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Calculated Shard: 129 (from laksa106)

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curl -X POST \
  'http://laksa129.int.ahrefs:8124/' \
  -H 'Content-Type: text/plain' \
  -H 'X-ClickHouse-Database: crawler3' \
  -H 'Authorization: Basic YXBpOg==' \
  -d 'SELECT getAhrefsURLFromUnparsed(src_unparsed) AS found_url, ifNull(toUnixTimestamp(download_stamp), 0) AS crawl_time, ifNull(toUnixTimestamp(props_url_first_seen), 0) AS first_indexed_time, download_http_code AS http_code, src_unparsed AS src_unparsed, src_root_hash AS src_root_hash, history_drop_reason AS history_drop_reason, meta_title AS meta_title, meta_descriptions AS meta_descriptions, attrs_boilerpipe_text AS attrs_boilerpipe_text, attrs_markdown AS attrs_markdown, attrs_readable_markdown AS attrs_readable_markdown, meta_canonical AS meta_canonical FROM crawler3.page_info_local FINAL PREWHERE (src_root_hash, src_unparsed) IN ((getAhrefsRootHashFromUnparsed(getAhrefsUnparsedNoserviceFromURL(\'https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/\')), getAhrefsUnparsedNoserviceFromURL(\'https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/\'))) FORMAT JSONEachRow'

Response:

{"found_url":"https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/","crawl_time":1771190867,"first_indexed_time":0,"http_code":200,"src_unparsed":"gov,nih!nlm,ncbi,pmc,\/articles\/PMC6334067\/ s443","src_root_hash":"7295144728021232729","history_drop_reason":null,"meta_title":"Clostridium difficile infection and antibiotic-associated diarrhoea - PMC","meta_descriptions":["Antibiotic-associated diarrhoea is among the most common adverse events related to antibiotic use. Most cases are mild, but Clostridium difficile infection causes a spectrum of disease, ranging from occasional diarrhoea to colitis, toxic megacolon, ..."],"attrs_boilerpipe_text":"ABSTRACT\nAntibiotic-associated diarrhoea is among the most common adverse events related to antibiotic use. Most cases are mild, but\nClostridium difficile\ninfection causes a spectrum of disease, ranging from occasional diarrhoea to colitis, toxic megacolon, and potentially death. Recent developments in our understanding of the biology of the gut microbiota have provided new insights into the pathogenesis of these conditions, and have revealed a role for manipulation of the gut microbiota as a novel therapeutic approach. This review will give an overview of the assessment of these conditions, before focusing on the rapidly developing area of their treatment.\nKEYWORDS:\nClostridium difficile\n, diarrhoea, antibiotics, faecal microbiota transplant, microbiota\nKey points\nAntibiotic use may result in diarrhoea through different mechanisms, including: osmotic diarrhoea (through the loss of gut bacteria that absorb short-chain fatty acids); and colonisation and overgrowth of toxin-secreting\nClostridium difficile\nTypical laboratory tests for the presence of\nC difficile\ndo not have high sensitivity and specificity in isolation, so a combination of tests should be used when making the diagnosis of CDI\nCDI has recently become harder to treat with conventional antibiotics for several reasons, including increased treatment failure with metronidazole, rising rates of CDI recurrence, and the emergence of hypervirulent strains of\nC difficile\n(eg NAP1\/027)\nFidaxomicin is a new antibiotic that has considerable efficacy in treating recurrent CDI, though there is uncertainty as to its use in particular situations, including treatment of the NAP1\/027 strain\nRandomised clinical trial evidence demonstrates that faecal microbiota transplant (FMT) is more effective than vancomycin for the treatment of recurrent or refractory CDI, and this treatment is now approved in guidelines\nIntroduction\nIn addition to being a potential reservoir for pathogenic bacteria, the gut also has an extensive ecosystem of microorganisms (∼10\n11\nbacteria per gram of intestinal content) with no overt pathogenicity. It is now appreciated that this ecosystem (often called the ‘gut microbiota’) performs roles that are essential for the maintenance of host health, including short chain fatty acid and bile acid metabolism.\n1\nAntibiotic-associated diarrhoea (AAD) is now understood to represent an imbalance of the gut microbiota resulting from antibiotic use, with several mechanisms appearing to contribute to the disease process.\nMost cases of AAD are mild and self-limiting, and are associated with negative stool culture results. Given the widespread use of antibiotics, it is not surprising that this condition is so common, affecting 5–39% of people treated with antibiotics.\n2\nOne key mechanism of AAD appears to be changes in the gut microbiota that cause decreased short-chain fatty acid absorption, resulting in osmotic diarrhoea.\n3\nOne particular form of AAD –\nClostridium difficile\ninfection (CDI) – can cause more severe gastrointestinal disease.\nClostridium difficile\n(now also referred to as\nClostridioides difficile\n) is a Gram-positive, spore-forming anaerobic bacillus. Spores of\nC difficile\ncan survive for long periods on inanimate objects (resisting heat, acid and antibiotics), a major reason why this bacterium can cause such problems within healthcare settings.\nClostridium difficile\nis spread via the faeco-oral route, and causes disease in humans through the production of two protein exotoxins (toxin A and toxin B), which are cytotoxic to colonic epithelial cells.\n4\nThe host's adaptive immune response following exposure to\nC difficile\nalso appears to be important in determining the severity of the disease, with high IgG antitoxin level production being protective.\n4\nAntibiotic use is the major risk factor for CDI, causing antibiotic-related loss of gut microbial communities that protect against gut infection, thereby facilitating the germination and vegetative growth of the organism when it enters the gut of vulnerable people. Risk factors for CDI are summarised in Table \n1\n. The range of clinical disease that can occur in CDI is wide: diarrhoea and fever occur in almost all cases, but the most severe cases are characterised by colitis, toxic megacolon (dilatation of the colon, with the risk of perforation), multi-organ failure, or even death.\nTable 1.\nRisk factors for\nClostridium difficile\ninfection\nRisk factor\nDetails\nAntibiotics\nAlmost all antibiotics can increase vulnerability to\nClostridium difficile\ninfection (CDI), but cephalosporins, fluoroquinolones, clindamycin and certain penicillins (eg co-amoxiclav) increase risk to the greatest extent\nAcid-suppressant medications\nBoth proton-pump inhibitors (PPI) and H\n2\n-receptor antagonists appear to increase risk (risk is increased with PPI especially)\nAge\nRates are ten-fold higher in those of >65 years than in the younger population\nHospitalisation\n•Recent hospitalisation, prolonged hospitalisation (>7 days), and\/or prolonged antibiotic courses all increase risk of CDI\n•Being admitted to a room where the previous patient had CDI is itself a risk factor for infection\nImmunosuppression\nRates of CDI (and associated morbidity\/mortality) peaked in the UK approximately 10 years ago (with about 70,000 cases in the UK, around 4000 of which were fatal, attributed to CDI in 2007).\n5\nRates have since decreased rapidly. There are currently around 12,000 cases per year in the UK,\n5\nwith the sharp recent decline in incidence being attributed to infection prevention and control interventions, including antibiotic stewardship.\n6\nDiagnosis\nTypical AAD is a clinical diagnosis, based on the relationship between recent antibiotic use and the development of diarrhoea, and on the exclusion of potential alternative causes of diarrhoea.\nDiagnosis of CDI may be difficult for several reasons. First, the currently available tests lack ideal sensitivity and specificity. Second,\nC difficile\nmay either cause asymptomatic colonisation or active gastrointestinal infection, and conventional tests do not clearly differentiate between these two states. Therefore, guidelines recommend testing for CDI only when a patient has diarrhoea and grounds for suspecting an infective aetiology.\n7\nLaboratory tests for CDI are summarised in Table \n2\n.\nTable 2.\nTests for\nClostridium difficile\ninfection\n7\nTest\nDetails\nGDH EIA\nGDH is a protein that is present in all isolates of\nC difficile.\nThis test is sensitive, quick and relatively cheap, but lacks high specificity for toxigenic forms of\nC difficile.\nIt is therefore often used as an initial screening test\nToxin A and B EIA\nThis test has high specificity but variable degrees of sensitivity\nToxin A and B PCR\nThis PCR test is specific for genes encoding toxins that are produced by\nC difficile\n, but a positive result does not help to distinguish active toxin production from asymptomatic carriage of toxigenic\nC difficile\nCell culture cytotoxicity assay\nThis is still widely recognised as the reference standard test, although it is rarely performed in most clinical laboratories\nGiven the variability of the sensitivity and specificity of these tests, a two-stage testing algorithm is widely applied. In the UK, toxin A\/B enzyme immunoassay (EIA) testing is often used after an initial glutamate dehydrogenase (GDH) or polymerase chain reaction (PCR) screen\n7\nSeveral other investigations may also be useful in the assessment of people with CDI. Leucocytosis (particularly neutrophilia) is common, and may be very marked. Abdominal radiograph is the preferred test for toxic megacolon, whereas abdominal CT is sensitive for the presence of CDI-related colitis. Lower gastrointestinal endoscopy may show only oedema or erythema, or may show the classical finding of pseudomembranes, ie raised yellowish plaques that may be intermittently scattered throughout affected colonic mucosa (Fig \n1\n).\nFig 1.\nPseudomembranous colitis.\nWhere clinicians have a strong clinical suspicion of CDI, empirical therapy should be considered regardless of the laboratory result; this is because with a high pre-test probability, the negative predictive value of the tests that are currently available is insufficient to exclude disease.\nTreatment\nIn all cases of AAD, initial care includes the removal of precipitating factors (ie cessation of antibiotics). This will resolve the majority of cases of typical AAD (and some cases of CDI), but most cases of CDI will require more specific intervention. In treating CDI, a severity assessment is important to establish the most appropriate treatment. The assessment described in the current Public Health England (PHE) guidelines\n8\nis the most commonly used version:\nwhite cell count > 15 × 10\n9\n\/L\nacutely rising creatinine (eg >50% increase above baseline)\ntemperature > 38.5\n°\nC\nsevere colitis (either from clinical abdominal signs or from radiological investigations).\nConventional treatment of CDI\nUntil recently, the antibiotics metronidazole and vancomycin were the only pharmacological options for the treatment of CDI. Metronidazole may be administered orally or intravenously, whereas vancomycin may be given orally or per rectum for this indication. Vancomycin is not used intravenously to treat CDI because it has very limited penetration into the gut mucosa. Intravenous immunoglobulin (IVIg) also has a role in treating severe disease. Until recently, these treatments were effective for most cases of CDI, with surgical intervention (colectomy) reserved for the small number of severe cases that were refractory to medical therapy.\n8\nHowever, over the past decade, CDI has become more difficult to treat with conventional therapies for several reasons. First, the rate of CDI treatment failure with metronidazole is increasing, with rate of non-response now quoted at >20%;\n9\nthis is one of the reasons why patients with CDI and markers of severity should be treated with vancomycin in preference to metronidazole.\n8\nSecond, rates of recurrent CDI (ie return of disease within a short period after stopping antibiotic therapy) are also increasing.\n9\nThird, hypervirulent strains of\nC difficile\nhave emerged, particularly the NAP1\/027 strain, which is associated with the secretion of large quantities of toxin and poor response to conventional antibiotics.\n10\nNovel approaches for therapy for CDI are urgently sought.\nNew antibiotics: fidaxomicin\nFidaxomicin is a novel macrocyclic antibiotic, administered orally, with a narrow spectrum of activity. Although fidaxomicin has been shown in clinical trials to have efficacy in treating recurrent CDI\n11\n(and has consequently been added into clinical guidelines\n8\n), there are still a number of concerns regarding its use. These include its apparently limited efficacy against the NAP1\/027 strain, the lack of evidence regarding its use in CDI with severe colitis, and its considerable expense (since it is 600 times more expensive than metronidazole.)\nManipulation of the gut microbiota: probiotics and faecal microbiota transplantation\nGiven that all forms of AAD represent a perturbation of the gut microbiota, restoration of the usual commensal microbiota is an appealing means of treating the condition.\nOne approach to achieve this is through the use of probiotics, ie the delivery of live microorganisms into the host (sometimes through a suspension or drink). There are limited data regarding the use of probiotics to treat AAD\/CDI, with relevant studies suggesting a possible modest benefit in treating non-severe CDI. However, significant uncertainties still exist in determining the specific organisms that should be included in the formulation, the dose to be used and so on, and probiotics are therefore not recommended at present.\nAnother approach has been the use of faecal microbiota transplantation (FMT), that is, taking a stool sample from a healthy screened donor (with presumed ‘normal’ gut microbiota), processing this in a laboratory into a liquidised bacterial suspension, and delivering it into the gut of affected people. A number of case reports and small case series have described this treatment over the past 60 years, but the first major randomised trial investigating its efficacy was carried out in 2013.\n12\nIn this study, patients with recurrent CDI were randomised to receive either bowel lavage followed by FMT (via a nasoduodenal tube), vancomycin alone, or vancomycin with bowel lavage. The study was stopped early on ethical grounds after a planned interim analysis because 81% of patients (n=13\/16) had recovered in the FMT arm, compared to 31% (n=4\/13) receiving vancomycin alone, and 23% (n=3\/13) receiving vancomycin and bowel lavage. Two of the three patients who did not respond to an initial FMT were successfully treated with a second. There were no major adverse effects. A subsequent randomised trial demonstrated that FMT was superior to vancomycin in treating recurrent CDI when administered colonoscopically.\n13\nThese and other studies have helped to establish optimal practical aspects related to FMT administration (Table \n3\n). FMT appears generally safe with mild, self-limiting gastrointestinal and constitutional symptoms being the most common complications described. However, there have been a small number of potential transmissions of infection, perforations associated with treatment administration, and even deaths related to its use (eg through aspiration of transplant material).\n14\nAs a result of these clinical studies (coupled with other studies demonstrating its cost effectiveness), FMT has now been accepted as an approved treatment for recurrent or refractory CDI by NICE\n15\nand in PHE guidelines.\n8\nFMT is now available as treatment for CDI within a growing number of UK centres, but the expense of establishing and maintaining a service, and ongoing discussions about the regulation and governance of FMT within the UK, have impacted upon more rapid adoption.\n16\nTable 3.\nPractical aspects of faecal microbiota transplantation (FMT). (Adapted from Mullish\net al\n18\nand Cammarota\net al\n19\n)\nCriteria\nDetails\nDonor selection\nScreening questionnaire\nPeople >60 years of age, those with recent antibiotic use (within six weeks), significant risk factors for blood-borne viruses, recent constitutional illness, and\/or recent travel to countries with high rates of infectious diarrhoea are typically excluded from further assessment\nMedical questionnaire\nPeople with a personal or family history of disorders associated with perturbation of the gut microbiota (including inflammatory bowel disease, irritable bowel syndrome, metabolic syndrome, autoimmune disorders and\/or gastrointestinal malignancy) are typically excluded from further assessment\nLaboratory testing, repeated at regular intervals, typically includes:\nBlood screening\nHepatitis A serology\nHepatitis B serology and hepatitis B DNA\nHepatitis C serology and hepatitis C RNA\nHIV-1 and -2 and HTLV-1 and -2 serology\nSyphilis serology\nCytomegalovirus and Epstein-Barr virus serology\nEntamoeba histolytica\nserology\nStrongyloides stercoralis\nserology\nStool screening\nMicroscopy, culture and sensitivity for enteric bacteria (at least three samples over three separate days)\nAnalysis for ova, cysts and parasites (at least three samples over three separate days)\nAcid-fast staining for\nCyclospora, Isospora\nand\nCryptosporidium\nScreening for carriage of antibiotic-resistant organisms, carbapenemase-producing\nEnterobacteriaceae\nClostridium difficile\ntoxin and polymerase chain reaction (PCR)\nAnalysis for rotavirus and adenovirus\nHelicobacter pylori\nfaecal antigen\nChoice of recipients\nIndications\nRecurrent or relapsing CDI\nLimited data regarding efficacy in severe or fulminant CDI colitis\nContraindications\nThere are only a small number of absolute contraindications, eg a life-threatening food allergy\nFMT seems to have similar efficacy (and no additional infective complications) when given to immunocompromised individuals, including solid organ transplant recipients, recipients of recent chemotherapy, people with HIV infection and people with inflammatory bowel disease (IBD) taking B\/T cell immunomodulatory therapy\n20\nTransplant preparation\nTypically >50–60 g of stool is mixed with 250–300 mL of diluent (most often saline), before filtering of the slurry. The exact protocols used vary between different centres\nTransplants are either prepared from fresh stool on the day of delivery, or prepared in advance and frozen (using glycerol as a bacterial cryopreservative) before thawing on the day\n21\nTransplant delivery\nThe transplant may be delivered either via the upper gastrointestinal route (gastroscopy, or nasogastric or nasoenteric tube) or by the lower gastrointestinal route (enema or colonoscopy). FMT capsules are an emerging delivery modality\nAnti-CDI antibiotics are typically stopped 12–72 hours prior to transplant; a polyethylene glycol preparation may be given on the day prior to administration\nA proton-pump inhibitor (PPI) and\/or a prokinetic (ie metoclopramide) are often administered prior to upper gastrointestinal administration. Loperamide is often administered after lower gastrointestinal administration to facilitate retention within colon\nGiven the obvious potential drawbacks of FMT (including its unpalatable nature and the invasive means of administration), there is great interest in refining FMT from its current state into a more acceptable pill or drink. ‘Capsulised’ FMT (in which faecal slurry or freeze-dried stool is placed into capsules) is now starting to become available and has recently been demonstrated to be of similar efficacy to colonoscopic FMT in a large randomised trial.