germany
| | - Harald Seifert
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Michaela Steib-Bauert
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Division of Infectious Diseases, Department of Medicine II, University Medical Centre and Faculty of Medicine, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Evelina Tacconelli
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Division of Infectious Diseases, Department of Internal Medicine 1, University Hospital Tübingen, Tübingen, Germany
| | - Janina Trauth
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- University Hospital Giessen and Marburg, Department of Medicine V (Internal Medicine, Infectious Diseases and Infection Control), Justus-Liebig-University Giessen, Giessen, Germany, member of the German Centre for Lung Research (DZL), member of the German Centre for Infection Research (DZIF) Department of Internal Medicine (Infectiology)
| | - Maria J G T Vehreschild
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
- Department of Internal Medicine, Infectious Diseases, Goethe University, Frankfurt am Main, Germany
| | - Sarah V Walker
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Winfried V Kern
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Division of Infectious Diseases, Department of Medicine II, University Medical Centre and Faculty of Medicine, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Nathalie Jazmati
- German Centre for Infection Research (DZIF), Healthcare-Associated and Antibiotic-Resistant Bacterial Infections, Braunschweig, Germany
- Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Labor Dr. Wisplinghoff, Cologne, Germany
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Kopacz K, Phadtare S. Probiotics for the Prevention of Antibiotic-Associated Diarrhea. Healthcare (Basel) 2022; 10:1450. [PMID: 36011108 PMCID: PMC9408191 DOI: 10.3390/healthcare10081450] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/22/2022] [Accepted: 07/30/2022] [Indexed: 11/24/2022] Open
Abstract
Several communities have started using probiotic-rich fermented foods as therapeutic options with presumed medicinal powers. We now know the importance of microbiome balance and how probiotics can restore imbalances in the microbiome. Probiotics have been tested for a number of clinical uses such as the prevention of antibiotic-associated diarrhea (AAD), the treatment of various diseases such as H. pylori infection, irritable bowel disease, vaginitis, the prevention of allergies, and necrotizing enterocolitis in newborns. AAD has been the most indicated therapeutic use for probiotics. AAD is a common side effect of antibiotic usage, which affects up to 30% of patients. The hypothesis behind using probiotics for AAD is that they help normalize an unbalanced flora. There are many potential mechanisms by which probiotics support intestinal health such as (i) boosting immunity, (ii) increasing gut barrier integrity, (iii) producing antimicrobial substances, (iv) modulating the gut microbiome, (v) increasing water absorption, and (vi) decreasing opportunistic pathogens. Many randomized-controlled trials including the strain-specific trials that use Lactobacillus and Saccharomyces and meta-analyses have shown the benefits of probiotics in addressing AAD. Although adverse events have been reported for probiotics, these are broadly considered to be a safe and inexpensive preventative treatment option for AAD and other gastrointestinal disorders.
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Influence of Probiotics on the Development of Clostridioides difficile Infection in Patients Receiving Fluoroquinolones. PHARMACY 2021; 9:pharmacy9030141. [PMID: 34449745 PMCID: PMC8396168 DOI: 10.3390/pharmacy9030141] [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] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/30/2021] [Accepted: 08/13/2021] [Indexed: 12/23/2022] Open
Abstract
Fluoroquinolones are associated with an increased risk of Clostridioides difficile infection (CDI). Probiotic supplementation has been shown to reduce the risk of antibiotic-associated diarrhea with variable effects on CDI. The objective of this study was to evaluate receipt of probiotics on development of primary CDI among hospitalized patients receiving fluoroquinolones. A retrospective cohort was evaluated that consisted of two groups of 100 patients each, admitted August 2018 through August 2020 that received ≥3 days of definitive monotherapy with levofloxacin or ciprofloxacin within 72 h of admission. Primary outcome was incidence of CDI. Secondary outcomes included rates of C. difficile diagnostic stool testing, additional infectious diagnostic testing, and non-CDI related gastrointestinal side effects. Patients on fluoroquinolones who received probiotics had a non-statistically significantly lower incidence in overall cases of CDI compared to those who did not receive probiotics (0% vs. 3%, p = 0.246). Patients who received probiotics had statistically significantly fewer C. difficile diagnostic stool tests performed (4% vs. 16%, p = 0.005) and fewer additional infectious diagnostic testing performed (4% vs. 10%, p = 0.096), respectively. Further research is warranted to optimize and standardize probiotic prescribing in high-risk patients.
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Interfacility patient sharing and Clostridioides difficile infection incidence in the Ontario hospital system: A 13-year cohort study. Infect Control Hosp Epidemiol 2021; 41:154-160. [PMID: 31762432 DOI: 10.1017/ice.2019.283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
OBJECTIVE Interfacility patient movement plays an important role in the dissemination of antimicrobial-resistant organisms throughout healthcare systems. We evaluated how 3 alternative measures of interfacility patient sharing were associated with C. difficile infection incidence in Ontario acute-care facilities. DESIGN The cohort included adult acute-care facility stays of ≥3 days between April 2003 and March 2016. We measured 3 facility-level metrics of patient sharing: general patient importation, incidence-weighted patient importation, and C. difficile case importation. Each of the 3 patient-sharing metrics were examined against the incidence of C. difficile infection in the facility per 1,000 stays, using Poisson regression models. RESULTS The analyzed cohort included 6.70 million stays at risk of C. difficile infection across 120 facilities. Over the 13-year period, we included 62,189 new cases of healthcare-associated CDI (incidence, 9.3 per 1,000 stays). After adjustment for facility characteristics, general importation was not strongly associated with C. difficile infection incidence (risk ratio [RR] per doubling, 1.10; 95% confidence interval [CI], 0.97-1.24; proportional change in variance [PCV], -2.0%). Incidence-weighted (RR per doubling, 1.18; 95% CI, 1.06-1.30; PCV, -8.4%) and C. difficile case importation (RR per doubling, 1.43; 95% CI, 1.29-1.58; PCV, -30.1%) were strongly associated with C. difficile infection incidence. CONCLUSIONS In this 13-year study of acute-care facilities in Ontario, interfacility variation in C. difficile infection incidence was associated with importation of patients from other high-incidence acute-care facilities or specifically of patients with a recent history of C. difficile infection. Regional infection control strategies should consider the potential impact of importation of patients at high risk of C. difficile shedding from outside facilities.
