Clostridium difficile
Encyclopedia
Clostridium difficile (pronunciation below) (from the Greek kloster (κλωστήρ), spindle, and Latin
difficile, difficult), also known as "CDF/cdf", or "C. diff", is a species
of Gram-positive
bacteria
of the genus Clostridium
that causes severe diarrhea
and other intestinal disease when competing bacteria in the gut flora
have been wiped out by antibiotics.
Clostridia are anaerobic
, spore
-forming rods (bacilli). C. difficile is the most serious cause of antibiotic-associated diarrhoea (AAD) and can lead to pseudomembranous colitis
, a severe infection of the colon
, often resulting from eradication of the normal gut flora
by antibiotic
s.
In a very small percentage of the adult population, C. difficile bacteria naturally reside in the gut. Other people accidentally ingest spores of the bacteria while they are patients in a hospital, nursing home, or similar facility. When the bacteria are in a colon in which the normal gut flora has been destroyed (usually after a broad-spectrum antibiotic such as clindamycin
has been used), the gut becomes overrun with C. difficile. This overpopulation is harmful because the bacteria release toxins that can cause bloating
and diarrhea
, with abdominal pain, which may become severe. C. difficile infections are the most common cause of pseudomembranous colitis, and in rare cases this can progress to toxic megacolon
, which can be life-threatening.
Latent symptoms of C. difficile infection often mimic some flu-like symptoms and can mimic disease flare in patients with inflammatory bowel disease
-associated colitis. Mild cases of C. difficile infection can often be cured by discontinuing the antibiotics responsible. In more serious cases, oral administration of, first, metronidazole
and - if that fails - then, second, vancomycin
are currently the treatments of choice. Relapses of C. difficile AAD have been reported in up to 20% of cases.
found the best signs
to be: significant diarrhea ("new onset of > 3 partially formed or watery stools per 24 hour period"), recent antibiotic exposure, colitis (abdominal pain), fever (up to 40.5°C), and foul stool odour. In a population of hospitalised patients prior antibiotic treatment plus diarrhoea or abdominal pain had a sensitivity of 86% and a specificity of 45%. In this study with a prevalence of positive cytotoxin assays of 14%, the positive predictive value
was 20% and the negative predictive value
was 95%.
in 1978, when a toxin was isolated from patients suffering from pseudomembranous colitis and Koch's postulates
were met.
The numerous spores formed by C. difficile are resistant to most routine cleaning methods that are used on surfaces (except for diluted bleach). Spores of these bacteria can remain viable outside of the human body for very long periods of time, and this means that patients in a medical facility are often exposed to situations where they end up accidentally ingesting spores. Extremely rigorous infection protocols are required in order to decrease or eliminate this risk.
C. difficile infection (CDI) can range in severity from asymptomatic to severe and life-threatening, especially among the elderly. People are most often nosocomially infected in hospital
s, nursing home
s, or other medical institutions, although C. difficile infection in the community, outpatient setting is increasing. The rate of C. difficile acquisition is estimated to be 13% in patients with hospital stays of up to 2 weeks, and 50% in those with hospital stays longer than 4 weeks. C. difficile-associated diarrhea (aka CDAD) is most strongly associated with fluoroquinolones. Fluoroquinolones are more strongly associated with C. difficile infections than other antibiotics including clindamycin
, 3rd generation cephalosporins and beta-lactamase inhibitor
s. One study found that fluoroquinolones were responsible for 55% of C. difficile infections. In addition to previous use of antimicrobials, use of proton pump inhibitors [PPIs] is associated with a 2-fold increase in risk for C. difficile infection.
The European Center for Disease Prevention and Control recommend that fluoroquinolones and the antibiotic clindamycin
be avoided in clinical practice due to their high association with subsequent Clostridium difficile infections. 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.
Increasing rates of community-acquired C. difficile infection are associated with the use of medication that suppress gastric acid
production: H2-receptor antagonist
s increased the risk 1.5 fold, and proton pump inhibitor
s by 1.7 with once daily use and 2.4 with more than once daily use.
The emergence of a new, highly toxic strain of C. difficile, resistant to fluoroquinolone antibiotics, such as ciprofloxacin
(Cipro) and levofloxacin
(Levaquin), said to be causing geographically dispersed outbreaks in North America was reported in 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.
In 2005, molecular analysis led to the identification of the C. difficile strain type that was characterized as group BI by restriction endo nuclease analysis (REA), as North American pulse-field-type NAP1 by pulse-field gel electrophoresis (PFGE) and as ribotype 027; the differing terminology reflects the predominant techniques that were used for epidemiological typing and this strain is referred to as C. difficile BI/NAP1/027.
Some recent research suggests that the overuse of antibiotics in the raising of livestock for meat consumption is contributing to outbreaks of bacterial infections such as C. difficile.
Clostridia are motile
bacteria
that are ubiquitous in nature and are especially prevalent in soil. Under the microscope, clostridia appear as long, irregularly (often "drumstick" or "spindle") shaped cells with a bulge at their terminal ends. Under Gram staining, Clostridium difficile cells are Gram-positive
and show optimum growth on blood agar at human body temperatures in the absence of oxygen
. When stressed, the bacteria produce spore
s that can tolerate extreme conditions that the active bacteria cannot tolerate.
C. difficile is a commensal bacterium of the human intestine
in 2-5% of the population. Long-term hospitalization or residence in a nursing home within the previous year are independent risk factors for increased colonization
. In small numbers, C. difficile does not result in significant disease. Antibiotic
s, especially those with a broad spectrum of activity (such as for example clindamycin
) cause disruption of normal intestinal flora, leading to an overgrowth of C. difficile, which flourishes under these conditions. This can lead to pseudomembranous colitis
(PMC), the generalized inflammation of the colon and the development of pseudomembrane, a viscous collection of inflammatory cells, fibrin
, and necrotic cells.
Pathogenic C. difficile strains produce several known toxin
s. The most well-characterized are enterotoxin
(Clostridium difficile toxin A
) and cytotoxin (Clostridium difficile toxin B
), both of which are responsible for the diarrhea
and inflammation
seen in infected patients, although their relative contributions have been debated. Toxins A and B are glucosyltransferases that target and inactivate the Rho family of GTPases
. Clostridium difficile toxin B
(cytotoxin) induces actin depolymerization by a mechanism correlated with a decrease in the ADP-ribosylation
of the low molecular mass GTP-binding Rho proteins. Another toxin, binary toxin, has also been described, but its role in disease is not yet fully understood.
Antibiotic treatment of C. difficile infections can be difficult, due both to antibiotic resistance
as well as physiological factors of the bacteria itself (spore formation, protective effects of the pseudomembrane). Pseudomembranous colitis caused by C. difficile is treated with specific antibiotics, for example, vancomycin
(Vancocin) or metronidazole
(Flagyl).
C. difficile is transmitted from person to person by the fecal-oral route
. However, the organism forms large numbers of heat-resistant spores, and these are not killed by alcohol-based hand cleansers or routine cleaning of surfaces. Thus, these spores remain viable in the hospital
or nursing home
environment for long periods of time, and, because of this, the bacteria can be cultured from almost any surface in the hospital. Once spores are ingested by a patient, they pass through the stomach unscathed because of their acid-resistance. They germinate into vegetative cells in the colon upon exposure to bile acids, and multiply.
Several disinfectants commonly used in hospitals are ineffective against C. difficile spores, and may actually promote spore formation. However, disinfectants containing bleach
are effective in killing the organisms.
and is the most sensitive and specific test, although it is slow and labour-intensive.