\n17\nOther novel approaches\nA number of novel approaches for the treatment of CDI are at various stages of development; these are summarised in Table \n4\n.\nTable 4.\nNovel approaches for the treatment of\nClostridium difficile\ninfection (CDI)\nApproach\nDetails\nAntimicrobials\nAntibiotics\nA number of novel antibiotics are in clinical trials\nRibaxamase\nThis is a beta-lactamase that may be co-administered with systemic broad-spectrum antibiotics, with the aim of degrading the antibiotics in the gut before they can affect the gut microbiota and create a propensity to CDI\nImmunisation\nPassive immunisation\nCo-administration of bezlotoxumab (an anti-toxin B antibody) together with conventional antibiotic therapy has been shown to reduce the rate of recurrence of CDI compared to antibiotic therapy alone\n22\nActive immunisation\nAnti-toxin vaccines are now in clinical trials. However, early data suggest reduced seroconversion in older people, those most at risk of CDI\nMicrobiome manipulation\nNon-toxigenic\nC difficile\n23\nIn a clinical trial, non-toxigenic\nC difficile\nwas administered to those with CDI, with the aim of outcompeting toxigenic\nC difficile\nfrom its reservoir within the gut. CDI recurrence rates were 30% in those receiving placebo in comparison with 11% in those receiving non-toxigenic\nC difficile\nConclusions\nAAD and CDI remain a common problems. Many cases are mild, but a significant number – especially of CDI – can be difficult to treat and potentially life-threatening. Developments in our understanding of the importance of the gut microbiota, and the marked efficacy of FMT in clinical trials, have raised the profile of CDI research and the search for more refined, targeted therapies.\nReferences\n1.\nMarchesi JR. Adams DH. Fava F, et al.  The gut microbiota and host health: a new clinical frontier. 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An evaluation of the impact of antibiotic stewardship on reducing the use of high-risk antibiotics and its effect on the incidence of Clostridium difficile infection in hospital settings. J Antimicrob Chemother. 2012;67:2988–96. doi: 10.1093\/jac\/dks330.\n[\nDOI\n] [\nPubMed\n] [\nGoogle Scholar\n]\n7.\nPublic Health England  Updated guidance on the diagnosis and reporting of Clostridium difficile. 2012.\nwww.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/215135\/dh_133016.pdf\n.  [Accessed 18 April 2018]\n[\nGoogle Scholar\n]\n8.\nPublic Health England  Updated guidance on the management and treatment of Clostridium difficile infection. 2013.\nwww.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/321891\/Clostridium_difficile_management_and_treatment.pdf\n.  [Accessed 18 April 2018]\n[\nGoogle Scholar\n]\n9.\nKelly CP. LaMont JT. Clostridium difficile – more difficult than ever. 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Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014;109:1065–71. doi: 10.1038\/ajg.2014.133.\n[\nDOI\n] [\nPMC free article\n] [\nPubMed\n] [\nGoogle Scholar\n]\n21.\nHamilton MJ. Weingarden AR. Sadowsky MJ. Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107:761–7. doi: 10.1038\/ajg.2011.482.\n[\nDOI\n] [\nPubMed\n] [\nGoogle Scholar\n]\n22.\nWilcox MH. Gerding DN. Poxton IR, et al.  Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305–17. doi: 10.1056\/NEJMoa1602615.\n[\nDOI\n] [\nPubMed\n] [\nGoogle Scholar\n]\n23.\nGerding DN. Meyer T. Lee C, et al.  Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection. JAMA. 2015;313:1719–27. doi: 10.1001\/jama.2015.3725.\n[\nDOI\n] [\nPubMed\n] [\nGoogle Scholar\n]","attrs_markdown":"[Skip to main content](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#main-content)\n\n![](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/us_flag.svg)\n\nAn official website of the United States government\n\nHere's how you know\n\nHere's how you know\n\n![](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/icon-dot-gov.svg)\n\n**Official websites use .gov**   \n A **.gov** website belongs to an official government organization in the United States.\n\n![](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/icon-https.svg)\n\n**Secure .gov websites use HTTPS**   \n A **lock** ( Locked padlock icon) or **https:\/\/** means you've safely connected to the .gov website. 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Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health.  \n Learn more: [PMC Disclaimer](https:\/\/pmc.ncbi.nlm.nih.gov\/about\/disclaimer\/) \\|  [PMC Copyright Notice](https:\/\/pmc.ncbi.nlm.nih.gov\/about\/copyright\/)\n\n![Clinical Medicine logo](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/banners\/logo-clinmed.png)\n\nClin Med (Lond)\n\n. 2018 Jun;18(3):237–241. doi: [10\\.7861\/clinmedicine.18-3-237](https:\/\/doi.org\/10.7861\/clinmedicine.18-3-237)\n\n- [Search in PMC](https:\/\/pmc.ncbi.nlm.nih.gov\/search\/?term=\"Clin%20Med%20\\(Lond\\)\"[jour])\n- [Search in PubMed](https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=\"Clin%20Med%20\\(Lond\\)\"[jour])\n- [View in NLM Catalog](https:\/\/www.ncbi.nlm.nih.gov\/nlmcatalog?term=\"Clin%20Med%20\\(Lond\\)\"[Title%20Abbreviation])\n- [Add to search](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/?term=\"Clin%20Med%20\\(Lond\\)\"[jour])\n\n# *Clostridium difficile* infection and antibiotic-associated diarrhoea\n[Benjamin H Mullish](https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=\"Mullish%20BH\"[Author])\n\n### Benjamin H Mullish\nASt Mary's Hospital Campus, Imperial College London, London, UK\n\nspecialty registrar and MRC clinical research training fellow\n\nFind articles by [Benjamin H Mullish](https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=\"Mullish%20BH\"[Author])\n\nA,✉, [Horace RT Williams](https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=\"Williams%20HRT\"[Author])\n\n### Horace RT Williams\nBSt Mary's Hospital Campus, Imperial College London, London, UK\n\nconsultant gastroenterologist and honorary senior lecturer\n\nFind articles by [Horace RT Williams](https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=\"Williams%20HRT\"[Author])\n\nB\n\n- Author information\n- Copyright and License information\n\nASt Mary's Hospital Campus, Imperial College London, London, UK\n\nBSt Mary's Hospital Campus, Imperial College London, London, UK\n\n✉\n\nAddress for correspondence: Dr Benjamin H Mullish, Division of Integrative Systems Medicine and Digestive Disease, 10th Floor, QEQM Wing, St Mary's Hospital Campus, Imperial College London, South Wharf Road, Paddington, London W2 1NY, UK. Email: b.mullish@imperial.ac.uk\n#### Roles\n**Benjamin H Mullish**: specialty registrar and MRC clinical research training fellow\n\n**Horace RT Williams**: consultant gastroenterologist and honorary senior lecturer\n\n© Royal College of Physicians 2018. All rights reserved.\n\n[PMC Copyright notice](https:\/\/pmc.ncbi.nlm.nih.gov\/about\/copyright\/)\n\nPMCID: PMC6334067 EMSID: [EMS79040](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/mid\/EMS79040\/) PMID: [29858434](https:\/\/pubmed.ncbi.nlm.nih.gov\/29858434\/)\n\n## ABSTRACT\nAntibiotic-associated diarrhoea is among the most common adverse events related to antibiotic use. Most cases are mild, but *Clostridium difficile* infection causes a spectrum of disease, ranging from occasional diarrhoea to colitis, toxic megacolon, and potentially death. Recent developments in our understanding of the biology of the gut microbiota have provided new insights into the pathogenesis of these conditions, and have revealed a role for manipulation of the gut microbiota as a novel therapeutic approach. This review will give an overview of the assessment of these conditions, before focusing on the rapidly developing area of their treatment.\n\n**KEYWORDS:** *Clostridium difficile*, diarrhoea, antibiotics, faecal microbiota transplant, microbiota\n\n## Key points\n- Antibiotic use may result in diarrhoea through different mechanisms, including: osmotic diarrhoea (through the loss of gut bacteria that absorb short-chain fatty acids); and colonisation and overgrowth of toxin-secreting *Clostridium difficile*\n- Typical laboratory tests for the presence of *C difficile* do not have high sensitivity and specificity in isolation, so a combination of tests should be used when making the diagnosis of CDI\n- CDI has recently become harder to treat with conventional antibiotics for several reasons, including increased treatment failure with metronidazole, rising rates of CDI recurrence, and the emergence of hypervirulent strains of *C difficile* (eg NAP1\/027)\n- Fidaxomicin is a new antibiotic that has considerable efficacy in treating recurrent CDI, though there is uncertainty as to its use in particular situations, including treatment of the NAP1\/027 strain\n- Randomised clinical trial evidence demonstrates that faecal microbiota transplant (FMT) is more effective than vancomycin for the treatment of recurrent or refractory CDI, and this treatment is now approved in guidelines\n\n## Introduction\nIn addition to being a potential reservoir for pathogenic bacteria, the gut also has an extensive ecosystem of microorganisms (∼1011 bacteria per gram of intestinal content) with no overt pathogenicity. It is now appreciated that this ecosystem (often called the ‘gut microbiota’) performs roles that are essential for the maintenance of host health, including short chain fatty acid and bile acid metabolism.[1](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R1) Antibiotic-associated diarrhoea (AAD) is now understood to represent an imbalance of the gut microbiota resulting from antibiotic use, with several mechanisms appearing to contribute to the disease process.\n\nMost cases of AAD are mild and self-limiting, and are associated with negative stool culture results. Given the widespread use of antibiotics, it is not surprising that this condition is so common, affecting 5–39% of people treated with antibiotics.[2](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R2) One key mechanism of AAD appears to be changes in the gut microbiota that cause decreased short-chain fatty acid absorption, resulting in osmotic diarrhoea.[3](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R3)\n\nOne particular form of AAD – *Clostridium difficile* infection (CDI) – can cause more severe gastrointestinal disease. *Clostridium difficile* (now also referred to as *Clostridioides difficile*) is a Gram-positive, spore-forming anaerobic bacillus. Spores of *C difficile* can survive for long periods on inanimate objects (resisting heat, acid and antibiotics), a major reason why this bacterium can cause such problems within healthcare settings. *Clostridium difficile* is spread via the faeco-oral route, and causes disease in humans through the production of two protein exotoxins (toxin A and toxin B), which are cytotoxic to colonic epithelial cells.[4](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R4) The host's adaptive immune response following exposure to *C difficile* also appears to be important in determining the severity of the disease, with high IgG antitoxin level production being protective.[4](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R4) Antibiotic use is the major risk factor for CDI, causing antibiotic-related loss of gut microbial communities that protect against gut infection, thereby facilitating the germination and vegetative growth of the organism when it enters the gut of vulnerable people. Risk factors for CDI are summarised in Table [1](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#T0001). The range of clinical disease that can occur in CDI is wide: diarrhoea and fever occur in almost all cases, but the most severe cases are characterised by colitis, toxic megacolon (dilatation of the colon, with the risk of perforation), multi-organ failure, or even death.\n\n### Table 1.\nRisk factors for *Clostridium difficile* infection\n\n| Risk factor | Details |\n|---|---|\n| Antibiotics | Almost all antibiotics can increase vulnerability to *Clostridium difficile* infection (CDI), but cephalosporins, fluoroquinolones, clindamycin and certain penicillins (eg co-amoxiclav) increase risk to the greatest extent |\n| Acid-suppressant medications | Both proton-pump inhibitors (PPI) and H2\\-receptor antagonists appear to increase risk (risk is increased with PPI especially) |\n| Age | Rates are ten-fold higher in those of \\>65 years than in the younger population |\n| Hospitalisation | •Recent hospitalisation, prolonged hospitalisation (\\>7 days), and\/or prolonged antibiotic courses all increase risk of CDI •Being admitted to a room where the previous patient had CDI is itself a risk factor for infection |\n| Immunosuppression |   |\n\n[Open in a new tab](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/table\/T0001\/)\n\nRates of CDI (and associated morbidity\/mortality) peaked in the UK approximately 10 years ago (with about 70,000 cases in the UK, around 4000 of which were fatal, attributed to CDI in 2007).[5](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R5) Rates have since decreased rapidly. There are currently around 12,000 cases per year in the UK,[5](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R5) with the sharp recent decline in incidence being attributed to infection prevention and control interventions, including antibiotic stewardship.[6](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R6)\n\n## Diagnosis\nTypical AAD is a clinical diagnosis, based on the relationship between recent antibiotic use and the development of diarrhoea, and on the exclusion of potential alternative causes of diarrhoea.\n\nDiagnosis of CDI may be difficult for several reasons. First, the currently available tests lack ideal sensitivity and specificity. Second, *C difficile* may either cause asymptomatic colonisation or active gastrointestinal infection, and conventional tests do not clearly differentiate between these two states. Therefore, guidelines recommend testing for CDI only when a patient has diarrhoea and grounds for suspecting an infective aetiology.[7](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R7) Laboratory tests for CDI are summarised in Table [2](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#T0002).\n\n### Table 2.\nTests for *Clostridium difficile* infection [7](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R7)\n\n| Test | Details |\n|---|---|\n| GDH EIA | GDH is a protein that is present in all isolates of *C difficile.* This test is sensitive, quick and relatively cheap, but lacks high specificity for toxigenic forms of *C difficile.* It is therefore often used as an initial screening test |\n| Toxin A and B EIA | This test has high specificity but variable degrees of sensitivity |\n| Toxin A and B PCR | This PCR test is specific for genes encoding toxins that are produced by *C difficile*, but a positive result does not help to distinguish active toxin production from asymptomatic carriage of toxigenic *C difficile* |\n| Cell culture cytotoxicity assay | This is still widely recognised as the reference standard test, although it is rarely performed in most clinical laboratories |\n\n[Open in a new tab](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/table\/T0002\/)\n\nGiven the variability of the sensitivity and specificity of these tests, a two-stage testing algorithm is widely applied. In the UK, toxin A\/B enzyme immunoassay (EIA) testing is often used after an initial glutamate dehydrogenase (GDH) or polymerase chain reaction (PCR) screen[7](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R7)\n\nSeveral other investigations may also be useful in the assessment of people with CDI. Leucocytosis (particularly neutrophilia) is common, and may be very marked. Abdominal radiograph is the preferred test for toxic megacolon, whereas abdominal CT is sensitive for the presence of CDI-related colitis. Lower gastrointestinal endoscopy may show only oedema or erythema, or may show the classical finding of pseudomembranes, ie raised yellowish plaques that may be intermittently scattered throughout affected colonic mucosa (Fig [1](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#F0001)).\n\n### Fig 1.\n![Fig 1.](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/blobs\/ab94\/6334067\/9e08457192b5\/clinmed-18-3-237fig1.jpg)\n\n[Open in a new tab](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/figure\/F0001\/)\n\nPseudomembranous colitis.\n\nWhere clinicians have a strong clinical suspicion of CDI, empirical therapy should be considered regardless of the laboratory result; this is because with a high pre-test probability, the negative predictive value of the tests that are currently available is insufficient to exclude disease.\n\n## Treatment\nIn all cases of AAD, initial care includes the removal of precipitating factors (ie cessation of antibiotics). This will resolve the majority of cases of typical AAD (and some cases of CDI), but most cases of CDI will require more specific intervention. In treating CDI, a severity assessment is important to establish the most appropriate treatment. The assessment described in the current Public Health England (PHE) guidelines[8](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R8) is the most commonly used version:\n\n- white cell count \\> 15 × 109\/L\n- acutely rising creatinine (eg \\>50% increase above baseline)\n- temperature \\> 38.5°C\n- severe colitis (either from clinical abdominal signs or from radiological investigations).\n\n### Conventional treatment of CDI\nUntil recently, the antibiotics metronidazole and vancomycin were the only pharmacological options for the treatment of CDI. Metronidazole may be administered orally or intravenously, whereas vancomycin may be given orally or per rectum for this indication. Vancomycin is not used intravenously to treat CDI because it has very limited penetration into the gut mucosa. Intravenous immunoglobulin (IVIg) also has a role in treating severe disease. Until recently, these treatments were effective for most cases of CDI, with surgical intervention (colectomy) reserved for the small number of severe cases that were refractory to medical therapy.