Infection with Clostridium difficile is increasing in both incidence and severity and is becoming more difficult to treat. Recent reports of a more virulent and more resistant strain of C. difficile causing epidemics in both North America and Europe have increased awareness of the importance of

WHAT IS CLOSTRIDIUM DIFFICILE?

C. difficile is a spore forming, gram positive anaerobic bacillus that was identified as the etiological agent of antibiotic-associated pseudomembranous colitis in the late 1970s. The organism produces two exotoxins: toxin A (primarily an enterotoxin) and toxin B (a cell cytotoxin); it is believed to be responsible for 15%-25% of antibiotic-associated diarrhea. Although pseudomembranous colitis has been the hallmark of infection, the clinical presentation of C. difficile infection may range from asymptomatic colonization to severe diarrhea, toxic megacolon, perforation and even death. Nearly all symptomatic patients present with diarrhea, but rare patients, particularly those receiving narcotics following surgery, may have little or no diarrhea due to ileus or even toxic megacolon, a late serious complication of C. difficile infection. Because there is a wide spectrum of disease processes, infection with this organism is referred to as C. difficile-associated disease (CDAD).

WHAT ARE RISK FACTORS FOR CDAD?

More than 90% of healthcare-associated CDAD occurs during or after antimicrobial therapy for an infection; the antimicrobial agents disrupt the indigenous microflora of the intestine allowing proliferation of C. difficile with resultant toxin production. Almost all antimicrobial agents, except the aminoglycosides, have been associated with CDAD. Fluoroquinolones (ciprofloxacin, levofloxacin) have the strongest association with disease but other agents, including clindamycin, ceftriaxone and other broad-spectrum cephalosporins, are also implicated. The risk increases when patients receive multiple antimicrobial agents and undergo longer courses of therapy. Other factors that increase risk of CDAD include advanced age, severe underlying illness, nasogastric intubation, medications that neutralize gastric acid and long hospitalizations. A typical presentation involves an older patient with frequent, loose, watery stools who has been recently treated with a course of antimicrobials while hospitalized for a chronic medical condition. It is estimated that CDAD extends a hospital stay by 4 to 14 days.

It is estimated that about 3% of healthy adults asymptomatically carry C. difficile in their intestinal tracts; carriage rate increases to 20% or more in hospitalized patients or residents of long term care facilities. Neonates have a much higher colonization rate, from 5%-70%, but paradoxically are much less likely than adults to develop symptomatic disease due to lack of receptors for toxin A in their immature gut mucosa. Hospitals and long term care facilities have the highest rates of CDAD, and this complication is often endemic or even epidemic in these facilities. This association is not surprising because large populations of patients or residents with high rates of exposure to antimicrobial agents are housed in close proximity in facilities with widespread contamination with C. difficile spores that persist in the environment for years. These patients or residents are often attended by healthcare workers who carry the spores on their hands and medical equipment. These factors emphasize the importance of hand hygiene and thorough environmental cleaning in controlling the spread of C. difficile.

HOW IS CDAD DIAGNOSED?

The diagnosis of CDAD is usually established by detection of C. difficile toxin A or B in stool. Most laboratories in the United States use an enzyme immunoassay (EIA) to detect toxin A, or toxins A and B. The reagents for this test are commercially available from multiple sources, test results are available within one hour and the technology is relatively simple. EIA is a very specific test (very unlikely to yield a false-positive result) but may lack sensitivity (30% or more of specimens yield false-negative results). Because toxins A and B are very unstable at room temperature, specimens should be sent to the lab as soon as possible or refrigerated. If the first specimen sent for toxin assay is negative but there is a high suspicion of CDAD, a second specimen should be submitted before ruling out C. difficile.

Cytotoxin assay can also be used to detect C. difficile toxin and is considered by many to be the gold standard for detection of toxin in stool. The test involves observing characteristic actinomorphic changes in fibroblasts in tissue culture and is extremely sensitive. This test, however, is expensive, technically demanding and requires up to 48 hours for test results. Stool can also be cultured for the presence of C. difficile using selective media incubated in an anaerobic environment. Culture, however, does not distinguish between asymptomatic carriage of the organism and CDAD.

It should be noted that while testing for C. difficile toxin is highly effective in establishing the diagnosis of CDAD, it has not been useful for evaluating response to therapy or as a "test of cure." The reasons for this are unclear, but therapeutic decisions are best made on the basis of clinical response. Occasionally use of either CT scan or endoscopy may be useful adjuncts in diagnosing CDAD. Colonoscopy (preferred over sigmoidoscopy) may show the presence of pseudomembranes, a late and serious complication of C. difficile. CT imaging may show characteristic features such as thickening of the colonic wall (indicating colitis), absence of small bowel involvement and the presence of ascites.

