Infection Control Today - 06/2004: Clinical Update

June 1, 2004

Clostridium Difficile Toxin:
Diagnosis, Treatment, and Prevention of Disease

By Marcia Hardick, RN, BS, CGRN

Bacteria present themselves under themicroscope in various shapes, including spheres (cocci), curves, spirals androds (bacilli). Bacteria can be divided broadly into two main groups accordingto their reaction to gram staining, which is a process that reveals the cellwall structure. Some bacteria stain gram positive while others stain gramnegative. Bacterial groups are also divided by their ability to grow in thepresence (aerobic) or absence (anaerobic) of oxygen, and their ability to formspores. Once a bacterium is identified and defined by its genus name, it isfurther classified by its species name.

Clostridium is an anaerobic, spore-forming, gram positivebacillus. The four main clostridia species include: Clostridium perfringens (associatedwith gas gangrene); Clostridium tetani (causes tetanus infections), Clostridiumbotulinum (causes botulism from improperly preserved foods), and Clostridiumdifficile (causes pseudomembranous colitis, a complication of antibiotictherapy).

The spores and vegetative forms of the bacteria are found insoil and in the gastrointestinal tracts of mammals. Clostridia survive inhostile environments, and may persist on surfaces for months. They are resistantto many methods of heat and chemical disinfection and many commonly usedcleaning 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

Transmission

The transmission of C. difficile is primarily throughcontaminated environmental surfaces and the contaminated hands of healthcareworkers (HCWs) in hospitals and extended care facilities. The term environmentalsurfaces includes medical and patient-care equipment in addition toroom surfaces (patient rooms). Occasionally, transmission occurs by direct patient-to-patientcontact as well.

Any contamination of HCWs hands also contaminates all theenvironmental surfaces they touch, such as doors, countertops, bedrails, andbathroom surfaces, as well as equipment. The prevalence of contamination on thehands of HCWs is thought to be linked proportionally to the level ofenvironmental contamination in their facility. This is difficult to prove,however, because hand carriage (transmission) is transient and may occur withmultiple HCWs. Workers are not at risk of contracting C. difficile diarrheaor infection unless they are taking antibiotics, but they present a risk topatients for nosocomial (hospital- acquired) infections.

There have been no reports of C. difficile transmissionvia medical instrumentation or food, or from food preparation areas inhospitals. There are, however, reported cases of transmissions from theuse of blood pressure cuffs, toilets, bedside commodes, electronic rectalthermometers, bed rails, call buttons, furniture, and improper gloving or gloveremoval techniques.

Clinical Symptoms

C. difficile spores ingested intothe gastrointestinal tract survive the acidic environment of the stomach. Thespores then convert to their bacterial forms in the colon and produce toxins. It is the presence of the toxins that causes clinicalsymptoms. Presenting symptoms range from a mild, self-limiting state tofulminant, life-threatening disease. Diarrhea is the major manifestation of thedisease. In addition to diarrhea (mild to severe), patients may experiencecramping, abdominal pain and fever. Leukocytosis is also present in these patients. Ifpseudomembranous colitis develops, the patient experiences abdominal distention. Consequently, toxic megacolon, colonic perforation, and sepsismay develop. As a result, the patient also experiences fluid and electrolyteimbalance, dehydration, protein-losing enteropathy, cardiac dysrhythmias, and/orhypotension. Extraintestinal symptoms include polyarthritis and impaired skinintegrity. Although severe symptoms are uncommon, Clostridiumdifficile causes significant disease and often lengthens a patients hospital stay.2

Incidence

Clostridium difficile toxin is themost frequent cause of nosocomial diarrhea. It affects millions of patients eachyear. C. difficile causes pseudomembranous colitis, a complication ofantibiotic therapy. Those antibiotics that are most causative includesecond-generation cephalosporins, clindamycin, and extended spectrumpenicillins. There are fewer cases reported after taking ciprofloxacin, but theincidence will relate to the level of this antibiotics use within thefacility. Pseudomembranous colitis has been associated with the use of everyantibiotic, including vancomycin and metronidazole, which are the standardtherapies for C. difficile diseases. Any person whodevelops diarrhea after taking an antibiotic for at least six days or within sixweeks of beginning therapy should be considered to harbor C. difficile untilit is ruled out. Many cases are diagnosed after the patient has been dischargedfrom the hospital. Any hospitalized patient who experiences an onset of diarrheashould be evaluated as soon as possible.

