Clostridium difficile infection (CDI) is a unique colonic disease that is acquired almost exclusively in association with antimicrobial use and the consequent disruption of the normal colonic flora. The most commonly diagnosed diarrheal illness acquired in the hospital, CDI results from the ingestion of spores of C. difficile that vegetate, multiply, and secrete toxins, causing diarrhea and pseudomembranous colitis (PMC).
Etiology and Epidemiology
C. difficile is an obligately anaerobic, gram-positive, spore-forming bacillus whose spores are found widely in nature, particularly in the environment of hospitals and chronic-care facilities. CDI occurs most frequently in hospitals and nursing homes where the level of antimicrobial use is high and the environment is contaminated by C. difficile spores.
Clindamycin, ampicillin, and cephalosporins were the first antibiotics associated with CDI. The second- and third-generation cephalosporins, particularly cefotaxime, ceftriaxone, cefuroxime, and ceftazidime, are agents frequently responsible for this condition, and the fluoroquinolones (ciprofloxacin, levofloxacin, and moxifloxacin) are the most recent drug class to be implicated in hospital outbreaks. Penicillin/β-lactamase-inhibitor combinations such as ticarcillin/clavulanate and piperacillin/tazobactam pose significantly less risk. However, all antibiotics, including vancomycin and metronidazole (the agents most commonly used to treat CDI), have been found to carry a risk of subsequent CDI. Rare cases are reported in patients without prior antibiotic exposure.
C. difficile is acquired exogenously, most frequently in the hospital or nursing home, and is carried in the stool of symptomatic and asymptomatic patients. The rate of fecal colonization is often ≥20% among adult patients hospitalized for >1 week; in contrast, the rate is 1–3% among community residents. Community-onset CDI without recent hospitalization probably accounts for ≤10% of all cases. The risk of C. difficile acquisition increases in proportion to length of hospital stay. Asymptomatic fecal carriage of C. difficile in healthy neonates is very common, with rates often exceeding 50% during the first 6 months of life, but associated disease in this population is rare. Spores of C. difficile are found on environmental surfaces (where the organism can persist for months) and on the hands of hospital personnel who fail to practice good hand hygiene. Hospital epidemics of CDI have been attributed to a single C. difficile strain and to multiple strains present simultaneously. Other identified risk factors for CDI include older age, greater severity of underlying illness, gastrointestinal surgery, use of electronic rectal thermometers, enteral tube feeding, and antacid treatment. Use of proton pump inhibitors may be a risk factor, but this risk is probably modest, and no firm data have implicated these agents in patients who are not already receiving antibiotics.
Pathology and Pathogenesis
Spores of toxigenic C. difficile are ingested, survive gastric acidity, germinate in the small bowel, and colonize the lower intestinal tract, where they elaborate two large toxins: toxin A (an enterotoxin) and toxin B (a cytotoxin). These toxins initiate processes resulting in the disruption of epithelial-cell barrier function, diarrhea, and pseudomembrane formation. Toxin A is a potent neutrophil chemoattractant, and both toxins glucosylate the GTP-binding proteins of the Rho subfamily that regulate the actin cell cytoskeleton. Data from studies using molecular disruption of toxin genes in isogenic mutants suggest that toxin B is the essential virulence factor; this possibility, if confirmed, might account for the occurrence of clinical disease caused by toxin A–negative strains. Disruption of the cytoskeleton results in loss of cell shape, adherence, and tight junctions, with consequent fluid leakage. A third toxin, binary toxin CDT, was previously found in only ∼6% of strains but is present in all isolates of the newly recognized epidemic strain (see “Global Considerations,” below); this toxin is related to C. perfringens iota toxin. Its role in the pathogenesis of CDI has not yet been defined.