[8](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R8)\n\nHowever, over the past decade, CDI has become more difficult to treat with conventional therapies for several reasons. First, the rate of CDI treatment failure with metronidazole is increasing, with rate of non-response now quoted at \\>20%;[9](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R9) this is one of the reasons why patients with CDI and markers of severity should be treated with vancomycin in preference to metronidazole.[8](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R8) Second, rates of recurrent CDI (ie return of disease within a short period after stopping antibiotic therapy) are also increasing.[9](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R9) Third, hypervirulent strains of *C difficile* have emerged, particularly the NAP1\/027 strain, which is associated with the secretion of large quantities of toxin and poor response to conventional antibiotics.[10](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R10) Novel approaches for therapy for CDI are urgently sought.\n\n### New antibiotics: fidaxomicin\nFidaxomicin is a novel macrocyclic antibiotic, administered orally, with a narrow spectrum of activity. Although fidaxomicin has been shown in clinical trials to have efficacy in treating recurrent CDI[11](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R11) (and has consequently been added into clinical guidelines[8](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R8)), there are still a number of concerns regarding its use. These include its apparently limited efficacy against the NAP1\/027 strain, the lack of evidence regarding its use in CDI with severe colitis, and its considerable expense (since it is 600 times more expensive than metronidazole.)\n\n### Manipulation of the gut microbiota: probiotics and faecal microbiota transplantation\nGiven that all forms of AAD represent a perturbation of the gut microbiota, restoration of the usual commensal microbiota is an appealing means of treating the condition.\n\nOne approach to achieve this is through the use of probiotics, ie the delivery of live microorganisms into the host (sometimes through a suspension or drink). There are limited data regarding the use of probiotics to treat AAD\/CDI, with relevant studies suggesting a possible modest benefit in treating non-severe CDI. However, significant uncertainties still exist in determining the specific organisms that should be included in the formulation, the dose to be used and so on, and probiotics are therefore not recommended at present.\n\nAnother approach has been the use of faecal microbiota transplantation (FMT), that is, taking a stool sample from a healthy screened donor (with presumed ‘normal’ gut microbiota), processing this in a laboratory into a liquidised bacterial suspension, and delivering it into the gut of affected people. A number of case reports and small case series have described this treatment over the past 60 years, but the first major randomised trial investigating its efficacy was carried out in 2013.[12](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R12) In this study, patients with recurrent CDI were randomised to receive either bowel lavage followed by FMT (via a nasoduodenal tube), vancomycin alone, or vancomycin with bowel lavage. The study was stopped early on ethical grounds after a planned interim analysis because 81% of patients (n=13\/16) had recovered in the FMT arm, compared to 31% (n=4\/13) receiving vancomycin alone, and 23% (n=3\/13) receiving vancomycin and bowel lavage. Two of the three patients who did not respond to an initial FMT were successfully treated with a second. There were no major adverse effects. A subsequent randomised trial demonstrated that FMT was superior to vancomycin in treating recurrent CDI when administered colonoscopically.[13](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R13)\n\nThese and other studies have helped to establish optimal practical aspects related to FMT administration (Table [3](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#T0003)). FMT appears generally safe with mild, self-limiting gastrointestinal and constitutional symptoms being the most common complications described. However, there have been a small number of potential transmissions of infection, perforations associated with treatment administration, and even deaths related to its use (eg through aspiration of transplant material).[14](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R14) As a result of these clinical studies (coupled with other studies demonstrating its cost effectiveness), FMT has now been accepted as an approved treatment for recurrent or refractory CDI by NICE[15](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R15) and in PHE guidelines.[8](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R8) FMT is now available as treatment for CDI within a growing number of UK centres, but the expense of establishing and maintaining a service, and ongoing discussions about the regulation and governance of FMT within the UK, have impacted upon more rapid adoption.[16](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R16)\n\n#### Table 3.\nPractical aspects of faecal microbiota transplantation (FMT). (Adapted from Mullish *et al*[18](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R18) and Cammarota *et al*[19](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R19))\n\n| Criteria | Details |   |   |\n|---|---|---|---|\n| Donor selection | Screening questionnaire | People \\>60 years of age, those with recent antibiotic use (within six weeks), significant risk factors for blood-borne viruses, recent constitutional illness, and\/or recent travel to countries with high rates of infectious diarrhoea are typically excluded from further assessment |   |\n|   | Medical questionnaire | People with a personal or family history of disorders associated with perturbation of the gut microbiota (including inflammatory bowel disease, irritable bowel syndrome, metabolic syndrome, autoimmune disorders and\/or gastrointestinal malignancy) are typically excluded from further assessment |   |\n|   | Laboratory testing, repeated at regular intervals, typically includes: | Blood screening | Hepatitis A serology Hepatitis B serology and hepatitis B DNA Hepatitis C serology and hepatitis C RNA HIV-1 and -2 and HTLV-1 and -2 serology Syphilis serology Cytomegalovirus and Epstein-Barr virus serology *Entamoeba histolytica* serology *Strongyloides stercoralis* serology |\n|   |   | Stool screening | Microscopy, culture and sensitivity for enteric bacteria (at least three samples over three separate days) Analysis for ova, cysts and parasites (at least three samples over three separate days) Acid-fast staining for *Cyclospora, Isospora* and *Cryptosporidium* Screening for carriage of antibiotic-resistant organisms, carbapenemase-producing *Enterobacteriaceae* *Clostridium difficile* toxin and polymerase chain reaction (PCR) Analysis for rotavirus and adenovirus *Helicobacter pylori* faecal antigen |\n| Choice of recipients | Indications | Recurrent or relapsing CDI Limited data regarding efficacy in severe or fulminant CDI colitis |   |\n|   | Contraindications | There are only a small number of absolute contraindications, eg a life-threatening food allergy FMT seems to have similar efficacy (and no additional infective complications) when given to immunocompromised individuals, including solid organ transplant recipients, recipients of recent chemotherapy, people with HIV infection and people with inflammatory bowel disease (IBD) taking B\/T cell immunomodulatory therapy[20](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R20) |   |\n| Transplant preparation | Typically \\>50–60 g of stool is mixed with 250–300 mL of diluent (most often saline), before filtering of the slurry. The exact protocols used vary between different centres Transplants are either prepared from fresh stool on the day of delivery, or prepared in advance and frozen (using glycerol as a bacterial cryopreservative) before thawing on the day[21](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R21) |   |   |\n| Transplant delivery | The transplant may be delivered either via the upper gastrointestinal route (gastroscopy, or nasogastric or nasoenteric tube) or by the lower gastrointestinal route (enema or colonoscopy). FMT capsules are an emerging delivery modality Anti-CDI antibiotics are typically stopped 12–72 hours prior to transplant; a polyethylene glycol preparation may be given on the day prior to administration A proton-pump inhibitor (PPI) and\/or a prokinetic (ie metoclopramide) are often administered prior to upper gastrointestinal administration. Loperamide is often administered after lower gastrointestinal administration to facilitate retention within colon |   |   |\n\n[Open in a new tab](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/table\/T0003\/)\n\nGiven the obvious potential drawbacks of FMT (including its unpalatable nature and the invasive means of administration), there is great interest in refining FMT from its current state into a more acceptable pill or drink. ‘Capsulised’ FMT (in which faecal slurry or freeze-dried stool is placed into capsules) is now starting to become available and has recently been demonstrated to be of similar efficacy to colonoscopic FMT in a large randomised trial.[17](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R17)\n\n### Other novel approaches\nA number of novel approaches for the treatment of CDI are at various stages of development; these are summarised in Table [4](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#T0004).\n\n#### Table 4.\nNovel approaches for the treatment of *Clostridium difficile* infection (CDI)\n\n| Approach | Details |   |\n|---|---|---|\n| Antimicrobials | Antibiotics | A number of novel antibiotics are in clinical trials |\n|   | Ribaxamase | This is a beta-lactamase that may be co-administered with systemic broad-spectrum antibiotics, with the aim of degrading the antibiotics in the gut before they can affect the gut microbiota and create a propensity to CDI |\n| Immunisation | Passive immunisation | Co-administration of bezlotoxumab (an anti-toxin B antibody) together with conventional antibiotic therapy has been shown to reduce the rate of recurrence of CDI compared to antibiotic therapy alone[22](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R22) |\n|   | Active immunisation | Anti-toxin vaccines are now in clinical trials. However, early data suggest reduced seroconversion in older people, those most at risk of CDI |\n| Microbiome manipulation | Non-toxigenic *C difficile*[23](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R23) | In a clinical trial, non-toxigenic *C difficile* was administered to those with CDI, with the aim of outcompeting toxigenic *C difficile* from its reservoir within the gut. CDI recurrence rates were 30% in those receiving placebo in comparison with 11% in those receiving non-toxigenic *C difficile* |\n\n[Open in a new tab](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/table\/T0004\/)\n\n## Conclusions\nAAD and CDI remain a common problems. Many cases are mild, but a significant number – especially of CDI – can be difficult to treat and potentially life-threatening. 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JAMA. 2015;313:1719–27. doi: 10.1001\/jama.2015.3725.\n  \\[[DOI](https:\/\/doi.org\/10.1001\/jama.2015.3725)\\] \\[[PubMed](https:\/\/pubmed.ncbi.nlm.nih.gov\/25942722\/)\\] \\[[Google Scholar](https:\/\/scholar.google.com\/scholar_lookup?journal=JAMA&title=Administration%20of%20spores%20of%20nontoxigenic%20Clostridium%20difficile%20strain%20M3%20for%20prevention%20of%20recurrent%20C.%20difficile%20infection&author=DN%20Gerding&author=T%20Meyer&author=C%20Lee&volume=313&publication_year=2015&pages=1719-27&pmid=25942722&doi=10.1001\/jama.2015.3725&)\\]\n\n***\nArticles from Clinical Medicine are provided here courtesy of **Royal College of Physicians**\n\n![Close](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/usa-icons\/close.svg)\n\n## ACTIONS\n- [![View on publisher site icon](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/launch.svg) View on publisher site](https:\/\/doi.org\/10.7861\/clinmedicine.18-3-237)\n- [![Download PDF icon](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/file_download.svg) PDF (116.2 KB)](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/pdf\/clinmed-18-3-237.pdf)\n- ![Cite icon](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/format_quote.svg) Cite\n- ![Collections icon](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/action-bookmark-full.svg) ![Collections icon](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/action-bookmark-empty.svg) Collections\n- ![Permalink icon](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/share.svg) Permalink\n  ## PERMALINK\n  ![Copy icon](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/content_copy.svg) Copy\n\n## RESOURCES\n### Similar articles\n### Cited by other articles\n### Links to NCBI Databases\n\n## Cite\n![Close icon](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/close.svg)\n\n- ![Copy icon](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/content_copy.svg) Copy\n- [![Download icon](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/file_download.svg) Download .nbib .nbib](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/ \"Download a file for external citation management software\")\n- Format:\n## Add to Collections\n\nFollow NCBI\n\n[NCBI on X (formerly known as Twitter)](https:\/\/twitter.com\/ncbi)\n\n[NCBI on Facebook](https:\/\/www.facebook.com\/ncbi.nlm)\n\n[NCBI on LinkedIn](https:\/\/www.linkedin.com\/company\/ncbinlm)\n\n[NCBI on GitHub](https:\/\/github.com\/ncbi)\n\n[NCBI RSS feed](https:\/\/ncbiinsights.ncbi.nlm.nih.gov\/)\n\nConnect with NLM\n\n[NLM on X (formerly known as Twitter)](https:\/\/twitter.com\/nlm_nih)\n\n[NLM on Facebook](https:\/\/www.facebook.com\/nationallibraryofmedicine)\n\n[NLM on YouTube](https:\/\/www.youtube.com\/user\/NLMNIH)\n\n[National Library of Medicine   8600 Rockville Pike  Bethesda, MD 20894](https:\/\/www.google.com\/maps\/place\/8600+Rockville+Pike,+Bethesda,+MD+20894\/%4038.9959508,%0A%20%20%20%20%20%20%20%20%20%20%20%20-77.101021,17z\/data%3D!3m1!4b1!4m5!3m4!1s0x89b7c95e25765ddb%3A0x19156f88b27635b8!8m2!3d38.9959508!%0A%20%20%20%20%20%20%20%20%20%20%20%204d-77.0988323)\n\n- [Web Policies](https:\/\/www.nlm.nih.gov\/web_policies.html)\n- [FOIA](https:\/\/www.nih.gov\/institutes-nih\/nih-office-director\/office-communications-public-liaison\/freedom-information-act-office)\n- [HHS Vulnerability Disclosure](https:\/\/www.hhs.gov\/vulnerability-disclosure-policy\/index.html)\n\n- [Help](https:\/\/support.nlm.nih.gov\/)\n- [Accessibility](https:\/\/www.nlm.nih.gov\/accessibility.html)\n- [Careers](https:\/\/www.nlm.nih.gov\/careers\/careers.html)\n\n- [NLM](https:\/\/www.nlm.nih.gov\/)\n- [NIH](https:\/\/www.nih.gov\/)\n- [HHS](https:\/\/www.hhs.gov\/)\n- [USA.gov](https:\/\/www.usa.gov\/)\n\nBack to Top\n\n![back to top icon](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/pd-medc-pmc-cloudpmc-viewer\/production\/8a2a0396\/var\/data\/static\/img\/arrow_upward.svg)","attrs_readable_markdown":"## ABSTRACT\nAntibiotic-associated diarrhoea is among the most common adverse events related to antibiotic use. Most cases are mild, but *Clostridium difficile* infection causes a spectrum of disease, ranging from occasional diarrhoea to colitis, toxic megacolon, and potentially death. Recent developments in our understanding of the biology of the gut microbiota have provided new insights into the pathogenesis of these conditions, and have revealed a role for manipulation of the gut microbiota as a novel therapeutic approach. This review will give an overview of the assessment of these conditions, before focusing on the rapidly developing area of their treatment.\n\n**KEYWORDS:** *Clostridium difficile*, diarrhoea, antibiotics, faecal microbiota transplant, microbiota\n\n## Key points\n- Antibiotic use may result in diarrhoea through different mechanisms, including: osmotic diarrhoea (through the loss of gut bacteria that absorb short-chain fatty acids); and colonisation and overgrowth of toxin-secreting *Clostridium difficile*\n- Typical laboratory tests for the presence of *C difficile* do not have high sensitivity and specificity in isolation, so a combination of tests should be used when making the diagnosis of CDI\n- CDI has recently become harder to treat with conventional antibiotics for several reasons, including increased treatment failure with metronidazole, rising rates of CDI recurrence, and the emergence of hypervirulent strains of *C difficile* (eg NAP1\/027)\n- Fidaxomicin is a new antibiotic that has considerable efficacy in treating recurrent CDI, though there is uncertainty as to its use in particular situations, including treatment of the NAP1\/027 strain\n- Randomised clinical trial evidence demonstrates that faecal microbiota transplant (FMT) is more effective than vancomycin for the treatment of recurrent or refractory CDI, and this treatment is now approved in guidelines\n\n## Introduction\nIn addition to being a potential reservoir for pathogenic bacteria, the gut also has an extensive ecosystem of microorganisms (∼1011 bacteria per gram of intestinal content) with no overt pathogenicity. It is now appreciated that this ecosystem (often called the ‘gut microbiota’) performs roles that are essential for the maintenance of host health, including short chain fatty acid and bile acid metabolism.[1](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R1) Antibiotic-associated diarrhoea (AAD) is now understood to represent an imbalance of the gut microbiota resulting from antibiotic use, with several mechanisms appearing to contribute to the disease process.\n\nMost cases of AAD are mild and self-limiting, and are associated with negative stool culture results. Given the widespread use of antibiotics, it is not surprising that this condition is so common, affecting 5–39% of people treated with antibiotics.[2](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R2) One key mechanism of AAD appears to be changes in the gut microbiota that cause decreased short-chain fatty acid absorption, resulting in osmotic diarrhoea.[3](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R3)\n\nOne particular form of AAD – *Clostridium difficile* infection (CDI) – can cause more severe gastrointestinal disease. *Clostridium difficile* (now also referred to as *Clostridioides difficile*) is a Gram-positive, spore-forming anaerobic bacillus. Spores of *C difficile* can survive for long periods on inanimate objects (resisting heat, acid and antibiotics), a major reason why this bacterium can cause such problems within healthcare settings. *Clostridium difficile* is spread via the faeco-oral route, and causes disease in humans through the production of two protein exotoxins (toxin A and toxin B), which are cytotoxic to colonic epithelial cells.