(ELISA) for toxin A or B (or both) has a sensitivity of 63–99% and a specificity of 93–100%: At a prevalence of 15%, this leads to a positive predictive value
(PPV) of 73% and a negative predictive value
(NPV) of 96%.
Previously, experts recommended sending as many as three stool samples to rule out disease if initial tests are negative. However, recent evidence suggests that repeat testing during the same episode of diarrhea is of limited value and should be discouraged.C. difficile toxin should clear from the stool of previously infected patients if treatment is effective. However, many hospitals test only for the prevalent toxin A. Strains that express only the B toxin are now present in many hospitals, and ordering both toxins should occur. Not testing for both may contribute to a delay in obtaining laboratory results, which is often the cause of prolonged illness and poor outcomes.
levels have also been proposed as diagnostic tests, but may have limited diagnostic accuracy.
(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, the best ancillary findings were pericolonic stranding, ascites
, and colon wall nodularity. The presence of wall thickness plus any one of these ancillary findings is 70% sensitive and 93% specific.
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. In this study with a prevalence of positive C. difficile toxin of 54%, the PPV was 88%. Patients who have antibiotic-associated diarrhea with CT findings diagnostic of CDC merit consideration for treatment on that basis.
Prodesse offers another kit-based IVD Real-Time PCR test (ProGastro Cd), which uses an external extraction and purification on the Roche MagnaPure. Prodesse (Gen-Probe) tech support claims that this external separation produces higher yields than the BD GeneOhm. The Prodesse technique is similar in price to the BD GeneOhm technique after one includes the price of the extraction and takes about three hours from sample to result.
The final IVD Clostridium difficile Real Time PCR test on the market since 2009 is from BD GeneOhm. The protocol uses a glass-bead lysis rather than an extraction, but results are reported to be good and the method shaves a little over an hour off the protocol time (about 1 hour 45 minutes from sample to result). Total costs for the Prodesse and BD GeneOhm tests are approximately the same.
For each test, sensitivities are generally reported as 88-91% and specificities as 96-97%, depending on the tests, prevalence of the disease and the size of the patient pool.
In Britain, the testing of all hospital inpatients over the age of 65 with diarrhea for C. difficile became a compulsory NHS
practice in January 2008, when it became evident that many UK outbreaks were being disguised as Norovirus by hospital Risk Managers. Risk Managers can be dismissed by the Department of Health if C. difficile infection rates are too high, but they cannot be dismissed as a result of a Norovirus outbreak. Patients most at risk are those with recent broad-spectrum antibiotic aor proton-pump inhibitor treatments.
Infection control measures, such as wearing gloves when caring for patients with CDAD, have been proven to be effective at prevention. This works by limiting the spread of C. difficile in the hospital setting. In addition, washing with soap and water will eliminate the spores from contaminated hands, but alcohol-based hand rubs are ineffective. Bleach wipes containing 0.55 percent sodium hypochlorite have been shown to kill the spores and prevent transmission between patients.
Soil-containing potted plants can serve as a reservoir for the development of multidrug-resistant bacteria and fungi, and, for this reason, many hospital systems restrict the use of soil-containing potted plants. To help mitigate serious infections and development of multidrug-resistant organisms in long-term and acute hospital settings, soil-containing potted plants should not be used, especially in areas of direct patient care, such as offices, rooms, and hallways of hospital wards. Alternatives to soil-containing plants are available.
Treatment with various oral supplements containing live bacteria has been studied in efforts to prevent Clostridium difficile-associated infection/disease. A randomized controlled trial
using a probiotic
drink containing Lactobacillus casei
, L bulgaricus, and Streptococcus salivarius subsp. thermophilus
was reported to have some efficacy. This study was sponsored by the company that produces the drink studied. Although intriguing, several other studies have been unable to demonstrate any benefit of oral supplements of similar bacteria at preventing CDAD. Of note, patients on the antibiotics most strongly associated with CDAD were excluded from this study.
Hydrogen peroxide vapor
(HPV) systems used to sterilize a patient room post discharge has been shown to reduce infection rates and to reduce risk of infection to subsequent patients. One study (Boyce et al. 2008) showed that incidence of CDAD was reduced by 53% though use of HPV. A second study (Manian et al. 2010) showed only a 42% reduction in CDAD rates through use of HPV.
In a limited clinical trial, a C. difficile anti-toxoid
vaccine
was reported to improve patient outcomes. Further testing will be required to validate this trial. Recent advancements have been made at the University of Guelph
by Professor Monteiro on a polysaccharide vaccine currently in its pre-clinical stage.
and how it intersects with public health policy. In general, mild cases do not require specific treatment.
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. To reduce complications, physicians often begin treatment based on clinical presentation before definitive results are available. Knowledge of the local epidemiology of intestinal flora of a particular institution can guide therapy. In addition, oral rehydration therapy (ORT)
is useful in retaining fluids during the duration of diarrhoea.
:
Drugs used to stop diarrhea
frequently worsen the course of C. difficile-related pseudomembranous colitis. Loperamide
, diphenoxylate
and bismuth
compounds are contraindicated: slowing of fecal transit time is thought to result in extended toxin-associated damage.
Cholestyramine
, a powder drink (an ion exchange resin
), which is occasionally used to lower cholesterol, is effective in binding both Toxin A and B, slowing bowel motility and helping prevent dehydration. The dosage can be 4 grams daily, to up to four doses a day; however caution should be exercised to prevent constipation, or drug interactions, most notably the binding of drugs by cholestyramine, preventing their absorption. Cholestyramine is not an anti-infective; it dramatically reduces many of the symptoms of a C. difficile infection, but it is not appropriate to use by itself, as it does not change the infection status. Cholestyramine is usually used in concert with vancomycin. Powdered banana flakes given twice daily are an alternative to cholestyramine, and allow for stool bulking.
Treatment with probiotics ("good" intestinal flora) has also been shown effective. Provision of Saccharomyces boulardii
(Florastor) or Lactobacillus acidophilus
twice daily times 30 days along with antibiotics has been clinically shown to shorten the duration of diarrhea. A last-resort treatment in immunosuppressed
patients is intravenous immunoglobulin
(IVIG).
may improve the outcome if performed before the need for vasopressors.
, known in colloquial terms as stool transplant, a procedure related to probiotic
research, has preliminarily been shown to cure the disease. It involves infusion of bacterial flora acquired from the feces of a healthy donor to reverse the bacterial imbalance responsible for the recurring nature of the infection. In fecal transplantation, donor stool is collected from a close relative who has been tested for a wide array of bacterial, viral, and parasitic pathogens. The stool is often mixed with saline or milk to achieve the desired consistency, then delivered through a colonoscope or retention enema, or through a nasogastric or nasoduodenal tube. The procedure replaces normal, healthy colonic flora that had been wiped out by antibiotics, and reestablishes the patient's resistance to colonization by Clostridium difficile. However, there is often patient resistance due to the perceived unpleasantness of the procedure that must be overcome first before proceeding with this often-effective treatment.
