'''Clostridium difficile''' or CDF/cdf' (commonly mistaken , alternatively and correctly pronounced ) (also referred to as 'C. diff' or 'C-diff') is a species of
bacteria of the genus ''
Clostridium'' which are
gram-positive,
anaerobic,
spore-forming rods (bacillus).
[ Sherris Medical Microbiology, Ryan KJ; Ray CG (editors), , , McGraw Hill, 2004, ISBN 0-8385-8529-9 ] ''C. difficile'' is the most significant cause of
pseudomembranous colitis,
[ ] a severe infection of the
colon, often after normal
gut flora is eradicated by the use of
antibiotics. Treatment is by stopping any antibiotics and commencing specific anticlostridial antibiotics, e.g.
metronidazole.
Bacteriology
Clostridia are motile
bacteria that are ubiquitous in nature and are especially prevalent in
soil. Under the microscope after
Gram staining, they appear as long drumsticks with a bulge located at their terminal ends. ''Clostridium difficile'' cells are
Gram positive. ''Clostridium'' shows optimum growth when plated on
blood agar at human body temperatures. When the environment becomes stressed, however, the bacteria produce spores that tolerate the extreme conditions that the active bacteria cannot. First described by Hall and O'Toole in
1935, "the difficult clostridium" was resistant to early attempts at isolation and grew very slowly in culture.
[ Intestinal flora in newborn infants with a description of a new pathogenic anaerobe, ''Bacillus difficilis'', Hall I, O'Toole E, , , Am J Dis Child, 1935 ]
''C. difficile'' is a
commensal bacterium of the human
intestine in a minority of the population. Patients who have been staying long-term in a hospital or a nursing home have a higher likelihood of being
colonized by this bacterium. In small numbers it does not result in disease of any significance. Antibiotics, especially those with a broad spectrum of activity, cause disruption of normal
intestinal flora, leading to an overgrowth of ''C. difficile''. This leads to
pseudomembranous colitis.
''C. difficile'' is resistant to most
antibiotics. It flourishes under these conditions. It is transmitted from person to person by the
fecal-oral route. Because the organism forms heat-resistant spores, it can remain in the
hospital or
nursing home environment for long periods of time. It can be cultured from almost any surface in the hospital. Once spores are ingested, they pass through the stomach unscathed because of their acid-resistance. They change to their active form in the colon and multiply.
It has been observed that several
disinfectants commonly used in hospitals may fail to kill the bacteria, and may actually promote spore formation. However, disinfectants containing
bleach are effective in killing the organisms
[1].
Pseudomembranous colitis caused by ''C. difficile'' is treated with antibiotics, for example,
vancomycin,
metronidazole, bacitracin or fusidic acid.
Toxins
Pathogenic ''C. difficile'' strains produce various
toxins. The most well-characterized are
enterotoxin (''toxin A'') and
cytotoxin (''toxin B'').
These two toxins are both responsible for the
diarrhea and
inflammation seen in infected patients, although their relative contributions have been debated by researchers. Another toxin, ''binary toxin'', has also been described, but its role in disease is not yet fully understood.
[2]
Role in disease
With the introduction of
broad-spectrum antibiotics in the latter half of the twentieth century, antibiotic-associated diarrhea became more common.
Pseudomembranous colitis was first described as a complication of ''C. difficile''
infection in
1978,
[ ''Clostridium difficile'' and the aetiology of pseudomembranous colitis, Larson H, Price A, Honour P, Borriello S, , , Lancet, 1978 ] when a toxin was isolated from patients suffering from pseudomembranous colitis and
Koch's postulates were met.
''Clostridium Difficile Infection'' (CDI), can range in severity from asymptomatic to severe and life threatening, and many deaths have been reported, especially amongst the aged. People are most often infected in
hospitals,
nursing homes, or institutions, although ''C. difficile'' infection in the community, outpatient setting is increasing. ''Clostridium difficile'' associated diarrhea (aka CDAD) has been linked to use of broad-spectrum antibiotics such as
cephalosporins and
clindamycin, which are frequently used in hospital settings. Frequency and severity of ''C. difficile'' colitis remains high and seems to be associated with increased death rates. Immunocompromised status and delayed diagnosis appear to result in elevated risk of death. Early intervention and aggressive management are key factors to recovery.