[4](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R4) The host's adaptive immune response following exposure to *C difficile* also appears to be important in determining the severity of the disease, with high IgG antitoxin level production being protective.[4](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R4) Antibiotic use is the major risk factor for CDI, causing antibiotic-related loss of gut microbial communities that protect against gut infection, thereby facilitating the germination and vegetative growth of the organism when it enters the gut of vulnerable people. Risk factors for CDI are summarised in Table [1](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#T0001). The range of clinical disease that can occur in CDI is wide: diarrhoea and fever occur in almost all cases, but the most severe cases are characterised by colitis, toxic megacolon (dilatation of the colon, with the risk of perforation), multi-organ failure, or even death.\n\n### Table 1.\nRisk factors for *Clostridium difficile* infection\n\n| Risk factor | Details |\n|---|---|\n| Antibiotics | Almost all antibiotics can increase vulnerability to *Clostridium difficile* infection (CDI), but cephalosporins, fluoroquinolones, clindamycin and certain penicillins (eg co-amoxiclav) increase risk to the greatest extent |\n| Acid-suppressant medications | Both proton-pump inhibitors (PPI) and H2\\-receptor antagonists appear to increase risk (risk is increased with PPI especially) |\n| Age | Rates are ten-fold higher in those of \\>65 years than in the younger population |\n| Hospitalisation | •Recent hospitalisation, prolonged hospitalisation (\\>7 days), and\/or prolonged antibiotic courses all increase risk of CDI •Being admitted to a room where the previous patient had CDI is itself a risk factor for infection |\n| Immunosuppression |   |\n\nRates of CDI (and associated morbidity\/mortality) peaked in the UK approximately 10 years ago (with about 70,000 cases in the UK, around 4000 of which were fatal, attributed to CDI in 2007).[5](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R5) Rates have since decreased rapidly. There are currently around 12,000 cases per year in the UK,[5](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R5) with the sharp recent decline in incidence being attributed to infection prevention and control interventions, including antibiotic stewardship.[6](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R6)\n\n## Diagnosis\nTypical AAD is a clinical diagnosis, based on the relationship between recent antibiotic use and the development of diarrhoea, and on the exclusion of potential alternative causes of diarrhoea.\n\nDiagnosis of CDI may be difficult for several reasons. First, the currently available tests lack ideal sensitivity and specificity. Second, *C difficile* may either cause asymptomatic colonisation or active gastrointestinal infection, and conventional tests do not clearly differentiate between these two states. Therefore, guidelines recommend testing for CDI only when a patient has diarrhoea and grounds for suspecting an infective aetiology.[7](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R7) Laboratory tests for CDI are summarised in Table [2](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#T0002).\n\n### Table 2.\nTests for *Clostridium difficile* infection [7](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R7)\n\n| Test | Details |\n|---|---|\n| GDH EIA | GDH is a protein that is present in all isolates of *C difficile.* This test is sensitive, quick and relatively cheap, but lacks high specificity for toxigenic forms of *C difficile.* It is therefore often used as an initial screening test |\n| Toxin A and B EIA | This test has high specificity but variable degrees of sensitivity |\n| Toxin A and B PCR | This PCR test is specific for genes encoding toxins that are produced by *C difficile*, but a positive result does not help to distinguish active toxin production from asymptomatic carriage of toxigenic *C difficile* |\n| Cell culture cytotoxicity assay | This is still widely recognised as the reference standard test, although it is rarely performed in most clinical laboratories |\n\nGiven the variability of the sensitivity and specificity of these tests, a two-stage testing algorithm is widely applied. In the UK, toxin A\/B enzyme immunoassay (EIA) testing is often used after an initial glutamate dehydrogenase (GDH) or polymerase chain reaction (PCR) screen[7](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R7)\n\nSeveral other investigations may also be useful in the assessment of people with CDI. Leucocytosis (particularly neutrophilia) is common, and may be very marked. Abdominal radiograph is the preferred test for toxic megacolon, whereas abdominal CT is sensitive for the presence of CDI-related colitis. Lower gastrointestinal endoscopy may show only oedema or erythema, or may show the classical finding of pseudomembranes, ie raised yellowish plaques that may be intermittently scattered throughout affected colonic mucosa (Fig [1](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#F0001)).\n\n### Fig 1.\n![Fig 1.](https:\/\/cdn.ncbi.nlm.nih.gov\/pmc\/blobs\/ab94\/6334067\/9e08457192b5\/clinmed-18-3-237fig1.jpg)\n\nPseudomembranous colitis.\n\nWhere clinicians have a strong clinical suspicion of CDI, empirical therapy should be considered regardless of the laboratory result; this is because with a high pre-test probability, the negative predictive value of the tests that are currently available is insufficient to exclude disease.\n\n## Treatment\nIn all cases of AAD, initial care includes the removal of precipitating factors (ie cessation of antibiotics). This will resolve the majority of cases of typical AAD (and some cases of CDI), but most cases of CDI will require more specific intervention. In treating CDI, a severity assessment is important to establish the most appropriate treatment. The assessment described in the current Public Health England (PHE) guidelines[8](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R8) is the most commonly used version:\n\n- white cell count \\> 15 × 109\/L\n- acutely rising creatinine (eg \\>50% increase above baseline)\n- temperature \\> 38.5°C\n- severe colitis (either from clinical abdominal signs or from radiological investigations).\n\n### Conventional treatment of CDI\nUntil recently, the antibiotics metronidazole and vancomycin were the only pharmacological options for the treatment of CDI. Metronidazole may be administered orally or intravenously, whereas vancomycin may be given orally or per rectum for this indication. Vancomycin is not used intravenously to treat CDI because it has very limited penetration into the gut mucosa. Intravenous immunoglobulin (IVIg) also has a role in treating severe disease. Until recently, these treatments were effective for most cases of CDI, with surgical intervention (colectomy) reserved for the small number of severe cases that were refractory to medical therapy.[8](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R8)\n\nHowever, over the past decade, CDI has become more difficult to treat with conventional therapies for several reasons. First, the rate of CDI treatment failure with metronidazole is increasing, with rate of non-response now quoted at \\>20%;[9](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R9) this is one of the reasons why patients with CDI and markers of severity should be treated with vancomycin in preference to metronidazole.[8](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R8) Second, rates of recurrent CDI (ie return of disease within a short period after stopping antibiotic therapy) are also increasing.[9](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R9) Third, hypervirulent strains of *C difficile* have emerged, particularly the NAP1\/027 strain, which is associated with the secretion of large quantities of toxin and poor response to conventional antibiotics.[10](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R10) Novel approaches for therapy for CDI are urgently sought.\n\n### New antibiotics: fidaxomicin\nFidaxomicin is a novel macrocyclic antibiotic, administered orally, with a narrow spectrum of activity. Although fidaxomicin has been shown in clinical trials to have efficacy in treating recurrent CDI[11](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R11) (and has consequently been added into clinical guidelines[8](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R8)), there are still a number of concerns regarding its use. These include its apparently limited efficacy against the NAP1\/027 strain, the lack of evidence regarding its use in CDI with severe colitis, and its considerable expense (since it is 600 times more expensive than metronidazole.)\n\n### Manipulation of the gut microbiota: probiotics and faecal microbiota transplantation\nGiven that all forms of AAD represent a perturbation of the gut microbiota, restoration of the usual commensal microbiota is an appealing means of treating the condition.\n\nOne approach to achieve this is through the use of probiotics, ie the delivery of live microorganisms into the host (sometimes through a suspension or drink). There are limited data regarding the use of probiotics to treat AAD\/CDI, with relevant studies suggesting a possible modest benefit in treating non-severe CDI. However, significant uncertainties still exist in determining the specific organisms that should be included in the formulation, the dose to be used and so on, and probiotics are therefore not recommended at present.\n\nAnother approach has been the use of faecal microbiota transplantation (FMT), that is, taking a stool sample from a healthy screened donor (with presumed ‘normal’ gut microbiota), processing this in a laboratory into a liquidised bacterial suspension, and delivering it into the gut of affected people. A number of case reports and small case series have described this treatment over the past 60 years, but the first major randomised trial investigating its efficacy was carried out in 2013.[12](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R12) In this study, patients with recurrent CDI were randomised to receive either bowel lavage followed by FMT (via a nasoduodenal tube), vancomycin alone, or vancomycin with bowel lavage. The study was stopped early on ethical grounds after a planned interim analysis because 81% of patients (n=13\/16) had recovered in the FMT arm, compared to 31% (n=4\/13) receiving vancomycin alone, and 23% (n=3\/13) receiving vancomycin and bowel lavage. Two of the three patients who did not respond to an initial FMT were successfully treated with a second. There were no major adverse effects. A subsequent randomised trial demonstrated that FMT was superior to vancomycin in treating recurrent CDI when administered colonoscopically.[13](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R13)\n\nThese and other studies have helped to establish optimal practical aspects related to FMT administration (Table [3](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#T0003)). FMT appears generally safe with mild, self-limiting gastrointestinal and constitutional symptoms being the most common complications described. However, there have been a small number of potential transmissions of infection, perforations associated with treatment administration, and even deaths related to its use (eg through aspiration of transplant material).[14](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R14) As a result of these clinical studies (coupled with other studies demonstrating its cost effectiveness), FMT has now been accepted as an approved treatment for recurrent or refractory CDI by NICE[15](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R15) and in PHE guidelines.[8](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R8) FMT is now available as treatment for CDI within a growing number of UK centres, but the expense of establishing and maintaining a service, and ongoing discussions about the regulation and governance of FMT within the UK, have impacted upon more rapid adoption.[16](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R16)\n\n#### Table 3.\nPractical aspects of faecal microbiota transplantation (FMT). (Adapted from Mullish *et al*[18](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R18) and Cammarota *et al*[19](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R19))\n\n| Criteria | Details |   |   |\n|---|---|---|---|\n| Donor selection | Screening questionnaire | People \\>60 years of age, those with recent antibiotic use (within six weeks), significant risk factors for blood-borne viruses, recent constitutional illness, and\/or recent travel to countries with high rates of infectious diarrhoea are typically excluded from further assessment |   |\n|   | Medical questionnaire | People with a personal or family history of disorders associated with perturbation of the gut microbiota (including inflammatory bowel disease, irritable bowel syndrome, metabolic syndrome, autoimmune disorders and\/or gastrointestinal malignancy) are typically excluded from further assessment |   |\n|   | Laboratory testing, repeated at regular intervals, typically includes: | Blood screening | Hepatitis A serology Hepatitis B serology and hepatitis B DNA Hepatitis C serology and hepatitis C RNA HIV-1 and -2 and HTLV-1 and -2 serology Syphilis serology Cytomegalovirus and Epstein-Barr virus serology *Entamoeba histolytica* serology *Strongyloides stercoralis* serology |\n|   |   | Stool screening | Microscopy, culture and sensitivity for enteric bacteria (at least three samples over three separate days) Analysis for ova, cysts and parasites (at least three samples over three separate days) Acid-fast staining for *Cyclospora, Isospora* and *Cryptosporidium* Screening for carriage of antibiotic-resistant organisms, carbapenemase-producing *Enterobacteriaceae* *Clostridium difficile* toxin and polymerase chain reaction (PCR) Analysis for rotavirus and adenovirus *Helicobacter pylori* faecal antigen |\n| Choice of recipients | Indications | Recurrent or relapsing CDI Limited data regarding efficacy in severe or fulminant CDI colitis |   |\n|   | Contraindications | There are only a small number of absolute contraindications, eg a life-threatening food allergy FMT seems to have similar efficacy (and no additional infective complications) when given to immunocompromised individuals, including solid organ transplant recipients, recipients of recent chemotherapy, people with HIV infection and people with inflammatory bowel disease (IBD) taking B\/T cell immunomodulatory therapy[20](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R20) |   |\n| Transplant preparation | Typically \\>50–60 g of stool is mixed with 250–300 mL of diluent (most often saline), before filtering of the slurry. The exact protocols used vary between different centres Transplants are either prepared from fresh stool on the day of delivery, or prepared in advance and frozen (using glycerol as a bacterial cryopreservative) before thawing on the day[21](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R21) |   |   |\n| Transplant delivery | The transplant may be delivered either via the upper gastrointestinal route (gastroscopy, or nasogastric or nasoenteric tube) or by the lower gastrointestinal route (enema or colonoscopy). FMT capsules are an emerging delivery modality Anti-CDI antibiotics are typically stopped 12–72 hours prior to transplant; a polyethylene glycol preparation may be given on the day prior to administration A proton-pump inhibitor (PPI) and\/or a prokinetic (ie metoclopramide) are often administered prior to upper gastrointestinal administration. Loperamide is often administered after lower gastrointestinal administration to facilitate retention within colon |   |   |\n\nGiven the obvious potential drawbacks of FMT (including its unpalatable nature and the invasive means of administration), there is great interest in refining FMT from its current state into a more acceptable pill or drink. ‘Capsulised’ FMT (in which faecal slurry or freeze-dried stool is placed into capsules) is now starting to become available and has recently been demonstrated to be of similar efficacy to colonoscopic FMT in a large randomised trial.[17](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R17)\n\n### Other novel approaches\nA number of novel approaches for the treatment of CDI are at various stages of development; these are summarised in Table [4](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#T0004).\n\n#### Table 4.\nNovel approaches for the treatment of *Clostridium difficile* infection (CDI)\n\n| Approach | Details |   |\n|---|---|---|\n| Antimicrobials | Antibiotics | A number of novel antibiotics are in clinical trials |\n|   | Ribaxamase | This is a beta-lactamase that may be co-administered with systemic broad-spectrum antibiotics, with the aim of degrading the antibiotics in the gut before they can affect the gut microbiota and create a propensity to CDI |\n| Immunisation | Passive immunisation | Co-administration of bezlotoxumab (an anti-toxin B antibody) together with conventional antibiotic therapy has been shown to reduce the rate of recurrence of CDI compared to antibiotic therapy alone[22](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R22) |\n|   | Active immunisation | Anti-toxin vaccines are now in clinical trials. However, early data suggest reduced seroconversion in older people, those most at risk of CDI |\n| Microbiome manipulation | Non-toxigenic *C difficile*[23](https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6334067\/#R23) | In a clinical trial, non-toxigenic *C difficile* was administered to those with CDI, with the aim of outcompeting toxigenic *C difficile* from its reservoir within the gut. CDI recurrence rates were 30% in those receiving placebo in comparison with 11% in those receiving non-toxigenic *C difficile* |\n\n## Conclusions\nAAD and CDI remain a common problems. Many cases are mild, but a significant number – especially of CDI – can be difficult to treat and potentially life-threatening. Developments in our understanding of the importance of the gut microbiota, and the marked efficacy of FMT in clinical trials, have raised the profile of CDI research and the search for more refined, targeted therapies.\n\n## References\n- 1\\.\n  Marchesi JR. Adams DH. Fava F, et al. 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Meta Title	Clostridium difficile infection and antibiotic-associated diarrhoea - PMC
Meta Description	Antibiotic-associated diarrhoea is among the most common adverse events related to antibiotic use. Most cases are mild, but Clostridium difficile infection causes a spectrum of disease, ranging from occasional diarrhoea to colitis, toxic megacolon, ...