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Kipnis M, Schwab F, Kramer TS, Stegemann MS, Isner C, Pilarski G, Märtin N, Bui MT, Boldt AC, Behnke M, Denkel LA, Wiese-Posselt M, Zweigner J, Gastmeier P, Rohde AM. Incidence of healthcare-associated Clostridioides difficile infections and association with ward-level antibiotic consumption in a German university hospital: an ecological study. J Antimicrob Chemother 2020; 74:2400-2404. [PMID: 31098633 DOI: 10.1093/jac/dkz195] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 04/03/2019] [Accepted: 04/06/2019] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES Clostridioides difficile infection (CDI) is one of the most important healthcare-associated infections. We aimed to describe the incidence density of healthcare-associated CDI (HA-CDI) in Germany's largest hospital and to identify associations with ward-level antimicrobial consumption. METHODS We used surveillance data on CDI and antimicrobial consumption from 2014 to 2017 and analysed a potential association by means of multivariable regression analysis. RESULTS We included 77 wards with 404998 admitted patients and 1850862 patient-days. Six hundred and seventy-one HA-CDI cases were identified, resulting in a pooled mean incidence density of 0.36/1000 patient-days (IQR = 0.34-0.39). HA-CDI incidence density on ICU and haematological-oncological wards was about three times higher than on surgical wards [incidence rate ratio (IRR) = 3.00 (95% CI = 1.96-4.60) and IRR = 2.78 (95% CI = 1.88-4.11), respectively]. Ward-level consumption of third-generation cephalosporins was the sole antimicrobial risk factor for HA-CDI. With each DDD/100 patient-days administered, a ward's HA-CDI incidence density increased by 2% [IRR = 1.02 (95% CI = 1.01-1.04)]. Other risk factors were contemporaneous community-associated CDI cases [IRR = 1.32 (95% CI = 1.07-1.63)] and CDI cases in the previous month [IRR = 1.27 (95% CI = 1.07-1.51)]. Furthermore, we found a significant decrease in HA-CDI in 2017 compared with 2014 [IRR = 0.68 (95% CI = 0.54-0.86)]. CONCLUSIONS We confirmed that ward-level antimicrobial use influences HA-CDI and specifically identified third-generation cephalosporin consumption as a risk factor.
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Affiliation(s)
- Marina Kipnis
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine, Berlin, Germany
| | - Frank Schwab
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine, Berlin, Germany
| | - Tobias S Kramer
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine, Berlin, Germany
| | - Miriam S Stegemann
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Respiratory Medicine, Berlin, Germany
| | - Caroline Isner
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Respiratory Medicine, Berlin, Germany
| | - Georg Pilarski
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine, Berlin, Germany
| | - Nayana Märtin
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine, Berlin, Germany
| | - Minh Trang Bui
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine, Berlin, Germany
| | - Anne-C Boldt
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine, Berlin, Germany
| | - Michael Behnke
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine, Berlin, Germany
| | - Luisa A Denkel
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine, Berlin, Germany
| | - Miriam Wiese-Posselt
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine, Berlin, Germany
| | - Janine Zweigner
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine, Berlin, Germany
| | - Petra Gastmeier
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine, Berlin, Germany.,German Centre for Infection Research (DZIF), Braunschweig, Germany
| | - Anna M Rohde
- Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Hygiene and Environmental Medicine, Berlin, Germany.,German Centre for Infection Research (DZIF), Braunschweig, Germany
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12
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Lodise TP, Izmailyan S, Olesky M, Lawrence K. An Evaluation of Treatment Patterns and Associated Outcomes Among Adult Hospitalized Patients With Lower-Risk Community-Acquired Complicated Intra-abdominal Infections: How Often Are Expert Guidelines Followed? Open Forum Infect Dis 2020; 7:ofaa237. [PMID: 32676511 PMCID: PMC7353956 DOI: 10.1093/ofid/ofaa237] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/12/2020] [Indexed: 12/31/2022] Open
Abstract
Background Expert guidelines discourage use of antipseudomonal β-lactams and fluoroquinolones in lower-risk patients with community-acquired complicated intra-abdominal infection (CA cIAI). Compliance with these recommendations across US hospitals is unclear. This study sought to determine treatment patterns and associated outcomes among adult hospitalized lower-risk patients with CA cIAI. Methods A study using data from the Premier Healthcare Database (10/2015–12/2017) was performed. Inclusion criteria: age ≥18 years; hospitalized; had a cIAI at admission; and received antibiotics within the first 4 hospital days. Patients were excluded if they were high risk, were transferred from another health care facility, had a recent hospital admission, or received dialysis within 30 days of admission. Empiric antibiotic treatment patterns and associated outcomes were quantified. Results Overall, 46 722 (66%) patients with cIAIs met the lower-risk CA IAI study criteria. Among lower-risk CA IAI patients, the mean (SD) age was 53.4 (18.2) years, and 71% had a Charlson Comorbidity Index score of 0. The most common diagnosis was acute appendicitis with peritonitis (59.7%). Among lower-risk CA IAI patients, 54% received piperacillin/tazobactam, 20% received a fluoroquinolone (FQ), 11% received ceftriaxone, and 7% received ampicillin/sulbactam. Overall, the median hospital length of stay was 4 days and median costs were $12 345 USD. Nearly 90% of patients were discharged home, and <1% died. Outcomes were similar across all empiric treatments received. Conclusions Overuse of antipseudomonal β-lactams and fluoroquinolones was commonplace among lower-risk CA IAI patients. These findings can serve as the basis for an antimicrobial stewardship initiative in hospitals aspiring to reduce the use of broad-spectrum antibiotics.
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Affiliation(s)
- Thomas P Lodise
- Albany College of Pharmacy and Health Sciences, Albany, New York, USA
| | | | - Melanie Olesky
- Tetraphase Pharmaceuticals, Inc., Watertown, Massachusetts, USA
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Puro N, Joseph R, Zengul FD, Cochran KJ, Camins BC, Ray M. Predictors of Hospital-Acquired Clostridioides difficile Infection: A Systematic Review. J Healthc Qual 2020; 42:127-135. [PMID: 31821178 DOI: 10.1097/jhq.0000000000000236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Clostridioides difficile infections (CDIs) have been identified as a major health concern due to the high morbidity, mortality, and cost of treatment. The aim of this study was to review the extant literature and identify the various patient-related, medication-related, and organizational risk factors associated with developing hospital-acquired CDIs in adult patients in the United States. METHODS A systematic review of four (4) online databases, including Scopus, PubMed, CINAHL, and Cochrane Library, was conducted to identify empirical studies published from 2007 to 2017 pertaining to risk factors of developing hospital-acquired CDIs. FINDINGS Thirty-eight studies (38) were included in the review. Various patient-level and medication-related risk factors were identified including advanced patient age, comorbidities, length of hospital stay, previous hospitalizations, use of probiotic medications and proton pump inhibitors. The review also identified organizational factors such as room size, academic affiliation, and geographic location to be significantly associated with hospital-acquired CDIs. CONCLUSION Validation of the factors associated with high risk of developing hospital-acquired CDIs identified in this review can aid in the development of risk prediction models to identify patients who are at a higher risk of developing CDIs and developing quality improvement interventions that might improve patient outcomes by minimizing risk of infection.