The pseudomembranes of PMC are confined to the colonic mucosa and initially appear as 1- to 2-mm whitish-yellow plaques. The intervening mucosa appears unremarkable, but, as the disease progresses, the pseudomembranes coalesce to form larger plaques and become confluent over the entire colon wall (Fig. 129-1). The whole colon is usually involved, but 10% of patients have rectal sparing. Viewed microscopically, the pseudomembranes have a mucosal attachment point and contain necrotic leukocytes, fibrin, mucus, and cellular debris. The epithelium is eroded and necrotic in focal areas, with neutrophil infiltration of the mucosa.
Autopsy specimen showing confluent pseudomembranes covering the cecum of a patient with pseudomembranous colitis. Note the sparing of the terminal ileum (arrow).
Patients colonized with C. difficile were initially thought to be at high risk for CDI. However, four prospective studies have shown that colonized patients actually have a decreased risk of subsequent CDI. At least three events are proposed as essential for the development of CDI (Fig. 129-2). Exposure to antimicrobial agents is the first event and establishes susceptibility to C. difficile infection. The second event is exposure to toxigenic C. difficile. Given that the majority of patients do not develop CDI after the first two events, a third event is clearly essential for its occurrence. Candidate third events include exposure to a C. difficile strain of particular virulence, exposure to antimicrobial agents especially likely to cause CDI, and an inadequate host immune response. The host anamnestic serum IgG antibody response to toxin A of C. difficile is the most likely third event that determines which patients develop diarrhea and which patients remain asymptomatic. The majority of humans first develop antibody to C. difficile toxins when colonized asymptomatically during the first year of life. Infants are thought not to develop symptomatic CDI because they lack suitable mucosal toxin receptors that develop later in life. In adulthood, serum levels of IgG antibody to toxin A increase more in response to infection in individuals who become asymptomatic carriers than in those who develop CDI. For persons who develop CDI, increasing levels of antitoxin A during treatment correlate with a lower risk of recurrence of CDI. A clinical trial using monoclonal antibodies to both toxin A and toxin B in addition to standard therapy showed rates of recurrence lower than those obtained with placebo plus standard therapy.
Pathogenesis model for hospital-acquired Clostridium difficile infection (CDI). At least three events are integral to C. difficile pathogenesis. Exposure to antibiotics establishes susceptibility to infection. Once susceptible, the patient may acquire nontoxigenic (nonpathogenic) or toxigenic strains of C. difficile as a second event. Acquisition of toxigenic C. difficile may be followed by asymptomatic colonization or CDI, depending on one or more additional events, including an inadequate host anamnestic IgG response to C. difficile toxin A.
Rates and severity of CDI in the United States, Canada, and Europe have increased markedly since the year 2000. Rates in U.S. hospitals tripled between 2000 and 2005. Hospitals in Montreal, Quebec, have reported rates four times higher than the 1997 baseline, with directly attributable mortality of 6.9% (increased from 1.5%). An epidemic strain, variously known as toxinotype III, REA type BI, PCR ribotype 027, and pulsed-field type NAP1, is thought to account for much of the increase in incidence and has been found in North America, Europe, and Asia. The epidemic organism is characterized by (1) an ability to produce 16–23 times as much toxin A and toxin B as control strains in vitro; (2) the presence of a third toxin (binary toxin CDT); and (3) high-level resistance to all fluoroquinolones. New strains have been and will probably continue to be implicated in outbreaks; their emergence may be explained in part by patterns of antibiotic use, particularly in hospitals.
Diarrhea is the most common manifestation caused by C. difficile. Stools are almost never grossly bloody and range from soft and unformed to watery or mucoid in consistency, with a characteristic odor. Patients may have as many as 20 bowel movements per day. Clinical and laboratory findings include fever in 28% of cases, abdominal pain in 22%, and leukocytosis in 50%. When adynamic ileus (which is seen on x-ray in ∼20% of cases) results in cessation of stool passage, the diagnosis of CDI is frequently overlooked. A clue to the presence of unsuspected CDI in these patients is unexplained leukocytosis, with ≥15,000 white blood cells (WBCs)/μL. Such patients are at high risk for complications of C. difficile infection, particularly toxic megacolon and sepsis.
