Clostridioides difficile infection: Difference between revisions - Wikipedia

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| deaths = 29,000 (US)<ref name=AHRQ2016/><ref name=Lessa2015/>

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~~~~'''''Clostridioides difficile'' infection'''<ref>~~Taxonomy.~~{{Cite ~~Lawson~~web et|title=Taxonomy albrowser (~~2016~~Clostridioides difficile)~~. NCBI.~~ |url=https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=1496&lvl=3&lin=f&keep=1&srchmode=1&unlock |access-date=2024-09-08 |website=www.ncbi.nlm.nih.gov}}</ref> ('''CDI''' or '''C-diff'''), also known as '''''Clostridium difficile'' infection''', is a symptomatic [[infection]] due to the [[bacterial spores|spore]]-forming bacterium ''[[Clostridioides difficile]]''.<ref>{{Cite journal |~~last~~last1=Di Bella |~~first~~first1=Stefano |last2=Sanson |first2=Gianfranco |last3=Monticelli |first3=Jacopo |last4=Zerbato |first4=Verena |last5=Principe |first5=Luigi |last6=Giuffrè |first6=Mauro |last7=Pipitone |first7=Giuseppe |last8=Luzzati |first8=Roberto |date=2024-02-29 |title=Clostridioides difficile infection: history, epidemiology, risk factors, prevention, clinical manifestations, treatment, and future options |url=https://journals.asm.org/doi/10.1128/cmr.00135-23 |journal=Clinical Microbiology Reviews |volume=37 |issue=2 |pages=e0013523 |language=en |doi=10.1128/cmr.00135-23 |pmid=38421181 |pmc=11324037 |pmc-embargo-date=February 28, 2025 |issn=0893-8512 |access-date=10 March 2024 |archive-date=4 March 2024 |archive-url=https://web.archive.org/web/20240304211848/https://journals.asm.org/doi/10.1128/cmr.00135-23 |url-status=live }}</ref> Symptoms include watery [[diarrhea]], fever, nausea, and [[abdominal pain]].<ref name="CDC2012" /> It makes up about 20% of cases of [[antibiotic-associated diarrhea]].<ref name="CDC2012" /> Antibiotics can contribute to detrimental changes in [[gut microbiota]]; specifically, they decrease short-chain fatty acid absorption which results in osmotic, or watery, diarrhea.<ref>{{cite journal | vauthors = Mullish BH, Williams HR | title = ''Clostridium difficile'' infection and antibiotic-associated diarrhoea | journal = Clinical Medicine | volume = 18 | issue = 3 | pages = 237–241 | date = June 2018 | pmid = 29858434 | pmc = 6334067 | doi = 10.7861/clinmedicine.18-3-237 }}</ref> Complications may include [[colitis#Infectious|pseudomembranous colitis]], [[toxic megacolon]], [[perforation of the colon]], and [[sepsis]].<ref name="CDC2012" /~~><!-- Cause and diagnosis --~~>

''Clostridioides difficile'' infection is spread by bacterial spores found within [[feces]].<ref name=CDC2012/> Surfaces may become contaminated with the spores with further spread occurring via the hands of healthcare workers.<ref name=CDC2012/> Risk factors for infection include [[antibiotic]] or [[proton pump inhibitor]] use, hospitalization, hypoalbuminemia,<ref>{{cite journal | vauthors = di Masi A, Leboffe L, Polticelli F, Tonon F, Zennaro C, Caterino M, Stano P, Fischer S, Hägele M, Müller M, Kleger A, Papatheodorou P, Nocca G, Arcovito A, Gori A, Ruoppolo M, Barth H, Petrosillo N, Ascenzi P, Di Bella S | title = Human Serum Albumin Is an Essential Component of the Host Defense Mechanism Against Clostridium difficile Intoxication | journal = The Journal of Infectious Diseases | volume = 218 | issue = 9 | pages = 1424–1435 | date = September 2018 | pmid = 29868851 | doi = 10.1093/infdis/jiy338 | doi-access = free }}</ref> other health problems, and older age.<ref name=CDC2012/> Diagnosis is by [[stool culture]] or testing for the bacteria's [[DNA]] or [[toxins]].<ref name=CDC2012/> If a person tests positive but has no symptoms, the condition is known as ''C. difficile'' [[Colonisation (biology)|colonization]] rather than an infection.<ref name=CDC2012>{{cite web|title=Frequently Asked Questions about Clostridium difficile for Healthcare Providers|url=https://www.cdc.gov/HAI/organisms/cdiff/Cdiff_faqs_HCP.html|website=CDC|access-date=5 September 2016|date=March 6, 2012|url-status=live|archive-url=https://web.archive.org/web/20160902025954/http://www.cdc.gov/hai/organisms/cdiff/cdiff_faqs_hcp.html|archive-date=2 September 2016|df=dmy-all}}</ref>

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''C. difficile'' infections occur in all areas of the world.<ref name=NEJM2015/> About 453,000 cases occurred in the United States in 2011, resulting in 29,000 deaths.<ref name=AHRQ2016/><ref name=Lessa2015>{{cite journal | vauthors = Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, Dunn JR, Farley MM, Holzbauer SM, Meek JI, Phipps EC, Wilson LE, Winston LG, Cohen JA, Limbago BM, Fridkin SK, Gerding DN, McDonald LC | title = Burden of Clostridium difficile infection in the United States | journal = The New England Journal of Medicine | volume = 372 | issue = 9 | pages = 825–34 | date = February 2015 | pmid = 25714160 | doi = 10.1056/NEJMoa1408913 | pmc = 10966662 | hdl = 11603/29071 | s2cid = 20441835 | hdl-access = free }}</ref> Global rates of disease increased between 2001 and 2016.<ref name=AHRQ2016/><ref name=NEJM2015/> ''C. difficile'' infections occur more often in women than men.<ref name=AHRQ2016/> The bacterium was discovered in 1935 and found to be disease-causing in 1978.<ref name=NEJM2015>{{cite journal | vauthors = Lessa FC, Gould CV, McDonald LC | title = Current status of Clostridium difficile infection epidemiology | journal = Clinical Infectious Diseases | volume = 55 | issue = Suppl 2 | pages = S65-70 | date = August 2012 | pmid = 22752867 | pmc = 3388017 | doi = 10.1093/cid/cis319 }}</ref> Attributable costs for ''Clostridioides difficile'' infection in hospitalized adults range from

$4500 to $15,000.<ref>{{cite journal | vauthors = Asensio A, Di Bella S, Lo Vecchio A, Grau S, Hart WM, Isidoro B, Scotto R, Petrosillo N, Watt M, Nazir J | title = The impact of Clostridium difficile infection on resource use and costs in hospitals in Spain and Italy: a matched cohort study | journal = International Journal of Infectious Diseases | volume = 36 | pages = 31–38 | date = July 2015 | pmid = 26003403 | doi = 10.1016/j.ijid.2015.05.013 | hdl-access = free | doi-access = free | hdl = 11368/2934734 }}</ref> In the United States, [[Hospital-acquired infection|healthcare-associated infections]] increase the cost of care by US$1.5 billion each year.<ref>{{cite journal | vauthors = Leffler DA, Lamont JT | title = Clostridium difficile infection | journal = The New England Journal of Medicine | volume = 372 | issue = 16 | pages = 1539–1548 | date = April 2015 | pmid = 25875259 | doi = 10.1056/NEJMra1403772 | s2cid = 2536693 }}</ref> Although ''C. difficile'' is a common healthcare-associated infection, at most 30% of infections are transmitted within hospitals.<ref>{{cite journal | vauthors = Eyre DW, Cule ML, Wilson DJ, Griffiths D, Vaughan A, O'Connor L, Ip CL, Golubchik T, Batty EM, Finney JM, Wyllie DH, Didelot X, Piazza P, Bowden R, Dingle KE, Harding RM, Crook DW, Wilcox MH, Peto TE, Walker AS | title = Diverse sources of C. difficile infection identified on whole-genome sequencing | journal = The New England Journal of Medicine | volume = 369 | issue = 13 | pages = 1195–1205 | date = September 2013 | pmid = 24066741 | pmc = 3868928 | doi = 10.1056/NEJMoa1216064 }}</ref> The majority of infections are acquired outside of hospitals, where medications and a recent history of diarrheal illnesses (e.g. [[laxative abuse]] or food poisoning due to [[Salmonellosis]]) are thought to drive the risk of colonization.<ref name=":0">{{cite journal | vauthors = VanInsberghe D, Elsherbini JA, Varian B, Poutahidis T, Erdman S, Polz MF | title = Diarrhoeal events can trigger long-term Clostridium difficile colonization with recurrent blooms | journal = Nature Microbiology | volume = 5 | issue = 4 | pages = 642–650 | date = April 2020 | pmid = 32042128 | doi = 10.1038/s41564-020-0668-2 | s2cid = 211074075 }}</ref>

