Clostridium difficile Infection: What You Need to Know
ABSTRACT: The incidence, mortality, and associated medical care costs of Clostridium difficile infection are increasing. Clinical manifestations range from asymptomatic carriage (particularly in neonates) to a fulminant, relapsing, and occasionally fatal colitis. Traditionally, laboratory tests have focused on detecting either the toxins or the causative organism; in general, toxin detection tests are more sensitive, specific, and clinically useful than tests used to detect the organism. New medications have recently been approved for the treatment of C difficile infection; however, therapeutic options remain limited. Nonpharmacologic therapies, such as stool transplantation (fecal bacteriotherapy), are being employed with some success. Even with appropriate treatment, the relapse rate is high, making C difficile infection one of the more challenging infections to treat.
Key words: Clostridium difficile infection, diarrhea, colitis
Clostridium difficile infections are among the most common and most serious healthcare-associated infections in the United States. During the past decade, the incidence of C difficile infection has increased and more virulent strains have emerged, causing significant morbidity and increased mortality among high-risk persons. Several diagnostic tests for C difficile infection, with various sensitivity and specificity profiles, are now available.
Although new medications have recently been approved for the treatment of C difficile infection, therapeutic options remain limited. Nonpharmacologic therapies are being employed with some success. Even with appropriate treatment, the relapse rate is high, making
C difficile infection one of the more challenging infections to treat. This article provides a brief review of the epidemiology, manifestations, diagnosis, treatment, and prevention of this infection.
HISTORICAL PERSPECTIVE
Clostridium difficile is a spore-forming, gram-positive anaerobic bacillus that produces 2 exotoxins: toxin A and toxin B (Figure 1). In 1935, C difficile was isolated during a study of intestinal biota of healthy newborn infants.1 Because of the difficulty in isolating the bacteria, it was originally named Bacillus difficilis (difficult bacillus).2 In the late 1960s, antibiotic-associated diarrhea was described, and in 1978, C difficile was identified as the causative pathogen in up to 25% of cases. The earliest cases of C difficile infection were attributed largely to previous exposure to clindamycin, but soon after, this infection was also recognized in patients who had received cephalosporin and quinolones.3
Figure 1 – Clostridium difficile bacilli are shown here. (Courtesy of the CDC.)
From 2003 to 2006, a more severe, difficult to treat, and relapsing disease was recognized and was attributed to a new emerging hyper-virulent strain designated as restriction enzyme analysis type BI, North American Pulsed Field type 1 (NAP1), or polymerase chain reaction (PCR) ribotype 027 (or NAP1/BI/027 strain).4 The enhanced virulence of this strain is attributed to greater production of toxins A and B and other virulence factors.5 Fluoroquinolone use is strongly correlated with the emergence of this strain.6
IMPACT ON PATIENTS, HOSPITALS, AND SOCIETY
The incidence, mortality, and attributable medical care costs of C difficile infection are increasing.7 The impact on patients’ lives has been enormous. Mortality associated with C difficile infection increased from 3000 per year during 1999 to 2000 to 14,000 per year during 2006 to 2007; more than 90% of the deaths occurred in persons aged 65 years or older.8 The financial impact is also tremendous, with excess healthcare costs of about $6000 per case and national annual excess medical costs totaling about $1 billion.9 The increase in incidence and mortality is partly attributable to the emergence and spread of the NAP1/BI/027 hyper-virulent resistant strain of C difficile.
CAUSES AND CLINICAL MANIFESTATIONS
A key factor in the pathogenesis of C difficile infection is the disruption of normal colonic biota (a major host defense system) by antibiotics (or antineoplastic agents with antibacterial activity), which facilitates colonization with toxigenic C difficile.10 The elaboration of toxin A or toxin B (or both) mediates cytoskeletal derangement in target cells, resulting in mucosal injury and inflammation.11 The transmission is fecal-oral. Stomach acid kills vegetative C difficile cells, but the acid-resistant spores pass undamaged to the small bowel, where they geminate to the vegetative toxin-producing form.12 The 2 large exotoxins rank among the most lethal bacterial toxins studied.13 These toxins mediate diarrhea and colitis, and the higher toxin levels are associated with a greater severity of colitis.14
Clinical manifestations range from asymptomatic carriage (particularly in neonates) to a fulminant, relapsing, and occasionally fatal colitis. Symptoms of C difficile infection usually occur within the first week of antibacterial treatment, but diarrhea may develop as early as the first day of therapy or as late as 10 weeks after cessation of therapy.15 Therefore, for any patient presenting with diarrhea, it is very important to inquire about the use of antibiotics during the previous 2 to 3 months. The diarrhea may occur briefly, or it may be severe and frequent (Table 1).