C. difficile diarrhea recurs after treatment in ∼15–30% of cases, and this figure may be increasing. Recurrences may represent either relapses due to the same strain or reinfections with a new strain. Susceptibility to recurrence of clinical CDI is likely a result of continued disruption of the normal fecal flora caused by the antibiotic used to treat CDI.
The diagnosis of CDI is based on a combination of clinical criteria: (1) diarrhea (≥3 unformed stools per 24 h for ≥2 days) with no other recognized cause plus (2) toxin A or B detected in the stool, toxin-producing C. difficile detected in the stool by polymerase chain reaction (PCR) or culture, or pseudomembranes seen in the colon. PMC is a more advanced form of CDI and is visualized at endoscopy in only ∼50% of patients with diarrhea who have a positive stool culture and toxin assay for C. difficile(Table 129–1). Endoscopy is a rapid diagnostic tool in seriously ill patients with suspected PMC and an acute abdomen, but a negative result in this examination does not rule out CDI.
Table 129–1 Relative Sensitivity and Specificity of Diagnostic Tests for Clostridium Difficile Infection (CDI) |Favorite Table|Download (.pdf)
Table 129–1 Relative Sensitivity and Specificity of Diagnostic Tests for Clostridium Difficile Infection (CDI)
|Type of Test||Relative Sensitivitya||Relative Specificitya||Comment|
|Stool culture for C. difficile||+ + + +||+ + +||Most sensitive test; specificity of + + + + if the C. difficile isolate tests positive for toxin; with clinical data, is diagnostic of CDI; turnaround time too slow for practical use|
|Cell culture cytotoxin test on stool||+ + +||+ + + +||With clinical data, is diagnostic of CDI; highly specific but not as sensitive as stool culture; slow turnaround time|
|Enzyme immunoassay for toxin A or toxins A and B in stool||+ + to + + +||+ + +||With clinical data, is diagnostic of CDI; rapid results, but not as sensitive as stool culture or cell culture cytotoxin test|
|Enzyme immunoassay for C. difficile common antigen in stool||+ + + to + + + +||+ + +||Detects glutamate dehydrogenase found in toxigenic and nontoxigenic strains of C. difficile and other stool organisms; more sensitive and less specific than enzyme immunoassay for toxins; rapid results|
|PCR for C. difficile toxin B gene in stool||+ + + +||+ + + +||Detects toxigenic C. difficile in stool; newly approved for clinical testing, but appears to be more sensitive than enzyme immunoassay toxin testing and at least as specific|
|Colonoscopy or sigmoidoscopy||+||+ + + +||Highly specific if pseudomembranes are seen; insensitive compared with other tests|
Despite the array of tests available for C. difficile and its toxins (Table 129–1), no single test has high sensitivity, high specificity, and rapid turnaround. Most laboratory tests for toxins, including enzyme immunoassays (EIAs), lack sensitivity. However, testing of multiple additional stool specimens is not recommended. PCR assays have now been approved for diagnostic testing and appear to be both rapid and sensitive while retaining high specificity. Empirical treatment is appropriate if CDI is strongly suspected on clinical grounds. Testing of asymptomatic patients is not recommended except for epidemiologic study purposes. In particular, so-called tests of cure following treatment are not recommended because many patients continue to harbor the organism and toxin after diarrhea has ceased and test results do not always predict recurrence of CDI. Thus these results should not be used to restrict placement of patients in long-term-care or nursing home facilities.
Treatment: Clostridium difficile Infection
When possible, discontinuation of any ongoing antimicrobial administration is recommended as the first step in treatment of CDI. Earlier studies indicated that 15–23% of patients respond to this simple measure. However, with the advent of the current epidemic strain and the associated rapid clinical deterioration of some patients, prompt initiation of specific CDI treatment has become the standard. General treatment guidelines include hydration and the avoidance of antiperistaltic agents and opiates, which may mask symptoms and possibly worsen disease. Nevertheless, antiperistaltic agents have been used safely with vancomycin or metronidazole for mild to moderate CDI.