There are currently over 150 published reports dating back to 1958, though many more have been performed. It has a success rate of about 90%. A guide was released in 2010 for home fecal transplantation.
or vancomycin
, Clostridium difficile recurs in about 20% of people. This increases to 40% and 60% with subsequent recurrences.
s of organisms are Latin or Latinised Greek, in this case one of each. The anglicized pronunciation klɒsˈtrɪdiəm dɨˈfɪsɨliː is common, though a more Classical /dɨˈfɪkɨleɪ/ is also used. A common practice has developed of pronouncing difficile as /diːfiˈsiːl, as though it were French. The pronunciation varies because this is an example of international scientific vocabulary
(ISV). The Classical Latin
sound is /dɨˈffɪkɨle/. One may also hear Spanish-influenced sound (/di.ˈfi.si.le/) and Italian- or Church-Latin-influenced sound (/dɪfˈfi.tʃi.le/).
in the UK. This was of the C. difficile strain 630, a virulent and multidrug-resistant strain isolated in Switzerland in 1982. Scientists at Sanger Institute
have also recently sequenced genomes of about 30 Clostridium difficile isolates using next generation sequencing
technologies from 454 Life Sciences
and Illumina
.
Researchers at McGill University
in Montreal
, Quebec
sequenced the genome
of the highly virulent Quebec strain of C. difficile in 2005 using ultra-high-throughput sequencing technology. The tests involved doing 400,000 DNA parallel-sequencing reactions of the bacterium's genome, which had been fragmented for sequencing. These sequences were assembled computationally to form a complete genome sequence.
Latin
Latin is an Italic language originally spoken in Latium and Ancient Rome. It, along with most European languages, is a descendant of the ancient Proto-Indo-European language. Although it is considered a dead language, a number of scholars and members of the Christian clergy speak it fluently, and...
difficile, difficult), also known as "CDF/cdf", or "C. diff", is a species
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
of Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
of the genus Clostridium
Clostridium
Clostridium is a genus of Gram-positive bacteria, belonging to the Firmicutes. They are obligate anaerobes capable of producing endospores. Individual cells are rod-shaped, which gives them their name, from the Greek kloster or spindle...
that causes severe diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
and other intestinal disease when competing bacteria in the gut flora
Gut flora
Gut flora consists of microorganisms that live in the digestive tracts of animals and is the largest reservoir of human flora. In this context, gut is synonymous with intestinal, and flora with microbiota and microflora....
have been wiped out by antibiotics.
Clostridia are anaerobic
Anaerobic organism
An anaerobic organism or anaerobe is any organism that does not require oxygen for growth. It could possibly react negatively and may even die if oxygen is present...
, spore
Endospore
An endospore is a dormant, tough, and temporarily non-reproductive structure produced by certain bacteria from the Firmicute phylum. The name "endospore" is suggestive of a spore or seed-like form , but it is not a true spore . It is a stripped-down, dormant form to which the bacterium can reduce...
-forming rods (bacilli). C. difficile is the most serious cause of antibiotic-associated diarrhoea (AAD) and can lead to pseudomembranous colitis
Pseudomembranous colitis
Pseudomembranous colitis, a cause of antibiotic-associated diarrhea , is an infection of the colon. It is often, but not always, caused by the bacterium Clostridium difficile. Because of this, the informal name C. difficile colitis is also commonly used. The illness is characterized by...
, a severe infection of the colon
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
, often resulting from eradication of the normal gut flora
Gut flora
Gut flora consists of microorganisms that live in the digestive tracts of animals and is the largest reservoir of human flora. In this context, gut is synonymous with intestinal, and flora with microbiota and microflora....
by antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s.
In a very small percentage of the adult population, C. difficile bacteria naturally reside in the gut. Other people accidentally ingest spores of the bacteria while they are patients in a hospital, nursing home, or similar facility. When the bacteria are in a colon in which the normal gut flora has been destroyed (usually after a broad-spectrum antibiotic such as clindamycin
Clindamycin
Clindamycin rINN is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria...
has been used), the gut becomes overrun with C. difficile. This overpopulation is harmful because the bacteria release toxins that can cause bloating
Bloating
Bloating is any abnormal general swelling, or increase in diameter of the abdominal area. As a symptom, the patient feels a full and tight abdomen, which may cause abdominal pain sometimes accompanied by increased borborygmus or more seriously the total lack of borborygmus.-Symptoms:The most common...
and diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, with abdominal pain, which may become severe. C. difficile infections are the most common cause of pseudomembranous colitis, and in rare cases this can progress to toxic megacolon
Toxic megacolon
Toxic megacolon is an acute form of colonic distension. It is characterized by a very dilated colon , accompanied by abdominal distension , and sometimes fever, abdominal pain, or shock....
, which can be life-threatening.
Latent symptoms of C. difficile infection often mimic some flu-like symptoms and can mimic disease flare in patients with inflammatory bowel disease
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
-associated colitis. Mild cases of C. difficile infection can often be cured by discontinuing the antibiotics responsible. In more serious cases, oral administration of, first, metronidazole
Metronidazole
Metronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....
and - if that fails - then, second, vancomycin
Vancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
are currently the treatments of choice. Relapses of C. difficile AAD have been reported in up to 20% of cases.
Signs and symptoms
In adults, a clinical prediction ruleClinical prediction rule
A clinical prediction rule is type of medical research study in which researchers try to identify the best combination of medical sign, symptoms, and other findings in predicting the probability of a specific disease or outcome....
found the best signs
Medical sign
A medical sign is an objective indication of some medical fact or characteristic that may be detected by a physician during a physical examination of a patient....
to be: significant diarrhea ("new onset of > 3 partially formed or watery stools per 24 hour period"), recent antibiotic exposure, colitis (abdominal pain), fever (up to 40.5°C), and foul stool odour. In a population of hospitalised patients prior antibiotic treatment plus diarrhoea or abdominal pain had a sensitivity of 86% and a specificity of 45%. In this study with a prevalence of positive cytotoxin assays of 14%, the positive predictive value
Positive predictive value
In statistics and diagnostic testing, the positive predictive value, or precision rate is the proportion of subjects with positive test results who are correctly diagnosed. It is a critical measure of the performance of a diagnostic method, as it reflects the probability that a positive test...
was 20% and the negative predictive value
Negative predictive value
In statistics and diagnostic testing, the negative predictive value is a summary statistic used to describe the performance of a diagnostic testing procedure. It is defined as the proportion of subjects with a negative test result who are correctly diagnosed. A high NPV means that when the test...
was 95%.
Cause
With the introduction of broad-spectrum antibiotics and chemotherapeutic antineoplastic drugs in the second half of the twentieth century, antibiotic- (and chemotherapy-) associated diarrhea became more common. Pseudomembranous colitis was first described as a complication of C. difficile infectionInfection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
in 1978, when a toxin was isolated from patients suffering from pseudomembranous colitis and Koch's postulates
Koch's postulates
Koch's postulates are four criteria designed to establish a causal relationship between a causative microbe and a disease. The postulates were formulated by Robert Koch and Friedrich Loeffler in 1884 and refined and published by Koch in 1890...
were met.
The numerous spores formed by C. difficile are resistant to most routine cleaning methods that are used on surfaces (except for diluted bleach). Spores of these bacteria can remain viable outside of the human body for very long periods of time, and this means that patients in a medical facility are often exposed to situations where they end up accidentally ingesting spores. Extremely rigorous infection protocols are required in order to decrease or eliminate this risk.
