CLOSTRIDIUM DIFFICILE TOXIN
Clostridium difficile (C.difficile) Toxin is an important nosocomial pathogen and the most frequently diagnosed cause of infectious hospital-acquired diarrhea. The incidence of C.difficile disease continues to rise despite a continued focus on methods to reduce the number of hospital cases, to eradicate the spores from the environment, and to find effective strategies for treating patients with recurrent disease.
The rates of C.difficile infection have tripled in the United States from 2000-2005. Disease severity and mortality rates have also increased particularly among the elderly population. It is estimated that the disease is costing the U.S. healthcare system more than $1 billion yearly. This is a huge burden to an already stressed healthcare system for a disease that has the ability to be controlled.
Description
The symptoms of C.difficile associated disease were first described in
1935 when it was thought that staph aureus was the culprit. However, in
1978 when the toxins of C.difficile were identified, doctors realized that
staph aureus was not the causative bacteria and that there was a new microorganism
causing these related diseases. The C.difficile bacteria was given the
name “difficile” because
the bacteria is very difficult to culture and because it took such a long time
to identify and to isolate the toxins it produces. The Clostridia genre is
a gram-positive, rod-shaped, spore-forming, anaerobic bacterium. In other words,
it survives in an oxygen free environment, and is very resistant to being killed.
It is transmitted through the fecal-oral route. It exists both vegetative and
spore forms. Both forms of C.difficile are found in oxygen free
environments like soil and the intestinal tract of mammals. When the vegetative
form is found in an aerobic (containing oxygen) environment, usually for
just a short time, it is relatively easy to kill with germicidal disinfectant
solutions.However, the spore form of C.difficile is very hearty and because
it is in a protective spore, it can live up to 6 months or longer in the
environment. The spores can survive even after being exposed repeatedly to
germicidal disinfectant solutions.
In healthy adults, when C.difficile is found in the colon, it is kept under control by the normal colon flora (the good bacteria). This is referred to as colonization resistance because this normal colon flora resistance limits the growth of any invading pathogenic microorganisms. When a patient is on antibiotic or other drug therapy, the normal colonic flora is greatly decreased which allows the C.difficile bacteria to flourish without competition for the nutrients present in the colon. This can contribute to the diarrhea associated with antibiotic use. When the competition from the normal colonic flora is decreased because of antibiotic use, the C.difficile spores germinate to the vegetative form. The vegetative form increases and begins to produce toxins that cause the symptoms of this disease. The C.difficile bacteria themselves do not invade the colon tissue or colon wall, but instead produces two toxins, Toxin A and Toxin B that cause an acute inflammatory response. Most strains of C.difficile that cause disease in humans contain both toxins A & B. Strains that do not produce either toxin A or B do not cause disease in humans.
A third toxin, called a binary toxin, is only in a minority of C.difficile strains, and is encoded in a separate part of the gene. This third toxin is identified as NAP 1/027 and is produced in the more severe cases of the disease. This is the new strain that is causing all the concern and is more virulent than in past outbreaks. This strain is resistant to the fluoroquinolone group of antimicrobials.
It is a logical assumption then that higher levels of toxin will increase bowel damage, frequency of diarrhea and morbidity. The increase in diarrhea will in turn facilitate spread of spores and promote epidemic out breaks.
Previous C.difficile infections were primarily associated with antibiotic
use, hospitalization, and the elderly or those people with a severe underlying
disease.
Essentially, all antimicrobials can induce C.difficile by disrupting
the gut ecology.
For many years C.difficile has been recognized as a major cause
of antibiotic-associated diarrhea but it has only been in recent years
that the disease has resulted in an increase in severe illness and death.
The broad-spectrum antibiotics most associated with the C.difficile diseases
are Penicillin, cephalosporin and clindamycin. Recently the fluoroquinolone
flor-o-kwin-o-loan group of antibiotics have been added to this list. Actually,
C.difficile spores
are more resistant to the fluoroquinolone antibiotics than the broad
spectrum antibiotics. The importance of an antibiotic’s activity
against a particular C.difficile strain should not be underestimated.
Antibiotic effects on vegetation of spores and time for recovery of normal
flora after antibiotic use are important. The main risk factor for C.difficile infection is antimicrobial use, which increases risk through an alteration
in the in normal lower-intestinal tract flora. It is thought that the alteration
in the complex ecology of the large bowel provides C.difficile an opportunity
to thrive and produce disease.