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Antibiotic treatment of CDIs may be difficult, due both to [[antibiotic resistance]] and physiological factors of the bacteria (spore formation, protective effects of the pseudomembrane).<ref name=Sherris /> The emergence of a new and highly toxic strain of ''C. difficile'' that is resistant to [[Quinolone antibiotic|fluoroquinolone]] antibiotics such as [[ciprofloxacin]] and [[levofloxacin]], said to be causing geographically dispersed outbreaks in North America, was reported in 2005.<ref name=Loo_2005>{{cite journal | vauthors = Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S, Bourgault AM, Nguyen T, Frenette C, Kelly M, Vibien A, Brassard P, Fenn S, Dewar K, Hudson TJ, Horn R, René P, Monczak Y, Dascal A | title = A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality | journal = The New England Journal of Medicine | volume = 353 | issue = 23 | pages = 2442–9 | date = December 2005 | pmid = 16322602 | doi = 10.1056/NEJMoa051639 | s2cid = 14818750 | doi-access = free }}</ref> The U.S. [[Centers for Disease Control and Prevention]]  in Atlanta warned of the emergence of an epidemic strain with increased virulence, antibiotic resistance, or both.<ref name=McDonald_2005>{{cite journal | vauthors = McDonald LC | title = Clostridium difficile: responding to a new threat from an old enemy | journal = Infection Control and Hospital Epidemiology | volume = 26 | issue = 8 | pages = 672–5 | date = August 2005 | pmid = 16156321 | doi = 10.1086/502600 | s2cid = 44919184 | url = https://www.cdc.gov/ncidod/dhqp/pdf/infDis/Cdiff_ICHE08_05.pdf | url-status = live | archive-url = https://web.archive.org/web/20110604191632/http://www.cdc.gov/ncidod/dhqp/pdf/infDis/Cdiff_ICHE08_05.pdf | df = dmy-all | archive-date = 4 June 2011 | doi-access = free }}</ref>

''C. difficile'' is transmitted from person to person by the [[fecal-oral route]]. The organism forms heat-resistant spores that are not killed by alcohol-based hand cleansers or routine surface cleaning. Thus, these spores survive in clinical environments for long periods. Because of this, the bacteria may be cultured from almost any surface. Once spores are ingested, their acid-resistance allows them to pass through the stomach unscathed. Upon exposure to [[bile acid]]s, they germinate and multiply into vegetative cells in the colon. The presence of the bile acid [[deoxycholic acid]] in the intestinal environment can promote induction of ''C. difficle'' [[biofilm]] formation.<ref>{{cite journal |vauthors=Schüler MA, Daniel R, Poehlein A |title=Novel insights into phage biology of the pathogen Clostridioides difficile based on the active virome |journal=Front Microbiol |volume=15 |issue= |pages=1374708 |date=2024 |pmid=38577680 |pmc=10993401 |doi=10.3389/fmicb.2024.1374708 |doi-access=free |url=}}</ref> People without a history of gastrointestinal disturbances due to antibiotic use or diarrheal illness are less likely to become colonized by ''C. difficile''.<ref name=":0" />

In 2005, molecular analysis led to the identification of the ''C. difficile'' strain type characterized as group BI by [[Restriction enzyme|restriction endonuclease]] analysis, as North American pulse-field-type NAP1 by [[pulsed-field gel electrophoresis]]  and as [[ribotyping|ribotype]] 027; the differing terminology reflects the predominant techniques used for epidemiological typing. This strain is referred to as ''C. difficile'' BI/NAP1/027.<ref name=Rupnik_2009>{{cite journal | vauthors = Rupnik M, Wilcox MH, Gerding DN | s2cid = 23376891 | title = Clostridium difficile infection: new developments in epidemiology and pathogenesis | journal = Nature Reviews. Microbiology | volume = 7 | issue = 7 | pages = 526–36 | date = July 2009 | pmid = 19528959 | doi = 10.1038/nrmicro2164 }}</ref>

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''C. difficile'' colitis is associated most strongly with the use of these antibiotics: [[fluoroquinolones]], [[cephalosporins]], and [[clindamycin]].<ref>{{cite journal | vauthors = Luciano JA, Zuckerbraun BS | title = Clostridium difficile infection: prevention, treatment, and surgical management | journal = The Surgical Clinics of North America | volume = 94 | issue = 6 | pages = 1335–49 | date = December 2014 | pmid = 25440127 | doi = 10.1016/j.suc.2014.08.006 }}</ref>

Some research suggests the routine [[Use of antibiotics in livestock|use of antibiotics in the raising of livestock]] is contributing to outbreaks of bacterial infections such as ''C. difficile''.<ref>{{cite news|url=~~http~~https://www.cbc.ca/~~health~~news/~~story~~science/~~2006/10/04/cdifficile~~scientists-probe-whether-c-difficile-is-linked-to-eating-meat-1.~~html~~621681 |publisher=CBC News |title=Scientists probe whether ''C. difficile'' is linked to eating meat |date=2006-10-04 |url-status=~~dead~~live |archive-url=https://web.archive.org/web/20061024034645/http://www.cbc.ca/health/story/2006/10/04/cdifficile-meat.html |archive-date=24 October 2006 }}</ref>

==== Healthcare environment ====

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As a result of suppression of healthy bacteria, via a loss of bacterial food source, prolonged use of an [[elemental diet]] increases the risk of developing ''C. difficile'' infection.<ref name="pmid20066732">{{cite journal | vauthors = O'Keefe SJ | title = Tube feeding, the microbiota, and Clostridium difficile infection | journal = World Journal of Gastroenterology | volume = 16 | issue = 2 | pages = 139–42 | date = January 2010 | pmid = 20066732 | pmc = 2806551 | doi = 10.3748/wjg.v16.i2.139 | doi-access = free }}</ref> Low serum albumin levels is a risk factor for the development of ''C. difficile'' infection and when infected for severe disease.<ref>{{cite journal | vauthors = Crook DW, Walker AS, Kean Y, Weiss K, Cornely OA, Miller MA, Esposito R, Louie TJ, Stoesser NE, Young BC, Angus BJ, Gorbach SL, Peto TE | title = Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials | journal = Clinical Infectious Diseases | volume = 55 | issue = Suppl 2 | pages = S93-103 | date = August 2012 | pmid = 22752871 | pmc = 3388031 | doi = 10.1093/cid/cis499 }}</ref><ref name=Sar2019/> The protective effects of serum albumin may be related to the capability of this protein to bind ''C. difficile'' toxin A and toxin B, thus impairing entry into enterocytes.<ref name=Sar2019>{{cite journal | vauthors = Sartelli M, Di Bella S, McFarland LV, Khanna S, Furuya-Kanamori L, Abuzeid N, Abu-Zidan FM, Ansaloni L, Augustin G, Bala M, Ben-Ishay O, Biffl WL, Brecher SM, Camacho-Ortiz A, Caínzos MA, Chan S, Cherry-Bukowiec JR, Clanton J, Coccolini F, Cocuz ME, Coimbra R, Cortese F, Cui Y, Czepiel J, Demetrashvili Z, Di Carlo I, Di Saverio S, Dumitru IM, Eckmann C, Eiland EH, Forrester JD, Fraga GP, Frossard JL, Fry DE, Galeiras R, Ghnnam W, Gomes CA, Griffiths EA, Guirao X, Ahmed MH, Herzog T, Kim JI, Iqbal T, Isik A, Itani KM, Labricciosa FM, Lee YY, Juang P, Karamarkovic A, Kim PK, Kluger Y, Leppaniemi A, Lohsiriwat V, Machain GM, Marwah S, Mazuski JE, Metan G, Moore EE, Moore FA, Ordoñez CA, Pagani L, Petrosillo N, Portela F, Rasa K, Rems M, Sakakushev BE, Segovia-Lohse H, Sganga G, Shelat VG, Spigaglia P, Tattevin P, Tranà C, Urbánek L, Ulrych J, Viale P, Baiocchi GL, Catena F | title = difficile infection in surgical patients | journal = World Journal of Emergency Surgery | volume = 14 | pages = 8 | date = 2019 | pmid = 30858872 | pmc = 6394026 | doi = 10.1186/s13017-019-0228-3 | doi-access = free }}</ref>