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Boilerpipe Text	ABSTRACT Antibiotic-associated diarrhoea is among the most common adverse events related to antibiotic use. Most cases are mild, but Clostridium difficile infection causes a spectrum of disease, ranging from occasional diarrhoea to colitis, toxic megacolon, and potentially death. Recent developments in our understanding of the biology of the gut microbiota have provided new insights into the pathogenesis of these conditions, and have revealed a role for manipulation of the gut microbiota as a novel therapeutic approach. This review will give an overview of the assessment of these conditions, before focusing on the rapidly developing area of their treatment. KEYWORDS: Clostridium difficile , diarrhoea, antibiotics, faecal microbiota transplant, microbiota Key points Antibiotic use may result in diarrhoea through different mechanisms, including: osmotic diarrhoea (through the loss of gut bacteria that absorb short-chain fatty acids); and colonisation and overgrowth of toxin-secreting Clostridium difficile Typical laboratory tests for the presence of C difficile do not have high sensitivity and specificity in isolation, so a combination of tests should be used when making the diagnosis of CDI CDI has recently become harder to treat with conventional antibiotics for several reasons, including increased treatment failure with metronidazole, rising rates of CDI recurrence, and the emergence of hypervirulent strains of C difficile (eg NAP1/027) Fidaxomicin is a new antibiotic that has considerable efficacy in treating recurrent CDI, though there is uncertainty as to its use in particular situations, including treatment of the NAP1/027 strain Randomised clinical trial evidence demonstrates that faecal microbiota transplant (FMT) is more effective than vancomycin for the treatment of recurrent or refractory CDI, and this treatment is now approved in guidelines Introduction In addition to being a potential reservoir for pathogenic bacteria, the gut also has an extensive ecosystem of microorganisms (∼10 11 bacteria per gram of intestinal content) with no overt pathogenicity. It is now appreciated that this ecosystem (often called the ‘gut microbiota’) performs roles that are essential for the maintenance of host health, including short chain fatty acid and bile acid metabolism. 1 Antibiotic-associated diarrhoea (AAD) is now understood to represent an imbalance of the gut microbiota resulting from antibiotic use, with several mechanisms appearing to contribute to the disease process. Most cases of AAD are mild and self-limiting, and are associated with negative stool culture results. Given the widespread use of antibiotics, it is not surprising that this condition is so common, affecting 5–39% of people treated with antibiotics. 2 One key mechanism of AAD appears to be changes in the gut microbiota that cause decreased short-chain fatty acid absorption, resulting in osmotic diarrhoea. 3 One particular form of AAD – Clostridium difficile infection (CDI) – can cause more severe gastrointestinal disease. Clostridium difficile (now also referred to as Clostridioides difficile ) is a Gram-positive, spore-forming anaerobic bacillus. Spores of C difficile can survive for long periods on inanimate objects (resisting heat, acid and antibiotics), a major reason why this bacterium can cause such problems within healthcare settings. Clostridium difficile is spread via the faeco-oral route, and causes disease in humans through the production of two protein exotoxins (toxin A and toxin B), which are cytotoxic to colonic epithelial cells. 4 The host's adaptive immune response following exposure to C difficile also appears to be important in determining the severity of the disease, with high IgG antitoxin level production being protective. 4 Antibiotic use is the major risk factor for CDI, causing antibiotic-related loss of gut microbial communities that protect against gut infection, thereby facilitating the germination and vegetative growth of the organism when it enters the gut of vulnerable people. Risk factors for CDI are summarised in Table 1 . The range of clinical disease that can occur in CDI is wide: diarrhoea and fever occur in almost all cases, but the most severe cases are characterised by colitis, toxic megacolon (dilatation of the colon, with the risk of perforation), multi-organ failure, or even death. Table 1. Risk factors for Clostridium difficile infection Risk factor Details Antibiotics Almost all antibiotics can increase vulnerability to Clostridium difficile infection (CDI), but cephalosporins, fluoroquinolones, clindamycin and certain penicillins (eg co-amoxiclav) increase risk to the greatest extent Acid-suppressant medications Both proton-pump inhibitors (PPI) and H 2 -receptor antagonists appear to increase risk (risk is increased with PPI especially) Age Rates are ten-fold higher in those of >65 years than in the younger population Hospitalisation •Recent hospitalisation, prolonged hospitalisation (>7 days), and/or prolonged antibiotic courses all increase risk of CDI •Being admitted to a room where the previous patient had CDI is itself a risk factor for infection Immunosuppression Rates of CDI (and associated morbidity/mortality) peaked in the UK approximately 10 years ago (with about 70,000 cases in the UK, around 4000 of which were fatal, attributed to CDI in 2007). 5 Rates have since decreased rapidly. There are currently around 12,000 cases per year in the UK, 5 with the sharp recent decline in incidence being attributed to infection prevention and control interventions, including antibiotic stewardship. 6 Diagnosis Typical AAD is a clinical diagnosis, based on the relationship between recent antibiotic use and the development of diarrhoea, and on the exclusion of potential alternative causes of diarrhoea. Diagnosis of CDI may be difficult for several reasons. First, the currently available tests lack ideal sensitivity and specificity. Second, C difficile may either cause asymptomatic colonisation or active gastrointestinal infection, and conventional tests do not clearly differentiate between these two states. Therefore, guidelines recommend testing for CDI only when a patient has diarrhoea and grounds for suspecting an infective aetiology. 7 Laboratory tests for CDI are summarised in Table 2 . Table 2. Tests for Clostridium difficile infection 7 Test Details GDH EIA GDH is a protein that is present in all isolates of C difficile. This test is sensitive, quick and relatively cheap, but lacks high specificity for toxigenic forms of C difficile. It is therefore often used as an initial screening test Toxin A and B EIA This test has high specificity but variable degrees of sensitivity Toxin A and B PCR This PCR test is specific for genes encoding toxins that are produced by C difficile , but a positive result does not help to distinguish active toxin production from asymptomatic carriage of toxigenic C difficile Cell culture cytotoxicity assay This is still widely recognised as the reference standard test, although it is rarely performed in most clinical laboratories Given the variability of the sensitivity and specificity of these tests, a two-stage testing algorithm is widely applied. In the UK, toxin A/B enzyme immunoassay (EIA) testing is often used after an initial glutamate dehydrogenase (GDH) or polymerase chain reaction (PCR) screen 7 Several other investigations may also be useful in the assessment of people with CDI. Leucocytosis (particularly neutrophilia) is common, and may be very marked. Abdominal radiograph is the preferred test for toxic megacolon, whereas abdominal CT is sensitive for the presence of CDI-related colitis. Lower gastrointestinal endoscopy may show only oedema or erythema, or may show the classical finding of pseudomembranes, ie raised yellowish plaques that may be intermittently scattered throughout affected colonic mucosa (Fig 1 ). Fig 1. Pseudomembranous colitis. Where clinicians have a strong clinical suspicion of CDI, empirical therapy should be considered regardless of the laboratory result; this is because with a high pre-test probability, the negative predictive value of the tests that are currently available is insufficient to exclude disease. Treatment In all cases of AAD, initial care includes the removal of precipitating factors (ie cessation of antibiotics). This will resolve the majority of cases of typical AAD (and some cases of CDI), but most cases of CDI will require more specific intervention. In treating CDI, a severity assessment is important to establish the most appropriate treatment. The assessment described in the current Public Health England (PHE) guidelines 8 is the most commonly used version: white cell count > 15 × 10 9 /L acutely rising creatinine (eg >50% increase above baseline) temperature > 38.5 ° C severe colitis (either from clinical abdominal signs or from radiological investigations). Conventional treatment of CDI Until recently, the antibiotics metronidazole and vancomycin were the only pharmacological options for the treatment of CDI. Metronidazole may be administered orally or intravenously, whereas vancomycin may be given orally or per rectum for this indication. Vancomycin is not used intravenously to treat CDI because it has very limited penetration into the gut mucosa. Intravenous immunoglobulin (IVIg) also has a role in treating severe disease. Until recently, these treatments were effective for most cases of CDI, with surgical intervention (colectomy) reserved for the small number of severe cases that were refractory to medical therapy. 8 However, over the past decade, CDI has become more difficult to treat with conventional therapies for several reasons. First, the rate of CDI treatment failure with metronidazole is increasing, with rate of non-response now quoted at >20%; 9 this is one of the reasons why patients with CDI and markers of severity should be treated with vancomycin in preference to metronidazole. 8 Second, rates of recurrent CDI (ie return of disease within a short period after stopping antibiotic therapy) are also increasing. 9 Third, hypervirulent strains of C difficile have emerged, particularly the NAP1/027 strain, which is associated with the secretion of large quantities of toxin and poor response to conventional antibiotics. 10 Novel approaches for therapy for CDI are urgently sought. New antibiotics: fidaxomicin Fidaxomicin is a novel macrocyclic antibiotic, administered orally, with a narrow spectrum of activity. Although fidaxomicin has been shown in clinical trials to have efficacy in treating recurrent CDI 11 (and has consequently been added into clinical guidelines 8 ), there are still a number of concerns regarding its use. These include its apparently limited efficacy against the NAP1/027 strain, the lack of evidence regarding its use in CDI with severe colitis, and its considerable expense (since it is 600 times more expensive than metronidazole.) Manipulation of the gut microbiota: probiotics and faecal microbiota transplantation Given that all forms of AAD represent a perturbation of the gut microbiota, restoration of the usual commensal microbiota is an appealing means of treating the condition. One approach to achieve this is through the use of probiotics, ie the delivery of live microorganisms into the host (sometimes through a suspension or drink). There are limited data regarding the use of probiotics to treat AAD/CDI, with relevant studies suggesting a possible modest benefit in treating non-severe CDI. However, significant uncertainties still exist in determining the specific organisms that should be included in the formulation, the dose to be used and so on, and probiotics are therefore not recommended at present. Another approach has been the use of faecal microbiota transplantation (FMT), that is, taking a stool sample from a healthy screened donor (with presumed ‘normal’ gut microbiota), processing this in a laboratory into a liquidised bacterial suspension, and delivering it into the gut of affected people. A number of case reports and small case series have described this treatment over the past 60 years, but the first major randomised trial investigating its efficacy was carried out in 2013. 12 In this study, patients with recurrent CDI were randomised to receive either bowel lavage followed by FMT (via a nasoduodenal tube), vancomycin alone, or vancomycin with bowel lavage. The study was stopped early on ethical grounds after a planned interim analysis because 81% of patients (n=13/16) had recovered in the FMT arm, compared to 31% (n=4/13) receiving vancomycin alone, and 23% (n=3/13) receiving vancomycin and bowel lavage. Two of the three patients who did not respond to an initial FMT were successfully treated with a second. There were no major adverse effects. A subsequent randomised trial demonstrated that FMT was superior to vancomycin in treating recurrent CDI when administered colonoscopically. 13 These and other studies have helped to establish optimal practical aspects related to FMT administration (Table 3 ). FMT appears generally safe with mild, self-limiting gastrointestinal and constitutional symptoms being the most common complications described. However, there have been a small number of potential transmissions of infection, perforations associated with treatment administration, and even deaths related to its use (eg through aspiration of transplant material). 14 As a result of these clinical studies (coupled with other studies demonstrating its cost effectiveness), FMT has now been accepted as an approved treatment for recurrent or refractory CDI by NICE 15 and in PHE guidelines. 8 FMT is now available as treatment for CDI within a growing number of UK centres, but the expense of establishing and maintaining a service, and ongoing discussions about the regulation and governance of FMT within the UK, have impacted upon more rapid adoption. 16 Table 3. Practical aspects of faecal microbiota transplantation (FMT). (Adapted from Mullish et al 18 and Cammarota et al 19 ) Criteria Details Donor selection Screening questionnaire People >60 years of age, those with recent antibiotic use (within six weeks), significant risk factors for blood-borne viruses, recent constitutional illness, and/or recent travel to countries with high rates of infectious diarrhoea are typically excluded from further assessment Medical questionnaire People with a personal or family history of disorders associated with perturbation of the gut microbiota (including inflammatory bowel disease, irritable bowel syndrome, metabolic syndrome, autoimmune disorders and/or gastrointestinal malignancy) are typically excluded from further assessment Laboratory testing, repeated at regular intervals, typically includes: Blood screening Hepatitis A serology Hepatitis B serology and hepatitis B DNA Hepatitis C serology and hepatitis C RNA HIV-1 and -2 and HTLV-1 and -2 serology Syphilis serology Cytomegalovirus and Epstein-Barr virus serology Entamoeba histolytica serology Strongyloides stercoralis serology Stool screening Microscopy, culture and sensitivity for enteric bacteria (at least three samples over three separate days) Analysis for ova, cysts and parasites (at least three samples over three separate days) Acid-fast staining for Cyclospora, Isospora and Cryptosporidium Screening for carriage of antibiotic-resistant organisms, carbapenemase-producing Enterobacteriaceae Clostridium difficile toxin and polymerase chain reaction (PCR) Analysis for rotavirus and adenovirus Helicobacter pylori faecal antigen Choice of recipients Indications Recurrent or relapsing CDI Limited data regarding efficacy in severe or fulminant CDI colitis Contraindications There are only a small number of absolute contraindications, eg a life-threatening food allergy FMT seems to have similar efficacy (and no additional infective complications) when given to immunocompromised individuals, including solid organ transplant recipients, recipients of recent chemotherapy, people with HIV infection and people with inflammatory bowel disease (IBD) taking B/T cell immunomodulatory therapy 20 Transplant preparation Typically >50–60 g of stool is mixed with 250–300 mL of diluent (most often saline), before filtering of the slurry. The exact protocols used vary between different centres Transplants are either prepared from fresh stool on the day of delivery, or prepared in advance and frozen (using glycerol as a bacterial cryopreservative) before thawing on the day 21 Transplant delivery The transplant may be delivered either via the upper gastrointestinal route (gastroscopy, or nasogastric or nasoenteric tube) or by the lower gastrointestinal route (enema or colonoscopy). FMT capsules are an emerging delivery modality Anti-CDI antibiotics are typically stopped 12–72 hours prior to transplant; a polyethylene glycol preparation may be given on the day prior to administration A proton-pump inhibitor (PPI) and/or a prokinetic (ie metoclopramide) are often administered prior to upper gastrointestinal administration. Loperamide is often administered after lower gastrointestinal administration to facilitate retention within colon Given the obvious potential drawbacks of FMT (including its unpalatable nature and the invasive means of administration), there is great interest in refining FMT from its current state into a more acceptable pill or drink. ‘Capsulised’ FMT (in which faecal slurry or freeze-dried stool is placed into capsules) is now starting to become available and has recently been demonstrated to be of similar efficacy to colonoscopic FMT in a large randomised trial. 