C. difficile infection (CDI) can range in severity from asymptomatic to severe and life-threatening, especially among the elderly. People are most often nosocomially infected in hospital
Hospital
A hospital is a health care institution providing patient treatment by specialized staff and equipment. Hospitals often, but not always, provide for inpatient care or longer-term patient stays....
s, nursing home
Nursing home
A nursing home, convalescent home, skilled nursing unit , care home, rest home, or old people's home provides a type of care of residents: it is a place of residence for people who require constant nursing care and have significant deficiencies with activities of daily living...
s, or other medical institutions, although C. difficile infection in the community, outpatient setting is increasing. The rate of C. difficile acquisition is estimated to be 13% in patients with hospital stays of up to 2 weeks, and 50% in those with hospital stays longer than 4 weeks. C. difficile-associated diarrhea (aka CDAD) is most strongly associated with fluoroquinolones. Fluoroquinolones are more strongly associated with C. difficile infections than other antibiotics including clindamycin
Clindamycin
Clindamycin rINN is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria...
, 3rd generation cephalosporins and beta-lactamase inhibitor
Beta-lactamase inhibitor
A beta-lactamase inhibitor is a drug given in conjunction with a beta-lactam antibiotic. Although the inhibitor does not usually have significant antibiotic activity on its own, it inhibits activity of beta-lactamase, a protein that confers resistance of beta-lactam antibiotics to...
s. One study found that fluoroquinolones were responsible for 55% of C. difficile infections. In addition to previous use of antimicrobials, use of proton pump inhibitors [PPIs] is associated with a 2-fold increase in risk for C. difficile infection.
The European Center for Disease Prevention and Control recommend that fluoroquinolones and the antibiotic clindamycin
Clindamycin
Clindamycin rINN is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria...
be avoided in clinical practice due to their high association with subsequent Clostridium difficile infections. 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.
Increasing rates of community-acquired C. difficile infection are associated with the use of medication that suppress gastric acid
Gastric acid
Gastric acid is a digestive fluid, formed in the stomach. It has a pH of 1 to 2 and is composed of hydrochloric acid , and large quantities of potassium chloride and sodium chloride...
production: H2-receptor antagonist
H2-receptor antagonist
The H2 receptor antagonists are a class of drugs used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells. H2 antagonists are used in the treatment of dyspepsia, although they have been surpassed in popularity by the more effective ...
s increased the risk 1.5 fold, and proton pump inhibitor
Proton pump inhibitor
Proton-pump inhibitors are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. The group followed and has largely superseded another group of pharmaceuticals with similar...
s by 1.7 with once daily use and 2.4 with more than once daily use.
The emergence of a new, highly toxic strain of C. difficile, resistant to fluoroquinolone antibiotics, such as ciprofloxacin
Ciprofloxacin
Ciprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
(Cipro) and levofloxacin
Levofloxacin
Levofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class and is used to treat severe or life-threatening bacterial infections or bacterial infections that have failed to respond to other antibiotic classes. It is sold under various brand names, such as Levaquin and...
(Levaquin), said to be causing geographically dispersed outbreaks in North America was reported in 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.
In 2005, molecular analysis led to the identification of the C. difficile strain type that was characterized as group BI by restriction endo nuclease analysis (REA), as North American pulse-field-type NAP1 by pulse-field gel electrophoresis (PFGE) and as ribotype 027; the differing terminology reflects the predominant techniques that were used for epidemiological typing and this strain is referred to as C. difficile BI/NAP1/027.
Some recent research suggests that the overuse of antibiotics in the raising of livestock for meat consumption is contributing to outbreaks of bacterial infections such as C. difficile.
Bacteriology
Motility
Motility is a biological term which refers to the ability to move spontaneously and actively, consuming energy in the process. Most animals are motile but the term applies to single-celled and simple multicellular organisms, as well as to some mechanisms of fluid flow in multicellular organs, in...
bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
that are ubiquitous in nature and are especially prevalent in soil. Under the microscope, clostridia appear as long, irregularly (often "drumstick" or "spindle") shaped cells with a bulge at their terminal ends. Under Gram staining, Clostridium difficile cells are Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
and show optimum growth on blood agar at human body temperatures in the absence of oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
. When stressed, the bacteria produce spore
Spore
In biology, a spore is a reproductive structure that is adapted for dispersal and surviving for extended periods of time in unfavorable conditions. Spores form part of the life cycles of many bacteria, plants, algae, fungi and some protozoa. According to scientist Dr...
s that can tolerate extreme conditions that the active bacteria cannot tolerate.
C. difficile is a commensal bacterium of the human intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
in 2-5% of the population. Long-term hospitalization or residence in a nursing home within the previous year are independent risk factors for increased colonization
Colony (biology)
In biology, a colony reference to several individual organisms of the same species living closely together, usually for mutual benefit, such as stronger defense or the ability to attack bigger prey. Some insects live only in colonies...
. In small numbers, C. difficile does not result in significant disease. Antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s, especially those with a broad spectrum of activity (such as for example clindamycin
Clindamycin
Clindamycin rINN is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria...
) cause disruption of normal intestinal flora, leading to an overgrowth of C. difficile, which flourishes under these conditions. This can lead to pseudomembranous colitis
Pseudomembranous colitis
Pseudomembranous colitis, a cause of antibiotic-associated diarrhea , is an infection of the colon. It is often, but not always, caused by the bacterium Clostridium difficile. Because of this, the informal name C. difficile colitis is also commonly used. The illness is characterized by...
(PMC), the generalized inflammation of the colon and the development of pseudomembrane, a viscous collection of inflammatory cells, fibrin
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....
, and necrotic cells.
Pathogenic C. difficile strains produce several known toxin
Toxin
A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...
s. The most well-characterized are enterotoxin
Enterotoxin
An enterotoxin is a protein toxin released by a microorganism in the intestine. Enterotoxins are chromosomally encoded exotoxins that are produced and secreted from several bacterial organisms. They are often heat-stable, and are of low molecular weight and water-soluble...
(Clostridium difficile toxin A
Clostridium difficile toxin A
Clostridium difficile toxin A is a toxin generated by Clostridium difficile. It is similar to Clostridium difficile Toxin B.It is usually described as a enterotoxin, but it also has some activity as a cytotoxin....
) and cytotoxin (Clostridium difficile toxin B
Clostridium difficile toxin B
Clostridium difficile toxin B is a toxin generated by Clostridium difficile. It is similar to Clostridium difficile Toxin A.It is a cytotoxin....
), both of which are responsible for the diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
and inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
seen in infected patients, although their relative contributions have been debated. Toxins A and B are glucosyltransferases that target and inactivate the Rho family of GTPases
Rho family of GTPases
The Rho family of GTPases is a family of small signaling G protein , and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic organisms including yeasts and some plants...
. Clostridium difficile toxin B
Clostridium difficile toxin B
Clostridium difficile toxin B is a toxin generated by Clostridium difficile. It is similar to Clostridium difficile Toxin A.It is a cytotoxin....
(cytotoxin) induces actin depolymerization by a mechanism correlated with a decrease in the ADP-ribosylation
ADP-ribosylation
ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. These reactions are involved in cell signaling and the control of many cell processes, including DNA repair and apoptosis.-ADP-ribosylation enzymes:...
of the low molecular mass GTP-binding Rho proteins. Another toxin, binary toxin, has also been described, but its role in disease is not yet fully understood.
Antibiotic treatment of C. difficile infections can be difficult, due both to antibiotic resistance
Antibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
as well as physiological factors of the bacteria itself (spore formation, protective effects of the pseudomembrane). Pseudomembranous colitis caused by C. difficile is treated with specific antibiotics, for example, vancomycin
Vancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
(Vancocin) or metronidazole
Metronidazole
Metronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....
