Clostridium difficile is a gram-positive, spore-forming, toxin-producing, anaerobic bacillus that causes diseases of the gastrointestinal tract ranging from asymptomatic colonization to a life-threatening condition known as "toxic megacolon." Antimicrobial agent exposure is an important risk factor for Clostridium difficile–associated disease (CDAD).
Because antimicrobial agents frequently are used to treat or prevent dental infections, dentists should be aware of this disease. We highlight the clinical presentation of CDAD by describing two previously published case examples1 followed by an in-depth review of the literature.
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CASE EXAMPLES
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Case 1.
A healthy 48-year-old woman underwent endodontic therapy and was prescribed a 10-day course of the antimicrobial agent oral clindamycin. Approximately eight days after she finished her course of this medication, she began having liquid brown diarrhea with some mucus and a small amount of blood. She called her primary care physician who advised her to take bismuth subsalicylate (Pepto-Bismol, Procter & Gamble, Cincinnati) and loperamide (Imodium, McNeil Consumer Healthcare, Fort Washington, Pa.). She continued to have eight to 10 bowel movements per day while taking these medications, so she scheduled a clinic appointment with her physician. At this visit, she provided a stool sample, which tested positive for C. difficile toxin. She was given a prescription for metronidazole, and her symptoms resolved slowly over the next 10 days.
Case 2.
A 31-year-old woman who was 14 weeks pregnant with twins went to the emergency department with a complaint of having had intermittent diarrhea for three weeks followed by abdominal cramping and watery black stools for three days. Her most recent antimicrobial agent exposure had been to trimethoprim-sulfamethoxazole, which she was prescribed for a urinary tract infection approximately two months before the onset of her diarrhea. Her stool samples tested positive for C. difficile toxin, and she was admitted to the hospital. She was treated with metronidazole, cholestyramine and oral vancomycin. She improved while taking the oral vancomycin and was discharged after an 18-day hospital stay. Four days later, however, she was readmitted to the intensive care unit with diarrhea, hypotension and spontaneous abortion of the fetuses. A subtotal colectomy was performed, and histopathology of the colon showed pseudomembranous colitis and toxic megacolon. She died on the third day of her hospitalization.
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DISCUSSION
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The patient in the first case developed CDAD after taking a short course of antimicrobial agents after undergoing endodontic surgery. Although the term CDAD encompasses a spectrum of gastrointestinal diseases that vary in severity, the most common manifestation has been uncomplicated antimicrobial-agent–associated diarrhea. The patient initially took over-the-counter (OTC) medications, which provided no benefit. One of these OTC medications, loperamide, slows gastrointestinal motility, and its use has been identified as a risk factor for development of severe CDAD. The patient experienced no adverse effects from the loperamide. Once her physician determined that she had CDAD and treated it with metronidazole, she responded well and her symptoms resolved.
Her story is of particular interest because she received the antimicrobial agents from her dentist but called her primary care physician when she developed diarrhea. This situation highlights the fact that dentists may not always be aware of the complications resulting from the antimicrobial agents they prescribe.
The second case is an example of the changing epidemiology of CDAD. There is growing evidence of more frequent and severe occurrences of the disease, not only among hospitalized patients but also among otherwise healthy people in the community.1 This patient was a young woman with no significant medical comorbidities who was having a normal twin pregnancy until she developed CDAD. She had been experiencing symptoms for more than three weeks before she sought medical care.
Because young, healthy people often see their dentists more frequently than they do their physicians, awareness of CDAD among members of the dental community may increase the likelihood that dentists will identify patients who have CDAD and arrange for them to receive appropriate treatment as soon as possible.
Pathogenesis.
C. difficile is spread by the fecal-oral route and can be ingested in a vegetative or spore form. The spore form of the bacterium is extremely durable, allowing it to survive not only harsh conditions outside of the human body but also the acidic environment of the stomach. After ingestion, spores germinate into the vegetative form in the small intestines. These bacteria then colonize the mucosal crypts of the large intestines and proliferate when the normal flora of the large intestines is disrupted. One of the most common ways that the normal gastrointestinal flora is disrupted is through the use of antimicrobial agents, especially broad-spectrum agents with antianaerobic activity.