17 Other novel approaches A number of novel approaches for the treatment of CDI are at various stages of development; these are summarised in Table 4 . Table 4. Novel approaches for the treatment of Clostridium difficile infection (CDI) Approach Details Antimicrobials Antibiotics A number of novel antibiotics are in clinical trials Ribaxamase This is a beta-lactamase that may be co-administered with systemic broad-spectrum antibiotics, with the aim of degrading the antibiotics in the gut before they can affect the gut microbiota and create a propensity to CDI Immunisation Passive immunisation Co-administration of bezlotoxumab (an anti-toxin B antibody) together with conventional antibiotic therapy has been shown to reduce the rate of recurrence of CDI compared to antibiotic therapy alone 22 Active immunisation Anti-toxin vaccines are now in clinical trials. However, early data suggest reduced seroconversion in older people, those most at risk of CDI Microbiome manipulation Non-toxigenic C difficile 23 In a clinical trial, non-toxigenic C difficile was administered to those with CDI, with the aim of outcompeting toxigenic C difficile from its reservoir within the gut. CDI recurrence rates were 30% in those receiving placebo in comparison with 11% in those receiving non-toxigenic C difficile Conclusions AAD and CDI remain a common problems. Many cases are mild, but a significant number – especially of CDI – can be difficult to treat and potentially life-threatening. Developments in our understanding of the importance of the gut microbiota, and the marked efficacy of FMT in clinical trials, have raised the profile of CDI research and the search for more refined, targeted therapies. References 1. Marchesi JR. Adams DH. Fava F, et al. The gut microbiota and host health: a new clinical frontier. Gut. 2016;65:330–9. doi: 10.1136/gutjnl-2015-309990. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 2. McFarland LV. Epidemiology, risk factors and treatments for antibiotic-associated diarrhea. Dig Dis. 16:292–307. doi: 10.1159/000016879. [ DOI ] [ PubMed ] [ Google Scholar ] 3. Högenauer C. Hammer HF. Krejs GJ. Reisinger EC. Mechanisms and management of antibiotic-associated diarrhea. Clin Infect Dis. 1998;27:702–10. doi: 10.1086/514958. [ DOI ] [ PubMed ] [ Google Scholar ] 4. Rupnik M. Wilcox MH. Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol. 2009;7:526–36. doi: 10.1038/nrmicro2164. [ DOI ] [ PubMed ] [ Google Scholar ] 5. Public Health England Clostridium difficile: guidance, data and analysis. www.gov.uk/government/collections/clostridium-difficile-guidance-data-and-analysis . [Accessed 8 April 2018] 6. Aldeyab MA. Kearney MP. Scott MG, et al. An evaluation of the impact of antibiotic stewardship on reducing the use of high-risk antibiotics and its effect on the incidence of Clostridium difficile infection in hospital settings. J Antimicrob Chemother. 2012;67:2988–96. doi: 10.1093/jac/dks330. [ DOI ] [ PubMed ] [ Google Scholar ] 7. Public Health England Updated guidance on the diagnosis and reporting of Clostridium difficile. 2012. www.gov.uk/government/uploads/system/uploads/attachment_data/file/215135/dh_133016.pdf . [Accessed 18 April 2018] [ Google Scholar ] 8. Public Health England Updated guidance on the management and treatment of Clostridium difficile infection. 2013. www.gov.uk/government/uploads/system/uploads/attachment_data/file/321891/Clostridium_difficile_management_and_treatment.pdf . [Accessed 18 April 2018] [ Google Scholar ] 9. Kelly CP. LaMont JT. Clostridium difficile – more difficult than ever. N Engl J Med. 2008;359:193–240. doi: 10.1056/NEJMra0707500. [ DOI ] [ PubMed ] [ Google Scholar ] 10. Martin JSH. Monaghan TM. Wilcox MH. Clostridium difficile infection: epidemiology, diagnosis and understanding transmission. Nat Rev Gastroenterol Hepatol. 2016;13:206–16. doi: 10.1038/nrgastro.2016.25. [ DOI ] [ PubMed ] [ Google Scholar ] 11. Louie TJ. Miller MA. Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile Infection. N Engl J Med. 2011;364:422–31. doi: 10.1056/NEJMoa0910812. [ DOI ] [ PubMed ] [ Google Scholar ] 12. van Nood E Vrieze A. Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–15. doi: 10.1056/NEJMoa1205037. [ DOI ] [ PubMed ] [ Google Scholar ] 13. Cammarota G. Masucci L. Ianiro G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015;41:835–43. doi: 10.1111/apt.13144. [ DOI ] [ PubMed ] [ Google Scholar ] 14. Baxter M. Colville A. Adverse events in faecal microbiota transplant: a review of the literature. J Hosp Infect. 2016;92:117–27. doi: 10.1016/j.jhin.2015.10.024. [ DOI ] [ PubMed ] [ Google Scholar ] 15. National Institute for Health Care Excellence Faecal microbiota transplant for recurrent Clostridium difficile infection. Interventional procedure guidance; 2014. www.nice.org.uk/guidance/ipg485/resources/faecal-microbiota-transplant-for-recurrent-clostridium-difficile-infection-1899869993554885 . [Accessed 20 March, 2017] [ Google Scholar ] 16. Mullish BH. Williams HRT. Obstacles to establishing an NHS faecal transplant programme. BMJ. 2015;351:h6043. doi: 10.1136/bmj.h6043. [ DOI ] [ PubMed ] [ Google Scholar ] 17. Kao D. Roach B. Silva M, et al. Effect of oral capsule-vs colonoscopy-delivered fecal microbiota transplantation on recurrent Clostridum difficile infection. JAMA. 2017;318:1985–93. doi: 10.1001/jama.2017.17077. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 18. Mullish BH. Marchesi JR. Thursz MR. Williams HRT. Microbiome manipulation with faecal microbiome transplantation as a therapeutic strategy in Clostridium difficile infection. QJM. 2015;108:355–9. doi: 10.1093/qjmed/hcu182. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 19. Cammarota G. Ianiro G. Tilg H, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017;66:569–80. doi: 10.1136/gutjnl-2016-313017. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 20. Kelly CR. Ihunnah C. Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014;109:1065–71. doi: 10.1038/ajg.2014.133. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 21. Hamilton MJ. Weingarden AR. Sadowsky MJ. Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. 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Learn more: [PMC Disclaimer](https://pmc.ncbi.nlm.nih.gov/about/disclaimer/) \\| [PMC Copyright Notice](https://pmc.ncbi.nlm.nih.gov/about/copyright/) ![Clinical Medicine logo](https://cdn.ncbi.nlm.nih.gov/pmc/banners/logo-clinmed.png) Clin Med (Lond) . 2018 Jun;18(3):237–241. doi: [10\.7861/clinmedicine.18-3-237](https://doi.org/10.7861/clinmedicine.18-3-237) - [Search in PMC](https://pmc.ncbi.nlm.nih.gov/search/?term="Clin%20Med%20\(Lond\)"[jour]) - [Search in PubMed](https://pubmed.ncbi.nlm.nih.gov/?term="Clin%20Med%20\(Lond\)"[jour]) - [View in NLM Catalog](https://www.ncbi.nlm.nih.gov/nlmcatalog?term="Clin%20Med%20\(Lond\)"[Title%20Abbreviation]) - [Add to search](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/?term="Clin%20Med%20\(Lond\)"[jour]) # Clostridium difficile infection and antibiotic-associated diarrhoea [Benjamin H Mullish](https://pubmed.ncbi.nlm.nih.gov/?term="Mullish%20BH"[Author]) ### Benjamin H Mullish ASt Mary's Hospital Campus, Imperial College London, London, UK specialty registrar and MRC clinical research training fellow Find articles by [Benjamin H Mullish](https://pubmed.ncbi.nlm.nih.gov/?term="Mullish%20BH"[Author]) A,✉, [Horace RT Williams](https://pubmed.ncbi.nlm.nih.gov/?term="Williams%20HRT"[Author]) ### Horace RT Williams BSt Mary's Hospital Campus, Imperial College London, London, UK consultant gastroenterologist and honorary senior lecturer Find articles by [Horace RT Williams](https://pubmed.ncbi.nlm.nih.gov/?term="Williams%20HRT"[Author]) B - Author information - Copyright and License information ASt Mary's Hospital Campus, Imperial College London, London, UK BSt Mary's Hospital Campus, Imperial College London, London, UK ✉ Address for correspondence: Dr Benjamin H Mullish, Division of Integrative Systems Medicine and Digestive Disease, 10th Floor, QEQM Wing, St Mary's Hospital Campus, Imperial College London, South Wharf Road, Paddington, London W2 1NY, UK. Email: b.mullish@imperial.ac.uk #### Roles Benjamin H Mullish: specialty registrar and MRC clinical research training fellow Horace RT Williams: consultant gastroenterologist and honorary senior lecturer © Royal College of Physicians 2018. All rights reserved. [PMC Copyright notice](https://pmc.ncbi.nlm.nih.gov/about/copyright/) PMCID: PMC6334067 EMSID: [EMS79040](https://pmc.ncbi.nlm.nih.gov/articles/mid/EMS79040/) PMID: [29858434](https://pubmed.ncbi.nlm.nih.gov/29858434/) ## ABSTRACT Antibiotic-associated diarrhoea is among the most common adverse events related to antibiotic use. Most cases are mild, but Clostridium difficile infection causes a spectrum of disease, ranging from occasional diarrhoea to colitis, toxic megacolon, and potentially death. Recent developments in our understanding of the biology of the gut microbiota have provided new insights into the pathogenesis of these conditions, and have revealed a role for manipulation of the gut microbiota as a novel therapeutic approach. This review will give an overview of the assessment of these conditions, before focusing on the rapidly developing area of their treatment. KEYWORDS: Clostridium difficile, diarrhoea, antibiotics, faecal microbiota transplant, microbiota ## Key points - Antibiotic use may result in diarrhoea through different mechanisms, including: osmotic diarrhoea (through the loss of gut bacteria that absorb short-chain fatty acids); and colonisation and overgrowth of toxin-secreting Clostridium difficile - Typical laboratory tests for the presence of C difficile do not have high sensitivity and specificity in isolation, so a combination of tests should be used when making the diagnosis of CDI - CDI has recently become harder to treat with conventional antibiotics for several reasons, including increased treatment failure with metronidazole, rising rates of CDI recurrence, and the emergence of hypervirulent strains of C difficile (eg NAP1/027) - Fidaxomicin is a new antibiotic that has considerable efficacy in treating recurrent CDI, though there is uncertainty as to its use in particular situations, including treatment of the NAP1/027 strain - Randomised clinical trial evidence demonstrates that faecal microbiota transplant (FMT) is more effective than vancomycin for the treatment of recurrent or refractory CDI, and this treatment is now approved in guidelines ## Introduction In addition to being a potential reservoir for pathogenic bacteria, the gut also has an extensive ecosystem of microorganisms (∼1011 bacteria per gram of intestinal content) with no overt pathogenicity. It is now appreciated that this ecosystem (often called the ‘gut microbiota’) performs roles that are essential for the maintenance of host health, including short chain fatty acid and bile acid metabolism.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R1) Antibiotic-associated diarrhoea (AAD) is now understood to represent an imbalance of the gut microbiota resulting from antibiotic use, with several mechanisms appearing to contribute to the disease process. Most cases of AAD are mild and self-limiting, and are associated with negative stool culture results. Given the widespread use of antibiotics, it is not surprising that this condition is so common, affecting 5–39% of people treated with antibiotics.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R2) One key mechanism of AAD appears to be changes in the gut microbiota that cause decreased short-chain fatty acid absorption, resulting in osmotic diarrhoea.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R3) One particular form of AAD – Clostridium difficile infection (CDI) – can cause more severe gastrointestinal disease. Clostridium difficile (now also referred to as Clostridioides difficile) is a Gram-positive, spore-forming anaerobic bacillus. Spores of C difficile can survive for long periods on inanimate objects (resisting heat, acid and antibiotics), a major reason why this bacterium can cause such problems within healthcare settings. Clostridium difficile is spread via the faeco-oral route, and causes disease in humans through the production of two protein exotoxins (toxin A and toxin B), which are cytotoxic to colonic epithelial cells.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R4) The host's adaptive immune response following exposure to C difficile also appears to be important in determining the severity of the disease, with high IgG antitoxin level production being protective.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R4) Antibiotic use is the major risk factor for CDI, causing antibiotic-related loss of gut microbial communities that protect against gut infection, thereby facilitating the germination and vegetative growth of the organism when it enters the gut of vulnerable people. Risk factors for CDI are summarised in Table [1](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#T0001). The range of clinical disease that can occur in CDI is wide: diarrhoea and fever occur in almost all cases, but the most severe cases are characterised by colitis, toxic megacolon (dilatation of the colon, with the risk of perforation), multi-organ failure, or even death. ### Table 1. Risk factors for Clostridium difficile infection \| Risk factor \| Details \| \|---\|---\| \| Antibiotics \| Almost all antibiotics can increase vulnerability to Clostridium difficile infection (CDI), but cephalosporins, fluoroquinolones, clindamycin and certain penicillins (eg co-amoxiclav) increase risk to the greatest extent \| \| Acid-suppressant medications \| Both proton-pump inhibitors (PPI) and H2\-receptor antagonists appear to increase risk (risk is increased with PPI especially) \| \| Age \| Rates are ten-fold higher in those of \>65 years than in the younger population \| \| Hospitalisation \| •Recent hospitalisation, prolonged hospitalisation (\>7 days), and/or prolonged antibiotic courses all increase risk of CDI •Being admitted to a room where the previous patient had CDI is itself a risk factor for infection \| \| Immunosuppression \| \| [Open in a new tab](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/table/T0001/) Rates of CDI (and associated morbidity/mortality) peaked in the UK approximately 10 years ago (with about 70,000 cases in the UK, around 4000 of which were fatal, attributed to CDI in 2007).[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R5) Rates have since decreased rapidly. There are currently around 12,000 cases per year in the UK,[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R5) with the sharp recent decline in incidence being attributed to infection prevention and control interventions, including antibiotic stewardship.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R6) ## Diagnosis Typical AAD is a clinical diagnosis, based on the relationship between recent antibiotic use and the development of diarrhoea, and on the exclusion of potential alternative causes of diarrhoea. Diagnosis of CDI may be difficult for several reasons. First, the currently available tests lack ideal sensitivity and specificity. Second, C difficile may either cause asymptomatic colonisation or active gastrointestinal infection, and conventional tests do not clearly differentiate between these two states. Therefore, guidelines recommend testing for CDI only when a patient has diarrhoea and grounds for suspecting an infective aetiology.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R7) Laboratory tests for CDI are summarised in Table [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#T0002). ### Table 2. Tests for Clostridium difficile infection [7](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R7) \| Test \| Details \| \|---\|---\| \| GDH EIA \| GDH is a protein that is present in all isolates of C difficile. This test is sensitive, quick and relatively cheap, but lacks high specificity for toxigenic forms of C difficile. It is therefore often used as an initial screening test \| \| Toxin A and B EIA \| This test has high specificity but variable degrees of sensitivity \| \| Toxin A and B PCR \| This PCR test is specific for genes encoding toxins that are produced by C difficile, but a positive result does not help to distinguish active toxin production from asymptomatic carriage of toxigenic C difficile \| \| Cell culture cytotoxicity assay \| This is still widely recognised as the reference standard test, although it is rarely performed in most clinical laboratories \| [Open in a new tab](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/table/T0002/) Given the variability of the sensitivity and specificity of these tests, a two-stage testing algorithm is widely applied. In the UK, toxin A/B enzyme immunoassay (EIA) testing is often used after an initial glutamate dehydrogenase (GDH) or polymerase chain reaction (PCR) screen[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R7) Several other investigations may also be useful in the assessment of people with CDI. Leucocytosis (particularly neutrophilia) is common, and may be very marked. Abdominal radiograph is the preferred test for toxic megacolon, whereas abdominal CT is sensitive for the presence of CDI-related colitis. Lower gastrointestinal endoscopy may show only oedema or erythema, or may show the classical finding of pseudomembranes, ie raised yellowish plaques that may be intermittently scattered throughout affected colonic mucosa (Fig [1](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#F0001)). ### Fig 1. ![Fig 1.