Clostridium difficile

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A sporing bacterium from the genus Clostridium that can be regarded as a normal part of the gut flora, and usually effectively kept in its place by other gut flora. Formation of p-cresol as the main fermentation product of tyrosine by C. difficile is unique among clostridial species. The particular pattern of volatile products does seem distinctive and presumably compounds such as 5-methyl-2-furancarboxaldehyde allow the organism to be often recognised by smell[1] although dogs[2] are almost certainly better than nurses[3].

Pseudomembranous colitis.

It generally causes a diarrhoeal disease due to pseudomembranous colitis, so named because of endoscopic appearances, but can rarely also affect the small bowel as well as seen by the accumulating number of case reports.[4][5][6][7][8][9][10]

Contents

Aetiology

Ubiquitous environmental contaminant, with spores that are both resistant and excreted in massive quantities in an overgrowth situation such as can occur with. The spores are transfered by several routes including the hands.[11] The polymerase-chainreaction ribotype O27 strain (Also known as NAP1/B1/O27, North American Pulsed Field type 1, restriction-endonuclease analysis type B1) outbreaks in USA, Canada and Europe from 2003 onwards are associated with different antibiotic exposure patterns to other ribotypes and this is extremely important in controlling this pathogen.[12]

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Clinical

Most cases present with characteristic profuse diarrhoea which many health care workers can diagnose by the distinctive p-cresol smell (you can only smell it if you have the right genetics!). Unhappily mortality is connected to ribotype and the public scandals where such issues have been brought to the fore at least concentrate minds.

Epidemiology

There has been a trend from 1990s for reduced rates of clinical response and increased recurrence rates with more involvement of younger patients and peripartum women.There have been serotype changes and changes in the prior antibiotic exposure most likely to be associated with infection. This is a field where old knowledge is exactly that. The spread via environmental contamination has proved very challenging to address in hospital environments. Investment in good cleaning, antimicrobial stewardship and hygiene practices can markedly reduce incidence. For example simply treating a prior patient occupying a given hospital bed increases the risk of the next bed occupant getting infection by 22%[13]

Investigations

Stool tests

  • Stool toxin assay is very useful but can be negative (especially early in infection) and very occasionally positive due to other Clostridium spp..
  • Serotyping is effectively retrospective

Radiology

  • Toxic megacolon is the feared complication

Treatment

C. difficile can be spread among hospital patients and isolation is important.

Medical

A Cochrane review of randomised controlled trials reveals that only vancomycin has evidence against placebo[14].

  • First line Metronidazole PO TDS x7-10days (but give iv if patient can not take orally) for which there is high quality evidence
  • Second line Vancomycin 250mg PO QDS x 7-10 days for which there is high quality evidence
  • Third line: There is moderate quality evidence for prolonged courses of above. Other antibiotics such as fidaxomicin are clinically effective but only likely to be economic third line[15]
  • Probiotics have an unclear place in treatment (see below for prevention) and positive evidence of any benefit seems confined to children.

Surgical

  • Toxic megacolon may require urgent resection for which there is strong recommendation as it is life saving.

Stool Transfer

Donated stool from healthy individuals with normal flora can be transferred to afflicted patients as a form of faecal bacteriotherapy (faecal microbiota transplantation).[16]. As of 2013 the best proven regime in recurrent C. difficile is 4 days of oral vancomycin followed by duodenal infusion which achieves a 80% cure rate versus 30% for vancomycin at 10 weeks[17].

Prevention

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  1. high standards of cleanness and actual hand washing
  2. Narrow spectrum antibiotics

The proven interventions are:

C. difficile rates related to changes in antibiotic policy for a large acute hospital
  • Good hygiene, infection control and cleaning practices has high quality evidence
  • Reducing broad spectrum antibiotic load has high quality evidence. This requires removal of drugs like co-amoxiclav, Cephalosporins and ciprofloxacin from use in common indications like chest infections, exacerbation of COPD, soft tissue infections and urinary tract infections. Reversion to more narrow spectrum drugs which deal with the nastier pathogens and use of doxycycline and gentamicin reduces over all mortality and morbidity, something that those doctors who want to give the best possible therapy to the individual and have traditionally chosen the antibiotic that killed all known causes of the infection in question might bear in mind.

These can have a good sustained effect on C. difficile attack rates, even with the O27 ribotype.

  • Probiotics have low quality evidence[18]
    • The evidence base is product specific and even then challenging to interpret[19]

There are a number of associations that may or may not translate into useful interventions:

  • Initial reports that Clostridium difficile diarrhoea was associated with a higher rates of PPI use which makes some sense, then had to be tempered by the not unexpected discovery that use of H2-receptor blockers is also correlated with incidence. There is no evidence base to confirm that primary intervention works but in the context that PPIs increase the rate of recurrence by over four times there is a case for discontinuing PPIs on diagnosis of C difficile [20].

According to Bandolier, "the estimated cost of a case of Clostridium difficile diarrhoea in hospital usually to an older and sicker patient, is about £5000, and prolongs length of stay by 21 days. Reduction of PPI use may be an additional strategy to reduce the incidence of this infection, as vegetative cells are highly susceptible to acid." This is also relevant to observations such as that hospitals with higher rates of C. difficile infection tend to have higher bed occupancy.