All drugs, particularly vancomycin, should be given orally if possible. When IV metronidazole is administered, fecal bactericidal drug concentrations are achieved during acute diarrhea, and CDI treatment has been successful; however, in the presence of adynamic ileus, IV metronidazole treatment of PMC has failed. In previous randomized trials, diarrhea response rates to oral therapy with vancomycin or metronidazole were ≥94%, but four recent observational studies found that response rates for metronidazole had declined to 62–78%. Although the mean time to resolution of diarrhea is 2–4 days, the response to metronidazole may be much slower. Treatment should not be deemed a failure until a drug has been given for at least 6 days. On the basis of data for shorter courses of vancomycin, it is recommended that metronidazole and vancomycin be given for at least 10 days, although no controlled comparisons are available. Metronidazole is not approved for this indication by the U.S. Food and Drug Administration (FDA), but most patients with mild to moderate illness respond to 500 mg given by mouth three times a day for 10 days; extension of the treatment period may be needed for slow responders. In addition to the reports of increases in metronidazole failures, a prospective, randomized, double-blind, placebo-controlled study has demonstrated the superiority of vancomycin over metronidazole for treatment of severe CDI. The severity assessment score in that study included age as well as laboratory parameters (elevated temperature, low albumin level, or elevated WBC count), documentation of PMC by endoscopy, or treatment of CDI in the intensive care unit. Although a validated severity score is not yet available, it is important to initiate treatment with oral vancomycin for patients who appear seriously ill, particularly if they have a high WBC count (>15,000/μL) or a creatinine level that is ≥1.5 times higher than the premorbid value (Table 129–2). Small randomized trials of nitazoxanide, bacitracin, rifaximin, and fusidic acid for treatment of CDI have been conducted. While these drugs have not yet been extensively studied, shown to be superior, or approved by the FDA for this indication, they provide potential alternatives to vancomycin and metronidazole.
Table 129–2 Recommendations for the Treatment of Clostridium Difficile Infection (CDI) |Favorite Table|Download (.pdf)
Table 129–2 Recommendations for the Treatment of Clostridium Difficile Infection (CDI)
|Initial episode, mild to moderate||Oral metronidazole (500 mg tid × 10–14 d)|
|Initial episode, severe||Oral vancomycin (125 mg qid × 10–14 d)||Indicators of severe disease may include leukocytosis (≥15,000 white blood cells/μL) and a creatinine level ≥ 1.5 times the premorbid value.|
|Initial episode, severe complicated or fulminant|
Vancomycin (500 mg PO or via nasogastric tube) plus metronidazole (500 mg IV q8h) plus consider
Rectal instillation of vancomycin (500 mg in 100 mL of normal saline as a retention enema q6–8h)
|Severe complicated or fulminant CDI is defined as severe CDI with the addition of hypotension, shock, ileus, or toxic megacolon. The duration of treatment may need to be >2 weeks and is dictated by response. Consider using IV tigecycline (50 mg q12h after a 100-mg loading dose) in place of metronidazole.|
|First recurrence||Same as for initial episode|
|Second recurrence||Vancomycin in tapered/pulsed regimen||Typical taper/pulse regimen: 125 mg qid × 10–14 d, then bid × 1 week, then daily × 1 week, then q2–3d for 2–8 weeks|
Consider the following options:
• Repeat vancomycin taper/pulse
• Vancomycin (500 mg qid × 10 d) plus Saccharomyces boulardii (500 mg bid × 28 d)
• Vancomycin (125 mg qid × 10–14 d); then stop vancomycin and start rifaximin (400 mg bid × 2 weeks)
• Nitazoxanide (500 mg bid × 10 d)
• Fecal transplantation
• IV immunoglobulin (400 mg/kg)
|The only controlled study of treatment for recurrent CDI used S. boulardii and showed borderline significance compared with placebo.|