Associated symptoms include fever (in about 40% of patients)16,17 and leukocytosis (in about 50% to 60%), including a particularly high white blood cell count (greater than 35,000/µL).18,19 Leukocytosis of increasing severity in hospitalized patients should prompt a clinical evaluation for C difficile infection in the appropriate setting. Abdominal pain occurs in about one third of patients.17 Nausea, malaise, anorexia, and occult colonic bleeding have also been reported. Acute abdominal syndrome, toxic megacolon, and sepsis are occasional presentations of C difficile infection that carry high mortality (64% in one series).20 In severeC difficile infection, colonic perforation is a major sequela that may result from delayed surgical intervention. Therefore, early surgical consultation is recommended in severe cases.
Recurrent C difficile–associated diarrhea occurs in approximately 20% of patients,21 although why the disease recurs in certain individuals is not entirely clear. One explanation is that C difficile spores are resistant to antibiotics so that several days after antibiotic therapy is discontinued, the surviving spores transform into active bacterial forms which will multiply and produce toxins again. This is the rationale behind using pulsed, tapered oral vancomycin in the treatment of recurrent C difficile infection. Interrupted dosing allows the spores to germinate and then be killed by subsequent antibiotic doses.
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Figure 2 – Colonoscopy reveals pseudomembranous plaques in the colon of a patient with Clostridium difficile infection (A, B, and C). A normal colon is shown for comparison (D). (Used with permission from Arthi Sanjeevi, MD, and Oleana Lamendola, MD; department of gastroenterology, University of South Florida College of Medicine, Tampa, Florida.)
Another explanation for the recurrence of C difficile infection is the host’s inadequate production of antibodies against the bacterial toxins. Studies have shown that asymptomatic carriers of C difficile have high levels of antitoxin A and/or antitoxin B, whereas those with recurrent disease have low antibody levels.22 This observation provides the rationale behind using immunoglobulin (against toxins A and B) in the treatment of recurrent or severe C difficile infection. The host’s susceptibility and the virulence factors of the bacterial strain ultimately determine the outcome of the infection.
Rarely, extraintestinal manifestations of C difficile infection may occur, including bacteremia, often with concurrent isolation of other bowel flora from the blood, splenic abscess, osteomyelitis, and reactive arthritis.23-26
Figure 3 – An abdominal radiograph (A) and CT scan (B) show a dilated colon (arrows) in a
patient with Clostridium difficile infection; a second scan (C) shows a thickened colon
(arrows).
(Used with permission from Sheldon Scheinert, MD, department of gastroenterology, Palms of Pasadena Hospital, St Petersburg, Florida.)
Endoscopically, the colonic mucosa appears studded with yellowish pseudomembranous plaques that are small and easily dislodged at the beginning of the infection and then enlarge and coalesce as the disease progresses (Figure 2). Pseudomembranes can occur throughout the entire colon, but they are usually most pronounced in the rectosigmoid colon and are very rarely found proximal to the ileocecal valve. Imaging may show thickened and/or dilated colon (Figure 3).
The differential diagnosis of C difficile infection includes diarrhea caused by other enteric pathogens (eg, Salmonella, Shigella, and Campylobacter species), ischemic colitis (especially in elderly hospitalized patients), inflammatory bowel disease, and intra-abdominal sepsis.
Although C difficile infection is classically acquired in healthcare settings, community-acquired infection is becoming increasingly recognized. Patients with community-acquired infection tend to be younger and have fewer comorbidities, but, again, most of these patients will have been previously exposed to antibiotics.27 Ongoing studies also indicate a rising incidence of C difficile infection among children that is primarily linked to excessive antibiotic use.