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab94/6334067/9e08457192b5/clinmed-18-3-237fig1.jpg) [Open in a new tab](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/figure/F0001/) Pseudomembranous colitis. Where clinicians have a strong clinical suspicion of CDI, empirical therapy should be considered regardless of the laboratory result; this is because with a high pre-test probability, the negative predictive value of the tests that are currently available is insufficient to exclude disease. ## Treatment In all cases of AAD, initial care includes the removal of precipitating factors (ie cessation of antibiotics). This will resolve the majority of cases of typical AAD (and some cases of CDI), but most cases of CDI will require more specific intervention. In treating CDI, a severity assessment is important to establish the most appropriate treatment. The assessment described in the current Public Health England (PHE) guidelines[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R8) is the most commonly used version: - white cell count \> 15 × 109/L - acutely rising creatinine (eg \>50% increase above baseline) - temperature \> 38.5°C - severe colitis (either from clinical abdominal signs or from radiological investigations). ### Conventional treatment of CDI Until recently, the antibiotics metronidazole and vancomycin were the only pharmacological options for the treatment of CDI. Metronidazole may be administered orally or intravenously, whereas vancomycin may be given orally or per rectum for this indication. Vancomycin is not used intravenously to treat CDI because it has very limited penetration into the gut mucosa. Intravenous immunoglobulin (IVIg) also has a role in treating severe disease. Until recently, these treatments were effective for most cases of CDI, with surgical intervention (colectomy) reserved for the small number of severe cases that were refractory to medical therapy.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R8) However, over the past decade, CDI has become more difficult to treat with conventional therapies for several reasons. First, the rate of CDI treatment failure with metronidazole is increasing, with rate of non-response now quoted at \>20%;[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R9) this is one of the reasons why patients with CDI and markers of severity should be treated with vancomycin in preference to metronidazole.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R8) Second, rates of recurrent CDI (ie return of disease within a short period after stopping antibiotic therapy) are also increasing.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R9) Third, hypervirulent strains of C difficile have emerged, particularly the NAP1/027 strain, which is associated with the secretion of large quantities of toxin and poor response to conventional antibiotics.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R10) Novel approaches for therapy for CDI are urgently sought. ### New antibiotics: fidaxomicin Fidaxomicin is a novel macrocyclic antibiotic, administered orally, with a narrow spectrum of activity. Although fidaxomicin has been shown in clinical trials to have efficacy in treating recurrent CDI[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R11) (and has consequently been added into clinical guidelines[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R8)), there are still a number of concerns regarding its use. These include its apparently limited efficacy against the NAP1/027 strain, the lack of evidence regarding its use in CDI with severe colitis, and its considerable expense (since it is 600 times more expensive than metronidazole.) ### Manipulation of the gut microbiota: probiotics and faecal microbiota transplantation Given that all forms of AAD represent a perturbation of the gut microbiota, restoration of the usual commensal microbiota is an appealing means of treating the condition. One approach to achieve this is through the use of probiotics, ie the delivery of live microorganisms into the host (sometimes through a suspension or drink). There are limited data regarding the use of probiotics to treat AAD/CDI, with relevant studies suggesting a possible modest benefit in treating non-severe CDI. However, significant uncertainties still exist in determining the specific organisms that should be included in the formulation, the dose to be used and so on, and probiotics are therefore not recommended at present. Another approach has been the use of faecal microbiota transplantation (FMT), that is, taking a stool sample from a healthy screened donor (with presumed ‘normal’ gut microbiota), processing this in a laboratory into a liquidised bacterial suspension, and delivering it into the gut of affected people. A number of case reports and small case series have described this treatment over the past 60 years, but the first major randomised trial investigating its efficacy was carried out in 2013.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R12) In this study, patients with recurrent CDI were randomised to receive either bowel lavage followed by FMT (via a nasoduodenal tube), vancomycin alone, or vancomycin with bowel lavage. The study was stopped early on ethical grounds after a planned interim analysis because 81% of patients (n=13/16) had recovered in the FMT arm, compared to 31% (n=4/13) receiving vancomycin alone, and 23% (n=3/13) receiving vancomycin and bowel lavage. Two of the three patients who did not respond to an initial FMT were successfully treated with a second. There were no major adverse effects. A subsequent randomised trial demonstrated that FMT was superior to vancomycin in treating recurrent CDI when administered colonoscopically.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R13) These and other studies have helped to establish optimal practical aspects related to FMT administration (Table [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#T0003)). FMT appears generally safe with mild, self-limiting gastrointestinal and constitutional symptoms being the most common complications described. However, there have been a small number of potential transmissions of infection, perforations associated with treatment administration, and even deaths related to its use (eg through aspiration of transplant material).[14](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R14) As a result of these clinical studies (coupled with other studies demonstrating its cost effectiveness), FMT has now been accepted as an approved treatment for recurrent or refractory CDI by NICE[15](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R15) and in PHE guidelines.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R8) FMT is now available as treatment for CDI within a growing number of UK centres, but the expense of establishing and maintaining a service, and ongoing discussions about the regulation and governance of FMT within the UK, have impacted upon more rapid adoption.[16](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R16) #### Table 3. Practical aspects of faecal microbiota transplantation (FMT). (Adapted from Mullish et al[18](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R18) and Cammarota et al[19](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R19)) \| Criteria \| Details \| \| \| \|---\|---\|---\|---\| \| Donor selection \| Screening questionnaire \| People \>60 years of age, those with recent antibiotic use (within six weeks), significant risk factors for blood-borne viruses, recent constitutional illness, and/or recent travel to countries with high rates of infectious diarrhoea are typically excluded from further assessment \| \| \| \| Medical questionnaire \| People with a personal or family history of disorders associated with perturbation of the gut microbiota (including inflammatory bowel disease, irritable bowel syndrome, metabolic syndrome, autoimmune disorders and/or gastrointestinal malignancy) are typically excluded from further assessment \| \| \| \| Laboratory testing, repeated at regular intervals, typically includes: \| Blood screening \| Hepatitis A serology Hepatitis B serology and hepatitis B DNA Hepatitis C serology and hepatitis C RNA HIV-1 and -2 and HTLV-1 and -2 serology Syphilis serology Cytomegalovirus and Epstein-Barr virus serology Entamoeba histolytica serology Strongyloides stercoralis serology \| \| \| \| Stool screening \| Microscopy, culture and sensitivity for enteric bacteria (at least three samples over three separate days) Analysis for ova, cysts and parasites (at least three samples over three separate days) Acid-fast staining for Cyclospora, Isospora and Cryptosporidium Screening for carriage of antibiotic-resistant organisms, carbapenemase-producing Enterobacteriaceae Clostridium difficile toxin and polymerase chain reaction (PCR) Analysis for rotavirus and adenovirus Helicobacter pylori faecal antigen \| \| Choice of recipients \| Indications \| Recurrent or relapsing CDI Limited data regarding efficacy in severe or fulminant CDI colitis \| \| \| \| Contraindications \| There are only a small number of absolute contraindications, eg a life-threatening food allergy FMT seems to have similar efficacy (and no additional infective complications) when given to immunocompromised individuals, including solid organ transplant recipients, recipients of recent chemotherapy, people with HIV infection and people with inflammatory bowel disease (IBD) taking B/T cell immunomodulatory therapy[20](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R20) \| \| \| Transplant preparation \| Typically \>50–60 g of stool is mixed with 250–300 mL of diluent (most often saline), before filtering of the slurry. The exact protocols used vary between different centres Transplants are either prepared from fresh stool on the day of delivery, or prepared in advance and frozen (using glycerol as a bacterial cryopreservative) before thawing on the day[21](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R21) \| \| \| \| Transplant delivery \| The transplant may be delivered either via the upper gastrointestinal route (gastroscopy, or nasogastric or nasoenteric tube) or by the lower gastrointestinal route (enema or colonoscopy). FMT capsules are an emerging delivery modality Anti-CDI antibiotics are typically stopped 12–72 hours prior to transplant; a polyethylene glycol preparation may be given on the day prior to administration A proton-pump inhibitor (PPI) and/or a prokinetic (ie metoclopramide) are often administered prior to upper gastrointestinal administration. Loperamide is often administered after lower gastrointestinal administration to facilitate retention within colon \| \| \| [Open in a new tab](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/table/T0003/) Given the obvious potential drawbacks of FMT (including its unpalatable nature and the invasive means of administration), there is great interest in refining FMT from its current state into a more acceptable pill or drink. ‘Capsulised’ FMT (in which faecal slurry or freeze-dried stool is placed into capsules) is now starting to become available and has recently been demonstrated to be of similar efficacy to colonoscopic FMT in a large randomised trial.[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R17) ### Other novel approaches A number of novel approaches for the treatment of CDI are at various stages of development; these are summarised in Table [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#T0004). #### Table 4. Novel approaches for the treatment of Clostridium difficile infection (CDI) \| Approach \| Details \| \| \|---\|---\|---\| \| Antimicrobials \| Antibiotics \| A number of novel antibiotics are in clinical trials \| \| \| Ribaxamase \| This is a beta-lactamase that may be co-administered with systemic broad-spectrum antibiotics, with the aim of degrading the antibiotics in the gut before they can affect the gut microbiota and create a propensity to CDI \| \| Immunisation \| Passive immunisation \| Co-administration of bezlotoxumab (an anti-toxin B antibody) together with conventional antibiotic therapy has been shown to reduce the rate of recurrence of CDI compared to antibiotic therapy alone[22](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R22) \| \| \| Active immunisation \| Anti-toxin vaccines are now in clinical trials. However, early data suggest reduced seroconversion in older people, those most at risk of CDI \| \| Microbiome manipulation \| Non-toxigenic C difficile[23](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R23) \| In a clinical trial, non-toxigenic C difficile was administered to those with CDI, with the aim of outcompeting toxigenic C difficile from its reservoir within the gut. CDI recurrence rates were 30% in those receiving placebo in comparison with 11% in those receiving non-toxigenic C difficile \| [Open in a new tab](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/table/T0004/) ## Conclusions AAD and CDI remain a common problems. Many cases are mild, but a significant number – especially of CDI – can be difficult to treat and potentially life-threatening. 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Readable Markdown	## ABSTRACT Antibiotic-associated diarrhoea is among the most common adverse events related to antibiotic use. Most cases are mild, but Clostridium difficile infection causes a spectrum of disease, ranging from occasional diarrhoea to colitis, toxic megacolon, and potentially death. Recent developments in our understanding of the biology of the gut microbiota have provided new insights into the pathogenesis of these conditions, and have revealed a role for manipulation of the gut microbiota as a novel therapeutic approach. This review will give an overview of the assessment of these conditions, before focusing on the rapidly developing area of their treatment. KEYWORDS: Clostridium difficile, diarrhoea, antibiotics, faecal microbiota transplant, microbiota ## Key points - Antibiotic use may result in diarrhoea through different mechanisms, including: osmotic diarrhoea (through the loss of gut bacteria that absorb short-chain fatty acids); and colonisation and overgrowth of toxin-secreting Clostridium difficile - Typical laboratory tests for the presence of C difficile do not have high sensitivity and specificity in isolation, so a combination of tests should be used when making the diagnosis of CDI - CDI has recently become harder to treat with conventional antibiotics for several reasons, including increased treatment failure with metronidazole, rising rates of CDI recurrence, and the emergence of hypervirulent strains of C difficile (eg NAP1/027) - Fidaxomicin is a new antibiotic that has considerable efficacy in treating recurrent CDI, though there is uncertainty as to its use in particular situations, including treatment of the NAP1/027 strain - Randomised clinical trial evidence demonstrates that faecal microbiota transplant (FMT) is more effective than vancomycin for the treatment of recurrent or refractory CDI, and this treatment is now approved in guidelines ## Introduction In addition to being a potential reservoir for pathogenic bacteria, the gut also has an extensive ecosystem of microorganisms (∼1011 bacteria per gram of intestinal content) with no overt pathogenicity. It is now appreciated that this ecosystem (often called the ‘gut microbiota’) performs roles that are essential for the maintenance of host health, including short chain fatty acid and bile acid metabolism.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R1) Antibiotic-associated diarrhoea (AAD) is now understood to represent an imbalance of the gut microbiota resulting from antibiotic use, with several mechanisms appearing to contribute to the disease process. Most cases of AAD are mild and self-limiting, and are associated with negative stool culture results. Given the widespread use of antibiotics, it is not surprising that this condition is so common, affecting 5–39% of people treated with antibiotics.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R2) One key mechanism of AAD appears to be changes in the gut microbiota that cause decreased short-chain fatty acid absorption, resulting in osmotic diarrhoea.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R3) One particular form of AAD – Clostridium difficile infection (CDI) – can cause more severe gastrointestinal disease. Clostridium difficile (now also referred to as Clostridioides difficile) is a Gram-positive, spore-forming anaerobic bacillus. Spores of C difficile can survive for long periods on inanimate objects (resisting heat, acid and antibiotics), a major reason why this bacterium can cause such problems within healthcare settings. Clostridium difficile is spread via the faeco-oral route, and causes disease in humans through the production of two protein exotoxins (toxin A and toxin B), which are cytotoxic to colonic epithelial cells.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R4) The host's adaptive immune response following exposure to C difficile also appears to be important in determining the severity of the disease, with high IgG antitoxin level production being protective.