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Clostridium difficile (C. difficile) is a species of bacteria of the genus Clostridium, which are gram-positive, anaerobic, spore-forming rods. It is present as one of the normal bacterial flora in the gut of up to about three per cent of healthy adults. It was first described by Hall and O’Toole in 1935.1 The species was named ‘difficile’ because initially it was hard to culture.2 It was resistant to early attempts at its isolation as it grew very slowly in culture.
The organism forms heat-resistance spores that can remain in the hospital environment and nursing home for a long period of time. It is a frequent cause of diarrhoea in hospitalised patients. During an outbreak, C. difficile spreads rapidly through the hospital where its spores can persist for several months.
Epidemiology
C. difficile is a frequent and clinically important cause of diarrhoea that has been strongly but not exclusively associated with the hospital setting.3
In the past decade, there has been an increasing rise in the number of reported cases of C. difficile infection (CDI) in England and Wales. It is estimated to be the leading cause of nosocomial infectious diarrhoea. This could be due to a real increase in the number of new cases. Another possibility is that professional awareness and DR laboratory facilities for diagnosing the disease have improved. Hands of personnel, as well as a variety of environmental sites within hospital settings, have also been found to be contaminated with C. difficile.
Incidence of Clostridium difficile
The incidence in England has been ascertained by reviewing hospital diagnosis, laboratory and case reports and death certificates. Latest figures from the Health Protection Agency (HPA) show there were 55,681 cases of Clostridium difficile infection reported in patients aged 65 years and above in England in 2006. This represents an annual increase in reported infections of eight per cent compared to 2005, when there were 51,767 cases reported.
Rates of infection remain high across England, particularly in small acute trusts, and the results show clearly the scope for improvement. This contrasts favourably with the 17 per cent increase in reported cases between 2004 and 2005.4 Since January 2004, it has been mandatory that all cases of CDI in people aged 65 years are reported as part of the Department of Health’s programme of mandatory surveillance of healthcare associated infections.
There are also concerns that CDI is beginning to affect the younger age groups although the evidence supporting this is inconclusive. However, from April 2007 all acute NHS trusts in England are required to report all cases of CDI in patients aged two years and over. Detection of trends in disease and mortality associated with CDI is a joint project between the Office of National Statistics (ONS) and the HPA. Deaths involving C. difficile mostly occurred at older ages. Mortality rates in 2005 for deaths involving C. difficile in the 85 years and over age group were 1,580 and 1,812 deaths per million populations for males and females respectively.
In the under 45 age group, there were 0.2 deaths per million populations for both males and females5 . Pathophysiology In the last few years, considerable advances have emerged in our understanding of the pathophysiology of CDI. Pathogenic C. difficile strains produce various toxins. The most well characterised are enterotoxin (toxin A) and cytotoxin (toxin B), encoded by the genes tcdA and tcdB, respectively.
The expression of tcdA and tcdB is down-regulated by the tcdC gene. Polymorphisms or partial deletions of tcdC may lead to increased production of toxin A and B.6 Antibiotic use plays an important trigger role for the emergence of the infection. A possible explanation for this is that antibiotics may lead to a partial deletion of tcdC genes in Clostridium difficile that may also confer an increased virulence.6 Even after the discontinuation of antibiotic therapy, Clostridium difficile associated diarrhoea can occur up to eight weeks after it was ceased.
Risk factors for Clostridium difficile
The risk of developing antibiotic-associated diarrhoea more than doubles with longer than three days of antibiotic therapy (risk ratio: 2.28)2 . Most cases occur on days four through nine of antibiotic therapy. The rate of C. difficile acquisition is estimated to be 13 per cent in patients with hospital stays of up to two weeks and 50 per cent in those with hospital stays longer than four weeks. Prospective studies have shown that patients can be contaminated from environmental surfaces, shared instrumentation, hospital personnel hands and infected roommates.7
The transmission of the infection among hospitals may be enhanced by inappropriate hygiene among staff and patients who are colonised with the infection. According to one systematic review, the following are the identifiable risk factors for Clostridium difficile:8
- Increasing age > 65 years
- Exposure to antibiotics
- Long duration of antibiotic use
- Multiple antibiotic use
- Long duration of hospital stay
- Immunocompromised patients
- Severe debilitating associated disease
- Nasogastric and PEG feeding
- Intensive unit stay
- Use of proton pump inhibitor
- Chemotherapy use.
Clinical presentation
Clostridium difficile is responsible for 15 to 20 per cent of antibiotic-related causes of diarrhoea and nearly all cases of pseudomembranous colitis. The majority of patients remain asymptomatic after exposure to Clostridium difficile but can be carriers. Clostridium difficile associated diarrhoea was defined by the presence of diarrhoea and a positive assay for Clostridium difficile toxin A, toxin B, or both; by the sudden onset of diarrhoea with no alternative explanation and a diagnosis of pseudomembranous colitis on the basis of endoscopy; or by histological evidence of the condition6 . A case will be regarded as nosocomial if it occurs after 72 hours of hospital stay. The infection may also present as mild, moderate and fulminant. Clinical differentiation between mild and moderate disease may be difficult to delineate. In the mild cases, symptoms may begin shortly after a short period of exposure to antibiotics with diarrhoea.
In most cases, there may not be other systematic symptoms. Physical examination may be normal or reveal abdominal tenderness. The stool will be positive for C. difficile toxins. In the severe forms, there is presence of colitis, which can manifest with profuse diarrhoea, abdominal pain and distension. Other systemic symptoms such as malaise, nausea, fever and vomiting and dehydration may be present. The patient may have bleeding from the rectum. Peripheral blood will show leukocytosis and elevated C-reactive protein.