[[Chronic kidney disease]] (CKD) has been identified as a risk factor in the development of a ''C. difficile'' infection.<ref name="Mayo2021">{{cite web |title=C. difficile-Symptoms and causes |website=Mayo Clinic |date=27 August 2021 |url=https://www.mayoclinic.org/diseases-conditions/c-difficile/symptoms-causes/syc-20351691 |access-date=23 October 2022 |archive-date=8 October 2013 |archive-url=https://web.archive.org/web/20131008071549/http://www.mayoclinic.com/health/c-difficile/DS00736/DSECTION%3Dprevention |url-status=live }}</ref><ref name="pmid26767866">{{cite journal |vauthors=Kim SC, Seo MY, Lee JY, Kim KT, Cho E, Kim MG, Jo SK, Cho WY, Kim HK |title=Advanced chronic kidney disease: a strong risk factor for Clostridium difficile infection |journal=The Korean Journal of Internal Medicine |volume=31 |issue=1 |pages=125–33 |date=January 2016 |pmid=26767866 |pmc=4712416 |doi=10.3904/kjim.2016.31.1.125}}</ref> Patients with CKD have a higher risk of both initial and recurring infection, as well as a higher chance of severe infection, than those without CKD.<ref name="pmid30876614">{{cite journal |vauthors=Ramesh MS, Yee J |title=Clostridioides difficile Infection in Chronic Kidney Disease/End-Stage Renal Disease |journal=Advances in Chronic Kidney Disease |volume=26 |issue=1 |pages=30–34 |date=January 2019 |pmid=30876614 |doi=10.1053/j.ackd.2019.01.001|s2cid=80621282 }}</ref> Patients with Inflammatory Bowel Disease are also at higher risk for infection and a recent study suggests they may have intermittent ''C. difficile'' infection masked by IBD symptoms, and testing should be considered in patients with changes in disease activity.<ref>{{cite journal | vauthors = Cook L, Wong MQ, Rees WD, Schick A, Lisko DJ, Lunken GR, Wang X, Peters H, Oliveira L, Lau T, Mah R, Bressler B, Levings MK, Steiner TS | title = Dysregulated Immunity to Clostridioides difficile in IBD Patients Without a History of Recognized Infection | journal = Inflammatory Bowel Diseases | date = October 2023 | volume = 30 | issue = 5 | pages = 820–828 | pmid = 37874904 | doi = 10.1093/ibd/izad238 | doi-access = free | pmc = 11063544 }}</ref>

== Pathophysiology ==

The use of systemic antibiotics, including broad-spectrum penicillins/cephalosporins, fluoroquinolones, and clindamycin, causes the normal microbiota of the bowel to be altered. In particular, when the [[antibiotic]] kills off other competing bacteria in the intestine, any bacteria remaining will have less competition for space and nutrients. The net effect is to permit more extensive growth than normal of certain bacteria. ''C. difficile'' is one such type of bacterium. In addition to proliferating in the bowel, ''C. difficile'' also produces [[toxins]]. Without either toxin A or toxin B, ''C. difficile'' may colonize the gut, but is unlikely to cause pseudomembranous colitis.<ref>{{cite journal | vauthors = Kuehne SA, Cartman ST, Heap JT, Kelly ML, Cockayne A, Minton NP | s2cid = 4417414 | title = The role of toxin A and toxin B in Clostridium difficile infection | journal = Nature | volume = 467 | issue = 7316 | pages = 711–3 | date = October 2010 | pmid = 20844489 | doi = 10.1038/nature09397 | url = http://spiral.imperial.ac.uk/bitstream/10044/1/15560/2/Nature_467_7316_2010.pdf | bibcode = 2010Natur.467..711K | hdl = 10044/1/15560 | hdl-access = free | access-date = 2 September 2019 | archive-date = 9 August 2017 | archive-url = https://web.archive.org/web/20170809155249/http://spiral.imperial.ac.uk/bitstream/10044/1/15560/2/Nature_467_7316_2010.pdf | url-status = live }}</ref> The colitis associated with severe infection is part of an inflammatory reaction, with the "pseudomembrane" formed by a viscous collection of inflammatory cells, [[fibrin]], and necrotic cells.<ref name="Sherris">{{cite book | veditors = Ryan KJ, Ray CG | title = Sherris Medical Microbiology | edition = 4th | pages = 322–4 | publisher = McGraw Hill | year = 2004 | isbn= 978-0-8385-8529-0 }}</ref>

== Diagnosis ==

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=== Probiotics ===

Some evidence indicates [[probiotics]] may be useful to prevent infection and recurrence.<ref name="springerlink">{{cite journal | vauthors = Heineman J, Bubenik S, McClave S, Martindale R | s2cid = 22813174 | title = Fighting fire with fire: is it time to use probiotics to manage pathogenic bacterial diseases? | journal = Current Gastroenterology Reports | volume = 14 | issue = 4 | pages = 343–8 | date = August 2012 | pmid = 22763792 | doi = 10.1007/s11894-012-0274-4 | doi-access = free }}</ref><ref name=John2012>{{cite journal | vauthors = Johnston BC, Ma SS, Goldenberg JZ, Thorlund K, Vandvik PO, Loeb M, Guyatt GH | s2cid = 72364505 | title = Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis | journal = Annals of Internal Medicine | volume = 157 | issue = 12 | pages = 878–88 | date = December 2012 | pmid = 23362517 | doi = 10.7326/0003-4819-157-12-201212180-00563 }}</ref> Treatment with ''[[Saccharomyces boulardii]]'' in those who are not immunocompromised with ''C. difficile'' also may be useful.<ref name=Na2011>{{cite journal | vauthors = Na X, Kelly C | title = Probiotics in clostridium difficile Infection | journal = Journal of Clinical Gastroenterology | volume = 45 | issue = Suppl | pages = S154-8 | date = November 2011 | pmid = 21992956 | pmc = 5322762 | doi = 10.1097/MCG.0b013e31822ec787 }}</ref><ref>{{cite journal | vauthors = McFarland LV | title = Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease | journal = The American Journal of Gastroenterology | volume = 101 | issue = 4 | pages = 812–22 | date = April 2006 | doi = 10.1111/j.1572-0241.2006.00465.x | pmid = 16635227 | s2cid = 7557917 | url = https://zenodo.org/record/1230694 | type = Submitted manuscript | access-date = 4 July 2019 | archive-date = 28 July 2020 | archive-url = https://web.archive.org/web/20200728163339/https://zenodo.org/record/1230694 | url-status = live }}</ref> Initially, in 2010, the [[Infectious Diseases Society of America]] recommended against their use due to the risk of complications.<ref name="springerlink" /><ref name=Na2011 /> Subsequent reviews, however, did not find an increase in adverse effects with treatment,<ref name=John2012 /> and overall treatment appears safe and moderately effective in preventing C. difficile-associated diarrhea.<ref>{{cite journal | vauthors = Goldenberg JZ, Yap C, Lytvyn L, Lo CK, Beardsley J, Mertz D, Johnston BC | title = Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD006095 | date = December 2017 | issue = 12 | pmid = 29257353 | pmc = 6486212 | doi = 10.1002/14651858.CD006095.pub4 }}</ref>

One study in particular found that there does appear to be a "protective effect" of probiotics, specifically reducing the risk of antibiotic-associated diarrhea (AAD) by 51% in 3,631 outpatients, but it is important to note that the types of infections in the subjects were not specified.<ref>{{cite journal | vauthors = Blaabjerg S, Artzi DM, Aabenhus R | title = Probiotics for the Prevention of Antibiotic-Associated Diarrhea in Outpatients-A Systematic Review and Meta-Analysis | journal = Antibiotics | volume = 6 | issue = 4 | pages = 21 | date = October 2017 | pmid = 29023420 | pmc = 5745464 | doi = 10.3390/antibiotics6040021 | doi-access = free }}</ref> Yogurt, tablets, dietary supplements are just a few examples of probiotics available for people.{{citation needed|date=December 2022}}