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14
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Use of ribaxamase (SYN-004), a β-lactamase, to prevent Clostridium difficile infection in β-lactam-treated patients: a double-blind, phase 2b, randomised placebo-controlled trial. THE LANCET. INFECTIOUS DISEASES 2019; 19:487-496. [DOI: 10.1016/s1473-3099(18)30731-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 10/18/2018] [Accepted: 11/20/2018] [Indexed: 12/15/2022]
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15
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Zhou Y, Mao L, Yu J, Lin Q, Luo Y, Zhu X, Sun Z. Epidemiology of Clostridium difficile infection in hospitalized adults and the first isolation of C. difficile PCR ribotype 027 in central China. BMC Infect Dis 2019; 19:232. [PMID: 30845918 PMCID: PMC6407249 DOI: 10.1186/s12879-019-3841-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 02/21/2019] [Indexed: 02/08/2023] Open
Abstract
Background Clostridium difficile infection (CDI) is an emerging healthcare problem in the world. The purpose of this study was to perform a systematic epidemiological research of CDI in Tongji hospital, the central of China. Methods Stool samples from hospitalized adults suspected of CDI were enrolled. The diagnosis of CDI were based on the combination of clinical symptoms and laboratory results. Clinical features of CDI and non-CDI patients were compared by appropriate statistical tests to determine the risk factors of CDI. Multilocus sequence typing (MLST) was employed for molecular epidemiological analysis. Susceptibility testing and relevant antimicrobial agent resistance genes were performed as well. Results From June 2016 to September 2017, 839 hospitalized adults were enrolled. Among them, 107 (12.8%, 107/839) patients were C. difficile culture positive, and 73 (8.7%, 73/839) were infected with toxigenic C. difficile (TCD), with tcdA + tcdB+ strains accounting for 90.4% (66/73) and tcdA-tcdB+ for 9.6% (7/73). Meanwhile, two TCD strains were binary toxin positive and one of them was finally identified as CD027. Severe symptoms were observed in these two cases. Multivariate analysis indicated antibiotic exposure (p = 0.001, OR = 5.035) and kidney disease (p = 0.015, OR = 8.329) significantly increased the risk of CDI. Phylogenetic tree analysis demonstrated 21 different STs, including one new ST (ST467); and the most dominant type was ST54 (35.6%, 26/73). Multidrug-resistant (MDR) TCD were 53.4% (39/73); resistance to ciprofloxacin, erythromycin, and clindamycin were > 50%. Other antibiotics showed relative efficiency and all strains were susceptible to metronidazole and vancomycin. All moxifloxacin-resistant isolates carried a mutation in GyrA (Thr82 → Ile), with one both having mutation in GyrB (Ser366 → Ala). Conclusions Knowledge of epidemiological information for CDI is limited in China. Our finding indicated tcdA + tcdB+ C. difficile strains were the dominant for CDI in our hospital. Significant risk factors for CDI in our setting appeared to be antibiotic exposure and kidney disease. Metronidazole and vancomycin were still effective for CDI. Although no outbreak was observed, the first isolation of CD027 in center China implied the potential spread of this hypervirulent clone. Further studies are needed to enhance our understanding of the epidemiology of CDI in China. Electronic supplementary material The online version of this article (10.1186/s12879-019-3841-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yu Zhou
- Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Zhejiang, 310014, Hangzhou, China
| | - Liyan Mao
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430030, China
| | - Jing Yu
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430030, China
| | - Qun Lin
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430030, China
| | - Ying Luo
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430030, China
| | - Xuhui Zhu
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430030, China.
| | - Ziyong Sun
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430030, China.
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Abstract
Stress ulcer prophylaxis (SUP) with acid-suppressive drug therapy is widely utilized in critically ill patients following neurologic injury for the prevention of clinically important stress-related gastrointestinal bleeding (CIB). Data supporting SUP, however, largely originates from studies conducted during an era where practices were vastly different than what is considered routine by today's standard. This is particularly true in neurocritical care patients. In fact, the routine provision of SUP has been challenged due to an increasing prevalence of adverse drug events with acid-suppressive therapy and the perception that CIB rates are sparse. This narrative review will discuss current controversies with SUP as they apply to neurocritical care patients. Specifically, the pathophysiology, prevalence, and risk factors for CIB along with the comparative efficacy, safety, and cost-effectiveness of acid-suppressive therapy will be described.
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Affiliation(s)
- Jeffrey F Barletta
- Midwestern University, College of Pharmacy-Glendale, 19555 N 59th Avenue, Glendale, AZ, 85308, USA.
| | | | - Joseph F Sucher
- Honor Health- John C. Lincoln Medical Center, Phoenix, AZ, USA
| | - Victor Zach
- Honor Health, A.T. Still University School of Osteopathic Medicine, Phoenix, AZ, USA
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17
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Fuchs BB, Tharmalingam N, Mylonakis E. Vulnerability of long-term care facility residents to Clostridium difficile infection due to microbiome disruptions. Future Microbiol 2018; 13:1537-1547. [PMID: 30311778 DOI: 10.2217/fmb-2018-0157] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Aging presents a significant risk factor for Clostridium difficile infection (CDI). A disproportionate number of CDIs affect individuals in long-term care facilities compared with the general population, likely due to the vulnerable nature of the residents and shared environment. Review of the literature cites a number of underlying medical conditions such as the use of antibiotics, proton pump inhibitors, chemotherapy, renal disease and feeding tubes as risk factors. These conditions alter the intestinal environment through direct bacterial killing, changes to pH that influence bacterial stabilities or growth, or influence nutrient availability that direct population profiles. In this review, we examine some of the contributing risk factors for elderly associated CDI and the toll they take on the microbiome.
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Affiliation(s)
- Beth Burgwyn Fuchs
- Rhode Island Hospital, Alpert Medical School & Brown University, Providence, Rhode Island 02903
| | - Nagendran Tharmalingam
- Rhode Island Hospital, Alpert Medical School & Brown University, Providence, Rhode Island 02903
| | - Eleftherios Mylonakis
- Rhode Island Hospital, Alpert Medical School & Brown University, Providence, Rhode Island 02903
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18
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Nguyen CT, Li J, Anders S, Garcia-Diaz J, Staffeld-Coit C, Hand J. Comparison of outcomes with vancomycin or metronidazole for mild-to-moderate Clostridium difficile associated diarrhea among solid organ transplant recipients: A retrospective cohort study. Transpl Infect Dis 2018; 20:e12867. [PMID: 29512244 DOI: 10.1111/tid.12867] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 12/11/2017] [Accepted: 01/07/2018] [Indexed: 01/01/2023]
Abstract
BACKGROUND Current guidelines recommend oral vancomycin or fidaxomicin for the treatment of mild-to-moderate Clostridium difficile associated diarrhea (CDAD), while metronidazole is recommended as an alternative when oral vancomycin and fidaxomicin are unavailable. However, data are lacking among the solid organ transplant (SOT) population. METHODS This single center, retrospective cohort study evaluated adult SOT recipients with mild-to-moderate CDAD. Analysis 1 evaluated patients receiving initial therapy with metronidazole vs oral vancomycin for at least 72 hours. Analysis 2 evaluated patients receiving metronidazole vs oral vancomycin for at least 70% of the treatment duration. The primary outcome was treatment failure. Secondary outcomes included CDAD recurrence and all-cause mortality. RESULTS Analysis 1 included 71 patients (metronidazole n = 50, oral vancomycin n = 21) and analysis 2 included 75 patients (metronidazole n = 42, oral vancomycin n = 33). No significant differences in C. difficile risk factors were observed between groups in either analysis. However, in both analyses, more patients in the oral vancomycin arm received antibiotics during the CDAD episode (analysis 1, 52% vs 26%, P = .03; analysis 2, 55% vs 32%, P < .01). Neither analysis demonstrated differences in treatment failure (analysis 1, metronidazole 16%, oral vancomycin 10%, P = .71; analysis 2, metronidazole 2%, oral vancomycin 6%, P = .58). CDAD recurrence and all-cause mortality were similar across groups in both analyses. CONCLUSIONS Results suggest that both metronidazole and oral vancomycin are reasonable options for the treatment of mild-to-moderate CDAD in patients with SOT. No difference in treatment failure was observed; however, oral vancomycin may be preferred for higher risk patients, such as those receiving concurrent antibiotics.