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R4) Antibiotic use is the major risk factor for CDI, causing antibiotic-related loss of gut microbial communities that protect against gut infection, thereby facilitating the germination and vegetative growth of the organism when it enters the gut of vulnerable people. Risk factors for CDI are summarised in Table [1](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#T0001). The range of clinical disease that can occur in CDI is wide: diarrhoea and fever occur in almost all cases, but the most severe cases are characterised by colitis, toxic megacolon (dilatation of the colon, with the risk of perforation), multi-organ failure, or even death. ### Table 1. Risk factors for Clostridium difficile infection \| Risk factor \| Details \| \|---\|---\| \| Antibiotics \| Almost all antibiotics can increase vulnerability to Clostridium difficile infection (CDI), but cephalosporins, fluoroquinolones, clindamycin and certain penicillins (eg co-amoxiclav) increase risk to the greatest extent \| \| Acid-suppressant medications \| Both proton-pump inhibitors (PPI) and H2\-receptor antagonists appear to increase risk (risk is increased with PPI especially) \| \| Age \| Rates are ten-fold higher in those of \>65 years than in the younger population \| \| Hospitalisation \| •Recent hospitalisation, prolonged hospitalisation (\>7 days), and/or prolonged antibiotic courses all increase risk of CDI •Being admitted to a room where the previous patient had CDI is itself a risk factor for infection \| \| Immunosuppression \| \| Rates of CDI (and associated morbidity/mortality) peaked in the UK approximately 10 years ago (with about 70,000 cases in the UK, around 4000 of which were fatal, attributed to CDI in 2007).[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R5) Rates have since decreased rapidly. There are currently around 12,000 cases per year in the UK,[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R5) with the sharp recent decline in incidence being attributed to infection prevention and control interventions, including antibiotic stewardship.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R6) ## Diagnosis Typical AAD is a clinical diagnosis, based on the relationship between recent antibiotic use and the development of diarrhoea, and on the exclusion of potential alternative causes of diarrhoea. Diagnosis of CDI may be difficult for several reasons. First, the currently available tests lack ideal sensitivity and specificity. Second, C difficile may either cause asymptomatic colonisation or active gastrointestinal infection, and conventional tests do not clearly differentiate between these two states. Therefore, guidelines recommend testing for CDI only when a patient has diarrhoea and grounds for suspecting an infective aetiology.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R7) Laboratory tests for CDI are summarised in Table [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#T0002). ### Table 2. Tests for Clostridium difficile infection [7](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R7) \| Test \| Details \| \|---\|---\| \| GDH EIA \| GDH is a protein that is present in all isolates of C difficile. This test is sensitive, quick and relatively cheap, but lacks high specificity for toxigenic forms of C difficile. It is therefore often used as an initial screening test \| \| Toxin A and B EIA \| This test has high specificity but variable degrees of sensitivity \| \| Toxin A and B PCR \| This PCR test is specific for genes encoding toxins that are produced by C difficile, but a positive result does not help to distinguish active toxin production from asymptomatic carriage of toxigenic C difficile \| \| Cell culture cytotoxicity assay \| This is still widely recognised as the reference standard test, although it is rarely performed in most clinical laboratories \| Given the variability of the sensitivity and specificity of these tests, a two-stage testing algorithm is widely applied. In the UK, toxin A/B enzyme immunoassay (EIA) testing is often used after an initial glutamate dehydrogenase (GDH) or polymerase chain reaction (PCR) screen[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R7) Several other investigations may also be useful in the assessment of people with CDI. Leucocytosis (particularly neutrophilia) is common, and may be very marked. Abdominal radiograph is the preferred test for toxic megacolon, whereas abdominal CT is sensitive for the presence of CDI-related colitis. Lower gastrointestinal endoscopy may show only oedema or erythema, or may show the classical finding of pseudomembranes, ie raised yellowish plaques that may be intermittently scattered throughout affected colonic mucosa (Fig [1](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#F0001)). ### Fig 1. ![Fig 1.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab94/6334067/9e08457192b5/clinmed-18-3-237fig1.jpg) Pseudomembranous colitis. Where clinicians have a strong clinical suspicion of CDI, empirical therapy should be considered regardless of the laboratory result; this is because with a high pre-test probability, the negative predictive value of the tests that are currently available is insufficient to exclude disease. ## Treatment In all cases of AAD, initial care includes the removal of precipitating factors (ie cessation of antibiotics). This will resolve the majority of cases of typical AAD (and some cases of CDI), but most cases of CDI will require more specific intervention. In treating CDI, a severity assessment is important to establish the most appropriate treatment. The assessment described in the current Public Health England (PHE) guidelines[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R8) is the most commonly used version: - white cell count \> 15 × 109/L - acutely rising creatinine (eg \>50% increase above baseline) - temperature \> 38.5°C - severe colitis (either from clinical abdominal signs or from radiological investigations). ### Conventional treatment of CDI Until recently, the antibiotics metronidazole and vancomycin were the only pharmacological options for the treatment of CDI. Metronidazole may be administered orally or intravenously, whereas vancomycin may be given orally or per rectum for this indication. Vancomycin is not used intravenously to treat CDI because it has very limited penetration into the gut mucosa. Intravenous immunoglobulin (IVIg) also has a role in treating severe disease. Until recently, these treatments were effective for most cases of CDI, with surgical intervention (colectomy) reserved for the small number of severe cases that were refractory to medical therapy.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R8) However, over the past decade, CDI has become more difficult to treat with conventional therapies for several reasons. First, the rate of CDI treatment failure with metronidazole is increasing, with rate of non-response now quoted at \>20%;[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R9) this is one of the reasons why patients with CDI and markers of severity should be treated with vancomycin in preference to metronidazole.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R8) Second, rates of recurrent CDI (ie return of disease within a short period after stopping antibiotic therapy) are also increasing.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R9) Third, hypervirulent strains of C difficile have emerged, particularly the NAP1/027 strain, which is associated with the secretion of large quantities of toxin and poor response to conventional antibiotics.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R10) Novel approaches for therapy for CDI are urgently sought. ### New antibiotics: fidaxomicin Fidaxomicin is a novel macrocyclic antibiotic, administered orally, with a narrow spectrum of activity. Although fidaxomicin has been shown in clinical trials to have efficacy in treating recurrent CDI[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R11) (and has consequently been added into clinical guidelines[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R8)), there are still a number of concerns regarding its use. These include its apparently limited efficacy against the NAP1/027 strain, the lack of evidence regarding its use in CDI with severe colitis, and its considerable expense (since it is 600 times more expensive than metronidazole.) ### Manipulation of the gut microbiota: probiotics and faecal microbiota transplantation Given that all forms of AAD represent a perturbation of the gut microbiota, restoration of the usual commensal microbiota is an appealing means of treating the condition. One approach to achieve this is through the use of probiotics, ie the delivery of live microorganisms into the host (sometimes through a suspension or drink). There are limited data regarding the use of probiotics to treat AAD/CDI, with relevant studies suggesting a possible modest benefit in treating non-severe CDI. However, significant uncertainties still exist in determining the specific organisms that should be included in the formulation, the dose to be used and so on, and probiotics are therefore not recommended at present. Another approach has been the use of faecal microbiota transplantation (FMT), that is, taking a stool sample from a healthy screened donor (with presumed ‘normal’ gut microbiota), processing this in a laboratory into a liquidised bacterial suspension, and delivering it into the gut of affected people. A number of case reports and small case series have described this treatment over the past 60 years, but the first major randomised trial investigating its efficacy was carried out in 2013.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R12) In this study, patients with recurrent CDI were randomised to receive either bowel lavage followed by FMT (via a nasoduodenal tube), vancomycin alone, or vancomycin with bowel lavage. The study was stopped early on ethical grounds after a planned interim analysis because 81% of patients (n=13/16) had recovered in the FMT arm, compared to 31% (n=4/13) receiving vancomycin alone, and 23% (n=3/13) receiving vancomycin and bowel lavage. Two of the three patients who did not respond to an initial FMT were successfully treated with a second. There were no major adverse effects. A subsequent randomised trial demonstrated that FMT was superior to vancomycin in treating recurrent CDI when administered colonoscopically.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R13) These and other studies have helped to establish optimal practical aspects related to FMT administration (Table [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#T0003)). FMT appears generally safe with mild, self-limiting gastrointestinal and constitutional symptoms being the most common complications described. However, there have been a small number of potential transmissions of infection, perforations associated with treatment administration, and even deaths related to its use (eg through aspiration of transplant material).[14](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R14) As a result of these clinical studies (coupled with other studies demonstrating its cost effectiveness), FMT has now been accepted as an approved treatment for recurrent or refractory CDI by NICE[15](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R15) and in PHE guidelines.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R8) FMT is now available as treatment for CDI within a growing number of UK centres, but the expense of establishing and maintaining a service, and ongoing discussions about the regulation and governance of FMT within the UK, have impacted upon more rapid adoption.[16](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R16) #### Table 3. Practical aspects of faecal microbiota transplantation (FMT). (Adapted from Mullish et al[18](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R18) and Cammarota et al[19](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R19)) \| Criteria \| Details \| \| \| \|---\|---\|---\|---\| \| Donor selection \| Screening questionnaire \| People \>60 years of age, those with recent antibiotic use (within six weeks), significant risk factors for blood-borne viruses, recent constitutional illness, and/or recent travel to countries with high rates of infectious diarrhoea are typically excluded from further assessment \| \| \| \| Medical questionnaire \| People with a personal or family history of disorders associated with perturbation of the gut microbiota (including inflammatory bowel disease, irritable bowel syndrome, metabolic syndrome, autoimmune disorders and/or gastrointestinal malignancy) are typically excluded from further assessment \| \| \| \| Laboratory testing, repeated at regular intervals, typically includes: \| Blood screening \| Hepatitis A serology Hepatitis B serology and hepatitis B DNA Hepatitis C serology and hepatitis C RNA HIV-1 and -2 and HTLV-1 and -2 serology Syphilis serology Cytomegalovirus and Epstein-Barr virus serology Entamoeba histolytica serology Strongyloides stercoralis serology \| \| \| \| Stool screening \| Microscopy, culture and sensitivity for enteric bacteria (at least three samples over three separate days) Analysis for ova, cysts and parasites (at least three samples over three separate days) Acid-fast staining for Cyclospora, Isospora and Cryptosporidium Screening for carriage of antibiotic-resistant organisms, carbapenemase-producing Enterobacteriaceae Clostridium difficile toxin and polymerase chain reaction (PCR) Analysis for rotavirus and adenovirus Helicobacter pylori faecal antigen \| \| Choice of recipients \| Indications \| Recurrent or relapsing CDI Limited data regarding efficacy in severe or fulminant CDI colitis \| \| \| \| Contraindications \| There are only a small number of absolute contraindications, eg a life-threatening food allergy FMT seems to have similar efficacy (and no additional infective complications) when given to immunocompromised individuals, including solid organ transplant recipients, recipients of recent chemotherapy, people with HIV infection and people with inflammatory bowel disease (IBD) taking B/T cell immunomodulatory therapy[20](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R20) \| \| \| Transplant preparation \| Typically \>50–60 g of stool is mixed with 250–300 mL of diluent (most often saline), before filtering of the slurry. The exact protocols used vary between different centres Transplants are either prepared from fresh stool on the day of delivery, or prepared in advance and frozen (using glycerol as a bacterial cryopreservative) before thawing on the day[21](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R21) \| \| \| \| Transplant delivery \| The transplant may be delivered either via the upper gastrointestinal route (gastroscopy, or nasogastric or nasoenteric tube) or by the lower gastrointestinal route (enema or colonoscopy). FMT capsules are an emerging delivery modality Anti-CDI antibiotics are typically stopped 12–72 hours prior to transplant; a polyethylene glycol preparation may be given on the day prior to administration A proton-pump inhibitor (PPI) and/or a prokinetic (ie metoclopramide) are often administered prior to upper gastrointestinal administration. Loperamide is often administered after lower gastrointestinal administration to facilitate retention within colon \| \| \| Given the obvious potential drawbacks of FMT (including its unpalatable nature and the invasive means of administration), there is great interest in refining FMT from its current state into a more acceptable pill or drink. ‘Capsulised’ FMT (in which faecal slurry or freeze-dried stool is placed into capsules) is now starting to become available and has recently been demonstrated to be of similar efficacy to colonoscopic FMT in a large randomised trial.[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R17) ### Other novel approaches A number of novel approaches for the treatment of CDI are at various stages of development; these are summarised in Table [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#T0004). #### Table 4. Novel approaches for the treatment of Clostridium difficile infection (CDI) \| Approach \| Details \| \| \|---\|---\|---\| \| Antimicrobials \| Antibiotics \| A number of novel antibiotics are in clinical trials \| \| \| Ribaxamase \| This is a beta-lactamase that may be co-administered with systemic broad-spectrum antibiotics, with the aim of degrading the antibiotics in the gut before they can affect the gut microbiota and create a propensity to CDI \| \| Immunisation \| Passive immunisation \| Co-administration of bezlotoxumab (an anti-toxin B antibody) together with conventional antibiotic therapy has been shown to reduce the rate of recurrence of CDI compared to antibiotic therapy alone[22](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R22) \| \| \| Active immunisation \| Anti-toxin vaccines are now in clinical trials. However, early data suggest reduced seroconversion in older people, those most at risk of CDI \| \| Microbiome manipulation \| Non-toxigenic C difficile[23](https://pmc.ncbi.nlm.nih.gov/articles/PMC6334067/#R23) \| In a clinical trial, non-toxigenic C difficile was administered to those with CDI, with the aim of outcompeting toxigenic C difficile from its reservoir within the gut. CDI recurrence rates were 30% in those receiving placebo in comparison with 11% in those receiving non-toxigenic C difficile \| ## Conclusions AAD and CDI remain a common problems. Many cases are mild, but a significant number – especially of CDI – can be difficult to treat and potentially life-threatening. Developments in our understanding of the importance of the gut microbiota, and the marked efficacy of FMT in clinical trials, have raised the profile of CDI research and the search for more refined, targeted therapies. ## References - 1\. Marchesi JR. Adams DH. Fava F, et al. 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