=== Infection control ===

Rigorous infection protocols are required to minimize this risk of transmission.<ref>{{Cite web|url=https://www.mayoclinic.org/diseases-conditions/c-difficile/symptoms-causes/syc-20351691|archiveurl=https://web.archive.org/web/20131008071549/http://www.mayoclinic.com/health/c-difficile/DS00736/DSECTION%3Dprevention|url-status=dead|title=C. difficile infection - Symptoms and causes|archivedate=8 October 2013|website=Mayo Clinic}}</ref> Infection control measures, such as wearing gloves and noncritical medical devices used for a single person with CDI, are effective at prevention.<ref name=Dubb2014>{{cite journal | vauthors = Dubberke ER, Carling P, Carrico R, Donskey CJ, Loo VG, McDonald LC, Maragakis LL, Sandora TJ, Weber DJ, Yokoe DS, Gerding DN | title = Strategies to prevent Clostridium difficile infections in acute care hospitals: 2014 Update | journal = Infection Control and Hospital Epidemiology | volume = 35 | issue = 6 | pages = 628–45 | date = June 2014 | pmid = 24799639 | doi = 10.1086/676023 | s2cid = 32258582 | url = https://digitalcommons.wustl.edu/open_access_pubs/2926 | type = Submitted manuscript | access-date = 4 November 2018 | archive-date = 1 August 2020 | archive-url = https://web.archive.org/web/20200801012841/https://digitalcommons.wustl.edu/open_access_pubs/2926/ | url-status = live }}</ref> This works by limiting the spread of ''C. difficile'' in the hospital setting. In addition, washing with soap and water will wash away the spores from contaminated hands, but alcohol-based hand rubs are ineffective.<ref>{{cite web | vauthors = Roehr B |title=Alcohol Rub, Antiseptic Wipes Inferior at Removing ''Clostridium difficile'' |date=21 September 2007 |publisher=Medscape |url=http://www.medscape.com/viewarticle/563232 |url-status=live |archive-url=https://web.archive.org/web/20131030025331/http://www.medscape.com/viewarticle/563232 |archive-date=30 October 2013 |df=dmy-all }}</ref> These precautions should remain in place among those in hospital for at least 2 days after the diarrhea has stopped.<ref name=Ban2018>{{cite journal | vauthors = Banach DB, Bearman G, Barnden M, Hanrahan JA, Leekha S, Morgan DJ, Murthy R, Munoz-Price LS, Sullivan KV, Popovich KJ, Wiemken TL | title = Duration of Contact Precautions for Acute-Care Settings | journal = Infection Control and Hospital Epidemiology | volume = 39 | issue = 2 | pages = 127–144 | date = February 2018 | pmid = 29321078 | doi = 10.1017/ice.2017.245 | doi-access = free }}</ref>

Bleach wipes containing 0.55% [[sodium hypochlorite]] have been shown to kill the spores and prevent transmission.<ref>{{cite journal | vauthors = Savidge TC, Urvil P, Oezguen N, Ali K, Choudhury A, Acharya V, Pinchuk I, Torres AG, English RD, Wiktorowicz JE, Loeffelholz M, Kumar R, Shi L, Nie W, Braun W, Herman B, Hausladen A, Feng H, Stamler JS, Pothoulakis C | title = Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins | journal = Nature Medicine | volume = 17 | issue = 9 | pages = 1136–41 | date = August 2011 | pmid = 21857653 | pmc = 3277400 | doi = 10.1038/nm.2405 }}</ref> Installing lidded toilets and closing the lid prior to flushing also reduces the risk of contamination.<ref>{{cite web | vauthors = Laidman J |title=Flush With Germs: Lidless Toilets Spread ''C. difficile'' |date=29 December 2011 |publisher=Medscape |url=http://www.medscape.com/viewarticle/756189 |url-status=live |archive-url=https://web.archive.org/web/20160420144825/http://www.medscape.com/viewarticle/756189 |archive-date=20 April 2016 |df=dmy-all }}</ref>

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Those who have CDIs should be in rooms with other people with CDIs or by themselves when in hospital.<ref name=Dubb2014 />

Common hospital [[disinfectant]]s are ineffective against ''C. difficile'' spores, and may promote spore formation, but various [[oxidant]]s (e.g 1% sodium [[hypochlorite]] solution) rapidly destroy spores.<ref>{{cite news | url=http://news.bbc.co.uk/1/hi/health/4871840.stm | title=Cleaning agents 'make bug strong' | publisher=BBC News Online | date=2006-04-03 | access-date=2008-11-17 | url-status=live | archive-url=https://web.archive.org/web/20061108192447/http://news.bbc.co.uk/1/hi/health/4871840.stm | archive-date=8 November 2006 | df=dmy-all }}</ref> [[Vaporized hydrogen peroxide|Hydrogen peroxide vapor]] (HPV) systems used to sterilize a room after treatment is completed have been shown to reduce infection rates and to reduce risk of infection to others. The incidence of CDI was reduced by 53%<ref name="pmid18636950">{{cite journal | vauthors = Boyce JM, Havill NL, Otter JA, McDonald LC, Adams NM, Cooper T, Thompson A, Wiggs L, Killgore G, Tauman A, Noble-Wang J | title = Impact of hydrogen peroxide vapor room decontamination on Clostridium difficile environmental contamination and transmission in a healthcare setting | journal = Infection Control and Hospital Epidemiology | volume = 29 | issue = 8 | pages = 723–729 | date = August 2008 | pmid = 18636950 | doi = 10.1086/589906 | s2cid = 25070569 }}</ref> or 42%<ref name="pmid23219675">{{cite journal | vauthors = Manian FA, Griesnauer S, Bryant A | title = Implementation of hospital-wide enhanced terminal cleaning of targeted patient rooms and its impact on endemic Clostridium difficile infection rates | journal = American Journal of Infection Control | volume = 41 | issue = 6 | pages = 537–41 | date = June 2013 | pmid = 23219675 | doi = 10.1016/j.ajic.2012.06.014 }}</ref> through use of HPV. Ultraviolet cleaning devices, and housekeeping staff especially dedicated to disinfecting the rooms of people with ''C. difficile'' after discharge may be effective.<ref>{{cite web |publisher=Agency for Healthcare Research and Quality |url=https://innovations.ahrq.gov/profiles/performance-feedback-ultraviolet-cleaning-device-and-dedicated-housekeeping-team |title=Performance Feedback, Ultraviolet Cleaning Device, and Dedicated Housekeeping Team Significantly Improve Room Cleaning, Reduce Potential for Spread of Common, Dangerous Infection |date=2014-01-15 | access-date=2014-01-20 |archive-date=9 September 2017 |archive-url=https://web.archive.org/web/20170909052314/https://innovations.ahrq.gov/profiles/performance-feedback-ultraviolet-cleaning-device-and-dedicated-housekeeping-team |url-status=live }}</ref>

== Treatment ==

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[[Fecal microbiota transplant]], also known as a stool transplant, is roughly 85% to 90% effective in those for whom antibiotics have not worked.<ref>{{cite journal | vauthors = Baunwall SM, Lee MM, Eriksen MK, Mullish BH, Marchesi JR, Dahlerup JF, Hvas CL | title = Faecal microbiota transplantation for recurrent ''Clostridioides difficile'' infection: An updated systematic review and meta-analysis | language = English | journal = eClinicalMedicine | volume = 29-30 | pages = 100642 | date = December 2020 | pmid = 33437951 | pmc = 7788438 | doi = 10.1016/j.eclinm.2020.100642 }}</ref><ref name=Burke2013>{{cite journal | vauthors = Burke KE, Lamont JT | title = Fecal transplantation for recurrent Clostridium difficile infection in older adults: a review | journal = Journal of the American Geriatrics Society | volume = 61 | issue = 8 | pages = 1394–1398 | date = August 2013 | pmid = 23869970 | doi = 10.1111/jgs.12378 | s2cid = 34998497 | doi-access = free }}</ref><ref name=Dre2015>{{cite journal | vauthors = Drekonja D, Reich J, Gezahegn S, Greer N, Shaukat A, MacDonald R, Rutks I, Wilt TJ | title = Fecal Microbiota Transplantation for Clostridium difficile Infection: A Systematic Review | journal = Annals of Internal Medicine | volume = 162 | issue = 9 | pages = 630–638 | date = May 2015 | pmid = 25938992 | doi = 10.7326/m14-2693 | s2cid = 1307726 }}</ref> It involves infusion of the microbiota acquired from the feces of a healthy donor to reverse the bacterial imbalance responsible for the recurring nature of the infection.<ref name="pmid23323867">{{cite journal | vauthors = van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ | title = Duodenal infusion of donor feces for recurrent Clostridium difficile | journal = The New England Journal of Medicine | volume = 368 | issue = 5 | pages = 407–415 | date = January 2013 | pmid = 23323867 | doi = 10.1056/NEJMoa1205037 | s2cid = 25879411 | doi-access = free }}</ref> The procedure replenishes the normal colonic microbiota that had been wiped out by antibiotics, and re-establishes resistance to colonization by ''Clostridioides difficile''.<ref>{{cite journal | vauthors = de Vrieze J | title = Medical research. The promise of poop | journal = Science | volume = 341 | issue = 6149 | pages = 954–957 | date = August 2013 | pmid = 23990540 | doi = 10.1126/science.341.6149.954 }}</ref> Side effects, at least initially, are few.<ref name=Dre2015 />