RISK FACTORS
Established risk factors for C difficile infection include the following28:
• Antibiotic exposure.
• A long length of stay in a healthcare setting.
• A serious underlying illness.
• Advanced age.
Possible risk factors include gastric acid suppression, enteral feeding, gastrointestinal surgery, immunosuppression, and cancer chemotherapy, which may have some antimicrobial effects.29
DIAGNOSIS
Clinical diagnosis. Suspect C difficile infection in patients with diarrhea who have received antibiotics within the previous 2 months or whose diarrhea begins 72 hours after hospitalization.30
Laboratory tests. Traditionally, laboratory tests have focused on detecting either the toxins (PCR assay, enzyme immunoassay [EIA], and tissue toxin assay) or the causative organism (glutamate dehydrogenase [GDH] antigen detection and bacterial culture). In general, toxin detection tests are more sensitive, specific, and clinically useful than tests used to detect the organism (Table 2).
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TOXIN DETECTION TESTS
Molecular tests. US Food and Drug Administration (FDA)-approved PCR assays (eg, Xpert C. difficile assay [Cepheid], BD GeneOhm Cdiff Assay [BD], and the in vitro diagnostic real-time PCR assay) that detect the gene-encoding toxin B are highly sensitive (97%) and specific (93%) for toxin-producing C difficile organisms.31 This is the preferred test and the best currently available, producing the highest negative predictive value among other tests. The number of hospitals performing PCR assays is increasing. The major limitation is cost.31
Toxin detection EIA. The toxin detection EIA detects toxin A, toxin B, or both. This test is relatively simple and less expensive than the PCR assay, and the results are available within 24 hours. Despite good specificity (up to 99%), the test has poor sensitivity (about 65%).32 The test also has a relatively high false-negative rate, since a certain threshold amount of toxin must be present to ensure a positive result and the toxins degrade quickly within 2 hours at room temperature. Therefore, any delay in processing specimens will increase the risk of a false-negative result.
Tissue cytotoxin assay. This test of the effect of toxin in tissue is generally more sensitive than the EIAs and was historically viewed as the gold standard test for the diagnosis of C difficile infection.33 However, it is more difficult to perform than the EIA and has a relatively slow turnaround time, which limits its usefulness in the clinical setting.
ORGANISM DETECTION TESTS
Antigen detection for C difficile. The antigen detection test can rapidly detect (within 1 hour) the presence of C difficile antigen by latex agglutination or immunochromatographic assay. This test is significantly less specific than PCR assays, as it detects GDH, a common antigen that is an essential enzyme produced constitutively by all C difficile isolates, not necessarily by toxigenic strains. This test is no longer recommended to be used alone. When it is used, the test is usually performed as a part of a 2-step testing algorithm whereby stools testing positive for GDH antigen will then undergo toxin or PCR tests. This 2-step algorithm is meant to reduce the cost incurred by PCR assay testing of all specimens.
Stool culture for C difficile. Stool culturing is not routinely used in the diagnosis of C difficile infection because it is time consuming and cumbersome and often associated with false-positive results due to the presence of nontoxigenic C difficile strains. Stool culturing is labor intensive, requires an appropriate culture environment to grow anaerobic microorganisms, and has a relatively long turn-around time (3 to 4 days), all of which make this test less clinically useful. The results of toxigenic cultures do serve as a gold standard against which other test modalities are compared in clinical trials of performance.
TREATMENT
Cessation of offending antibiotics. In about 20% of patients with C difficile infection, the disease will resolve within 2 to 3 days of discontinuing the antibiotic to which the patient was previously exposed.
Appropriate anti–C difficile antibiotics. The infection can usually be treated with an appropriate course of antibiotics, including metronidazole, oral vancomycin with or without rifaximin, or the recently approved fidaxomicin (Table 3).33-37 Metronidazole, which is not FDA-approved for treating C difficile infection, is reserved for mild disease. Stool levels of metronidazole are very low and its systemic absorption is high, making the drug less ideal for the treatment of an infection that primarily affects the bowel. Oral vancomycin, on the other hand, has negligible systemic absorption and high fecal concentration, making it a preferable agent. It is FDA-approved and is indicated for moderate and severe cases, such as C difficile infection occurring in elderly patients (aged 65 years or older) or disease associated with a high leukocyte count (15,000/µL or higher) and increasing serum creatinine level. Currently, to limit the spread of vancomycin resistance, especially among enterococci, oral vancomycin is not recommended for mild cases of C difficile infection.