Patients who have co-existing illness or extra-intestinalmanifestations of C. difficile, who are debilitated or have underlyinggastrointestinal pathologic conditions, or who have experienced a prolongedhospitalization have a poorer prognosis for a cure. There can be clusteroutbreaks among patient populations in specific hospital units, such asintensive care and post-op units, and among patients who are elderly orimmunocompromised. The longer a patient is hospitalized, the greater the risk ofacquiring C. difficile. Some outbreaks have been reported to have highermortality rates. Clostridium difficile-associated disease (CDAD) has beenreported with a prevalence of up to 10 percent of hospitalized patients during anon-outbreak period, and up to a 29 percent recurrence rate during outbreaks. Itis 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 becomeindefinitely cured. The spectrum of CDAD also includes toxic megacolon, C.difficile-associated arthritis, and septicemia.

Colonization

Colonization occurs in 50 percent of newborns where there areno 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 inHCWs is more frequent, occurring 13 to 15 percent of the time with stoolcultures testing positive. It is believed that nosocomial colonization occursafter workers hands have been in contact with infected patients and/orcontaminated surfaces.

Cases have been reported in HCWs who were colonized with C.difficile toxin. For example, three healthy nurses were found to have thetoxin present even when there was no history of recent antibiotic therapy.Another healthy nurse developed severe pseudomembranous colitis with ascitesafter 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

Diagnosis

Antibiotic therapy may disrupt the normal flora of thegastrointestinal tract for up to six weeks after stopping the medication. Aneffective therapy is needed that will destroy the vegetative cells of Clostridiumdifficile that produce the toxin and will interfere with the pathogenesisthat results after spore germination.

As previously stated, Clostridium difficile infectionshould be suspected in a patient with diarrhea who has taken antibiotics withinthe past six to eight weeks. A stool specimen should be tested for the presenceof leukocytes and C. difficile toxins. The spore-forming bacillusproduces two toxins: Clostridium difficile toxin A, primarily anenterotoxin which acts on the gut mucosa; and Clostridium difficile toxinB, 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 anantibiotic. The stool cytotoxin assay detects cytotoxigenic C. difficile inmore than 95 percent of cases diagnosed with pseudomembranous colitis.

Endoscopy is reserved for severe and rapidly progressingcases, to identify the presence of yellow-white plaques, the classicpseudomembrane. Sigmoidoscopy or colonoscopy should be carefully performedbecause of the high risk of colon perforation. Imaging studies include abdominalX-rays to identify haustral thickening with thumb-printing, toxic megacolon, andperforation. Ultrasound has greater specificity than computerized tomography(CT) and is used for critically ill patients. However, CT may be used forscreening to rule out abscess or other inflammation, for extent of disease andfor any potential complications (perforation).

Treatment

The medical approach to C. difficile toxin diarrhea isearly diagnosis. Treatment with metronidazole, 250-500 mg PO QID for seven to 14 days is a popular regimen. If treatment fails or thepatient is unable to tolerate metronidazole, 125 mg of oral vancomycin is oftenused, QID for seven to 14 days. It can also be given by enema or nasogastrictube. Treatment with metronidazole is preferred since it is much less expensive,and studies have shown that metronidazole and vancomycin have equivalentefficacy. In addition, there is currently grave concern about the resistance ofvancomycin against other bacteria, such as enterococci. Giving 25,000 units of Bacitracin PO QID for seven to 14 daysis a slightly more expensive alternative to metronidazole, but Bacitracin israrely used. Cholestyramine or other resin binders can be given for mild casesbut cannot be given with vancomycin because they bind the antibiotic, making itineffective. Patients who do not respond to treatment or cannot toleratemetronidazole or vancomycin are given glycopeptides or fusidic acid. Allunnecessary antibiotics must be discontinued as soon as possible, including the causative antibiotic.4