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Affiliation(s)
- Cynthia T Nguyen
- Department of Pharmacy, Ochsner Medical Center, New Orleans, LA, USA
| | - Julius Li
- Department of Pharmacy, Ochsner Medical Center, New Orleans, LA, USA
| | - Stephanie Anders
- Department of Pharmacy, Ochsner Medical Center, New Orleans, LA, USA
| | - Julia Garcia-Diaz
- Department of Infectious Diseases, Ochsner Medical Center, New Orleans, LA, USA.,University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA, USA
| | - Catherine Staffeld-Coit
- University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA, USA.,Ochsner Multi-Organ Transplant Institute, Ochsner Medical Center, New Orleans, LA, USA
| | - Jonathan Hand
- Department of Infectious Diseases, Ochsner Medical Center, New Orleans, LA, USA.,University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA, USA
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Oshima T, Wu L, Li M, Fukui H, Watari J, Miwa H. Magnitude and direction of the association between Clostridium difficile infection and proton pump inhibitors in adults and pediatric patients: a systematic review and meta-analysis. J Gastroenterol 2018; 53:84-94. [PMID: 28744822 DOI: 10.1007/s00535-017-1369-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 07/10/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Clostridium difficile infection (CDI) is a cause of increased morbidity and health care costs among hospitalized patients. Proton pump inhibitors (PPIs) are mainly used for the treatment of acid-related upper gastrointestinal diseases. The aim of the study was to assess the risks associated with initial and recurrent CDI in adult and pediatric patients treated with PPIs. METHODS A systematic search was performed using PubMed (Medline), Embase, and Web of Science with the following search terms: ("proton pump inhibitor," "PPI," or "acid suppression") AND ("infection," "diarrhea," "diarrhoea," "colitis," or "disease") AND ("Clostridium difficile"). Meta-analysis was performed using Revman5.3 software. Pooled odds ratios (ORs) presented as standard plots with 95% confidence intervals (CIs) were determined. RESULTS Sixty-seven eligible studies were selected. PPI use was significantly associated with risk of CDI (OR 2.34, 95% CI 1.94-2.82; P < 0.00001). Pooled data from twelve studies demonstrated a significant association between PPI use and recurrent CDI (OR 1.73, 95% CI 1.39-2.15; P = 0.02). Subgroup analysis revealed significant associations between PPI use and an increased incidence of CDI among adult (OR 2.30, 95% CI 1.89-2.80; P < 0.00001) and pediatric (OR 3.00, 95% CI 1.44-6.23; P < 0.00001) patients. CONCLUSIONS PPI use was associated with CDI in adult and pediatric patients, and with recurrent CDI. Although many risk factors are associated with the occurrence and recurrence of CDI, consideration should be given to not administering PPIs at any age if they are unnecessary.
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Affiliation(s)
- Tadayuki Oshima
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
| | - Liping Wu
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.,Department of Gastroenterology, The Third People's Hospital of Chengdu, Chengdu, China
| | - Min Li
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.,Department of Gastroenterology, The Third People's Hospital of Chengdu, Chengdu, China
| | - Hirokazu Fukui
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Jiro Watari
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
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Li B, Ma H, Wang Z, Liu L. When omeprazole met with asymptomatic Clostridium difficile colonization in a postoperative colon cancer patient: A case report. Medicine (Baltimore) 2017; 96:e9089. [PMID: 29245331 PMCID: PMC5728946 DOI: 10.1097/md.0000000000009089] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
RATIONALE Clostridium difficile infection (CDI) is a symptomatic infection due to the spore-forming bacterium, C. difficile. Asymptomatic C. difficile colonization is the stage in absence of symptoms, with a prevalence of 1.4% to 21% on hospital admission. Proton-pump inhibitors (PPIs) was implicated as a novel potential contributor to CDI. PPIs injection could make asymptomatic C. difficile colonization progress to C. difficile associated diarrhea (CDAD). PATIENT CONCERNS A postoperative colon cancer patient, who had been taking omeprazole for 4 years after operation, got asymptomatic C. difficile colonization. When he developed clinical symptoms of digestive tract, tumor recurrence was first suspected and intravenous omeprazole was prescribed, which ultimately led to progression to symptomatic CDI. In this report, we tell the confusing differential diagnosis of cancer-associated diseases and CDAD, and discuss the possibility of solving the PPIs overuse problem by making clinical pathway of PPIs use in Chinese hospitals. DIAGNOSES CDAD, incomplete intestinal obstruction, postoperation of colon cancer. INTERVENTION Electrolyte replacement and rehydration. Parenteral nutrition support. Omeprazole was prescribed but withdrawn later, and oral vancomycin was given at a dose of 0.25 g 4 times per day for 10 days. OUTCOMES Diarrhea was resolved, so long as the acid reflux and vomiting. LESSONS We have 2 lessons here: Be aware of PPIs induced CDI, especially the asymptomatic C. difficile colonization. Making clinical pathway specified on PPIs use by pharmacists could be a practical way to solve the problem of PPIs overuse.
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Affiliation(s)
| | - Huachong Ma
- Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Zhenjun Wang
- Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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Trifan A, Stanciu C, Girleanu I, Stoica OC, Singeap AM, Maxim R, Chiriac SA, Ciobica A, Boiculese L. Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis. World J Gastroenterol 2017; 23:6500-6515. [PMID: 29085200 PMCID: PMC5643276 DOI: 10.3748/wjg.v23.i35.6500] [Citation(s) in RCA: 183] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 08/11/2017] [Accepted: 08/25/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To perform a systematic review and meta-analysis on proton pump inhibitors (PPIs) therapy and the risk of Clostridium difficile infection (CDI).
METHODS
We conducted a systematic search of MEDLINE/PubMed and seven other databases through January 1990 to March 2017 for published studies that evaluated the association between PPIs and CDI. Adult case-control and cohort studies providing information on the association between PPI therapy and the development of CDI were included. Pooled odds ratios (ORs) estimates with 95% confidence intervals (CIs) were calculated using the random effect. Heterogeneity was assessed by I2 test and Cochran’s Q statistic. Potential publication bias was evaluated via funnel plot, and quality of studies by the Newcastle-Otawa Quality Assessment Scale (NOS).
RESULTS Fifty-six studies (40 case-control and 16 cohort) involving 356683 patients met the inclusion criteria and were analyzed. Both the overall pooled estimates and subgroup analyses showed increased risk for CDI despite substantial statistical heterogeneity among studies. Meta-analysis of all studies combined showed a significant association between PPI users and the risk of CDI (pooled OR = 1.99, CI: 1.73-2.30, P < 0.001) as compared with non-users. The association remained significant in subgroup analyses: by design-case-control (OR = 2.00, CI: 1.68-2.38, P < 0.0001), and cohort (OR = 1.98, CI: 1.51-2.59, P < 0.0001); adjusted (OR = 1.95, CI: 1.67-2.27, P < 0.0001) and unadjusted (OR = 2.02, CI: 1.41-2.91, P < 0.0001); unicenter (OR = 2.18, CI: 1.72-2.75, P < 0.0001) and multicenter (OR = 1.82, CI: 1.51-2.19, P < 0.0001); age ≥ 65 years (OR = 1.93, CI: 1.40-2.68, P < 0.0001) and < 65 years (OR = 2.06, CI: 1.11-3.81, P < 0.01). No significant differences were found in subgroup analyses (test for heterogeneity): P = 0.93 for case-control vs cohort, P = 0.85 for adjusted vs unadjusted, P = 0.24 for unicenter vs multicenter, P = 0.86 for age ≥ 65 years and < 65 years. There was significant heterogeneity across studies (I2 = 85.4%, P < 0.001) as well as evidence of publication bias (funnel plot asymmetry test, P = 0.002).