CHANGING EPIDEMIOLOGY OF CDAD

Over the past few years, an alarming trend in CDAD has been observed marked by increasing rates of disease, more severe and complicated cases, and diminishing responses to standard therapies. This changing epidemiology has been associated with the emergence of a new strain of C. difficile, referred to as the NAP1 strain based on its pulsed field gel electrophoresis pattern. The NAP1 strain of C. difficile produces up to 20 times more toxin than seen with other strains and is highly resistant to fluoroquinolones, including the newer gatifloxacin and moxifloxacin. This strain is also capable of hyper-sporulation, resulting in widespread environmental contamination. The Centers for Disease Prevention and Control (CDC) has reported outbreaks of this epidemic strain in at least 38 states. Although Vermont is not included among those states, we have certainly seen the increase in cases and severity of disease associated with this strain. Since 2001, discharge data from United States hospitals has shown a sharp increase in rates of CDAD with the rates doubled by 2003. The increased rates are twofold higher in persons aged 65 or older. During outbreaks of severe disease, an increased number of patients required colectomies and significantly more deaths were associated with CDAD. During a 2002 outbreak in Montreal, patients with CDAD spent an additional 7 days in the hospital; 10% required admission to an ICU and 2.5% require emergency colectomy. Severe cases of CDAD have also been reported in populations previously believed to be low risk for CDAD, including peripartum women and otherwise healthy persons living in the community, some with no documented prior antimicrobial exposure.

PREVENTION AND CONTROL OF CDAD

Prevention and control of C. difficile includes three prongs: judicious use of antimicrobials, adherence to meticulous infection control practices for hand hygiene and contact precautions, and thorough cleaning and disinfection of the environment. During episodes of diarrhea, C. difficile is shed in the feces of patients and can contaminate the environment and ultimately, the hands of healthcare workers. Once outside the body C. difficile readily forms spores, which may persist in the environment for very long periods of time. Although the spores may be removed by vigorous mechanical cleaning, they are not killed by the commonly used hospital-grade disinfectants. If a healthcare facility is experiencing an increase in CDAD, CDC recommends considering use of a fresh 10% dilution of household bleach for disinfection of patient rooms, as bleach does show some efficacy in killing spores. Because of the corrosive nature of bleach, it must be used carefully and long-term use may cause problems, particularly with metal surfaces.

The formation of spores also impacts hand hygiene, as the alcohol-based hand sanitizers currently recommended for healthcare are not sporocidal. If a healthcare facility is seeing an increase in CDAD rates, CDC recommends that staff wash their hands with soap and water after glove removal, as this will mechanically remove any spores that may be present. Patients diagnosed with CDAD should be placed in a private room, or cohorted with another patient with CDAD, and cared for using contact precautions. Gowns and gloves should be worn by all healthcare workers providing care in these rooms; equipment such as stethoscopes and blood pressure cuffs should not be used on other patients without appropriate disinfection.

Because prior exposure to antimicrobial agents is the major risk factor for CDAD, all healthcare facilities should periodically review their prescribing patterns and consider an antimicrobial restriction program. CDC estimates that between 20%-50% of all antimicrobials prescribed for human use each year are unnecessary. In particular, judicious use of clindamycin, thirdgeneration cephalosporins such as ceftriaxone, and the fluoroquinolones may help reduce the risk of CDAD.

TREATMENT OF CDAD

The Infectious Diseases Society of America is currently revising the treatment guideline for C. difficile; the guideline should be published soon. The most important first step, whenever possible, is discontinuation of the offending antimicrobial. Opioid analgesics and antiperistaltics (such as Lomotil and Imodium) should be avoided as they may worsen disease and obscure signs of clinical response to treatment. For moderate to severe infection, oral antibiotic therapy directed against C. difficile is required; empiric therapy should be initiated as soon as a diagnosis of CDAD is suspected. If the stool toxin assay is negative after empiric therapy has been initiated, the decision to continue treatment should be individualized based on clinical response. Oral metronidazole (Flagyl) has historically been used as firstline therapy, but there is a growing body of evidence that it may be associated with both increased failure rates and increased recurrence rates. Previously, use of vancomycin was discouraged because of cost and concerns about fostering vancomycin-resistant enterococci (VRE).

The updated guidelines are expected to separate patients into three treatment groups based on severity of disease: mild to moderate, severe, and severe complicated disease. For mild to moderate disease, the guidelines will continue to recommend metronidazole. Oral vancomycin will be recommended for treatment of severe disease (defined as a white blood cell count greater than 15,000/ mm3 or a 50% increase in serum creatinine level). Complicated CDAD includes hypotension, ileus, toxic megacolon or colonic perforation. Recommendations for the treatment of complicated disease in the absence of ileus will include oral higher-dose vancomycin in combination with intravenous metronidazole. For patients with severe disease who develop ileus, traditional treatment with oral or intravenous agents alone may not be sufficient, as fecal concentrations of antibiotics are inconsistent. Intravenous metronidazole should be used in combination with vancomycin administered via nasogastric tube or rectal instillation. Severe complicated disease has resulted in an increased number of colectomies and deaths. An early surgical consultation should be considered in patients with ileus or marked leukocytosis.

Despite successful therapy initially, up to 35% of patients will have a recurrence; after the second recurrence, the incidence of subsequent recurrence may be as high as 65%. Most cases of initial recurrence can be retreated with the same agent used initially, as these do not appear to be related to in vitro resistance. A combination of strategies may be needed to treat multiple episodes of recurrent disease; these include tapered or pulsed dosing of vancomycin and use of adjunctive therapies such as probiotics, intravenous immunoglobulin, rifampin and fecal replacement therapy.

Increasing rates of CDAD, more severe disease, and the emergence of a virulent, resistant strain of C. difficile are presenting healthcare providers with new challenges in the management of CDAD. Nurses must remain abreast of current epidemiologic trends and recognize the global effects of indiscriminate antimicrobial use. Nurses should work to promote and practice proper infection prevention and control measures and the prudent use of antimicrobials in their practice setting.

Susan Page, MT, MS, CIC

Infection Control Practitioner

Fletcher Allen Health Care