The pathogenicity of C. difficile is due to the various toxins that it produces, and only toxin-producing strains cause disease.2 The primary virulence factors are the large clostridial cytotoxins toxins A and B that cause inflammation and mucosal damage and lead to diarrhea or colitis.3 Colitis that is caused by C. difficile characteristically is pseudomembranous with raised white and yellowish plaques.
Clinical presentation.
The incubation period of C. difficile from ingestion of the organism to disease is not known. It is thought, however, that CDAD usually occurs relatively quickly after the person acquires the organism; people who become carriers (that is, those who do not develop CDAD within seven days of acquiring C. difficile) tend to develop protective antibodies to the toxins.4 In people who develop CDAD after taking antimicrobial agents, their signs and symptoms typically start within three weeks of initiating antimicrobial therapy,5 but they can begin as early as the first day of treatment or as late as two months after its completion.
The clinical presentation of CDAD is diverse, ranging from mild to severe disease. Most commonly, the disease starts with mild-to-moderate nonbloody diarrhea with few systemic symptoms.6 Mild CDAD can progress rapidly, however, to become moderate or severe CDAD. The signs and symptoms of moderate CDAD may include fever, abdominal pain and leukocytosis.7 Once systemic symptoms develop, appropriate treatment is crucial to prevent the disease’s progression to more severe CDAD, which is characterized by hemodynamic instability such as volume depletion, hypotension and other signs of a sepsis-like syndrome.7 The most serious complications include paralytic ileus, peritonitis and toxic megacolon; in many cases, these complications require surgical removal of the colon.8
The changing epidemiology of CDAD.
Over the past 10 years, the number of patients hospitalized as a result of CDAD in the United States has risen sharply. A national survey of acute care hospitals from across the United States showed that the rate of hospitalizations for CDAD increased from 31 per 100,000 in 1996 to 61 per 100,000 in 2003.9 In addition, the severity of CDAD in regional CDAD outbreaks also has increased, with more cases requiring surgery or leading to death.10,11
Quebec, Canada, was one of the first regions in the world in which the changing epidemiology of CDAD was recognized.12 The incidence of CDAD in that province increased to four times higher than during the pre-epidemic period, and the 30-day attributable mortality rate was estimated to be 6.9 percent.13 Additionally, patients older than 60 years are four to five times more likely to develop CDAD and are at an increased risk of dying from the disease.9,10,13
Laboratory evidence suggests that the most important factor associated with increases in incidence and severity of CDAD over the past several years is the emergence of a hypervirulent epidemic strain. This strain produces 16 to 23 times more toxins A and B, was responsible for an epidemic in Quebec and outbreaks in many parts of Europe and to date has been found in 38 U.S. states.12–15 This hypervirulent C. difficile strain, collectively referred to as the NAP1/BI/027 strain, was circulating as early as 1984 but was an infrequent cause of human disease in the United States before 2000.
One possible explanation for NAP1/BI/027’s recent emergence as an epidemic strain is that it has acquired an antimicrobial agent resistance pattern that has given it a selective advantage over other C. difficile strains.14 A notable difference between contemporary and historic isolates of NAP1/BI/027 is that contemporary isolates have increased resistance to fluoroquinolone agents. It has been hypothesized that this increased fluoroquinolone resistance, coupled with the increased use of fluoroquinolone agents in both hospital and community settings,16 has set the stage for the NAP1/BI/027 strain of C. difficile to spread globally.
Meanwhile, C. difficile infection may be emerging as a cause of disease in previously low-risk populations, such as peripartum women and healthy people living in the community.1 Although there always has been a low level of CDAD in the community in the United States,17 epidemiologic studies are underway to determine whether rates are increasing. A 2004 study found that a larger-than-expected proportion of CDAD cases in Sweden occurred in the community.18 Another 2004 study addressed the role of C. difficile in the food supply.19 It is unknown, however, whether the consumption of particular meats is a source by which either healthy or chronically ill people are exposed to C. difficile in the community.
Risk factors.