(Flagyl).
C. difficile is transmitted from person to person by the fecal-oral route
Fecal-oral route
The fecal-oral route, or alternatively, the oral-fecal route or orofecal route is a route of transmission of diseases, in which they are passed when pathogens in fecal particles from one host are introduced into the oral cavity of another potential host.There are usually intermediate steps,...
. However, the organism forms large numbers of heat-resistant spores, and these are not killed by alcohol-based hand cleansers or routine cleaning of surfaces. Thus, these spores remain viable in the hospital
Hospital
A hospital is a health care institution providing patient treatment by specialized staff and equipment. Hospitals often, but not always, provide for inpatient care or longer-term patient stays....
or nursing home
Nursing home
A nursing home, convalescent home, skilled nursing unit , care home, rest home, or old people's home provides a type of care of residents: it is a place of residence for people who require constant nursing care and have significant deficiencies with activities of daily living...
environment for long periods of time, and, because of this, the bacteria can be cultured from almost any surface in the hospital. Once spores are ingested by a patient, they pass through the stomach unscathed because of their acid-resistance. They germinate into vegetative cells in the colon upon exposure to bile acids, and multiply.
Several disinfectants commonly used in hospitals are ineffective against C. difficile spores, and may actually promote spore formation. However, disinfectants containing bleach
Bleach
Bleach refers to a number of chemicals that remove color, whiten, or disinfect, often via oxidation. Common chemical bleaches include household chlorine bleach , lye, oxygen bleach , and bleaching powder...
are effective in killing the organisms.
History
Initially named Bacillus difficilis by Hall and O'Toole in 1935 because it was resistant to early attempts at isolation and grew very slowly in culture, it was renamed in 1970.Cytotoxicity assay
C. difficile toxins have a 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 standardGold standard (test)
In medicine and statistics, gold standard test refers to a diagnostic test or benchmark that is the best available under reasonable conditions. It does not have to be necessarily the best possible test for the condition in absolute terms...
and is the most sensitive and specific test, although it is slow and labour-intensive.
Toxin ELISA
Assessment of the A and B toxins by enzyme-linked immunosorbent assayELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...
(ELISA) for toxin A or B (or both) has a sensitivity of 63–99% and a specificity of 93–100%: At a prevalence of 15%, this leads to a positive predictive value
Positive predictive value
In statistics and diagnostic testing, the positive predictive value, or precision rate is the proportion of subjects with positive test results who are correctly diagnosed. It is a critical measure of the performance of a diagnostic method, as it reflects the probability that a positive test...
(PPV) of 73% and a negative predictive value
Negative predictive value
In statistics and diagnostic testing, the negative predictive value is a summary statistic used to describe the performance of a diagnostic testing procedure. It is defined as the proportion of subjects with a negative test result who are correctly diagnosed. A high NPV means that when the test...
(NPV) of 96%.
Previously, experts recommended sending as many as three stool samples to rule out disease if initial tests are negative. However, recent evidence suggests that repeat testing during the same episode of diarrhea is of limited value and should be discouraged.C. difficile toxin should clear from the stool of previously infected patients if treatment is effective. However, many hospitals test only for the prevalent toxin A. Strains that express only the B toxin are now present in many hospitals, and ordering both toxins should occur. Not testing for both may contribute to a delay in obtaining laboratory results, which is often the cause of prolonged illness and poor outcomes.
Other stool tests
Stool leukocyte measurements and stool lactoferrinLactoferrin
Lactoferrin , also known as lactotransferrin , is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions...
levels have also been proposed as diagnostic tests, but may have limited diagnostic accuracy.
Computed tomography
In a recent study, a patient who received a diagnosis of CDC on the basis of computed tomographyComputed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
(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, the best ancillary findings were pericolonic stranding, ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
, and colon wall nodularity. The presence of wall thickness plus any one of these ancillary findings is 70% sensitive and 93% specific.
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. In this study with a prevalence of positive C. difficile toxin of 54%, the PPV was 88%. Patients who have antibiotic-associated diarrhea with CT findings diagnostic of CDC merit consideration for treatment on that basis.
Real-Time PCR
By the end of 2009, 3 different Real-Time PCR tests had achieved 510(k) clearance from the FDA. Cepheid's GeneXpert is by far the fastest and easiest of the three, but it is also the most expensive. Cepheid uses a cartridge-based kit that is tailored for small hospitals or labs without the ability to batch large numbers of samples together. In fact, batching is not required since the extraction occurs in the same vial as amplification of the target, positive, and negative controls. The reported time from sample to result is ~45 minutes.Prodesse offers another kit-based IVD Real-Time PCR test (ProGastro Cd), which uses an external extraction and purification on the Roche MagnaPure. Prodesse (Gen-Probe) tech support claims that this external separation produces higher yields than the BD GeneOhm. The Prodesse technique is similar in price to the BD GeneOhm technique after one includes the price of the extraction and takes about three hours from sample to result.
The final IVD Clostridium difficile Real Time PCR test on the market since 2009 is from BD GeneOhm. The protocol uses a glass-bead lysis rather than an extraction, but results are reported to be good and the method shaves a little over an hour off the protocol time (about 1 hour 45 minutes from sample to result). Total costs for the Prodesse and BD GeneOhm tests are approximately the same.
For each test, sensitivities are generally reported as 88-91% and specificities as 96-97%, depending on the tests, prevalence of the disease and the size of the patient pool.
Prevention
The most effective method for preventing CDAD is proper antimicrobial prescribing. In the hospital setting, where CDAD is most common, nearly all patients that develop CDAD are exposed to antimicrobials. Although proper antimicrobial prescribing sounds easy to do, approximately 50% of antimicrobial use is considered inappropriate. This is consistent whether in the hospital, clinic, community, or academic setting. Several studies have demonstrated a decrease in CDAD by limiting antibiotics most strongly associated with CDAD or by limiting unnecessary antimicrobial prescribing in general, both in outbreak and non-outbreak settings.In Britain, the testing of all hospital inpatients over the age of 65 with diarrhea for C. difficile became a compulsory NHS
National Health Service
The National Health Service is the shared name of three of the four publicly funded healthcare systems in the United Kingdom. They provide a comprehensive range of health services, the vast majority of which are free at the point of use to residents of the United Kingdom...
practice in January 2008, when it became evident that many UK outbreaks were being disguised as Norovirus by hospital Risk Managers. Risk Managers can be dismissed by the Department of Health if C. difficile infection rates are too high, but they cannot be dismissed as a result of a Norovirus outbreak. Patients most at risk are those with recent broad-spectrum antibiotic aor proton-pump inhibitor treatments.
Infection control measures, such as wearing gloves when caring for patients with CDAD, have been proven to be effective at prevention. This works by limiting the spread of C. difficile in the hospital setting. In addition, washing with soap and water will eliminate the spores from contaminated hands, but alcohol-based hand rubs are ineffective. Bleach wipes containing 0.55 percent sodium hypochlorite have been shown to kill the spores and prevent transmission between patients.
Soil-containing potted plants can serve as a reservoir for the development of multidrug-resistant bacteria and fungi, and, for this reason, many hospital systems restrict the use of soil-containing potted plants. To help mitigate serious infections and development of multidrug-resistant organisms in long-term and acute hospital settings, soil-containing potted plants should not be used, especially in areas of direct patient care, such as offices, rooms, and hallways of hospital wards. Alternatives to soil-containing plants are available.