The rate of ''Clostridium difficile'' acquisition is estimated to be 13 percent in patients with hospital stays of up to two weeks and 50 percent in those with hospital stays longer than four weeks.
Increasing rates of community-acquired ''Clostridium difficile''-associated infection/disease (CDAD) has also been linked to the use of medication to suppress
gastric acid production:
H2-receptor antagonists increased the risk twofold, and
proton pump inhibitors threefold, mainly in the elderly. It is presumed that increased gastric
pH, (alkalinity), leads to decreased destruction of spores.
[ Use of gastric acid-suppressive agents and the risk of community-acquired ''Clostridium difficile''-associated disease, Dial S, Delaney J, Barkun A, Suissa S, , , JAMA, 2005 ]
Prevention
The most effective method for preventing CDAD is proper antimicrobial prescribing. In the hospital setting, where CDAD is most common, nearly all patients who develop CDAD are exposed to antimicrobials. Although this sounds easy to do, approximately 50% of antimicrobial use is considered inappropriate. This is consistent whether in the hospital, clinic, community, or acedemic setting. Several studies have demostrated a decrease in CDAD by limiting antibitoics most strongly assoicated with CDAD or by limiting unnecessary antimicrobial prescribing in general, both in outbreak and non-outbreak settings.
Infection control measures, such as wearing gloves when caring for patients with CDAD, have been proven to be effective at preventing CDAD. This works by limiting the spread of ''C. difficile'' in the hospital setting.
Treatment with various oral supplements containing live bacteria has been studied in efforts to prevent ''Clostridium difficile''-associated infection/disease. A randomized, double- blind, placebo-controlled study using a probiotic drink containing ''Lactobacillus casei'', ''L bulgaricus'', and ''Streptococcus thermophilus'' was reported to have some efficacy. This study was sponsored by the company that produces the drink studied
[ Use of probiotic ''Lactobacillus'' preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial, Hickson M, D'Souza A, Muthu N, Rogers T, Want S, Rajkumar C, Bulpitt C,, , , BMJ, 29 June 2007 epub ahead of print ]. Although intreguing, several other studies have been unable to demonstrate any benefit of oral suppliments of similar bacteria at preventing CDAD. Of note, patients on the antibiotics most strongly associated with CDAD were excluded from this study.
Diagnosis and treatment
''C. difficile'' toxin detection as cytopathic effect in cell culture, and neutralized with specific anti-sera is the practical gold standard for studies investigating new CDAD diagnostic techniques. Toxigenic culture , in which organisms are cultured on selective medium and tested for toxin production remains the
gold standard and is the most sensitive and specific test, although it is slow and labour-intensive.
[ Manual of Clinical Microbiology, Murray PR, Baron EJ, Pfaller EA, Tenover F, Yolken RH (editors), , , ASM Press, , ] Assessment of the A and B toxins by
enzyme-linked immunoabsorbant assay (ELISA) for toxin A or B (or both) has a
sensitivity of 63-99% and a
specificity of 93-100%. In adults, the absence of diarrhea, exposure of antibiotics or absence of abdominal pain has a
negative predictive value of 94% in hospitalized patients. Experts recommend sending as many as three samples to rule-out disease if initial tests are negative. This strategy may not be necessary given the high sensitivity and specificity of the ELISA test. Stool
leukocyte measurements and stool
lactoferrin levels have also been proposed as diagnostic tests, but may have limited diagnostic accuracy.
[ Clostridium difficile toxin and faecal lactoferrin assays in adult patients, Vaishnavi C, Bhasin D, Kochhar R, Singh K, , , Microbes Infect, 2000 ] ''C. difficile'' toxin should clear from the stool of previously infected patients if treatment is effective.