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The usual recommended dosage of vancomycin is 125 mg orally 4 times daily. Higher dosages, such as 250 mg orally 4 times daily, have not proved to be more effective. Vancomycin can be administered rectally when ileus is evident, but caution should be exercised not to perforate a friable colon. A combination of intravenous metronidazole and oral vancomycin can be used in severe cases.
Fidaxomicin is the most recent FDA-approved anti–C difficile antibiotic. The rates of clinical cure after treatment with fidaxomicin were non-inferior to those after treatment with vancomycin, and fidaxomicin was associated with a significantly lower rate of recurrence of C difficile infection associated with non–North American Pulsed Field type 1 strains.35 Fidaxomicin appears to kill C difficile but preserve the rest of the intestinal microflora (ie, it has a narrower spectrum of activity than vancomycin), and that may be the reason for the reduced recurrence of C difficile infection. Fidaxomicin may be appropriate for patients with relapsing infection or as initial therapy in those at high risk for recurrent disease (eg, immunocompromised patients). The indications for appropriate fidaxomicin use are still being defined. The drug’s major limitation is its cost.
Adjunctive use of monoclonal antibodies. Monoclonal antibodies against C difficile toxins A and B (in addition to antibiotic therapy) appeared to reduce the rate of recurrent C difficile infection in some studies.36 Monoclonal antibodies are not yet available for routine clinical use, but studies are currently assessing their effect on disease recurrence and in the treatment of severe disease.
Antiperistaltics. The use of antiperistaltic agents is generally not recommended in the treatment of acute C difficile infection.
Stool transplantation (fecal bacteriotherapy). In fecal bacteriotherapy, stool obtained from a healthy individual is instilled in an infected patient from either end of the gastrointestinal tract. This method has emerged as a treatment for chronic relapsing C difficile infection and is gaining more acceptance among physicians and patients. The success rate of this method is impressive (up to 90%) and is higher than that associated with any other modality.37,38 Facilities performing fecal bacteriotherapy are not yet widely available but may become more numerous in the near future as clinicians recognize the increasing rate of C difficile infection and the effectiveness and lower cost of fecal bacteriotherapy in the treatment of the disease.
Colectomy. Surgical removal of colon may be necessary for severely ill patients. The procedure is indicated when the serum lactate level rises to 5 mmol/L and the white blood cell count increases to 50,0000/µL or higher; these findings are associated with increased mortality.33 When surgery is performed, a subtotal colectomy with preservation of rectum is the usual procedure.
Isolation and hygiene. All patients with C difficile infection and those, including healthcare workers, who establish contact with them should follow strict contact precautions. All should be especially vigilant about hand washing with soap and water. C difficile spores are resistant to alcohol-based hand sanitizers, which are therefore not effective in this setting.
Probiotics. Evidence of the effectiveness of Saccharomyces boulardii and other probiotics in preventing recurrent C difficile infection is mixed. Probiotics have been associated with serious complications among immunocompromised patients and critically ill patients, particularly those with central venous lines or feeding tubes; the administration of probiotic therapy to these patients is therefore not recommended.
After treatment, repeat C difficile testing for cure is not recommended if the patient’s symptoms have resolved, because the patient may remain colonized.
TRANSMISSION
Clostridium difficile is shed in feces. Any device or surface (eg, commodes, bathing tubs, and electronic rectal thermometers) that becomes contaminated with feces may serve as a reservoir for the C difficile spores. The spores are transferred to patients mainly via the hands of healthcare personnel who have touched a contaminated surface or item; contrary to common belief, only a minority of patients are colonized with C difficile. Most patients actually acquire C difficile from the contaminated environment. Therefore, good hand hygiene is the cornerstone in preventing hospital infections.
PREVENTION IN HEALTHCARE SETTINGS
Antibiotic stewardship and simple infection control measures, such as hand washing with soap and water, are key elements in decreasing the incidence of C difficile infection (Table 4).
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