Surgical intervention can reduce the risk of complications andreturn the patient to his/her previous quality of life. Indications for surgeryinclude complicated or severe infection that does not respond to medication,progression to toxic megacolon, uncontrolled bleeding, or perforation. It hasbeen reported that patients who require surgery range from less than 1 percentto 5 percent. Between 5 percent and 20 percent of patients with pseudomembranouscolitis may present with an acute abdomen requiring surgery. Patients whoexperience perforation have a mortality rate of about 33 percent.5

Financial Burden

This devastating illness causes a great economic burden on analready financially distressed healthcare industry. The spore infects millionsof people a year and causes complications and prolonged hospital stays. Anoutbreak in a hospital unit can also be devastating to a facility, as it causessubstantial clinical problems for patients and a great challenge to healthcareproviders.

A conservative estimate of the costs of the disease in theU.S. exceeds $1 billion per year. A study in Boston published in 2002 statesthat there is a great difference between the costs, length of hospital stay, andsurvival 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 thehospital for patients with Clostridium difficile-associated disease isjust over three days. In this same study of 271 patients who were admitted tothe hospital, 40 patients (15 percent) developed C. difficile-documenteddiarrhea. The total costs of the hospital stay were about $3,700 higher (a 54percent increase) for these patients than for patients who did not acquire thedisease. It is estimated that over $10,000 in total direct medical expenses areincurred per case, with an average cost for just the diagnosis and treatmentbeing $3,103 per patient. The first episode of Clostridium difficile illnesswith 10 days of standard antibiotic treatment averages $1,914.7

In order to decrease the major economic burden and thedevastating effects of the illness, a facilitys main objective should bepreventing nosocomial infections and colonization of C. difficile. It isalso necessary to limit the use of antibiotics that cause C. difficile-relatedcomplications. Instituting restrictive antibiotic treatment policies andprograms may be required in order to accomplish this.

Infection Control

It is absolutely critical to prevent transmission of C.difficile by establishing infection control policies and processes that allhealthcare personnel understand and adhere to. Since transmission of the diseaseis through contaminated surfaces and the hands of healthcare providers, ongoingprocedures 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

Hand Hygiene

Regular handwashing is the single most important measure thatwill decrease the incidence of Clostridium difficile-related illness. Hands must be washed whenever there is contact with bodyfluids, excretions, patient care equipment, and contaminated articles, andbefore leaving a patients room. HCWs must always be conscious of both theclean and contaminated surfaces in their work areas and patient environments,and must avoid cross-contamination. Gloves provide a protective barrier and prevent contaminationof the healthcare workers hands, but they must be changed regularly. Glovesare not a substitute for handwashing. All staff members need to be educated on proper hand washingtechniques. Special attention must be paid to fingertips, palm surfaces,the underside of nails and rings. Facilities should consider a policy for restricting jewelrywhen caregivers are taking care of infected patients.9

Isolation of Patients

In addition to standard precautions issued by the Centers forDisease Control and Prevention (CDC), which are the standard infection controlprotocol in hospitals, some institutions require that a patient who is colonizedwith, suspected to have, or diagnosed with C. difficile infection be putinto contact isolation. Under contact isolation protocols, all staff andvisitors must follow the restrictions of contact isolation, includingrestrictions on the transport of patients to other departments. All patient-careitems should be dedicated to the individual patient and kept in the room, andthis includes noncritical items such as blood pressure cuffs, thermometers,stethoscopes, commodes, and bedpans. In some hospitals, patients may also be assigned a singlededicated staff person.