Disease States
Clostridium difficile Associated Disease (CDAD) varies in severity
from mild to severe. Pseudmembraneous colitis is the most severe manifestation
with fever, pain, and decreased gut motility primarily located in the
distal left colon and rectum. There is a higher death rate if toxic megacolon
develops, especially if diagnosis is delayed. The period between exposure
to C.difficile in a health care facility in-patient and the development
of CDAD was estimated in one study to be less than 7 days. Patients with
CDAD onset after discharge had longer lengths of in-patient stay, obviously
with a longer period of possible exposure for transmission. However,
the increased risk of CDAD can persist for many weeks after stopping
the antimicrobial therapy because of the prolonged disturbance of normal
intestinal tract flora.
The C.difficile associated diseases present with frequent watery diarrhea. The diarrhea has a very foul smell, with mucous and in approximately 30% of the patients there is occult blood in the diarrhea. These cases can be mild or very severe resulting in more severe C.difficile associated disease. A fever and loss of appetite with abdominal pain or tenderness are usually present. The patient also becomes dehydrated. However, not everyone who has antibiotic-associated diarrhea has a C.difficile infection. You can differentiate the antibiotic-associated diarrhea not caused by C.difficile by noting that there are no other symptoms except the 3-4 loose stools. These cases can resolve the diarrhea by discontinuing the antibiotic. 99% of the Pseudomembranous colitis (PMC) cases are caused by the C.difficile toxins. It is one of the most severe C.difficile associated diseases. It occurs in 3% of patients and can quickly become life threatening if not treated immediately. These patients present with all the signs and symptoms mentioned earlier, but the fever is higher in PMC cases. The PMC is usually more severe in the rectum and distal colon.
There are some patients that present with abdominal distress, fever, nausea, vomiting and ileus but not the other usual symptom of frequent foul-smelling watery diarrhea. These are the patients that are often missed diagnosed. Since the frequent watery diarrhea is NOT present, the doctors do not consider C.difficile infection until the patient is quite ill, even septic with multiple organ shut down. When a sigmoidoscopy is done for diagnostic purposes, the colon wall/tissues are thickened. These patients also often present with ascites. The mortality rate is 24-38% and approximately two-thirds require surgical intervention.
Twenty percent of all patients that have a C.difficile associated disease have a relapse. The relapse can occur as soon as one week to months after the infection has been treated. The relapses are usually a more severe and two-thirds of patients with one relapse will have more. The resurgence of CDAD has also been associated with an increase in the number of recurrences. Relapses may be related to lack of the body’s ability to develop protective antibodies, re-exposure to antibiotics, and/or persistent alteration of the colon micro-flora. Recurrence with a different strain is more likely because of exposure to a contaminated environment during longer hospital stays.
Risks
Patients who are hospitalized are at the highest risk for
CDAD. Even so, ongoing or recent exposure to healthcare is
also a risk. Those who are immune-compromised, elderly, or
suffer from complex or severe illnesses are at risk. Antibiotic
usage still plays a major role in the development of CDAD
and cephalosporins and fluoroquinolones should be used judiciously.
Sources of community-based or non-healthcare settings of
C.difficile may include exposure to spores in the soil, carriage
by pets (dogs, cats, and horses), contaminated foods, and
exposure to household contacts with diarrhea. Children are
known to develop CDAD but reported outbreaks are less common than
in adult patients.
Clinical studies and articles in the literature confirm that poor infection control practices play a very large role in transmission of C.difficile. Nursing staff with increased work loads often take shortcuts, like not washing their hands, when they are busy multi-tasking. Environmental services staff members often do not understand the importance of their responsibilities to ensure all environmental surfaces and patient furniture is thoroughly cleaned and disinfected. Infected patients can shed the C.difficile spores in their stool. If patients do not wash their hands thoroughly, the shared surfaces of hospital rooms can become infected. Any furniture in a shared space can become contaminated.
Diagnosis
The standard test is the enzyme immunoassay test or Elisa. It is
the most commonly used test. The toxins are directly measured in
a stool sample within 4-6 hours. This test is not as sensitive as other
tests that require longer time for the results. It does have a high false-negative
rate. The gold standard test is the Cytotoxicity assay tissue culture.
This test does require a tissue culture, and is time consuming. Test
results require 24-48 hours but it is highly sensitive and specific.
Not all labs have the equipment or trained personnel to perform this
test. This test is the most sensitive test but it also is very expensive.
It requires greater lab expertise because C.difficile is very
difficult to culture. It measures the toxins and identifies what strain
of C.difficile is
causing the problem. This test is used during facility outbreaks to determine
which strain is causing the problem.
Endoscopy (flexible Sigmoidoscopy) is a rapid but invasive diagnostic test for C.difficile. It should be used with caution because of the risk of perforation and reserved for patients with severe colitis of unclear etiology when an immediate diagnosis is needed.