The most important modifiable risk factor associated with CDAD is exposure to antimicrobial agents. It is estimated that more than 90 percent of C. difficile infections occur during or after antimicrobial therapy.20 Virtually all antimicrobial agents have been implicated in inciting the disease at some point, but the ones traditionally associated with CDAD are cephalosporins, penicillins and clindamycin.21 CDAD incidence also may be affected by the duration of antimicrobial therapy, as well as the use of broad-spectrum antimicrobial agents and multiple agents.22
Other risk factors associated with CDAD include being older than 65 years, undergoing nasogastric intubation, having severe comorbidities and experiencing long hospital stays. Residents of long-term care facilities are more likely to be colonized with C. difficile than is the general population,23 and C. difficile is the most common infectious cause of acute diarrheal illness in these settings.23,24 Antiulcer medications, such as proton pump inhibitors, also have been implicated, although there is no consensus on their role in the disease.25–27
Diagnosis.
Clinicians should suspect C. difficile in patients who have diarrhea and have been exposed to antimicrobial agents within the previous two months. Prescribing therapy without testing for C. difficile, however, is not appropriate, since CDAD is only one of many potential causes of diarrhea.
The most common way to diagnose CDAD is by detecting C. difficile toxins in stool specimens. Most clinical laboratories use enzyme immunoassays to detect the toxins in stool specimens. Although these tests can provide results in as little as two hours, their overall sensitivity is low, necessitating the testing of more than one stool sample to detect toxins in patients with a high pretest likelihood of CDAD but a negative initial test. The tissue cytotoxic assay is considered the gold standard, but it is used less frequently than enzyme immunoassays because of its technical complexity and turnaround time of at least 48 hours. Anaerobic bacterial culture is a highly sensitive test,28 but it is used rarely because of the increased workload it places on laboratory personnel, its turnaround time of two to five days, and its inability to differentiate toxin-producing C. difficile strains from nontoxin-producing strains without further testing.
Clinicians should suspect Clostridium difficile in patients who have diarrhea and have been exposed to antimicrobial agents within the previous two months.
Although colitis resulting from C. difficile can be diagnosed via a colonoscopy through the detection of pseudomembranes, not all cases of CDAD are accompanied by pseudomembrane formation. Consequently, the use of colonoscopy to diagnose CDAD should be reserved for specific circumstances.29
Treatment.
The most important element in managing CDAD is to discontinue the use of any inciting antimicrobial agents whenever possible. The utility of this basic measure was first demonstrated in 1974 when 20 patients with pseudomembranous colitis all recovered after they stopped taking clindamycin.30 Although patients with CDAD who have a concurrent infection may need to continue receiving antimicrobial treatment, physicians should attempt to narrow the antimicrobial spectrum of that treatment as much as possible. In theory, the reduction of antimicrobial pressure may allow the bowel to repopulate with normal flora and, thus, limit the impact of C. difficile in a natural fashion.
In addition to discontinuing the use of inciting antimicrobial agents, clinicians should prescribe to patients with CDAD a 10-day course of an appropriate oral antimicrobial agent to treat C. difficile. For mild-to-moderate CDAD, oral metronidazole usually is effective. For severe CDAD, oral vancomycin may be a better choice. Because CDAD can progress despite treatment, clinicians need to follow patients with CDAD closely over the first one to two days of therapy. Because CDAD often resolves slowly, clinicians should not consider treatment to be a failure before the patient has completed six or seven days of therapy.6 Furthermore, clinicians should not order repeat toxin assays to evaluate the effect of treatment because patients may continue to be colonized with a low level of C difficile even after CDAD has been cured.
Recurrent CDAD.
