Clostridium Difficile Toxin:
Diagnosis, Treatment, and Prevention of Disease
By Marcia Hardick, RN, BS, CGRN
Bacteria present themselves under the microscope in various shapes, including spheres (cocci), curves, spirals and rods (bacilli). Bacteria can be divided broadly into two main groups according to their reaction to gram staining, which is a process that reveals the cell wall structure. Some bacteria stain gram positive while others stain gram negative. Bacterial groups are also divided by their ability to grow in the presence (aerobic) or absence (anaerobic) of oxygen, and their ability to form spores. Once a bacterium is identified and defined by its genus name, it is further classified by its species name.
Clostridium is an anaerobic, spore-forming, gram positive bacillus. The four main clostridia species include: Clostridium perfringens (associated with gas gangrene); Clostridium tetani (causes tetanus infections), Clostridium botulinum (causes botulism from improperly preserved foods), and Clostridium difficile (causes pseudomembranous colitis, a complication of antibiotic therapy).
The spores and vegetative forms of the bacteria are found in soil and in the gastrointestinal tracts of mammals. Clostridia survive in hostile environments, and may persist on surfaces for months. They are resistant to many methods of heat and chemical disinfection and many commonly used cleaning agents. In the hierarchy of microorganism resistance to germicides, spores are among those most resistant to being killed, and only prions are more resistant.1
The transmission of C. difficile is primarily through contaminated environmental surfaces and the contaminated hands of healthcare workers (HCWs) in hospitals and extended care facilities. The term environmental surfaces includes medical and patient-care equipment in addition to room surfaces (patient rooms). Occasionally, transmission occurs by direct patient-to-patient contact as well.
Any contamination of HCWs hands also contaminates all the environmental surfaces they touch, such as doors, countertops, bedrails, and bathroom surfaces, as well as equipment. The prevalence of contamination on the hands of HCWs is thought to be linked proportionally to the level of environmental contamination in their facility. This is difficult to prove, however, because hand carriage (transmission) is transient and may occur with multiple HCWs. Workers are not at risk of contracting C. difficile diarrhea or infection unless they are taking antibiotics, but they present a risk to patients for nosocomial (hospital- acquired) infections.
There have been no reports of C. difficile transmission via medical instrumentation or food, or from food preparation areas in hospitals. There are, however, reported cases of transmissions from the use of blood pressure cuffs, toilets, bedside commodes, electronic rectal thermometers, bed rails, call buttons, furniture, and improper gloving or glove removal techniques.
C. difficile spores ingested into the gastrointestinal tract survive the acidic environment of the stomach. The spores then convert to their bacterial forms in the colon and produce toxins. It is the presence of the toxins that causes clinical symptoms. Presenting symptoms range from a mild, self-limiting state to fulminant, life-threatening disease. Diarrhea is the major manifestation of the disease. In addition to diarrhea (mild to severe), patients may experience cramping, abdominal pain and fever. Leukocytosis is also present in these patients. If pseudomembranous colitis develops, the patient experiences abdominal distention. Consequently, toxic megacolon, colonic perforation, and sepsis may develop. As a result, the patient also experiences fluid and electrolyte imbalance, dehydration, protein-losing enteropathy, cardiac dysrhythmias, and/or hypotension. Extraintestinal symptoms include polyarthritis and impaired skin integrity. Although severe symptoms are uncommon, Clostridium difficile causes significant disease and often lengthens a patients hospital stay.2
Clostridium difficile toxin is the most frequent cause of nosocomial diarrhea. It affects millions of patients each year. C. difficile causes pseudomembranous colitis, a complication of antibiotic therapy. Those antibiotics that are most causative include second-generation cephalosporins, clindamycin, and extended spectrum penicillins. There are fewer cases reported after taking ciprofloxacin, but the incidence will relate to the level of this antibiotics use within the facility. Pseudomembranous colitis has been associated with the use of every antibiotic, including vancomycin and metronidazole, which are the standard therapies for C. difficile diseases. Any person who develops diarrhea after taking an antibiotic for at least six days or within six weeks of beginning therapy should be considered to harbor C. difficile until it is ruled out. Many cases are diagnosed after the patient has been discharged from the hospital. Any hospitalized patient who experiences an onset of diarrhea should be evaluated as soon as possible.