Treatment with various oral supplements containing live bacteria has been studied in efforts to prevent Clostridium difficile-associated infection/disease. A randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
using a probiotic
Probiotic
Probiotics are live microorganisms thought to be beneficial to the host organism. According to the currently adopted definition by FAO/WHO, probiotics are: "Live microorganisms which when administered in adequate amounts confer a health benefit on the host"...
drink containing Lactobacillus casei
Lactobacillus casei
Lactobacillus casei is a species of genus Lactobacillus found in the human intestine and mouth. As a lactic acid producer, it has been found to assist in the propagation of desirable bacteria. This particular species of Lactobacillus is documented to have a wide pH and temperature range, and...
, L bulgaricus, and Streptococcus salivarius subsp. thermophilus
Streptococcus salivarius subsp. thermophilus
Streptococcus salivarius subsp. thermophilus is a Gram-positive bacteria and a homofermentative facultative anaerobe, of the viridans group. It tests negative for cytochrome, oxidase and catalase, and positive for alpha-hemolytic activity...
was reported to have some efficacy. This study was sponsored by the company that produces the drink studied. Although intriguing, several other studies have been unable to demonstrate any benefit of oral supplements of similar bacteria at preventing CDAD. Of note, patients on the antibiotics most strongly associated with CDAD were excluded from this study.
Hydrogen peroxide vapor
Vaporized hydrogen peroxide
Vaporized hydrogen peroxide is a gaseous form of hydrogen peroxide with applications as a low-temperature antimicrobial gas used to decontaminate enclosed and sealed areas such as laboratory workstations, isolation and pass-through rooms, and even aircraft interiors. It is registered by the U.S...
(HPV) systems used to sterilize a patient room post discharge has been shown to reduce infection rates and to reduce risk of infection to subsequent patients. One study (Boyce et al. 2008) showed that incidence of CDAD was reduced by 53% though use of HPV. A second study (Manian et al. 2010) showed only a 42% reduction in CDAD rates through use of HPV.
In a limited clinical trial, a C. difficile anti-toxoid
Toxoid
A toxoid is a bacterial toxin whose toxicity has been weakened or suppressed either by chemical or heat treatment, while other properties, typically immunogenicity, are maintained. In international medical literature the preparation also is known as Anatoxin or Anatoxine...
vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
was reported to improve patient outcomes. Further testing will be required to validate this trial. Recent advancements have been made at the University of Guelph
University of Guelph
The University of Guelph, also known as U of G, is a comprehensive public research university in Guelph, Ontario, Canada. It was established in 1964 after the amalgamation of Ontario Agricultural College, the Macdonald Institute, and the Ontario Veterinary College...
by Professor Monteiro on a polysaccharide vaccine currently in its pre-clinical stage.
Treatment
Asymptomatic colonization with C. difficile is common. Treatment in asymptomatic patients is controversial, also leading into the debate of clinical surveillanceClinical surveillance
Clinical surveillance refers to the surveillance of health data about a clinical syndrome that has a significant impact on public health, which is then used to drive decisions about health policy and health education...
and how it intersects with public health policy. In general, mild cases do not require specific treatment.
Patients should be treated as soon as possible when the diagnosis of Clostridium difficile colitis (CDC) is made to avoid frank sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
or bowel perforation. To reduce complications, physicians often begin treatment based on clinical presentation before definitive results are available. Knowledge of the local epidemiology of intestinal flora of a particular institution can guide therapy. In addition, oral rehydration therapy (ORT)
Oral rehydration therapy
Oral rehydration therapy is a simple treatment for dehydration associated with diarrhoea, particularly gastroenteritis or gastroenteropathy, such as that caused by cholera or rotavirus. ORT consists of a solution of salts and sugars which is taken by mouth...
is useful in retaining fluids during the duration of diarrhoea.
Medications
Three antibiotics are specifically effective against C. difficile in vivoIn vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
:
- MetronidazoleMetronidazoleMetronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....
is the drug of choice, because of lower price and comparable efficacy. - Oral vancomycinVancomycinVancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
(125 mg four times daily) is second-line therapy, but is often avoided due to concerns of converting intestinal flora into vancomycin-resistant organisms. Vancomycin is the treatment of choice 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. Vancomycin must be administered orally because intravenous administration does not achieve gut lumen minimum therapeutic concentration. Patients unresponsive to Metronidazole can be placed on 14 days of Vancomycin followed by Rifaximin for another 14 days.
- A more recent study by Zar and others showed no difference between vancomycin and metronidazole in mild disease, but that vancomycin was superior to metronidazole for treating severe disease. In this study, severe disease was defined on a point score: One point each was given for age >60 years, temperature >38.3°C, albumin level <2.5 mg/dL, or peripheral WBC count >15,000 cells/mm3 within 48 h of enrollment. Two points were given for endoscopic evidence of pseudomembranous colitisPseudomembranous colitisPseudomembranous colitis, a cause of antibiotic-associated diarrhea , is an infection of the colon. It is often, but not always, caused by the bacterium Clostridium difficile. Because of this, the informal name C. difficile colitis is also commonly used. The illness is characterized by...
or treatment in the intensive care unit. Severe disease was defined as 2 or more points on this score. The main criticism of this study is that a low, non-standard dose of metronidazole (250 mg) was used instead of (500 mg).- FidaxomicinFidaxomicinFidaxomicin is the first in a new class of narrow spectrum macrocyclic antibiotic drugs. It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis...
has been found to be equally effective as vancomycin - The use of linezolidLinezolidLinezolid is a synthetic antibiotic used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics...
may be considered.
- Fidaxomicin
Drugs used to stop diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
frequently worsen the course of C. difficile-related pseudomembranous colitis. Loperamide
Loperamide
Loperamide , a synthetic piperidine derivative, is an opioid drug used against diarrhea resulting from gastroenteritis or inflammatory bowel disease. In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, and Pepto Diarrhea Control...
, diphenoxylate
Diphenoxylate
Diphenoxylate is an opioid agonist used for the treatment of diarrhea that acts by slowing intestinal contractions and peristalsis allowing the body to consolidate intestinal contents and prolong transit time, thus allowing the intestines to draw moisture out of them at a normal or higher rate and...
and bismuth
Bismuth
Bismuth is a chemical element with symbol Bi and atomic number 83. Bismuth, a trivalent poor metal, chemically resembles arsenic and antimony. Elemental bismuth may occur naturally uncombined, although its sulfide and oxide form important commercial ores. The free element is 86% as dense as lead...
compounds are contraindicated: slowing of fecal transit time is thought to result in extended toxin-associated damage.
Cholestyramine
Cholestyramine
Cholestyramine or colestyramine is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means that it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them...
, a powder drink (an ion exchange resin
Ion exchange resin
An ion-exchange resin or ion-exchange polymer is an insoluble matrix normally in the form of small beads, usually white or yellowish, fabricated from an organic polymer substrate. The material has highly developed structure of pores on the surface of which are sites with easily trapped and...
), which is occasionally used to lower cholesterol, is effective in binding both Toxin A and B, slowing bowel motility and helping prevent dehydration. The dosage can be 4 grams daily, to up to four doses a day; however caution should be exercised to prevent constipation, or drug interactions, most notably the binding of drugs by cholestyramine, preventing their absorption. Cholestyramine is not an anti-infective; it dramatically reduces many of the symptoms of a C. difficile infection, but it is not appropriate to use by itself, as it does not change the infection status. Cholestyramine is usually used in concert with vancomycin. Powdered banana flakes given twice daily are an alternative to cholestyramine, and allow for stool bulking.