[[Fecal microbiota, live]] (Rebyota) was approved for medical use in the United States in November 2022.<ref name="Ferring PR">{{cite news | title=Ferring Receives U.S. FDA Approval for Rebyota (fecal microbiota, live-jslm) – A Novel First-in-Class Microbiota-Based Live Biotherapeutic | website=Ferring Pharmaceuticals USA | date=1 December 2022 | url=https://ferringusa.com/?press=ferring-receives-u-s-fda-approval-for-rebyota-fecal-microbiota-live-jslm-a-novel-first-in-class-microbiota-based-live-biotherapeutic | access-date=1 December 2022 | archive-date=1 December 2022 | archive-url=https://web.archive.org/web/20221201050237/https://ferringusa.com/?press=ferring-receives-u-s-fda-approval-for-rebyota-fecal-microbiota-live-jslm-a-novel-first-in-class-microbiota-based-live-biotherapeutic | url-status=live }}</ref>

[[Fecal microbiota spores, live]] (Vowst) was approved for medical use in the United States in April 2023.<ref name="FDA PR 20230427">{{cite press release | title=FDA Approves First Orally Administered Fecal Microbiota Product for the Prevention of Recurrence of Clostridioides difficile Infection | website=U.S. [[Food and Drug Administration]] (FDA) | date=26 April 2023 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-orally-administered-fecal-microbiota-product-prevention-recurrence-clostridioides | access-date=27 April 2023 | archive-date=26 April 2023 | archive-url=https://web.archive.org/web/20230426230158/https://www.fda.gov/news-events/press-announcements/fda-approves-first-orally-administered-fecal-microbiota-product-prevention-recurrence-clostridioides | url-status=live }}</ref><ref>{{cite press release | title=Seres Therapeutics and Nestlé Health Science Announce FDA Approval of Vowst (fecal microbiota spores, live-brpk) for Prevention of Recurrence of C. difficile Infection in Adults Following Antibacterial Treatment for Recurrent CDI | publisher=Seres Therapeutics | via= Business Wire | date=26 April 2023 | url=https://www.businesswire.com/news/home/20230426006066/en/ | access-date=27 April 2023}}</ref> It is the first fecal microbiota product that is taken [[by mouth]].<ref name="FDA PR 20230427" /> A 2023 review article discusses the beneficial effects of fecal microbiota transplantation in recurrent ''Clostridioides difficile'' infection <ref>{{cite journal | vauthors = Yadegar A, Pakpoor S, Ibrahim FF, Nabavi-Rad A, Cook L, Walter J, Seekatz AM, Wong K, Monaghan TM, Kao D | title = Beneficial effects of fecal microbiota transplantation in recurrent Clostridioides difficile infection | journal = Cell Host & Microbe | volume = 31 | issue = 5 | pages = 695–711 | date = May 2023 | pmid = 37167952 | doi = 10.1016/j.chom.2023.03.019 | doi-access = free | pmc = 10966711 }}</ref>

=== Surgery ===

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===Recurrent infection===

Recurrent CDI occurs in 20 to 30% of the patients, with increasing rates of recurrence with each subsequent episode.<ref name="pmid18971494">{{cite journal | vauthors = Kelly CP, LaMont JT | title = Clostridium difficile--more difficult than ever | journal = The New England Journal of Medicine | volume = 359 | issue = 18 | pages = 1932–40 | date = October 2008 | pmid = 18971494 | doi = 10.1056/NEJMra0707500 }}</ref> In clinical settings, it is virtually impossible to distinguish a recurrence that develops as a relapse of CDI with the same strain of ''C. difficile'' versus reinfection that is the result of a new strain.{{citation needed|date=December 2022}} However, in ~~labratory~~laboratory settings paired isolates can be differentiated using [[Whole genome sequencing|Whole-Genome Sequencing]] or [[Multiple loci VNTR analysis|Multilocus Variable-Number Tandem-Repeat Analysis]].<ref>{{cite journal | vauthors = Eyre DW, Fawley WN, Best EL, Griffiths D, Stoesser NE, Crook DW, Peto TE, Walker AS, Wilcox MH | title = Comparison of multilocus variable-number tandem-repeat analysis and whole-genome sequencing for investigation of Clostridium difficile transmission | journal = Journal of Clinical Microbiology | volume = 51 | issue = 12 | pages = 4141–4149 | date = December 2013 | pmid = 24108611 | pmc = 3838059 | doi = 10.1128/JCM.01095-13 }}</ref>

Several treatment options exist for recurrent ''C. difficile'' infection. For the first episode of recurrent ''C. difficile'' infection, the 2017 IDSA guidelines recommend oral vancomycin at a dose of 125 mg four times daily for 10 days if metronidazole was used for the initial episode. If oral vancomycin was used for the initial episode, then a prolonged oral vancomycin pulse dose of 125 mg four times daily for 10-14 days followed by a taper (twice daily for one week, then every two to three days for 2-8 weeks) or fidaxomicin 200 mg twice daily for 10 days. For a second recurrent episode, the IDSA recommends options including the aforementioned oral vancomycin pulse dose followed by the prolonged taper; oral vancomycin 125 mg four times daily for 10 days followed by [[rifaximin]] 400 mg three times daily for 20 days; fidaxomicin 200 mg twice daily for 10 days, or a fecal microbiota transplant.<ref name="Rao2020"/>

For patients with C. diff infections that fail to be resolved with traditional antibiotic regimens, fecal microbiome transplants boasts an average cure rate of >90%.<ref>{{Cite journal |last1=Rohlke, ~~F., &~~|first1=Faith |last2=Stollman, N.|first2=Neil |date=November (2012). |title=Fecal microbiota transplantation in relapsing Clostridium difficile infection. |journal=Therapeutic ~~advances~~Advances in ~~gastroenterology,~~Gastroenterology |language=en |volume=5( |issue=6), |pages=403–420. ~~https://~~|doi~~.org/~~=10.1177/1756283X12453637 |issn=1756-2848 |pmc=3491681 |pmid=23152734}}</ref> In a review of 317 patients, it was shown to lead to resolution in 92% of the persistent and recurrent disease cases.<ref>{{Cite journal |last1=Cole, S.|first1=Shola A.~~, &~~ |last2=Stahl, T.|first2=Thomas J. (|date=June 2015). |title=Persistent and Recurrent Clostridium difficile Colitis. |journal=Clinics in ~~colon~~Colon and ~~rectal~~Rectal ~~surgery,~~Surgery |language=en |volume=28( |issue=2), ~~65–69.~~|pages=065–069 ~~https://~~|doi~~.org/~~=10.1055/s-0035-1547333 |issn=1531-0043 |pmc=4442717 |pmid=26034401}}</ref> It is clear that restoration of gut flora is paramount in the struggle against recurrent CDI. With effective antibiotic therapy, C. difficile can be reduced and natural colonization resistance can develop over time as the natural microbial community recovers. Reinfection or recurrence may occur before this process is complete. Fecal microbiota transplant may expedite this recovery by directly replacing the missing microbial community members.<ref>{{Cite journal |last1=Dieterle, M.|first1=Michael G., |last2=Rao, ~~K., &~~|first2=Krishna |last3=Young, V.|first3=Vincent B. (|date=January 2019). |title=Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections. |journal=Annals of the New York Academy of Sciences, |language=en |volume=1435( |issue=1), |pages=110–138. ~~https://~~|doi~~.org/~~=10.1111/nyas.13958 |issn=0077-8923 |pmc=6312459 |pmid=30238983|bibcode=2019NYASA1435..110D }}</ref> However, human-derived fecal matter is difficult to standardize and has multiple potential risks, including the transfer of infectious material and long-term consequences of inoculating the gut with a foreign fecal material. As a result, further research is necessary to study the long term effective outcomes of FMT.{{citation needed|date=August 2022}}