CONCLUSION This meta-analysis provides further evidence that PPI use is associated with an increased risk for development of CDI. Further high-quality, prospective studies are needed to assess whether this association is causal.
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Affiliation(s)
- Anca Trifan
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
| | - Carol Stanciu
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, 700111 Iasi, Romania
| | - Irina Girleanu
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
| | - Oana Cristina Stoica
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
| | - Ana Maria Singeap
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
| | - Roxana Maxim
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
| | - Stefan Andrei Chiriac
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
| | - Alin Ciobica
- Department of Research, Faculty of Biology, “Alexandru Ioan Cuza” University of Iasi, 700506 Iasi, Romania
| | - Lucian Boiculese
- Department of Preventive Medicine and Interdisciplinarity, “Grigore. T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
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22
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Updated meta-analysis of controlled observational studies: proton-pump inhibitors and risk of Clostridium difficile infection. J Hosp Infect 2017; 98:4-13. [PMID: 28842261 DOI: 10.1016/j.jhin.2017.08.017] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 08/18/2017] [Indexed: 12/18/2022]
Abstract
Attention has recently been directed toward a plausible link between Clostridium difficile infection (CDI) and proton-pump inhibitors (PPIs). However, the results of studies on the association between CDI and PPI remain controversial. We searched the literature databases from their inception to December 2016, without restriction of language, including all controlled observational studies examining the association between acid-suppressive therapy and CDI. Pooled analysis of 50 studies showed a significant association between PPI use and risk of developing CDI (odds ratio: 1.26; 95% confidence interval: 1.12-1.39) as compared with non-users. When stratified by study patients, the relative risk of hospital-acquired CDI and community-associated CDI were 1.29 (1.14-1.44) and 1.17 (0.74-1.59). After restricting the studies according to hospital department, the relative risks of hospital-acquired CDI in ICUs and general wards were 1.43 (0.74-2.11) and 1.29 (1.13-1.45). By implementing cumulative meta-analysis, it was clear that earlier trials of CDI conducted in the early 2000s demonstrated a high degree of heterogeneity and a high percentage of negative results. Since 2011, the overall association between PPI use and risk of developing CDI has remained relatively stable within an effect size between OR 1.20 and 1.26. Our findings indicate a significant associated risk of incident CDI among PPI users, especially in general ward patients. The totality of evidence, when using cumulative meta-analysis, showed that further trials are unlikely to overturn this positive result. Therefore establishing a guideline for the use of PPIs may help in future with the control of CDI.
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Mallina R, Craik J, Briffa N, Ahluwalia V, Clarke J, Cobb AG. Probiotic containing Lactobacillus casei, Lactobacillus bulgaricus, and Streptococcus thermophiles (ACTIMEL) for the prevention of Clostridium difficile associated diarrhoea in the elderly with proximal femur fractures. J Infect Public Health 2017; 11:85-88. [PMID: 28652125 DOI: 10.1016/j.jiph.2017.04.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 03/12/2017] [Accepted: 04/28/2017] [Indexed: 12/30/2022] Open
Abstract
The incidence of Clostridium difficile associated diarrhoea (CDAD) is greater in elderly patients. Probiotics may have a beneficial effect in the prevention of CDAD. However, their effect in elderly orthopaedic patients has not been previously reported. Between April 2013 and April 2014, 105 patients admitted with femoral neck fractures, and who required 3days of antibiotics for infection of any cause, were prescribed the probiotic ACTIMEL until 3days after the last antibiotic dose. The incidence of CDAD was compared with historical controls (April 2011¬タモApril 2012). There was no significant reduction in the incidence of CDAD in patients receiving probiotics (OR: 0.9; 95% CI 0.27¬タモ2.91; p=0.8) and therefore we cannot recommend the use of ACTIMEL containing Lactobacillus casei, Lactobacillus bulgaricus, and Streptococcus thermophiles for this purpose in this patient group.
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Affiliation(s)
- Ravi Mallina
- Department of Trauma & Orthopaedic Surgery, Epsom & St. Helier¬タルs Hospital, Carshalton, SM5 1AA, UK.
| | - J Craik
- Department of Trauma & Orthopaedic Surgery, Epsom & St. Helier¬タルs Hospital, Carshalton, SM5 1AA, UK
| | - N Briffa
- Department of Trauma & Orthopaedic Surgery, Epsom & St. Helier¬タルs Hospital, Carshalton, SM5 1AA, UK
| | - Viren Ahluwalia
- Academic Foundation Trainee, St George¬タルs Hospital, Tooting, London SW17 0QT, UK
| | - J Clarke
- Department of Microbiology, Epsom & St. Helier¬タルs Hospital, Carshalton, SM5 1AA, UK
| | - A G Cobb
- Department of Trauma & Orthopaedic Surgery, Epsom & St. Helier¬タルs Hospital, Carshalton, SM5 1AA, UK
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24
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Brown KA, Daneman N, Jones M, Nechodom K, Stevens V, Adler FR, Goetz MB, Mayer J, Samore M. The Drivers of Acute and Long-term Care Clostridium difficile Infection Rates: A Retrospective Multilevel Cohort Study of 251 Facilities. Clin Infect Dis 2017; 65:1282-1288. [DOI: 10.1093/cid/cix532] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 06/06/2017] [Indexed: 01/05/2023] Open
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Roberts T, Kokai-Kun JF, Coughlin O, Lopez BV, Whalen H, Bristol JA, Hubert S, Longstreth J, Lasseter K, Sliman J. Tolerability and Pharmacokinetics of SYN-004, an Orally Administered β-Lactamase for the Prevention of Clostridium difficile-Associated Disease and Antibiotic-Associated Diarrhea, in Two Phase 1 Studies. Clin Drug Investig 2017; 36:725-734. [PMID: 27283946 DOI: 10.1007/s40261-016-0420-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND SYN-004 is an orally administered β-lactamase enzyme, designed to be given concurrently with certain intravenous β-lactam antibiotics like cephalosporins. SYN-004 is intended to degrade residual antibiotics excreted into the intestine as a result of hepatobiliary excretion and to prevent the disruption of the gut microbiome by these excess antibiotics. Preserving the gut microbiome is expected to prevent secondary infections by pathogens like Clostridium difficile and protect against other antibiotic-associated diarrheas. METHODS Two, randomized, double blind, placebo-controlled Phase 1 clinical studies were conducted in normal healthy adult volunteers to assess the tolerability and systemic absorption of single and multiple doses of SYN-004. A single-ascending dose study investigated single oral doses of 75-750 mg SYN-004 and was conducted in 40 subjects (five cohorts of six active and two placebo subjects). A multiple-ascending dose study investigated doses of 75-300 mg SYN-004, administered every 6 h for 7 days and was conducted in 24 subjects (three cohorts of six active and two placebo subjects). The safety and tolerability of SYN-004 was assessed and serial plasma and serum samples were collected to assess the pharmacokinetics and potential immunogenicity of SYN-004. RESULTS Minimal and mild adverse events were reported in ~30 % of the subjects who received active drug and placebo and no antidrug antibodies were detected in any subject. Analysis of serial plasma samples demonstrated negligible systemic bioavailability of SYN-004 with most plasma concentrations being below the lower limit of quantitation (0.8 ng/mL) for the assay. SYN-004 was well tolerated in the 48 subjects who received active drug, and adverse events in those subjects were comparable to the 16 subjects who received placebo, up to the maximum doses administered in each study. CONCLUSION SYN-004 was well tolerated up to a single oral dose of 750 mg and multiple doses of 300 mg every 6 h for 7 days. The pharmacokinetic results support that SYN-004 remained localized in the intestine.