There is high quality evidence that alcohol hand-rubs may be relatively ineffective in preventing cross-infection by spore-forming organisms such as C diff.

References

  1. Probert CS, Jones PR, Ratcliffe NM. A novel method for rapidly diagnosing the causes of diarrhoea. Gut. 2004 Jan; 53(1):58-61.
  2. Rowley T. 'Pet scans': training dogs to sniff out disease. Lab animal. 2013 Feb; 42(2):42.(Link to article – subscription may be required.)
  3. Rao K, Berland D, Young C, Walk ST, Newton DW. The nose knows not: poor predictive value of stool sample odor for detection of Clostridium difficile. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2013 Feb; 56(4):615-6.(Link to article – subscription may be required.)
  4. Vesoulis Z, Williams G, Matthews B. Pseudomembranous enteritis after proctocolectomy: report of a case. Diseases of the colon and rectum. 2000 Apr; 43(4):551-4.
  5. Jacobs A, Barnard K, Fishel R, Gradon JD. Extracolonic manifestations of Clostridium difficile infections. Presentation of 2 cases and review of the literature. Medicine. 2001 Mar; 80(2):88-101.
  6. Freiler JF, Durning SJ, Ender PT. Clostridium difficile small bowel enteritis occurring after total colectomy. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2001 Oct 15; 33(8):1429-31; discussion 1432.(Link to article – subscription may be required.)
  7. Hayetian FD, Read TE, Brozovich M, Garvin RP, Caushaj PF. Ileal perforation secondary to Clostridium difficile enteritis: report of 2 cases. Archives of surgery (Chicago, Ill. : 1960). 2006 Jan; 141(1):97-9.(Link to article – subscription may be required.)
  8. Kim KA, Wry P, Hughes E, Butcher J, Barbot D. Clostridium difficile small-bowel enteritis after total proctocolectomy: a rare but fatal, easily missed diagnosis. Report of a case. Diseases of the colon and rectum. 2007 Jun; 50(6):920-3.(Link to article – subscription may be required.)
  9. Yafi FA, Selvasekar CR, Cima RR. Clostridium difficile enteritis following total colectomy. Techniques in coloproctology. 2008 Mar; 12(1):73-4.
  10. Fleming F, Khursigara N, O'Connell N, Darby S, Waldron D. Fulminant small bowel enteritis: A rare complication of Clostridium difficile-associated disease. Inflammatory bowel diseases. 2008 Oct 22.(Epub ahead of print) (Link to article – subscription may be required.)
  11. Johnson S, Gerding DN, Olson MM, Weiler MD, Hughes RA, Clabots CR, et al. Prospective, controlled study of vinyl glove use to interrupt Clostridium difficile nosocomial transmission. The American journal of medicine. 1990;88:137-40.
  12. Kuijper EJ, Coignard B, Tull P; the ESCMID Study Group for Clostridium difficile (ESGCD) Emergence of Clostridium difficile-associated disease in North America and Europe. Clin Microbiol Infect. 2006;12 Suppl 6:2-18
  13. Freedberg DE, Salmasian H, Cohen B, Abrams JA, Larson EL. Receipt of Antibiotics in Hospitalized Patients and Risk for Clostridium difficile Infection in Subsequent Patients Who Occupy the Same Bed. JAMA internal medicine. 2016 Dec; 176(12):1801-1808.(Print) (Link to article – subscription may be required.)
  14. Nelson RL, Kelsey P, Leeman H, Meardon N, Patel H, Paul K, Rees R, Taylor B, Wood E, Malakun R. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane database of systematic reviews (Online). 2011; (9):CD004610.(Epub) (Link to article – subscription may be required.)
  15. Wagner M, Lavoie L, Goetghebeur M. Clinical and economic consequences of vancomycin and fidaxomicin for the treatment of Clostridium difficile infection in Canada. The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie médicale / AMMI Canada. 2014 Mar; 25(2):87-94.
  16. Persky SE, Brandt LJ. Treatment of recurrent Clostridium difficile-associated diarrhea by administration of donated stool directly through a colonoscope. The American journal of gastroenterology. 2000 Nov; 95(11):3283-5.
  17. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. The New England journal of medicine. 2013 Jan 16.(Epub ahead of print) (Link to article – subscription may be required.)
  18. Goldenberg JZ, Ma SS, Saxton JD, Martzen MR, Vandvik PO, Thorlund K, Guyatt GH, Johnston BC. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. The Cochrane database of systematic reviews. 2013; 5:CD006095.(Epub) (Link to article – subscription may be required.)
  19. Claassen E. Cost-benefit relation of diet and probiotics in iatrogenic bowel irregularity (IBI). Frontiers in pharmacology. 2014; 5:14.(Epub) (Link to article – subscription may be required.)
  20. Cadle RM, Mansouri MD, Logan N, Kudva DR, Musher DM. Association of proton-pump inhibitors with outcomes in Clostridium difficile colitis. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2007 Nov 15; 64(22):2359-63.(Link to article – subscription may be required.)