== Prognosis ==

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== History ==

Ivan C. Hall and Elizabeth O'Toole first named the bacterium ''Bacillus difficilis'' in 1935, choosing its specific epithet because it was resistant to early attempts at isolation and grew very slowly in culture.<ref name=Kelly2008 /><ref name=Hall_1935>{{cite journal | vauthors = Hall IC, O'Toole E | title = Intestinal flora in newborn infants with a description of a new pathogenic anaerobe, ''Bacillus difficilis'' | journal = [[Archives of Pediatrics & Adolescent Medicine|American Journal of Diseases of Children]] | year = 1935 | volume = 49 | issue = 2 | pages = 390–402 | doi = 10.1001/archpedi.1935.01970020105010 | df = dmy-all }}</ref> [[André Romain Prévot]] subsequently transferred it to ''[[Clostridium]]'', binomen ''Clostridium difficile''.<ref name="Prevot, 1938">{{cite journal | vauthors = Prévot AR |title=Études de systématique bactérienne. IV. Critique de la conception actuelle du genre ''Clostridium'' |journal=Annales de l'Institut Pasteur |date=1938 |volume=61 |issue=1 |pages=84 |url=https://gallica.bnf.fr/ark:/12148/bpt6k5846341v/f79.item 84|access-date=26 December 2018 |archive-date=28 July 2020 |archive-url=https://web.archive.org/web/20200728175046/https://gallica.bnf.fr/ark:/12148/bpt6k5846341v/f79.item |url-status=live }}</ref><ref>{{cite book | veditors = De Vos P, Garrity GM, Jones D, Krieg NR, Ludwig W, Rainey FA, Schleifer K, Whitman WB |series=Bergey's Manual of Systematic Bacteriology |volume=3|title=The ''Firmicutes''|date=2009 |publisher=Springer |location=Dordrecht |isbn=978-0-387-68489-5 |edition=2nd |chapter=Family I. ''Clostridiaceae''|pages = 771}}</ref> Its combination was later changed to ''Clostridioides difficile'' after being transferred to the new genus ''[[Clostridioides]]''.<ref>{{cite journal | vauthors = Lawson PA, Citron DM, Tyrrell KL, Finegold SM | title = Reclassification of Clostridium difficile as Clostridioides difficile (Hall and O'Toole 1935) Prévot 1938 | journal = Anaerobe | volume = 40 | pages = 95–9 | date = August 2016 | pmid = 27370902 | doi = 10.1016/j.anaerobe.2016.06.008 }}</ref>

Pseudomembranous colitis first was described as a complication of ''C. difficile'' infection in 1978,<ref name=Larson_1978>{{cite journal | vauthors = Larson HE, Price AB, Honour P, Borriello SP | s2cid = 2502330 | title = Clostridium difficile and the aetiology of pseudomembranous colitis | journal = Lancet | volume = 1 | issue = 8073 | pages = 1063–6 | date = May 1978 | pmid = 77366 | doi = 10.1016/S0140-6736(78)90912-1 }}</ref> when a toxin was isolated from people with pseudomembranous colitis and [[Koch's postulates]] were met.

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* A similar outbreak took place at [[Stoke Mandeville Hospital]] in the [[United Kingdom]] between 2003 and 2005. The local [[epidemiology]] of ''C. difficile'' may offer clues on how its spread may relate to the time a patient spends in hospital and/or a rehabilitation center. It also samples the ability of institutions to detect increased rates, and their capacity to respond with more aggressive hand-washing campaigns, quarantine methods, and the availability of yogurt containing live cultures to patients at risk for infection.{{citation needed|date=March 2023}}

* Both the Canadian and English outbreaks possibly were related to the seemingly more virulent strain NAP1/027 of the bacterium. Known as Quebec strain, it has been implicated in an epidemic at two Dutch hospitals ([[Harderwijk]] and [[Amersfoort]], both 2005). A theory for explaining the increased virulence of 027 is that it is a hyperproducer of both toxins A and B and that certain antibiotics may stimulate the bacteria to hyperproduce.{{citation needed|date=March 2023}}

* On 1 October 2006, ''C. difficile'' was said to have killed at least 49 people at hospitals in [[Leicester]], [[England]], over eight months, according to a [[National Health Service]] investigation. Another 29 similar cases were investigated by [[coroner]]s.<ref>{{cite news |title=Trust confirms 49 superbug deaths |publisher=[[BBC News Online]] |url=http://news.bbc.co.uk/1/hi/england/leicestershire/5396800.stm |date=2006-10-01 |url-status=live |archive-url=https://web.archive.org/web/20070322074234/http://news.bbc.co.uk/1/hi/england/leicestershire/5396800.stm |archive-date=22 March 2007 |df=dmy-all }}</ref> A UK Department of Health memo leaked shortly afterward revealed significant concern in government about the bacterium, described as being "endemic throughout the health service"<ref name=hawkes2007>{{cite news | url=http://www.thetimes.co.uk/tto/news/article1894685.ece |title=Leaked memo reveals that targets to beat MRSA will not be met | vauthors = Hawkes N |date=2007-01-11 |newspaper=[[The Times]] |access-date=2007-01-11 |location=London |format=snippet |archive-date=6 September 2016 |archive-url=https://web.archive.org/web/20160906154356/http://www.thetimes.co.uk/tto/news/article1894685.ece |url-status=live }}{{subscription required}}</ref>

* On 27 October 2006, nine deaths were attributed to the bacterium in Quebec.<ref>{{cite web| url=http://cnews.canoe.ca/CNEWS/Canada/2006/10/27/2145519.html| title=''C. difficile'' blamed for 9 death in hospital near Montreal| date=27 October 2006| publisher=Canoe.ca| access-date=2007-01-11| url-status=usurped| archive-url=https://archive.today/20120708084747/http://cnews.canoe.ca/CNEWS/Canada/2006/10/27/2145519.html| archive-date=8 July 2012| df=dmy-all}}</ref>

* On 18 November 2006, the bacterium was reported to have been responsible for 12 deaths in Quebec. This 12th reported death was only two days after the St. Hyacinthe's Honoré Mercier announced the outbreak was under control. Thirty-one people were diagnosed with CDIs. Cleaning crews took measures in an attempt to clear the outbreak.<ref>{{cite news|title=12th person dies of ''C. difficile'' at Quebec hospital |publisher=[[CBC News]] |date=18 November 2006 |url=~~http~~https://www.cbc.ca/news/canada/~~story/2006/11/18/~~12th-person-dies-of-c-difficile-~~outbreak~~at-quebec-hospital-1.~~html~~622196 |url-status=~~dead~~live |archive-url=https://web.archive.org/web/20071021130323/http://www.cbc.ca/canada/story/2006/11/18/difficile-outbreak.html |archive-date=21 October 2007 }}</ref>

* ''C. difficile'' was mentioned on 6,480 death certificates in 2006 in UK.<ref>[http://www.metro.co.uk/news/article.html?in_article_id=146311&in_page_id=34 Hospitals struck by new killer bug] {{webarchive|url=https://web.archive.org/web/20080520052232/http://www.metro.co.uk/news/article.html?in_article_id=146311&in_page_id=34 |date=20 May 2008 }} An article by Manchester free newspaper 'Metro', 7 May 2008</ref>

* On 27 February 2007, a new outbreak was identified at [[Trillium Health Centre]] in [[Mississauga]], Ontario, where 14 people were diagnosed with CDIs. The bacteria were of the same strain as the one in Quebec. Officials have not been able to determine whether ''C. difficile'' was responsible for the deaths of four people over the prior two months.<ref>~~[https://toronto.ctvnews.ca/c~~{{Cite web |date=2007-~~difficile~~02-~~outbreak-linked-to-fatal-strain-1.231320~~28 ~~"''~~|title=C. difficile'' outbreak linked to fatal strain"] ~~{{webarchive~~|url=https://~~web.archive.org/web/20070303093436/http://www.~~toronto.~~ctv~~ctvnews.ca/~~servlet/an/local/CTVNews/20070228/cdifficile_mississauga_outbreak_070228/20070228/~~c-difficile-outbreak-linked-to-fatal-strain-1.231320 |access-date=32024-09-19 ~~March 2007~~|website=Toronto |language=en}}~~. CTV News. 28 February 2007.~~</ref>