Treatment with probiotics ("good" intestinal flora) has also been shown effective. Provision of Saccharomyces boulardii
Saccharomyces boulardii
Saccharomyces boulardii is a tropical strain of yeast first isolated from lychee and mangosteen fruit in 1923 by French scientist Henri Boulard. It is related to, but distinct from, Saccharomyces cerevisiae in several taxonomic, metabolic, and genetic properties. S...
(Florastor) or Lactobacillus acidophilus
Lactobacillus acidophilus
Lactobacillus acidophilus is a species in the genus Lactobacillus. L. acidophilus is a homofermentative species, fermenting sugars into lactic acid, which grows readily at rather low pH values and has an optimum growth temperature of 37 °C . L...
twice daily times 30 days along with antibiotics has been clinically shown to shorten the duration of diarrhea. A last-resort treatment in immunosuppressed
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
patients is intravenous immunoglobulin
Intravenous immunoglobulin
Intravenous immunoglobulin is a blood product administered intravenously. It contains the pooled IgG extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months...
(IVIG).
Colectomy
In those patients that develop systemic symptoms of CDC, colectomyColectomy
Colectomy consists of the surgical resection of any extent of the large intestine .-History:Sir William Arbuthnot-Lane was one of the early proponents of the usefulness of total colectomies, although his overuse of the procedure called the wisdom of the surgery into question.-Indications:Some of...
may improve the outcome if performed before the need for vasopressors.
Stool transplant
Fecal bacteriotherapyFecal bacteriotherapy
Fecal bacteriotherapy, also known as fecal transfusion, fecal transplant, stool transplant, or human probiotic infusion , is a medical treatment for patients with pseudomembranous colitis , or ulcerative colitis that involves restoration of colon homeostasis by reintroducing normal bacterial flora...
, known in colloquial terms as stool transplant, a procedure related to probiotic
Probiotic
Probiotics are live microorganisms thought to be beneficial to the host organism. According to the currently adopted definition by FAO/WHO, probiotics are: "Live microorganisms which when administered in adequate amounts confer a health benefit on the host"...
research, has preliminarily been shown to cure the disease. It involves infusion of bacterial flora acquired from the feces of a healthy donor to reverse the bacterial imbalance responsible for the recurring nature of the infection. In fecal transplantation, donor stool is collected from a close relative who has been tested for a wide array of bacterial, viral, and parasitic pathogens. The stool is often mixed with saline or milk to achieve the desired consistency, then delivered through a colonoscope or retention enema, or through a nasogastric or nasoduodenal tube. The procedure replaces normal, healthy colonic flora that had been wiped out by antibiotics, and reestablishes the patient's resistance to colonization by Clostridium difficile. However, there is often patient resistance due to the perceived unpleasantness of the procedure that must be overcome first before proceeding with this often-effective treatment.
There are currently over 150 published reports dating back to 1958, though many more have been performed. It has a success rate of about 90%. A guide was released in 2010 for home fecal transplantation.
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.Prognosis
After a first treatment with metronidazoleMetronidazole
Metronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....
or vancomycin
Vancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
, Clostridium difficile recurs in about 20% of people. This increases to 40% and 60% with subsequent recurrences.
Pronunciation
Scientific nameBinomial nomenclature
Binomial nomenclature is a formal system of naming species of living things by giving each a name composed of two parts, both of which use Latin grammatical forms, although they can be based on words from other languages...
s of organisms are Latin or Latinised Greek, in this case one of each. The anglicized pronunciation klɒsˈtrɪdiəm dɨˈfɪsɨliː is common, though a more Classical /dɨˈfɪkɨleɪ/ is also used. A common practice has developed of pronouncing difficile as /diːfiˈsiːl, as though it were French. The pronunciation varies because this is an example of international scientific vocabulary
International Scientific Vocabulary
International scientific vocabulary comprises scientific and specialized words whose language of origin may or may not be certain, but which are in current use in several modern languages. The name "International Scientific Vocabulary" was first used by Philip Gove in Webster’s Third New...
(ISV). The Classical Latin
Classical Latin
Classical Latin in simplest terms is the socio-linguistic register of the Latin language regarded by the enfranchised and empowered populations of the late Roman republic and the Roman empire as good Latin. Most writers during this time made use of it...
sound is /dɨˈffɪkɨle/. One may also hear Spanish-influenced sound (/di.ˈfi.si.le/) and Italian- or Church-Latin-influenced sound (/dɪfˈfi.tʃi.le/).
Notable outbreaks
- June 4, 2003, two outbreaks of a highly virulent strain of this bacterium were reported in Montreal, Quebec and Calgary, Alberta, in CanadaCanadaCanada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
. 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 healthcare 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 HospitalStoke Mandeville HospitalStoke Mandeville Hospital is a large National Health Service hospital within Aylesbury Urban Area to the south of the town of Aylesbury, near the village of Stoke Mandeville in Buckinghamshire...
in the United KingdomUnited KingdomThe United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
between 2003 and 2005. The local epidemiologyEpidemiologyEpidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...
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 containing live cultures to patients at risk for infection.
- It has been suggested that both the Canadian and English outbreaks were related to the seemingly more virulent Strain NAP1/027 of bacterium. This novel strain, also known as Quebec strain, has also been implicated in an epidemic at two Dutch hospitals (HarderwijkHarderwijk' is a municipality and a small city in the eastern Netherlands.- The history of Harderwijk :Harderwijk received city rights from Count Otto II of Guelders in 1231. A defensive wall surrounding the city was completed by the end of that century. The oldest part of the city is near where the...
and AmersfoortAmersfoortAmersfoort is a municipality and the second largest city of the province of Utrecht in central Netherlands. The city is growing quickly but has a well-preserved and protected medieval centre. Amersfoort is one of the largest railway junctions in the country, because of its location on two of the...
, both 2005). A theory for explaining the increased virulence of 027 is that it is a hyperproducer of both toxins A and B, and that certain antibiotics may actually stimulate the bacteria to hyperproduce.
- October 1, 2006, C. difficile was said to have killed at least 49 people at hospitals in LeicesterLeicesterLeicester is a city and unitary authority in the East Midlands of England, and the county town of Leicestershire. The city lies on the River Soar and at the edge of the National Forest...
, EnglandEnglandEngland is a country that is part of the United Kingdom. It shares land borders with Scotland to the north and Wales to the west; the Irish Sea is to the north west, the Celtic Sea to the south west, with the North Sea to the east and the English Channel to the south separating it from continental...
over eight months, according to a National Health ServiceNational Health ServiceThe National Health Service is the shared name of three of the four publicly funded healthcare systems in the United Kingdom. They provide a comprehensive range of health services, the vast majority of which are free at the point of use to residents of the United Kingdom...
investigation. Another 29 similar cases were investigated by coronerCoronerA coroner is a government official who* Investigates human deaths* Determines cause of death* Issues death certificates* Maintains death records* Responds to deaths in mass disasters* Identifies unknown dead* Other functions depending on local laws...
s. 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"
- October 27, 2006, 9 deaths were attributed to the bacterium in Quebec, Canada.
- November 18, 2006, the bacterium 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. Thirty-one 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.
- C. difficile was mentioned on 6,480 death certificates in 2006 in UK.