Patients who have co-existing illness or extra-intestinal manifestations of C. difficile, who are debilitated or have underlying gastrointestinal pathologic conditions, or who have experienced a prolonged hospitalization have a poorer prognosis for a cure. There can be cluster outbreaks among patient populations in specific hospital units, such as intensive care and post-op units, and among patients who are elderly or immunocompromised. The longer a patient is hospitalized, the greater the risk of acquiring C. difficile. Some outbreaks have been reported to have higher mortality rates. Clostridium difficile-associated disease (CDAD) has been reported with a prevalence of up to 10 percent of hospitalized patients during a non-outbreak period, and up to a 29 percent recurrence rate during outbreaks. It is estimated that 20 percent of patients will have at least one recurrence of C. difficile after the first antibiotic therapy has been discontinued. Many patients experience multiple recurrences. Patients who have more than one recurrence often do not become indefinitely cured. The spectrum of CDAD also includes toxic megacolon, C. difficile-associated arthritis, and septicemia.
Colonization occurs in 50 percent of newborns where there are no symptoms, although the stool will test positive for the cytotoxin. Colonization in adults occurs less than 1 percent of the time. Clinical symptoms are rarely reported in colonized patients. Colonization in HCWs is more frequent, occurring 13 to 15 percent of the time with stool cultures testing positive. It is believed that nosocomial colonization occurs after workers hands have been in contact with infected patients and/or contaminated surfaces.
Cases have been reported in HCWs who were colonized with C. difficile toxin. For example, three healthy nurses were found to have the toxin present even when there was no history of recent antibiotic therapy. Another healthy nurse developed severe pseudomembranous colitis with ascites after a course of clindamycin for a dental infection. A HCW developed C. difficile diarrhea after a course of ampicillin for an upper respiratory infection.3
Antibiotic therapy may disrupt the normal flora of the gastrointestinal tract for up to six weeks after stopping the medication. An effective therapy is needed that will destroy the vegetative cells of Clostridium difficile that produce the toxin and will interfere with the pathogenesis that results after spore germination.
As previously stated, Clostridium difficile infection should be suspected in a patient with diarrhea who has taken antibiotics within the past six to eight weeks. A stool specimen should be tested for the presence of leukocytes and C. difficile toxins. The spore-forming bacillus produces two toxins: Clostridium difficile toxin A, primarily an enterotoxin which acts on the gut mucosa; and Clostridium difficile toxin B, a cytotoxin which has a pathologic effect on tissue culture cells. C. difficile proliferates in the right environment in a susceptible host especially when normal colon flora have been reduced or destroyed by an antibiotic. The stool cytotoxin assay detects cytotoxigenic C. difficile in more than 95 percent of cases diagnosed with pseudomembranous colitis.
Endoscopy is reserved for severe and rapidly progressing cases, to identify the presence of yellow-white plaques, the classic pseudomembrane. Sigmoidoscopy or colonoscopy should be carefully performed because of the high risk of colon perforation. Imaging studies include abdominal X-rays to identify haustral thickening with thumb-printing, toxic megacolon, and perforation. Ultrasound has greater specificity than computerized tomography (CT) and is used for critically ill patients. However, CT may be used for screening to rule out abscess or other inflammation, for extent of disease and for any potential complications (perforation).