* Between February and June 2007, three people at Loughlinstown Hospital in Dublin, Ireland, were found by the coroner to have died as a result of ''C. difficile'' infection. In an inquest, the Coroner's Court found the hospital had no designated infection control team or consultant microbiologist on staff.<ref>{{cite news |title=Superbug in hospitals linked to four deaths |newspaper=Irish Independent |date=10 October 2007 |url=http://www.independent.ie/national-news/superbug-in-hospitals-linked-to-four-deaths-1139062.html |access-date=5 November 2007 |archive-date=16 October 2012 |archive-url=https://web.archive.org/web/20121016041223/http://www.independent.ie/national-news/superbug-in-hospitals-linked-to-four-deaths-1139062.html |url-status=live }}</ref>

* Between June 2007 and August 2008, Northern Health and Social Care Trust Northern Ireland, Antrim Area, Braid Valley, Mid Ulster Hospitals were the subject of inquiry. During the inquiry, expert reviewers concluded that ''C. difficile'' was implicated in 31 of these deaths, as the underlying cause in 15, and as a contributory cause in 16. During that time, the review also noted 375 instances of CDIs in those being treated at the hospital.<ref>{{Cite web|url=http://www.cdiffinquiry.org/index.htm|archiveurl=https://web.archive.org/web/20160304030738/http://www.cdiffinquiry.org/index.htm|url-status=dead|title="Welcome to the Public Inquiry into the Outbreak of ''Clostridium difficile'' in Northern Trust Hospitals"|archivedate=4 March 2016}}</ref>

* In October 2007, [[Maidstone and Tunbridge Wells NHS Trust]] was heavily criticized by the [[Healthcare Commission]] regarding its handling of a major outbreak of ''C. difficile'' in its hospitals in [[Kent]] from April 2004 to September 2006. In its report, the Commission estimated approximately 90 people "definitely or probably" died as a result of the infection.<ref name=hcpr2007>{{Citation | author= |date=11 October 2007 |title=Healthcare watchdog finds significant failings in infection control at Maidstone and Tunbridge Wells NHS Trust |type=press release |publisher=[[Healthcare Commission]] |location=United Kingdom |archive-date=21 December 2007 |url=http://www.healthcarecommission.org.uk/newsandevents/pressreleases.cfm/cit_id/5875/FAArea1/customWidgets.content_view_1/usecache/false |archive-url=https://web.archive.org/web/20071221000642/http://www.healthcarecommission.org.uk/newsandevents/pressreleases.cfm?cit_id=5875&FAArea1=customWidgets.content_view_1&usecache=false }}</ref><ref>{{cite news |title=Health Secretary intervenes in superbug row |newspaper=Daily Telegraph |date=11 October 2007 |url=https://www.telegraph.co.uk/news/main.jhtml?xml=/news/2007/10/11/ncdiff611.xml |location=London | vauthors = Smith R, Rayner G, Adams S |url-status=dead |archive-url=https://web.archive.org/web/20080420232805/http://www.telegraph.co.uk/news/main.jhtml?xml=%2Fnews%2F2007%2F10%2F11%2Fncdiff611.xml |archive-date=20 April 2008 |df=dmy-all }}</ref>

* In November 2007, the 027 strain spread into several hospitals in southern Finland, with 10 deaths out of 115 infected people reported on 2007-12-14.<ref>{{Cite web|url=http://www.hs.fi/kotimaa/artikkeli/%C3%84rh%C3%A4kk%C3%A4+suolistobakteeri+on+tappanut+jo+kymmenen+potilasta/1135232592793|archiveurl=https://web.archive.org/web/20071215190520/http://www.hs.fi/kotimaa/artikkeli/%C3%84rh%C3%A4kk%C3%A4+suolistobakteeri+on+tappanut+jo+kymmenen+potilasta/1135232592793|url-status=dead|title=Ärhäkkä suolistobakteeri on tappanut jo kymmenen potilasta – HS.fi – Kotimaa|archivedate=15 December 2007}}</ref>

* In November 2009, four deaths at Our Lady of Lourdes Hospital in Ireland have possible links to CDI. A further 12 people tested positive for infection, and another 20 showed signs of infection.<ref>{{cite news |title=Possible C Diff link to Drogheda deaths |publisher=RTÉ News |date=10 November 2009 |url=http://www.rte.ie/news/2009/1110/health.html |url-status=live |archive-url=https://web.archive.org/web/20121023214832/http://www.rte.ie/news/2009/1110/health.html |archive-date=23 October 2012 |df=dmy-all }}</ref>

* From February 2009 to February 2010, 199 people at Herlev hospital in Denmark were suspected of being infected with the 027 strain. In the first half of 2009, 29 died in hospitals in Copenhagen after they were infected with the bacterium.<ref>~~[http://www.bt.dk/sygdomme/199~~{{Cite web |last=Fogt |first=Lars |date=2010-~~ramt~~03-~~af-draeber-diarre-paa-herlev-sygehus~~03 |title=199 ~~hit~~ramt byaf ~~the killer diarrhea~~dræber-diarre atpå Herlev ~~Hospital]~~Sygehus ~~{{webarchive~~|url=https~~://web.archive.org/web/20160106155343/http~~://www.bt.dk/sygdomme/199-ramt-af-draeber-diarre-paa-herlev-sygehus |access-date=62024-09-19 ~~January 2016~~|website=www.bt.dk |language=da}}~~, BT 3 March 2010~~</ref>

* In May 2010, a total of 138 people at four different hospitals in Denmark were infected with the 027 strain <ref>(Herlev, Amager, Gentofte and Hvidovre)</ref> plus there were some isolated occurrences at other hospitals.<ref>[http://nyhederne.tv2.dk/article/30384149/ Four hospitals affected by the dangerous bacterium] {{webarchive|url=https://web.archive.org/web/20130705140243/http://nyhederne.tv2.dk/article/30384149/ |date= 5 July 2013 }}, TV2 News 7 May 2010</ref>

* In May 2010, 14 fatalities were related to the bacterium in the Australian state of Victoria. Two years later, the same strain of the bacterium was detected in New Zealand.<ref>{{cite news| url= http://3news.co.nz/Deadly-superbug-reaches-NZ/tabid/423/articleID/274618/Default.aspx| publisher= 3 News NZ| title= Deadly superbug reaches NZ| date= 30 October 2012| url-status= dead| archive-url= https://web.archive.org/web/20140415074534/http://www.3news.co.nz/Deadly-superbug-reaches-NZ/tabid/423/articleID/274618/Default.aspx| archive-date= 15 April 2014| df= dmy-all| access-date= 29 October 2012}}</ref>

* On 28 May 2011, an outbreak in Ontario had been reported, with 26 fatalities as of 24 July 2011.<ref>{{cite news|title=C. difficile linked to 26th death in Ontario|url=~~http~~https://www.cbc.ca/news/canada/~~ottawa~~toronto/~~story/2011/07/24/tor-~~c-difficile-linked-to-26th-death-~~stcatharines623~~in-ontario-1.~~html~~1121381|access-date=24 July 2011|publisher=CBC News|date=25 July 2011|url-status=live|archive-url=https://web.archive.org/web/20110724230856/http://www.cbc.ca/news/canada/ottawa/story/2011/07/24/tor-c-difficile-death-stcatharines623.html|archive-date=24 July 2011|df=dmy-all}}</ref>

* In 2012/2013, a total of 27 people at one hospital in the south of Sweden (Ystad) were infected with 10 deaths. Five died of the strain 017.<ref>{{cite web|url=http://www.skane.se/sv/Webbplatser/Lasarettet_i_Ystad/Om_Lasarettet_i_Ystad/Nyheter/Nyheter/10-punkter-for-att-forhindra-smittspridning-i-Region-Skane|title=10 punkter för att förhindra smittspridning i Region Skåne|language=sv|trans-title=10 points to prevent the spread of infection in Region Skåne|archive-url=https://web.archive.org/web/20150305042943/http://www.skane.se/sv/Webbplatser/Lasarettet_i_Ystad/Om_Lasarettet_i_Ystad/Nyheter/Nyheter/10-punkter-for-att-forhindra-smittspridning-i-Region-Skane/|archive-date=5 March 2015|url-status=dead}}</ref>

== Etymology and pronunciation ==

The genus name is from the [[Greek (language)|Greek]] ''klōstēr'' ({{lang|grc|κλωστήρ}}), "spindle",<ref>{{Cite journal| vauthors = Liddell-Scott |title= κλωστήρ |journal=Greek-English Lexicon}}</ref> and the specific name is from [[Latin]] ''difficile'', neuter singular form of ''difficilis'' "difficult, obstinate",<ref>{{Cite journal | vauthors = Cawley K |title=Difficilis |journal=Latin Dictionary and Grammar Aid |url=http://www.archives.nd.edu/cgi-bin/lookup.pl?stem=Difficilis&ending= |access-date=2013-03-16 |archive-date=13 December 2019 |archive-url=https://web.archive.org/web/20191213192306/http://www.archives.nd.edu/cgi-bin/lookup.pl?stem=Difficilis&ending= |url-status=live }}</ref> [[#History|chosen]] in reference to [[fastidious organism|fastidiousness]] upon culturing.