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Affiliation(s)
- Tracey Roberts
- Synthetic Biologics, Inc., 9605 Medical Center Drive, Suite 270, Rockville, MD, 20850, USA
| | - John F Kokai-Kun
- Synthetic Biologics, Inc., 9605 Medical Center Drive, Suite 270, Rockville, MD, 20850, USA.
| | - Olivia Coughlin
- Synthetic Biologics, Inc., 9605 Medical Center Drive, Suite 270, Rockville, MD, 20850, USA
| | | | - Heidi Whalen
- Synthetic Biologics, Inc., 9605 Medical Center Drive, Suite 270, Rockville, MD, 20850, USA
| | - J Andrew Bristol
- Synthetic Biologics, Inc., 9605 Medical Center Drive, Suite 270, Rockville, MD, 20850, USA
| | - Steven Hubert
- Synthetic Biologics, Inc., 9605 Medical Center Drive, Suite 270, Rockville, MD, 20850, USA
| | | | | | - Joseph Sliman
- Synthetic Biologics, Inc., 9605 Medical Center Drive, Suite 270, Rockville, MD, 20850, USA
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26
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Arriola V, Tischendorf J, Musuuza J, Barker A, Rozelle JW, Safdar N. Assessing the Risk of Hospital-Acquired Clostridium Difficile Infection With Proton Pump Inhibitor Use: A Meta-Analysis. Infect Control Hosp Epidemiol 2016; 37:1408-1417. [PMID: 27677811 PMCID: PMC5657489 DOI: 10.1017/ice.2016.194] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Clostridium difficile is the principal infectious cause of antibiotic-associated diarrhea and accounts for 12% of hospital-acquired infections. Recent literature has shown an increased risk of C. difficile infection (CDI) with proton pump inhibitor (PPI) use. OBJECTIVE To conduct a systematic assessment of the risk of hospital-acquired CDI following exposure to PPI. METHODS We searched multiple databases for studies examining the relationship between PPI and hospital-acquired CDI. Pooled odds ratios were generated and assessment for heterogeneity performed. RESULTS We found 23 observational studies involving 186,033 cases that met eligibility criteria. Across studies, 10,307 cases of hospital-acquired CDI were reported. Significant heterogeneity was present; therefore, a random effects model was used. The pooled odds ratio was 1.81 (95% CI, 1.52-2.14), favoring higher risk of CDI with PPI use. Significant heterogeneity was present, likely due to differences in assessment of exposure, study population, and definition of CDI. DISCUSSION This meta-analysis suggests PPIs significantly increase the risk of hospital-acquired CDI. Given the significant health and economic burden of CDI and the risks of PPI, optimization of PPI use should be included in a multifaceted approach to CDI prevention. Infect Control Hosp Epidemiol 2016;1408-1417.
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Affiliation(s)
- Vanessa Arriola
- Tulane University School of Public Health and Tropical Medicine, Department of Epidemiology, New Orleans, LA, USA
| | - Jessica Tischendorf
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Jackson Musuuza
- Institute of Clinical and Translational Research, University of Wisconsin, Madison, WI, USA
| | - Anna Barker
- University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Jeffrey W. Rozelle
- Tulane University School of Public Health and Tropical Medicine, Department of Epidemiology, New Orleans, LA, USA
| | - Nasia Safdar
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Department of Infectious Disease, University of Wisconsin Hospital and Clinics, Madison, WI, USA; William S. Middleton Memorial Veterans Affairs Hospital, Madison, WI, USA
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Abstract
Infectious diarrhea is very common; its severity ranges from uncomplicated, self-limiting courses to potentially life-threatening disease. A rapid diagnostic workup providing detailed information on the suspected pathogen should be performed only in patients at risk, analyzing one single stool sample for Salmonella, Shigella, Campylobacter, and Norovirus. In the presence of risk factors, such as a history of antibiotic exposure within the last 3 months, testing for Clostridium difficile should be performed. Immunocompetent patients do not require specific antibiotic therapy. Exceptions exist in patients with severe comorbidities, immunodeficiency, fever/SIRS, and in patients with Shigella or C. difficile infection. Empirical antibiotic treatment should be considered in patients with fever and/or bloody diarrhea and in patients at risk. In patients with traveler's diarrhea, microbiological diagnosis is required only in patients with fever, bloody diarrhea, prolonged course of disease (more than 5 days), severe clinical course with hypotension or dehydration, and during outbreaks. In these patients one single fecal sample should be collected for stool cultures of Campylobacter, Shigella, and Salmonella, as well as microscopic examination for amoebiasis and Giardiasis. The main therapeutic measure for infectious diarrhea is sufficient oral rehydration. As in community-acquired diarrhea, azithromycin or ciprofloxacin are recommended-taking into account local antimicrobial resistance in the country of travel and possible side effects.
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28
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Han S, Shannahan S, Pellish R. Fecal Microbiota Transplant. J Intensive Care Med 2016; 31:577-86. [DOI: 10.1177/0885066615594344] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 05/14/2015] [Indexed: 12/16/2022]
Abstract
Clostridium difficile infection (CDI) has steadily increased in incidence since the 1990s, with an associated increase in recurrence and severity, which has in turn lead to more intensive care unit (ICU) admissions. The development of recurrent CDI, in particular, has been associated with increasing patient morbidity and mortality as well as an immense financial burden on the health care system. Recently, fecal microbiota transplantation (FMT) has received much publicity as an effective means of treatment for recurrent CDI. The goal of this review is to provide evidence-based recommendations for the diagnosis and management of CDI, with a particular focus on FMT and its utilization in the ICU.