HCWs must wear clean, non-sterile gloves when entering anisolation room, and remove the gloves and thoroughly wash their hands beforeleaving. Caregivers should also wear disposable nonsterile gowns that are fluidresistant when providing direct patient care.

Environmental Cleaning

There is little evidence to support the effectiveness of anyparticular environmental cleaning and disinfection method against C.difficile, a spore that persists on surfaces for extended periods of timeand is resistant to heat and chemicals. Studies are ongoing, however, to identify a method that ismost effective against this spore, and other studies have confirmed that carefulphysical cleaning of environmental surfaces will assist in reducing microbialreservoirs and decreasing the risk of microbial transmission.

Hospital surfaces that have been found to be most contaminatedinclude toilets, bedpans, commodes, furniture, floors, sinks, bed rails, andtelephones. All these surfaces must be given special attention and be thoroughly cleaned.10

Mops and mop buckets with detergent water must be changedafter each isolated room cleaning. Walls should be spot cleaned for visiblesoil, 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 withintact skin are bagged in clear plastic and sent to the facilitys sterileprocessing department (SPD) to undergo appropriate decontamination,disinfection, and sterilization.

Additional items such as stretchers, IV poles, and wheelchairsshould be routinely cleaned, and periodically put through the cart washer inSPD. Bed pans must be decontaminated, disinfected, and must also be put throughthe cart washer.

Effective Agents

Studies have reported on the effectiveness of different agentsfor controlling C. difficile surface contamination. Ingeneral, detergent-based cleaning agents are not effective against spores.Neutral liquid detergents are effective at removing debris and othercontamination, but not at eradicating resistant microorganisms. When using aneutral detergent, it is important to be sure that the detergent itself is notalready contaminated with other microorganisms that can lead tocross-contamination and to follow label instructions for proper dilution rates.

Quaternary ammonium compounds are alkaline in chemistry. Theybind to and disrupt the cytoplasmic membrane, killing the cell. Quaternarycompounds are bactericidal, fungicidal, virucidal (against lipid viruses only),and effective against some bacilli. They are generally ineffective against TB and are notsporicidal. Quats are used to meet the OSHA Bloodborne Pathogen Standard.

Phenolic compounds are more aggressive disinfectants thanquaternary ammonium compounds. They penetrate the cell wall and causeprecipitation of the cell proteins. Phenolics are bactericidal, virucidal (lipidand non-lipid viruses), fungicidal, and tuberculocidal. They are not sporicidal,are irritating, and absorb into human skin and other materials. Phenolics aretoxic to newborns and are therefore not used in nurseries.

Chlorine compounds use hypochlorous acid as the activeingredient. It aggressively and quickly oxidizes, breaking down protein. (Sodium hypochlorite is household bleach, 5 percent equalsl/10 dilution rate.) Chlorine compounds are bactericidal, virucidal, fungicidal,and tuberculocidal. They are not sporicidal. They are inactivated by organic material (debris), arecorrosive, irritating, and must be diluted just before use. They can be used onfood-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 waterfirst, and then the surfaces cleaned with hypochlorite. Chlorine-based agentshave been found to reduce the level of C. difficile contamination, butcontamination may still persist. It will, however, significantly reduce, but noteliminate, the risk of C. difficile transmission.11

Developing the Infection Control Program

Healthcare personnel should be involved in the development ofthe infection control program from the beginning, to encourage participation andincrease understanding. Weekly infection control meetings can be opportunities forstaff to provide feedback, report instances of noncompliance, and participate inthe development of preventive measures that can be instituted. Compliance withthe program should be monitored unobtrusively, and corrective action taken asnecessary. A successful infection control program creates an overallawareness of the need for infection control and places personal and professionalresponsibility on each staff member. One facility reported a 60 percent decrease in the number ofdocumented C. difficile cases after a formalinfection control program was instituted.

Marcia Hardick, RN, BS, CGRN, is a clinical/ educationspecialist with STERIS Corporation.