Overall, ∼15–30% of patients experience recurrences of CDI, either as relapses caused by the original organism or as reinfections following treatment. Recurrence rates are higher among patients ≥65 years old, those who continue to take antibiotics while being treated for CDI, and those who remain in the hospital after the initial episode of CDI. Patients who have a first recurrence of CDI have a high rate of second recurrence (33–65%). In the first recurrence, re-treatment with metronidazole is comparable to treatment with vancomycin (Table 129–2). Recurrent disease, once thought to be relatively mild, has now been documented to pose a significant (11%) risk of serious complications (shock, megacolon, perforation, colectomy, or death within 30 days). There is no standard treatment for multiple recurrences, but long or repeated metronidazole courses should be avoided because of potential neurotoxicity. Approaches include the administration of vancomycin followed by the yeast Saccharomyces boulardii; the administration of vancomycin followed by a synthetic fecal bacterial enema; and the intentional colonization of the patient with a nontoxigenic strain of C. difficile. None of these biotherapeutic approaches has been approved by the FDA for use in the United States. Other strategies include (1) the use of vancomycin in tapering doses or with pulse dosing every other day for 2–8 weeks and (2) sequential treatment with vancomycin (125 mg four times daily for 10–14 days) followed by rifaximin (400 mg twice daily for 14 days). IV immunoglobulin, which has also been used with some success, presumably provides antibodies to C. difficile toxins.
Severe Complicated or Fulminant Cdi
Fulminant (rapidly progressive and severe) CDI presents the most difficult treatment challenge. Patients with fulminant disease often do not have diarrhea, and their illness mimics an acute surgical abdomen. Sepsis (hypotension, fever, tachycardia, leukocytosis) may result from severe CDI. An acute abdomen (with or without toxic megacolon) may include signs of obstruction, ileus, colon-wall thickening, and ascites on abdominal CT, often with peripheral-blood leukocytosis (≥20,000 WBCs/μL). With or without diarrhea, the differential diagnosis of an acute abdomen, sepsis, or toxic megacolon should include CDI if the patient has received antibiotics in the past 2 months. Cautious sigmoidoscopy or colonoscopy to visualize PMC and an abdominal CT examination are the best diagnostic tests in patients without diarrhea.
Medical management of fulminant CDI is suboptimal because of the difficulty of delivering metronidazole or vancomycin to the colon by the oral route in the presence of ileus (Table 129–2). The combination of vancomycin (given via nasogastric tube and by retention enema) plus IV metronidazole has been used with some success in uncontrolled studies, as has IV tigecycline in small-scale uncontrolled studies. Surgical colectomy may be life-saving if there is no response to medical management. If possible, colectomy should be performed before the serum lactate level reaches 5 mmol/L. The incidence of fulminant CDI requiring colectomy appears to be increasing in the evolving epidemic.
The mortality rate attributed to CDI, previously found to be 0.6–3.5%, has reached 6.9% in recent outbreaks and is progressively higher with increasing age. Most patients recover, but recurrences are common.
Strategies for the prevention of CDI are of two types: those aimed at preventing transmission of the organism to the patient and those aimed at reducing the risk of CDI if the organism is transmitted. Transmission of C. difficile in clinical practice has been prevented by gloving of personnel, elimination of the use of contaminated electronic thermometers, and use of hypochlorite (bleach) solution for environmental decontamination of patients′ rooms. Hand hygiene is critical; hand washing is recommended in CDI outbreaks because alcohol hand gels are not sporicidal. CDI outbreaks have been best controlled by restricting the use of specific antibiotics, such as clindamycin and second- and third-generation cephalosporins. Outbreaks of CDI due to clindamycin-resistant strains have resolved promptly when clindamycin use is restricted.