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Affiliation(s)
- Samuel Han
- University of Massachusetts Medical School, Worcester, MA, USA
| | - Sarah Shannahan
- University of Massachusetts Medical School, Worcester, MA, USA
| | - Randall Pellish
- University of Massachusetts Medical School, Worcester, MA, USA
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Akamine CM, Ing MB, Jackson CS, Loo LK. The efficacy of intracolonic vancomycin for severe Clostridium difficile colitis: a case series. BMC Infect Dis 2016; 16:316. [PMID: 27388627 PMCID: PMC4937541 DOI: 10.1186/s12879-016-1657-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 06/16/2016] [Indexed: 01/05/2023] Open
Abstract
Background Clostridium difficile infection (CDI) unresponsive to the standard treatments of metronidazole and oral vancomycin requires aggressive medical management and possible surgical intervention including colectomy. Intracolonic vancomycin therapy has been reported to be particularly promising in the setting of severe CDI in the presence of ileus. This is a descriptive case series exploring the effect of adjunctive intracolonic vancomycin therapy on the morbidity and mortality in patients with moderate to severe CDI. Methods A retrospective chart review was conducted on 696 patients with CDI seen at a single institution. Each patient was assigned a severity score and 127 patients with moderate to severe CDI were identified. We describe the clinical presentation, risk factors and hospital course comparing those that received adjunctive intracolonic vancomycin to those that only received standard therapy. Results The group that received adjunctive intracolonic vancomycin had higher rates of toxic megacolon, intensive care unit (ICU) admission, and colectomy, and yet maintained a similar mortality rate as the group that received only standard treatment. Conclusion The intracolonic vancomycin group experienced more complications but showed a similar mortality rate to the standard therapy group, suggesting that intracolonic vancomycin may impart a protective effect. This study adds further evidence for the need of a randomized controlled study using intracolonic vancomycin as adjunctive therapy in patients presenting with severe CDI.
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Affiliation(s)
- Christine M Akamine
- Department of Medicine, Loma Linda University School of Medicine, 11234 Anderson Street, Loma Linda, CA, 92354, USA
| | - Michael B Ing
- Department of Medicine, Loma Linda University School of Medicine, 11234 Anderson Street, Loma Linda, CA, 92354, USA.,Section of Infectious Disease, VA Loma Linda Healthcare System, 11201 Benton Street, Loma Linda, CA, 92357, USA
| | - Christian S Jackson
- Department of Medicine, Loma Linda University School of Medicine, 11234 Anderson Street, Loma Linda, CA, 92354, USA.,Section of Gastroenterology, VA Loma Linda Healthcare System, 11201 Benton Street, Loma Linda, CA, 92357, USA
| | - Lawrence K Loo
- Department of Medicine, Loma Linda University School of Medicine, 11234 Anderson Street, Loma Linda, CA, 92354, USA.
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31
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Association Between High-Risk Medication Usage and Healthcare Facility-Onset C. difficile Infection. Infect Control Hosp Epidemiol 2016; 37:909-915. [DOI: 10.1017/ice.2016.87] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVENational hospital performance measures for C. difficile infection (CD) are available; comparing antibacterial use among performance levels can aid in identifying effective antimicrobial stewardship strategies to reduce CDI rates.DESIGNHospital-level, cross-sectional analysis.METHODSHospital characteristics (ie, demographics, medications, patient mix) were obtained for 77 hospitals for 2013. Hospitals were assigned 1 of 3 levels of a CDI standardized infection ratio (SIR): ‘Worse than,’ ‘Better than,’ or ‘No different than’ a national benchmark. Analyses compared medication use (total and broad-spectrum antibacterials) for 3 metrics: days of therapy per 1,000 patient days; length of therapy; and proportion of patients receiving a medication across SIR levels. A multivariate, ordered-probit regression identified characteristics associated with SIR categories.RESULTSRegarding total average antimicrobial use per patient, there was a significant difference detected in mean length of therapy: ‘No different’ hospitals having the longest (4.93 days) versus ‘Worse’ (4.78 days) and ‘Better’ (4.43 days) (P<.01). ‘Better’ hospitals used fewer total antibacterials (693 days of therapy per 1,000 patient days) versus ‘No different’ (776 days) versus ‘Worse’ (777 days) (P<.05). The ‘Better’ hospitals used broad-spectrum antibacterials for a shorter average length of therapy (4.03 days) versus ‘No different’ (4.51 days) versus ‘Worse’ (4.38 days) (P<.05). ‘Better’ hospitals used fewer broad-spectrum antibacterials (310 days of therapy per 1,000 patient days) versus ‘No different’ (364 days) versus ‘Worse’ (349 days) (P<.05). Multivariate analysis revealed that the proportion of elderly patients and chemotherapy days of therapy per 1,000 patient days was significantly negatively associated with the SIR.CONCLUSIONSThese findings have potential implications regarding the need to fully account for hospital patient mix when carrying out inter-hospital comparisons of CDI rates.Infect Control Hosp Epidemiol 2016;37:909–915
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Lau CS, Chamberlain RS. Probiotics are effective at preventing Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Int J Gen Med 2016; 9:27-37. [PMID: 26955289 PMCID: PMC4769010 DOI: 10.2147/ijgm.s98280] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Clostridium difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea. CDI has increased in incidence and severity over the past decade, and is a growing worldwide health problem associated with substantial health care costs and significant morbidity and mortality. This meta-analysis examines the impact of probiotics on the incidence of Clostridium difficile-associated diarrhea (CDAD) among children and adults, in both hospital and outpatient settings. METHODS A comprehensive literature search of all published randomized control trials (RCTs) assessing the use of probiotics in the prevention of CDAD in patients receiving antibiotic therapy was conducted, and the incidence of CDAD was analyzed. RESULTS Twenty-six RCTs involving 7,957 patients were analyzed. Probiotic use significantly reduced the risk of developing CDAD by 60.5% (relative risk [RR] =0.395; 95% confidence interval [CI], 0.294-0.531; P<0.001). Probiotics proved beneficial in both adults and children (59.5% and 65.9% reduction), especially among hospitalized patients. Lactobacillus, Saccharomyces, and a mixture of probiotics were all beneficial in reducing the risk of developing CDAD (63.7%, 58.5%, and 58.2% reduction). CONCLUSION Probiotic supplementation is associated with a significant reduction in the risk of developing CDAD in patients receiving antibiotics. Additional studies are required to determine the optimal dose and strain of probiotic.
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Affiliation(s)
- Christine Sm Lau
- Department of Surgery, Saint Barnabas Medical Center, Livingston, NJ, USA; Saint George's University School of Medicine, Grenada, West Indies
| | - Ronald S Chamberlain
- Department of Surgery, Saint Barnabas Medical Center, Livingston, NJ, USA; Saint George's University School of Medicine, Grenada, West Indies; Department of Surgery, New Jersey Medical School, Rutgers University, Newark, NJ, USA
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A Comprehensive Assessment Across the Healthcare Continuum: Risk of Hospital-Associated Clostridium difficile Infection Due to Outpatient and Inpatient Antibiotic Exposure. Infect Control Hosp Epidemiol 2015; 36:1409-16. [PMID: 26387888 DOI: 10.1017/ice.2015.220] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Limitations in sample size, overly inclusive antibiotic classes, lack of adjustment of key risk variables, and inadequate assessment of cases contribute to widely ranging estimates of risk factors for Clostridium difficile infection (CDI). OBJECTIVE To incorporate all key CDI risk factors in addition to 27 antibiotic classes into a single comprehensive model. DESIGN Retrospective cohort study. SETTING Kaiser Permanente Southern California. PATIENTS Members of Kaiser Permanente Southern California at least 18 years old admitted to any of its 14 hospitals from January 1, 2011, through December 31, 2012. METHODS Hospital-acquired CDI cases were identified by polymerase chain reaction assay. Exposure to major outpatient antibiotics (10 classes) and those administered during inpatient stays (27 classes) was assessed. Age, sex, self-identified race/ethnicity, Charlson Comorbidity Score, previous hospitalization, transfer from a skilled nursing facility, number of different antibiotic classes, statin use, and proton pump inhibitor use were also assessed. Poisson regression estimated adjusted risk of CDI. RESULTS A total of 401,234 patients with 2,638 cases of incident CDI (0.7%) were detected. The final model demonstrated highest CDI risk associated with increasing age, exposure to multiple antibiotic classes, and skilled nursing facility transfer. Factors conferring the most reduced CDI risk were inpatient exposure to tetracyclines and first-generation cephalosporins, and outpatient macrolides. CONCLUSIONS Although type and aggregate antibiotic exposure are important, the factors that increase the likelihood of environmental spore acquisition should not be underestimated. Operationally, our findings have implications for antibiotic stewardship efforts and can inform empirical and culture-driven treatment approaches.