There has been debate about the emergence of a resistant strain: certain strains that express only the B toxin are now present in many hospitals and caution as to ordering both toxins should occur, in that many laboratories only test for the more prevalent toxin A. This can contribute to a delay in obtaining laboratory results, which is often the cause of prolonged illness and poor outcomes. Often clinicians begin treatment before results have come back based on clinical presentation to prevent such occurrences. Knowledge of the local epidemiology of intestinal flora of a particular institution can guide therapy. Many persons will also be asymptomatic and colonized with ''Clostridium difficile''. Treatment in asymptomatic patients is controversial, also leading into the debate of
clinical surveillance and how it intersects with public health policy.
Patients should be treated as soon as possible when the diagnosis of ''Clostridium difficile'' colitis (CDC) is made to avoid frank
sepsis or bowel perforation. In a recent study, a patient who received a diagnosis of CDC on the basis of CT scan had an 88% probability of testing positive on stool assay. Wall thickening is the key CT finding in this disease. Once colon wall thickening is identified as being >4 mm, ancillary findings of pericolonic stranding, ascites, and colon wall nodularity increase the specificity of CDC with additive effects. Using criteria of >=10 mm or a wall thickness of >4 mm and any of the more-specific findings does not add significantly to the diagnosis but gives equally satisfactory results. Patients who have antibiotic-associated diarrhea who have CT findings diagnostic of CDC merit consideration for treatment on that basis.
In those patients that develop systemic symptoms of CDC, colectomy may improve the outcome if performed before the need for
vasopressors.
Fecal bacteriotherapy, a procedure related to probiotic research, has been suggested as a potential cure for the disease. It involves infusion of bacterial flora acquired from the feces of a healthy donor in an attempt to reverse bacterial imbalance responsible for the recurring nature of the infection. It has a success rate of nearly 95% according to some sources.
[ Relapsing clostridium difficile enterocolitis cured by rectal infusion of homologous faeces., Schwan A, Sjölin S, Trottestam U, Aronsson B, , , Lancet, 1983 ][ Putting back the bugs: bacterial treatment relieves chronic diarrhoea., Paterson D, Iredell J, Whitby M, , , Med J Aust, 1994 ][ "Flora Power"-- fecal bacteria cure chronic C. difficile diarrhea., Borody T, , , Am J Gastroenterol, 2000 ]
Pharmacotherapy
It is possible that mild cases do not need treatment.
[3]
Three antibiotics are effective against ''C. difficile''.
Metronidazole 500mg orally three times daily is the drug of choice, because of superior tolerability, lower price and comparable efficacy
[4]. Oral
vancomycin 125 mg four times daily is second-line therapy, but is avoided due to theoretical concerns of converting intestinal flora into vancomycin resistant organisms. However, it is used in the following cases: no response to oral metronidazole; the organism is resistant to metronidazole; the patient is allergic to metronidazole; the patient is either pregnant or younger than 10 years of age; the patient is critically ill because of ''C. difficile'' diarrhea (the duration of diarrhea is reduced to 3 versus 4.6 days with metronidazole). Vancomycin must be administered orally because IV administration does not achieve gut lumen minimum therapeutic concentration. The use of
linezolid may be considered too.
It has been known that drugs traditionally used to stop diarrhea worsen the course of ''C. difficile''-related pseudomembranous colitis.
Loperamide,
diphenoxylate and
bismuth compounds are indeed contraindicated, because slowing of fecal transit time is thought to result in extended toxin-associated damage.
Cholestyramine, a powder drink occasionally used to lower cholesterol, is effective in binding both Toxin A and B, and slows bowel motility and helps prevent dehydration.
[ Treatment of ''Clostridium difficile'' Infection, Stroehlein J, , , Curr Treat Options Gastroenterol, 2004 ] The dosage can be 4 grams daily, to up to four doses a day: caution should be exercised to prevent constipation, or drug interactions, most notably the binding of drugs by cholestyramine, preventing their absorption. A last-resort treatment in
immunosuppressed patients is
intravenous immunoglobulin (IVIG).