- February 27, 2007, a new outbreak was identified at Trillium Health CentreTrillium Health CentreThe Trillium Health Centre Bus Terminal is located in Mississauga, Ontario, Canada. It is situated on the northern end of the Mississauga site..The bus terminal only contains a bus shelter.-Bus routes:...
in Mississauga, Ontario, where 14 people were diagnosed with the bacteria. The bacteria were of the same strain as the one in Quebec. Officials have not been able to determine whether C. difficile was responsible for deaths of four patients over the prior two months.
- Between February and June 2007, three patients at Loughlinstown Hospital in Dublin, Ireland were found by the coroner to have died as a result of C. difficile infection. In an inquest, the Coroner's Court found that the hospital had no designated infection control team or consultant microbiologist on staff.
- October 2007, Maidstone and Tunbridge Wells NHS TrustMaidstone and Tunbridge Wells NHS TrustMaidstone and Tunbridge Wells NHS Trust is a large NHS Trust in the British National Health Service that manages hospitals in the Maidstone and Tunbridge Wells region in Kent....
was heavily criticized by the Healthcare CommissionHealthcare CommissionThe Healthcare Commission was a non-departmental public body sponsored by the Department of Health of the United Kingdom. It was set up to promote and drive improvement in the quality of health care and public health in England and Wales...
regarding its handling of a major outbreak of C. difficile in its hospitals in KentKentKent is a county in southeast England, and is one of the home counties. It borders East Sussex, Surrey and Greater London and has a defined boundary with Essex in the middle of the Thames Estuary. The ceremonial county boundaries of Kent include the shire county of Kent and the unitary borough of...
from April 2004 to September 2006. In its report, the Commission estimated that about 90 patients "definitely or probably" died as a result of the infection.
- November 2007, the 027 strain has spread into several hospitals in southern Finland, with ten deaths out of 115 infected patients reported on 2007-12-14.
- November 2009, four deaths at Our Lady of Lourdes Hospital in Ireland, have possible links to Clostridium difficile infection. A further 12 patients tested positive for infection, and another 20 show signs of infection, 10 November 2009.
- March 2010, From February 2009 to February 2010 199 patients at Herlev hospital in Denmark was suspected of being infected with the 027 strain. In the first half of 2009, 29 died in hospitals in Copenhagen after they were infected with the bacterium
- May 2010, A total of 138 patients at four different hospitals in Denmark infected with the 027 strain ( Herlev, Amager, Gentofte and Hvidovre) plus some isolated occurrences at other hospitals.
- May 28, 2011 an outbreak in Ontario, Canada has been reported, with 26 fatalities as of July 24, 2011.
Genome sequencing
The first complete genome sequence of a Clostridium difficile strain was first published in 2005 by Sanger InstituteSanger Institute
The Wellcome Trust Sanger Institute is a non-profit, British genomics and genetics research institute, primarily funded by the Wellcome Trust....
in the UK. This was of the C. difficile strain 630, a virulent and multidrug-resistant strain isolated in Switzerland in 1982. Scientists at Sanger Institute
Sanger Institute
The Wellcome Trust Sanger Institute is a non-profit, British genomics and genetics research institute, primarily funded by the Wellcome Trust....
have also recently sequenced genomes of about 30 Clostridium difficile isolates using next generation sequencing
Sequencing
In genetics and biochemistry, sequencing means to determine the primary structure of an unbranched biopolymer...
technologies from 454 Life Sciences
454 Life Sciences
454 Life Sciences, is a biotechnology company based in Branford, Connecticut. It is a subsidiary of Roche, and specializes in high-throughput DNA sequencing.-History and Major Achievements:...
and Illumina
Illumina (company)
Illumina, Inc. is a company incorporated in April 1998 that develops, manufactures and markets integrated systems for the analysis of genetic variation and biological function. Using its technologies, the company provides a line of products and services that serve the sequencing, genotyping and...
.
Researchers at McGill University
McGill University
Mohammed Fathy is a public research university located in Montreal, Quebec, Canada. The university bears the name of James McGill, a prominent Montreal merchant from Glasgow, Scotland, whose bequest formed the beginning of the university...
in Montreal
Montreal
Montreal is a city in Canada. It is the largest city in the province of Quebec, the second-largest city in Canada and the seventh largest in North America...
, Quebec
Quebec
Quebec or is a province in east-central Canada. It is the only Canadian province with a predominantly French-speaking population and the only one whose sole official language is French at the provincial level....
sequenced the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
of the highly virulent Quebec strain of C. difficile in 2005 using ultra-high-throughput sequencing technology. The tests involved doing 400,000 DNA parallel-sequencing reactions of the bacterium's genome, which had been fragmented for sequencing. These sequences were assembled computationally to form a complete genome sequence.
Treatment
- CDA-1 and CDB-1 (also known as MDX-066/MDX-1388 and MBL-CDA1/MBL-CDB1) is an investigational, monoclonal antibody combination co-developed by MedarexMedarexMedarex is an American biotechnology company owned by Bristol Myers Squibb and based in Princeton, New Jersey. The company has manufacturing facilities in Bloomsbury and Annandale, New Jersey, and research facilities in Milpitas and Sunnyvale, California. Medarex specializes in therapeutic...
and Massachusetts Biologic Laboratories (MBL) to target and neutralize C. difficile toxins A and B, for the treatment of CDI. Merck & Co., Inc. gained worldwide rights to develop and commercialize CDA-1 and CDB-1 through an exclusive license agreement signed in April 2009. It is intended as an add-on therapy to one of the existing antibiotics to treat CDI. - NitazoxanideNitazoxanideNitazoxanide, also known by the brand names Alinia and Annita is a synthetic nitrothiazolyl-salicylamide derivative and an antiprotozoal agent.Nitazoxanide is a light yellow...
is a synthetic nitrothiazolyl-salicylamide derivative indicated as an antiprotozoal agent (FDA-approved for the treatment of infectious diarrhea caused by Cryptosporidium parvum and Giardia lamblia) and is also currently being studied in C. difficile infections vs. vancomycinVancomycinVancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
. - Rifaximin, is a clinical-stage semi synthetic, rifamycin-based non-systemic antibiotic for CDI. It is FDA-approved for the treatment of infectious diarrhea and being developed by Salix Pharmaceuticals.
- Rifalazil,
- FidaxomicinFidaxomicinFidaxomicin is the first in a new class of narrow spectrum macrocyclic antibiotic drugs. It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis...
, - Tigecyclin and
- RamoplaninRamoplaninRamoplanin is a glycolipodepsipeptide antibiotic drug derived from strain ATCC 33076 of Actinoplanes.-Mechanism:It exerts its bacteriocidal effect by inhibiting cell wall biosynthesis, acting by inhibiting the transglycosylation step of peptidoglycan synthesis.-Uses:Its development has been...
.
External links
- Clostridium difficile: Is your family at risk? AboutKidsHealth
- Wins Story (The risks of C Diff infection and hospital neglect) discussing C. difficile
- Pathema — Clostridium genomics resource
- from the UK Clostridium difficile Support Group (UK)
- MedscapeCME Healthcare-associated infections
- "Sea Change Anticipated in the Management of C. difficile Infection" July 2009
- Clostridium difficile genomes and related information at PATRIC, a Bioinformatics Resource Center funded by NIAID
- CDI Toolkit from the Provincial Infection Control Network of British Columbia (PICNet)
- CDI Surveillance System from the Provincial Infection Control Network of British Columbia (PICNet)
- C. difficile TcdA — information from the Consortium for Functional Glycomics on one of the major virulence factors from C. difficile