A recurrence of CDAD after initial treatment is the most common complication of C. difficile infection; it occurs in approximately 20 percent of cases.31 Although a recurrence can occur up to two months after treatment is completed, the majority of recurrences occur within the first 30 days.32 Risk factors for recurrences include age older than 65 years, a leukocytosis with initial illness and the use of antimicrobial agents between initial illness and relapse. The most important risk factor for recurrence is recurrence itself, as patients can have multiple recurrences. In fact, patients with at least two episodes of CDAD will have additional episodes 50 to 65 percent of the time.8
Until recently, experts believed that, in most cases, the strain of C. difficile that caused the initial infection was responsible for subsequent relapses. Molecular techniques, however, have suggested that new strains of C. difficile are responsible for recurrence in 30 to 50 percent of cases.33,34 These findings have raised the question of whether some patients are more susceptible to CDAD than are others. There is growing evidence to suggest that a patient’s failure to produce a systemic antitoxin immunoglobulin G response to an initial episode of CDAD increases the likelihood of recurrence.35 These observations corroborate reports that indicated that symptom-free carriers had a significantly higher antibody response than did those who developed CDAD.4,36 Patients who lack an immune response to C. difficile may not only be at risk of relapsing from the same strain but also may be at risk of acquiring a new strain from the environment. This suggests that outpatients being treated for CDAD may benefit from special environmental cleaning strategies to decontaminate their homes to prevent reinfection; this strategy is not recommended in evidence-based guidelines.
Treatment of recurrence.
The treatment of recurrent CDAD remains a significant challenge for the medical community. Popular approaches include retreatment with oral metronidazole or the use of oral vancomycin in a pulsed dose or tapered fashion over an extended period. Newer antimicrobial agents, such as rifaximin37 and nitazoxanide,38 are showing some effectiveness and may provide options for the future. Other creative approaches to treat recurrence, including the use of probiotics, stool transplants and intravenous immunoglobin, have not been proven.
Prevention.
Although clinicians can use a variety of tactics to decrease nosocomial transmission of C. difficile, simply reducing the unnecessary use of antimicrobial agents may be the most important way to decrease the risk of acquiring CDAD among outpatients. Studies in the hospital setting have shown that restricting the use of antimicrobial agents can decrease the rate of hospital-acquired CDAD.39,40 It is likely that a similar, yet less structured, approach on an outpatient basis would have an equally beneficial effect. There are, of course, many circumstances in which patients require the use of antimicrobial agents. The key in these circumstances is to use the antimicrobial agent with the narrowest spectrum of antibacterial activity for the shortest duration possible.
The American Heart Association (AHA) recently published revised recommendations for the use of antimicrobial prophylaxis before dental procedures.41 AHA now recommends that antimicrobial prophylaxis be used only for patients with cardiac conditions that place them at the highest risk of developing infective endocarditis. Compliance with these new recommendations could decrease the amount of antimicrobial agents prescribed by dentists, which, in turn, also may help reduce the incidence of CDAD.
While we know that C. difficile is transmitted primarily patient to patient in the hospital setting, we know much less about how the organism is transmitted in the community. Nonetheless, reasonable measures should be taken to prevent person-to-person transmission outside the hospital by asking symptomatic patients with CDAD to practice good hand hygiene and avoid sharing bathroom facilities until their diarrhea has resolved. If other members of a CDAD patient’s household must use the same bathroom, it may be prudent to clean the commode after each use with a 1:10 dilution of household bleach prepared fresh daily. Other household cleaners are less effective in killing C. difficile spores, which may persist in the environment and are the infectious form of the organism.
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CONCLUSIONS
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C. difficile causes a wide variety of gastrointestinal diseases. A large proportion of CDAD occurs after the use of antimicrobial agents, and dentists traditionally have prescribed antimicrobial agents both as a treatment for infections and as prophylaxis for invasive oral procedures. The new AHA recommendations to discontinue antibiotic prophylaxis for all patients undergoing dental procedures except those at highest risk of developing infective endocarditis may help reduce the number of people in the community exposed to antimicrobial agents.
Because the incidence and severity of CDAD appear to be increasing and may be spreading into the community, dentists should be cognizant that prescribing antimicrobial agents may have untoward consequences. In addition, a basic understanding of CDAD is increasingly important, as it may allow for earlier recognition and treatment of disease, which could lead to a reduction in the number of severe cases. This knowledge also may make it easier to manage the treatment of the growing number of people with a medical history of CDAD who are reluctant to take antimicrobial agents for new infections because they fear a recurrence of CDAD.
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ABSTRACT
CASE EXAMPLES