Recurrence
The evolution of protocols for patients with recurrent ''C. difficile'' diarrhea also present a challenge: there is no known proper length of time or universally accepted alternative drugs with which one should be treated. However, re-treatment with metronidazole or vancomycin at the previous dose for 10 to 14 days is generally successful. The addition of
rifampin to vancomycin also has been effective. Prophylaxis with competing, nonpathogenic organisms such as ''
Lactobacillus'' spp. or ''
Saccharomyces boulardii'' has been found to be helpful in preventing relapse in small numbers of patients (see, for example,
Florastor, or
Lactinex). It is thought that these organisms, also known as probiotics, help to restore the natural flora in the gut and make patients more resistant to colonization by ''C. difficile''.
Notable outbreaks
On June 4, 2004, two outbreaks of a highly virulent strain of this bacterium were reported in
Montreal, Quebec and
Calgary, Alberta, in
Canada. Sources put the death count as low as 36 and as high as 89, with approximately 1,400 cases in 2003 and within the first few months of 2004. ''C. difficile'' infections continued to be a problem in the Quebec health care system in late 2004. As of
March 2005, it had spread into the
Toronto, Ontario area, hospitalizing 10 people. One died while the others were being discharged.
A similar outbreak took place at
Stoke Mandeville Hospital in the
United Kingdom between 2003 and 2005. The local
epidemiology of ''C. difficile'' may offer clues on how its spread may relate to the amount of time a patient spends in hospital and/or a rehabilitation center. It also samples institutions' ability to detect increased rates, and their capacity to respond with more aggressive hand washing campaigns, quarantine methods, and availability of yoghurt to patients at risk for infection.
It has been suggested that both the Canadian and English outbreaks were related to the seemingly more virulent 027 strain of bacterium. This strain has also been implicated in an epidemic at two Dutch hospitals (
Harderwijk and
Amersfoort, both 2005). A theory for explaining the increased virulence of 027 is that it is a hyperproducer of both toxin A and B, and that certain antibiotics may actually stimulate the bacteria to hyperproduce.
On
December 2,
2005, The
New England Journal of Medicine, in an article spearheaded by Drs. Vivian Loo, Louise Poirier, and Mark Miller, reported the emergence of a new, highly toxic strain of ''C. difficile'', resistant to
fluoroquinolone antibiotics, such as
Cipro (ciprofloxacin) and
Levaquin (levofloxacin), said to be causing geographically dispersed outbreaks in North America.
[ A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality, Loo V, Poirier L, Miller M, Oughton M, Libman M, Michaud S, Bourgault A, Nguyen T, Frenette C, Kelly M, Vibien A, Brassard P, Fenn S, Dewar K, Hudson T, Horn R, René P, Monczak Y, Dascal A, , , N Engl J Med, 2005 ] The
Centers for Disease Control in
Atlanta has also warned of the emergence of an epidemic strain with increased virulence, antibiotic resistance, or both.
[ ''Clostridium difficile'': responding to a new threat from an old enemy, McDonald L, , , Infect Control Hosp Epidemiol, 2005 ]
As one analyzes the pool of patients with the spores, many who are asymptomatic will pass the organism to individuals who are immunocompromised and hence, susceptible to increasing rates of diarrhea and poor outcome. It seems notable that the clusters described above represent a challenge to epidemiologists trying to understand how the illness spreads via the convergence of
information technology with
clinical surveillance.
On
October 1,
2006, the bacteria was said to have killed at least 49 people at hospitals in
Leicester,
England over eight months, according to a
National Health Service investigation. Another 29 similar cases were investigated by
coroners.
[5] A UK Department of Health memo leaked shortly afterwards revealed significant concern in government about the bacterium, described as being "endemic throughout the health service"
[6]
On
October 27,
2006, the bacteria was attributed to 9 deaths in Quebec, Canada.