The medical approach to C. difficile toxin diarrhea is early diagnosis. Treatment with metronidazole, 250-500 mg PO QID for seven to 14 days is a popular regimen. If treatment fails or the patient is unable to tolerate metronidazole, 125 mg of oral vancomycin is often used, QID for seven to 14 days. It can also be given by enema or nasogastric tube. Treatment with metronidazole is preferred since it is much less expensive, and studies have shown that metronidazole and vancomycin have equivalent efficacy. In addition, there is currently grave concern about the resistance of vancomycin against other bacteria, such as enterococci. Giving 25,000 units of Bacitracin PO QID for seven to 14 days is a slightly more expensive alternative to metronidazole, but Bacitracin is rarely used. Cholestyramine or other resin binders can be given for mild cases but cannot be given with vancomycin because they bind the antibiotic, making it ineffective. Patients who do not respond to treatment or cannot tolerate metronidazole or vancomycin are given glycopeptides or fusidic acid. All unnecessary antibiotics must be discontinued as soon as possible, including the causative antibiotic.4
Surgical intervention can reduce the risk of complications and return the patient to his/her previous quality of life. Indications for surgery include complicated or severe infection that does not respond to medication, progression to toxic megacolon, uncontrolled bleeding, or perforation. It has been reported that patients who require surgery range from less than 1 percent to 5 percent. Between 5 percent and 20 percent of patients with pseudomembranous colitis may present with an acute abdomen requiring surgery. Patients who experience perforation have a mortality rate of about 33 percent.5
This devastating illness causes a great economic burden on an already financially distressed healthcare industry. The spore infects millions of people a year and causes complications and prolonged hospital stays. An outbreak in a hospital unit can also be devastating to a facility, as it causes substantial clinical problems for patients and a great challenge to healthcare providers.
A conservative estimate of the costs of the disease in the U.S. exceeds $1 billion per year. A study in Boston published in 2002 states that there is a great difference between the costs, length of hospital stay, and survival rates for patients who have developed Clostridium difficile- associated disease and those who have not. A conservative estimate of the extra length of time in the hospital for patients with Clostridium difficile-associated disease is just over three days. In this same study of 271 patients who were admitted to the hospital, 40 patients (15 percent) developed C. difficile-documented diarrhea. The total costs of the hospital stay were about $3,700 higher (a 54 percent increase) for these patients than for patients who did not acquire the disease. It is estimated that over $10,000 in total direct medical expenses are incurred per case, with an average cost for just the diagnosis and treatment being $3,103 per patient. The first episode of Clostridium difficile illness with 10 days of standard antibiotic treatment averages $1,914.7
In order to decrease the major economic burden and the devastating effects of the illness, a facilitys main objective should be preventing nosocomial infections and colonization of C. difficile. It is also necessary to limit the use of antibiotics that cause C. difficile-related complications. Instituting restrictive antibiotic treatment policies and programs may be required in order to accomplish this.
It is absolutely critical to prevent transmission of C. difficile by establishing infection control policies and processes that all healthcare personnel understand and adhere to. Since transmission of the disease is through contaminated surfaces and the hands of healthcare providers, ongoing procedures that provide a clean and disinfected environment are necessary. Unfortunately, no single reported method has proven uniformly effective, so the best preventative solution is a combination of activities.8
Regular handwashing is the single most important measure that will decrease the incidence of Clostridium difficile-related illness. Hands must be washed whenever there is contact with body fluids, excretions, patient care equipment, and contaminated articles, and before leaving a patients room. HCWs must always be conscious of both the clean and contaminated surfaces in their work areas and patient environments, and must avoid cross-contamination. Gloves provide a protective barrier and prevent contamination of the healthcare workers hands, but they must be changed regularly. Gloves are not a substitute for handwashing. All staff members need to be educated on proper hand washing techniques. Special attention must be paid to fingertips, palm surfaces, the underside of nails and rings. Facilities should consider a policy for restricting jewelry when caregivers are taking care of infected patients.9
Isolation of Patients
In addition to standard precautions issued by the Centers for Disease Control and Prevention (CDC), which are the standard infection control protocol in hospitals, some institutions require that a patient who is colonized with, suspected to have, or diagnosed with C. difficile infection be put into contact isolation. Under contact isolation protocols, all staff and visitors must follow the restrictions of contact isolation, including restrictions on the transport of patients to other departments. All patient-care items should be dedicated to the individual patient and kept in the room, and this includes noncritical items such as blood pressure cuffs, thermometers, stethoscopes, commodes, and bedpans. In some hospitals, patients may also be assigned a single dedicated staff person.