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Pilcante J, Rojas P, Ernst D, Sarmiento M, Ocqueteau M, Bertin P, García M, Rodriguez M, Jara V, Ajenjo M, Ramirez P. Clostridium difficile infection in Chilean patients submitted to hematopoietic stem cell transplantation. Rev Bras Hematol Hemoter 2015; 37:388-94. [PMID: 26670401 PMCID: PMC4678790 DOI: 10.1016/j.bjhh.2015.07.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 07/22/2015] [Accepted: 07/27/2015] [Indexed: 12/21/2022] Open
Abstract
Introduction Patients submitted to hematopoietic stem cell transplantation have an increased risk of Clostridium difficile infection and multiple risk factors have been identified. Published reports have indicated an incidence from 9% to 30% of transplant patients however to date there is no information about infection in these patients in Chile. Methods A retrospective analysis was performed of patients who developed C. difficile infection after hematopoietic stem cell transplantations from 2000 to 2013. Statistical analysis used the Statistical Package for the Social Sciences software. Results Two hundred and fifty patients were studied (mean age: 39 years; range: 17–69), with 147 (59%) receiving allogeneic transplants and 103 (41%) receiving autologous transplants. One hundred and ninety-two (77%) patients had diarrhea, with 25 (10%) cases of C. difficile infection being confirmed. Twenty infected patients had undergone allogeneic transplants, of which ten had acute lymphoblastic leukemia, three had acute myeloid leukemia and seven had other diseases (myelodysplastic syndrome, chronic myeloid leukemia, severe aplastic anemia). In the autologous transplant group, five patients had C. difficile infection; two had multiple myeloma, one had amyloidosis, one had acute myeloid leukemia and one had germinal carcinoma. The overall incidence of C. difficile infection was 4% within the first week, 6.4% in the first month and 10% in one year, with no difference in overall survival between infected and non-infected groups (72.0% vs. 67.6%, respectively; p-value = 0.56). Patients infected after allogeneic transplants had a slower time to neutrophil engraftment compared to non-infected patients (17.5 vs. 14.9 days, respectively; p-value = 0.008). In the autologous transplant group there was no significant difference in the neutrophil engraftment time between infected and non-infected patients (12.5 days vs. 11.8 days, respectively; p-value = 0.71). In the allogeneic transplant group, the median time to acute graft-versus-host disease was similar between the two groups (p-value = 0.08), as was the incidence of grades 1–4 acute graft-versus-host disease (40% vs. 48%; p-value >0.05). Conclusion The incidence of C. difficile infection after hematopoietic stem cell transplantation was low, with a significant number of cases occurring shortly after transplantation. Allogeneic transplants had a three-time higher risk of infection compared to autologous transplants, but this was not associated with increased mortality, decreased overall survival or higher risk of acute graft-versus-host disease.
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Affiliation(s)
| | | | - Daniel Ernst
- Pontificia Universidad Católica, Santiago, Chile
| | | | | | - Pablo Bertin
- Pontificia Universidad Católica, Santiago, Chile
| | - Maria García
- Pontificia Universidad Católica, Santiago, Chile
| | | | | | - Maria Ajenjo
- Pontificia Universidad Católica, Santiago, Chile
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MacLaren R, Kassel LE, Kiser TH, Fish DN. Proton pump inhibitors and histamine-2 receptor antagonists in the intensive care setting: focus on therapeutic and adverse events. Expert Opin Drug Saf 2014; 14:269-80. [DOI: 10.1517/14740338.2015.986456] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Acid suppression therapy does not predispose to Clostridium difficile infection: the case of the potential bias. PLoS One 2014; 9:e110790. [PMID: 25343667 PMCID: PMC4208782 DOI: 10.1371/journal.pone.0110790] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 09/17/2014] [Indexed: 01/05/2023] Open
Abstract
Objective An adverse effect of acid-suppression medications on the occurrence of Clostridium difficile infection (CDI) has been a common finding of many, but not all studies. We hypothesized that association between acid-suppression medications and CDI is due to the residual confounding in comparison between patients with infection to those without, predominantly from non-tested and less sick subjects. We aimed to evaluate the effect of acid suppression therapy on incidence of CDI by comparing patients with CDI to two control groups: not tested patients and patients suspected of having CDI, but with a negative test. Methods We conducted a case-control study of adult patients hospitalized in internal medicine department of tertiary teaching hospital between 2005–2010 for at least three days. Controls from each of two groups (negative for CDI and non-tested) were individually matched (1∶1) to cases by primary diagnosis, Charlson comorbidity index, year of hospitalization and gender. Primary outcomes were diagnoses of International Classification of Diseases (ICD-9)–coded CDI occurring 72 hours or more after admission. Results Patients with CDI were similar to controls with a negative test, while controls without CDI testing had lower clinical severity. In multivariable analysis, treatment by acid suppression medications was associated with CDI compared to those who were not tested (OR = 1.88, p-value = 0.032). Conversely, use of acid suppression medications in those who tested negative for the infection was not associated with CDI risk as compared to the cases (OR = 0.66; p = 0.059). Conclusions These findings suggest that the reported epidemiologic associations between use of acid suppression medications and CDI risk may be spurious. The control group choice has an important impact on the results. Clinical differences between the patients with CDI and those not tested and not suspected of having the infection may explain the different conclusions regarding the acid suppression effect on CDI risk.
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Vassallo A, Tran MCN, Goldstein EJC. Clostridium difficile: improving the prevention paradigm in healthcare settings. Expert Rev Anti Infect Ther 2014; 12:1087-102. [DOI: 10.1586/14787210.2014.942284] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- Angela Vassallo
- Department of Infection Prevention, Providence Saint John’s Health Center,
2121 Santa Monica Blvd, Santa Monica, CA 90404, USA
| | - Mai-Chi N Tran
- Department of Pharmacy, Providence Saint John’s Health Center,
2121 Santa Monica Blvd, Santa Monica, CA 90404, USA
| | - Ellie JC Goldstein
- Department of Infectious Diseases, Providence Saint John’s Health Center,
2121 Santa Monica Blvd, Santa Monica, CA 90404, USA
- The UCLA School of Medicine,
Los Angeles, CA 90073, USA
- The R M Alden Research Laboratory,
Santa Monica CA, 90404, USA
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