Treatment
When a patient presents with numerous episodes of watery foul-smelling
diarrhea, the first line of treatment is to discontinue
the antibiotic the patient was taking. When the antibiotic therapy is discontinued,
approx. 23% resolve with in 2-3 days. Those that do not
resolve the diarrhea problem are placed on IV fluids and given a 10 day
course of an antibiotic. Flagyl and Vancomycin are the 2 antibiotics usually
used to treat C.difficile related diseases. Flagyl has been the standard
recommended first line of treatment but has been becoming less responsive
even after 10 days of treatment. This decreased response may be due to
the complexity of the hospitalized patient’s condition. Flagyl
is used first because it is less costly and because of the risk of the patient
becoming resistant to Vancomycin. Vancomycin is used if Flagyl is not successful.
Vancomycin does kill the vegetative forms of C.difficile but when the Vancomycin
is discontinued the C.difficile spores can germinate; if the normal flora of
the colon is not restored the C.difficile can flourish and a relapse can occur.
25% of the patients treated with these drugs fail to respond. When there is
a recurrence or in a severe infection, the treatment is still Flagyl or oral
Vancomycin. In these cases the antibiotic is given over a longer period, usually
one month. The treatment starts with a full dose of the antibiotic and then
is tapered off gradually. This destroys the C.difficile and allows the normal
flora to restore itself. The normal flora then becomes the colonization resistance
to the C.difficile spores in the colon.
Probiotics have been recommended in the treatment of recurrent disease as an attempt to normalize the fecal flora and restore “colonization resistance”. Prebiotics are non-digestible food components (starch or fiber) that stimulate the growth of bifido-bacteria, a type of bacterium thought to play a major role in inhibiting the establishment of opportunistic pathogens in the intestine. Prebiotics are given alone, without a probiotic organism. In rare occasions when the relapse does not respond to the antibiotic therapy, immunoglobulin is given. IgG is the antibody against the A toxin. This treatment is not used on a regular basis.
Surgical intervention is required in about 2/3rds of the patients with toxic megacolon. When a patient has not responded to medical treatment within 7 days of intensive medical therapy then surgery is usually needed. This treatment is currently used only as a life-saving measure but 40% of these patients die.
Control/Prevention
For a long time microbiologists have been calling for more judicious
use of antibiotics. Infection control departments in
each and every hospital, nursing home, long term care facility and
community health department should have a very active surveillance program
in place so every outbreak of any infectious disease and especially C.difficile can be caught before it becomes an epidemic for the facility.
It is necessary to have an active surveillance program in place for identifying and co-horting any patients with C.difficile and to ensure early diagnosis. Regulatory agencies are very concerned about judicious and careful use of prescribing antibiotics. Healthcare workers must be knowledgeable about the proper and appropriate handling of medical devices and ensure environmental surfaces are disinfected. Most importantly, there must behavioral and cultural changes with regard to total compliance with infection control measures that each facility has put into place. Education of all staff with regard to prevention and control measures is necessary.
It has been documented that the two most effective interventions in controlling and preventing this infection is to minimize environmental contamination and the use of effective barrier precautions during patient and/or contaminated device contact. This spore is resistant to conventional cleaning disinfectants so environmental and disinfection strategies must be in place. It is important to keep surfaces clean, to clean body spills immediately and use an EPA registered hypochlorite-based disinfectant. If generic sources of hypochlorite (bleach) are used it must be diluted correctly. READ THE LABEL CLAIMS CAREFULLY: there are labels out there that say they kill C.difficile BUT in smaller print it claims kill in the VEGETATIVE form, not the SPORE form. There is also a time factor for the solution to be effective. Read the label for the contact time. Spraying the environmental surfaces and then wiping them dry does nothing toward disinfecting those surfaces. Keeping the surfaces clean and cleaning any spills immediately is very important. Use friction when cleaning the spills. Routine cleaning will loosen the bacterial spores which will enable the spores to be removed from the surfaces. Barrier precautions must be taken when at risk for contact with C.difficile spores. Wear personal protective equipment including gloves, gowns, and masks if you anticipate splashes. HCWs need to have a total awareness of “clean” and “dirty” or “clean” and “contaminated”. Every HCW needs to start focusing on aseptic technique. There must be a TOTAL AWARENESS FOR “CLEAN” AND “CONTAMINATED” at all times.
Frequent, meticulous hand-washing with soap and water is necessary. Friction must be used and included on finger tips and palms of hands. Bacteria harbor under jewelry and fingernails so it is best not to wear any rings/jewelry and keep fingernails short. Alcohol sanitizers should not be used as they have been found to be ineffective against C.difficile spores.
Conclusion
There are many ways to constantly educate ourselves on new and emerging
diseases. I urge each of you to search the
medical journals and go online to the CDC, FDA, NIH or WHO web sites to
learn more about any disease that can causes infections. We each need to
know as much as possible so we prevent the transmission rather than contribute
to the transmission.
Marcia Hardick, RN,BS,CSPDT
Education Advisor, NYSACSP