[7]
On November 18th, 2006, the bacteria was reported to have been responsible for 12 deaths in Quebec, Canada. This 12th reported death was only two days after the St. Hyacinthe's Honoré Mercier announced that the outbreak was under control. 31 patients were diagnosed with Clostridium difficile and four (as of Sat. Nov 18th) were still under observation. Cleaning crews took measures in an attempt to clear the outbreak.
[8]
On
February 27,
2007, a new outbreak was identified at Trillium Health Centre in Mississauga Ontario, where 14 people were diagnosed with the bacteria. The bacteria was the same strain as the one in Quebec. Officials were not been able to determine if C. difficile was responsible for deaths of four patients over the prior two months.
[9]
Cracking of the genetic code of the Quebec strain
On
December 14,
2005, researchers at
McGill University in
Montreal, Quebec, led by Dr. Ken Dewar and Dr. Andre Dascal and in collaboration with province-organized
NPO Genome Quebec's research facility, announced they had cracked the genetic code of the highly virulent Quebec strain of ''C. difficile''. This was accomplished by using ultra high-throughput sequencing technology. The tests involved doing 400,000 DNA parallel sequencing reactions which took the bacterium's genome apart and reassembled it so it could be studied.
It is expected this will allow quicker detection of the disease and better treatment.
References
1. Cleaning agents 'make bug strong'
2. Binary bacterial toxins: biochemistry, biology, and applications of common Clostridium and Bacillus proteins, Barth H, Aktories K, Popoff M, Stiles B, , , Microbiol Mol Biol Rev, 2004
3. Nelson R. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004610. PMID 17636768
4. Teasley DG, Gerding DN, Olson MM, Peterson LR, Gebhard RL, Schwartz MJ, Lee JT Jr. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet. 1983 Nov 5;2(8358):1043-6. PMID 6138597
5. Trust confirms 49 superbug deaths - BBC News
6. Leaked memo reveals that targets to beat MRSA will not be met Nigel Hawkes
7. C. difficile blamed for 9 death in hospital near Montreal
8. 12th person dies of C. difficile at Quebec hospital - CBC News
9. [1]
10. Scientists map C. difficile strain - Institute of Public Affairs, Montreal
Further reading
★
Fulminant ''Clostridium difficile'': an underappreciated and increasing cause of death and complications, Dallal R, Harbrecht B, Boujoukas A, Sirio C, Farkas L, Lee K, Simmons R, , , Ann Surg, 2002
★
Gastrointestinal infections and enterotoxigenic poisonings. In: Pharmacotherapy: A Pathophysiologic Approach (DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors)., Martin S, Jung R, , , McGraw-Hill, 2005, ISBN
★
An epidemic, toxin gene-variant strain of ''Clostridium difficile'', McDonald L, Killgore G, Thompson A, Owens R, Kazakova S, Sambol S, Johnson S, Gerding D, , , N Engl J Med, 2005
★
Textbook of Gastroenterology, Yamada T; Alpers DH (editors), , , Lippincott Williams & Wilkins, 2003, ISBN 0-7817-2861-4
★
''Clostridium difficile'' PCR ribotype 027 outbreaks in the Netherlands: recent surveillance data indicate that outbreaks are not easily controlled but interhospital transmission is limited, van den Hof S, van der Kooi T, van den Berg R, Kuijper E, Notermans D, , , Euro Surveill, 2006
★
''Clostridium difficile-associated disease: New challenges from an established pathogen'', Sunenshine R, McDonald L, , , Cleveland Clinic J. Med., 2006
See also
★
Nosocomial infection
External links
★
US CDC Report on Severe ''Clostridium difficile''--Associated Disease in Populations Previously at Low Risk--Four States, 2005
★
''UK Clostridium difficile'' Support Group
★
''Clostridium difficile'' Support Group
★
"From hand to mouth" Article from
The Economist discussing ''C. difficile'' (requires subscription)
★
Pathema-''Clostridium'' Resource
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