Endoscopy (flexible sigmoidoscopy) usually reveals diffuse or patchy inflammatory changes of colitis. The fulminant form usually presents like the severe form, but there is presence of pseudomembranous changes (these are yellow plaques adherent to the mucosa that vary from 0.2cm to 1cm in size) on endoscopy. The patient may become very ill and toxic with fever, tachycardia and abdominal pain. Complications such as paralytic ileus and megacolon may arise and the patient may die from septic shock.
Diagnosis
Clostridium difficile grown from culture (cytotoxin assay) is the gold standard for diagnosis and is the most sensitive test. Though this is a highly sensitive and specific test, it is difficult to culture the organism, so this is rarely required. Some hospital laboratories use the Triage Micro Clostridium difficile panel (Biosite) for the detection of glutamate dehydrogenase and toxin A in stool samples, and others use the colorPAC toxin A kit (Becton Dickinson).
The most commonly use test for Clostridium difficile infection is an enzyme immunoassay that detects toxins A and B. This provides results within two to six hours and has a specificity of 93 per cent and sensitivity of 63–99 per cent. Often, the stool sample may remain positive for an extended period of time in 25 per cent of patients after successful treatment for the infection. Therefore, patients who develop or present with nosocomial diarrhoea in hospitals should be systematically investigated to reduce and terminate the risk of an outbreak. There is no indication for testing asymptomatic patients, even after treatment of the disease.
Treatment of Clostridium difficile
Antimicrobial agents are usually not recommended in asymptomatic carriers or patients. In any case of suspected or confirmed Clostridium difficile infection, the offending antibiotic should be withdrawn. Other measures may include supportive treatment with adequate fluid and correction of any electrolyte imbalance.
Prompt treatment may be required in elderly patients and those with other risk factors. There is uncertainty as to current evidence whether mild C. difficile diarrhoea requires antibiotic treatment.9 An antibiotic is indicated if there is evidence of colitis eg. fever, leukocytosis and characteristic findings of colitis on CT scanning or endoscope. The recommended first line antibiotic is metronidazole in doses of 400mg orally three times daily for 10 to 14 days.10 It has about 90 per cent response rate. However, there are emerging strains of Clostridium difficile that are resistant to this initial therapy. In most hospitals, the first agent is metronidazole, and vancomycin is another first choice and may be used when the patient has not responded to metronidazole. It can be used at higher doses of 250mg qds, in severe forms of the disease and in refractory cases.
Impact of infection
Nosocomial infection results in an infection that can increase the length of the hospital stay ranging from eight to 21 days7 . It increases morbidity and mortality of patients, especially the elderly and those with multiple diseases. The severity of the infection has been shown to be an important predictor of mortality for a variety of conditions and is also a predictor of the acquisition of C. difficile6 . It can also increase the cost of patients’ care and there are reported cases of C. difficile infection as the main cause of death.
Prevention of Clostridium difficile
Clostridium difficile can be spread by faecal oral route, especially through its spores left on contaminated surfaces. The most important preventive measure is that all physicians should stress judicious use of antibiotics and should maintain a high index of suspicion for C. difficile infection in our hospitals and care homes. Most of the disinfectants commonly used in the hospitals may fail to kill the bacteria and may actually promote spore formation. However, disinfectants containing bleach are effective in killing the organisms.
The most important means of control measures is directed at reduction of symptomatic disease by use of antimicrobial agents such as metronidazole and vancomycin10. Healthcare workers should be well educated on preventive measures and strict use of antibiotics.
Conclusion
Clostridium difficile infection is the most recognised cause of antibiotic-associated diarrhoea and antibiotic-associated pseudomembranous colitis in patients admitted in hospitals in the UK. In recent years, the incidence of this disease is on the increase. It remains a concern on the best way to eradicate this infection in the various hospitals across the UK.
JAMES ALEGBELEYE is a specialist registrar in geriatric medicine at Basildon and Thurrock University Hospitals NHS Trust, Nethermayne, Basildon
References
1. Hall I, O’Toole E. Intestinal flora in newborn infants with a description of a new pathogenic anaerobe, Bacillus difficilis. Am J Dis Child J Dis Child 1935; 49: 390
2. Michael S, Schroeder MD. Clostridium difficile-associated diarrhea. American Family Physician 2005; 71(5) http:// www.aafp.org/ afp/20050301/921.html (date last accessed: 13/08/07)
3. Samone M. Epidemiology of nosocomial clostridium difficile diarrhoea. J Hosp Infect J Hosp Infect 1999; 43: S183–90
4. http://www.hpa.org.uk/hpa/ news/articles/press _ releases/2007/070426 _ clostridium _ mrsa.htm (date last accessed: 13/08/07)
5. http://www.statistics.gov.uk/cci/ nugget.asp?id=1735 (date last accessed: 13/08/07)
6. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multiinstitutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med N Engl J Med 2005; 353(23): 2442–9
7. Barbut F, Petit JC. Epidemiology of clostridium difficile associated infections. Clin Microbiol Infect 2001; 7(8): 405–10
8. Bignardi GE. Risk factors for Clostridium difficile infection. J Hosp Infect 1998; 40: 1–15
9. Bricker E, Garg R, Nelson R, Loza A, et al. Antibiotic treatment for Clostridium difficile associated diarrhoea in adults. Cochrane Database of Systematic Reviews 2005, Issue 1
10. Starr J. Clostridium diffi cile associated diarrhoea: diagnosis and treatment. BMJ 2005; 331: 498–501