HCWs must wear clean, non-sterile gloves when entering an isolation room, and remove the gloves and thoroughly wash their hands before leaving. Caregivers should also wear disposable nonsterile gowns that are fluid resistant when providing direct patient care.
There is little evidence to support the effectiveness of any particular environmental cleaning and disinfection method against C. difficile, a spore that persists on surfaces for extended periods of time and is resistant to heat and chemicals. Studies are ongoing, however, to identify a method that is most effective against this spore, and other studies have confirmed that careful physical cleaning of environmental surfaces will assist in reducing microbial reservoirs and decreasing the risk of microbial transmission.
Hospital surfaces that have been found to be most contaminated include toilets, bedpans, commodes, furniture, floors, sinks, bed rails, and telephones. All these surfaces must be given special attention and be thoroughly cleaned.10
Mops and mop buckets with detergent water must be changed after each isolated room cleaning. Walls should be spot cleaned for visible soil, and carpets deeply vacuumed. Linens must be carefully bagged in each room before removing, to avoid contaminating areas outside the room. Non-critical patient care items (blood pressure cuffs, stethoscopes, thermometers) that come into contact with intact skin are bagged in clear plastic and sent to the facilitys sterile processing department (SPD) to undergo appropriate decontamination, disinfection, and sterilization.
Additional items such as stretchers, IV poles, and wheelchairs should be routinely cleaned, and periodically put through the cart washer in SPD. Bed pans must be decontaminated, disinfected, and must also be put through the cart washer.
Studies have reported on the effectiveness of different agents for controlling C. difficile surface contamination. In general, detergent-based cleaning agents are not effective against spores. Neutral liquid detergents are effective at removing debris and other contamination, but not at eradicating resistant microorganisms. When using a neutral detergent, it is important to be sure that the detergent itself is not already contaminated with other microorganisms that can lead to cross-contamination and to follow label instructions for proper dilution rates.
Quaternary ammonium compounds are alkaline in chemistry. They bind to and disrupt the cytoplasmic membrane, killing the cell. Quaternary compounds are bactericidal, fungicidal, virucidal (against lipid viruses only), and effective against some bacilli. They are generally ineffective against TB and are not sporicidal. Quats are used to meet the OSHA Bloodborne Pathogen Standard.
Phenolic compounds are more aggressive disinfectants than quaternary ammonium compounds. They penetrate the cell wall and cause precipitation of the cell proteins. Phenolics are bactericidal, virucidal (lipid and non-lipid viruses), fungicidal, and tuberculocidal. They are not sporicidal, are irritating, and absorb into human skin and other materials. Phenolics are toxic to newborns and are therefore not used in nurseries.
Chlorine compounds use hypochlorous acid as the active ingredient. It aggressively and quickly oxidizes, breaking down protein. (Sodium hypochlorite is household bleach, 5 percent equals l/10 dilution rate.) Chlorine compounds are bactericidal, virucidal, fungicidal, and tuberculocidal. They are not sporicidal. They are inactivated by organic material (debris), are corrosive, irritating, and must be diluted just before use. They can be used on food-handling surfaces since there is no residual left behind.
Current guidelines for disinfection practices against C. difficile require that visible debris be removed with a detergent and water first, and then the surfaces cleaned with hypochlorite. Chlorine-based agents have been found to reduce the level of C. difficile contamination, but contamination may still persist. It will, however, significantly reduce, but not eliminate, the risk of C. difficile transmission.11
Developing the Infection Control Program
Healthcare personnel should be involved in the development of the infection control program from the beginning, to encourage participation and increase understanding. Weekly infection control meetings can be opportunities for staff to provide feedback, report instances of noncompliance, and participate in the development of preventive measures that can be instituted. Compliance with the program should be monitored unobtrusively, and corrective action taken as necessary. A successful infection control program creates an overall awareness of the need for infection control and places personal and professional responsibility on each staff member. One facility reported a 60 percent decrease in the number of documented C. difficile cases after a formal infection control program was instituted.
Marcia Hardick, RN, BS, CGRN, is a clinical/ education specialist with STERIS Corporation.