Regarding the pronunciation of the current and former genus assignments, ''Clostridioides'' is {{IPAc-en|k|l|ɒ|ˌ|s|t|r|ɪ|d|i|ˈ|ɔɪ|d|i|s}} and ''Clostridium'' is {{IPAc-en||k|l|ɒ|ˈ|s|t|r|ɪ|d|i|əm}}. Both genera still have species assigned to them, but this species is now classified in the former. Via the norms of [[binomial nomenclature]], it is understood that the former binomial name of this species is now an alias.{{citation needed|date=December 2022}}

Regarding the specific name, {{IPAc-en|d|ᵻ|ˈ|f|ɪ|s|ᵻ|l|i}}<ref name="StedmansOnline">{{Citation | publisher = Wolters-Kluwer |title=Stedman's Medical Dictionary |url=https://stedmansonline.com/index |access-date=2019-04-11 |postscript=. |archive-date=28 July 2020 |archive-url=https://web.archive.org/web/20200728175047/https://stedmansonline.com/index |url-status=live }}</ref> is the traditional norm, reflecting how medical English usually pronounces naturalized New Latin words (which in turn largely reflects [[traditional English pronunciation of Latin]]), although a restored pronunciation of {{IPAc-en|d|ᵻ|ˈ|f|ɪ|k|ᵻ|l|eɪ}} is also sometimes used (the [[classical Latin]] pronunciation is reconstructed as {{IPA-|la|kloːsˈtrɪdɪ.ũː dɪfˈfɪkɪlɛ|}}). The specific name is also commonly pronounced {{IPAc-en|ˌ|d|iː|f|i|ˈ|s|iː|l}}, as though it were French, which from a [[linguistic prescription|prescriptive]] viewpoint is a "mispronunciation"<ref name="StedmansOnline"/> but from a [[linguistic description|linguistically descriptive]] viewpoint cannot be described as erroneous because it is so widely used among health care professionals; it can be described as "the non-preferred variant" from the viewpoint of sticking most regularly to New Latin in [[binomial nomenclature]], which is also a valid viewpoint, although New Latin specific names contain such a wide array of extra-Latin roots (including surnames and jocular references) that extra-Latin pronunciation is involved anyway (as seen, for example, with ''[[Ba humbugi]]'', ''[[Spongiforma squarepantsii]]'', and hundreds of others).{{citation needed|date=December 2022}}

== Research ==

* As of 2019, vaccine candidates providing immunity against [[Clostridium difficile toxin A|''C. difficile'' toxin A]] and [[Clostridium difficile toxin B|''C. difficile'' toxin B]] have advanced the most in clinical research, but do not prevent bacterial colonization.<ref>{{cite journal | vauthors = Broecker F, Wegner E, Seco BM, Kaplonek P, Bräutigam M, Ensser A, Pfister F, Daniel C, Martin CE, Mattner J, Seeberger PH | title = Clostridioides difficile Infections | journal = ACS Chemical Biology | volume = 14 | issue = 12 | pages = 2720–2728 | date = December 2019 | pmid = 31692324 | pmc = 6929054 | doi = 10.1021/acschembio.9b00642 }}</ref> A vaccine candidate by [[Pfizer]] is in a phase 3 clinical trial that is estimated to be completed in September 2021 and a vaccine candidate by [[GlaxoSmithKline]] is in a phase 1 clinical trial that is estimated to be completed in July 2021.<ref>{{cite web |url=https://www.clinicaltrials.gov/ct2/show/NCT03090191 |title=Clostridium Difficile Vaccine Efficacy Trial (Clover) |author= |date=2020-02-21 |website=clinicaltrials.gov |access-date=2020-04-28 |archive-date=28 July 2020 |archive-url=https://web.archive.org/web/20200728175413/https://www.clinicaltrials.gov/ct2/show/NCT03090191 |url-status=live }}</ref><ref>{{cite web |url=https://clinicaltrials.gov/ct2/show/NCT04026009 |title=Study of GlaxoSmithKline's (GSK) Clostridium Difficile Vaccine to Investigate the Safety and Ability to Provoke an Immune Response in the Body When Administered in Healthy Adults Aged 18-45 Years and 50-70 Years |author= |date=2020-04-13 |website=clinicaltrials.gov |access-date=2020-04-28 |archive-date=28 July 2020 |archive-url=https://web.archive.org/web/20200728163552/https://clinicaltrials.gov/ct2/show/NCT04026009 |url-status=live }}</ref>

* CDA-1 and CDB-1 (also known as MDX-066/MDX-1388 and MBL-CDA1/MBL-CDB1) is an investigational, monoclonal antibody combination co-developed by [[Medarex]] and Massachusetts Biologic Laboratories (MBL) to target and neutralize ''C. difficile'' toxins A and B, for the treatment of CDI. [[Merck & Co., Inc.]] gained worldwide rights to develop and commercialize CDA-1 and CDB-1 through an exclusive license agreement signed in April 2009. It is intended as an add-on therapy to one of the existing antibiotics to treat CDI.<ref name="Campus">{{cite web|title=op-line data from randomized, double-blind, placebo controlled Phase 2 clinical trial indicate statistically significant reduction in recurrences of CDAD |url=http://www.umassmed.edu/Content.aspx?id=62670 | work = University of Massachusetts Worcester Campus |access-date=2011-08-16 |url-status=dead |archive-url=https://web.archive.org/web/20101227152634/http://umassmed.edu/Content.aspx?id=62670 |archive-date=27 December 2010 }}</ref><ref name="CenterWatch">{{cite web | title = ''Clostridium Difficile''-Associated Diarrhea | url = http://www.centerwatch.com/clinical-trials/results/new-therapies/nmt-details.aspx?CatID=554 | author = CenterWatch | access-date = 2011-08-16 | url-status = dead | archive-url = https://web.archive.org/web/20110929154200/http://www.centerwatch.com/clinical-trials/results/new-therapies/nmt-details.aspx?CatID=554 | archive-date = 29 September 2011 | df = dmy-all }}</ref><ref name="Business">{{cite web | title = MDX 066, MDX 1388 Medarex, University of Massachusetts Medical School clinical data (phase II)(diarrhea) | url = http://business.highbeam.com/436989/article-1G1-193894218/mdx-066-mdx-1388-medarex-university-massachusetts-medical | publisher = Highbeam | access-date = 2011-08-16 | archive-date = 14 October 2012 | archive-url = https://web.archive.org/web/20121014202844/http://business.highbeam.com/436989/article-1G1-193894218/mdx-066-mdx-1388-medarex-university-massachusetts-medical | url-status = dead }}</ref>

* [[Nitazoxanide]] is a synthetic nitrothiazolyl-salicylamide derivative indicated as an antiprotozoal agent (FDA-approved for the treatment of infectious diarrhea caused by ''[[Cryptosporidium parvum]]'' and ''[[Giardia lamblia]]'') and also is currently being studied in ''C. difficile'' infections vs. vancomycin.<ref name="Shah-2010">{{cite journal | vauthors = Shah D, Dang MD, Hasbun R, Koo HL, Jiang ZD, DuPont HL, Garey KW | title = Clostridium difficile infection: update on emerging antibiotic treatment options and antibiotic resistance | journal = Expert Review of Anti-Infective Therapy | volume = 8 | issue = 5 | pages = 555–64 | date = May 2010 | pmid = 20455684 | pmc = 3138198 | doi = 10.1586/eri.10.28 }}</ref>