Hospital Medicine

Clostridium difficile infection

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I. What every physician needs to know.

Clostridium difficile is an anaerobic gram-positive, spore-forming, toxin-producing bacillus that causes a toxin-mediated diarrhea and colitis in susceptible persons, and is transmitted through the fecal-oral route. The pathogenesis is related to the disruption of normal intestinal flora as a result of antibiotic therapy. The two exotoxins (TcdA and TcdB) produced bind to the intestinal cells producing inflammation and diarrhea. The disease spectrum ranges from asymptomatic carriers to fulminant colitis and toxic megacolon, which is a surgical emergency.

II. Diagnostic Confirmation: Are you sure your patient has Clostridium difficile infection (CDI)?

Detection of toxins by enzyme immunoassay or detection of the toxin genes by DNA-based tests in unformed stool is required for diagnosis of CDI. The DNA-based tests provide higher sensitivity and specificity than the enzyme immunoassay. Diagnosis can also be made by endoscopic visualization of pseudomembranes in the colon, but this method is not routinely used and is more expensive and less sensitive.

A. History Part I: Pattern Recognition:

Multiple episodes of watery diarrhea with or without lower abdominal pain and cramping, with or without fever and leukocytosis in the setting of recent antibiotic use is the typical presentation.

The clinical spectrum of CDI includes the following:

- Asymptomatic carrier (no symptoms)

- Non-severe CDI

- Severe CDI (white cell count >15,000 cells/microliter, creatinine >1.5 times the baseline)

- Severe complicated CDI (toxic megacolon, peritonitis, ileus, shock)

- Recurrent CDI: reappearance of symptoms within 8 weeks of completion of therapy and initial resolution of symptoms

The diarrhea may have mucus and occult blood but there is rarely hematochezia. Fevers are usually low-grade unless the patient has fulminant colitis. Leukocytosis with neutrophilic predominance is very common and sometimes may precede the diarrhea by 1-2 days. The key feature is the association of the diarrhea with antibiotic usage, usually within 2 weeks of antibiotic administration.

In fulminant colitis, patients have systemic signs of toxicity such as abdominal distension, diffuse abdominal pain, high-grade fevers, hypovolemia, lactic acidosis, and significant leukocytosis. Diarrhea maybe less prominent secondary to dilated, atonic colonic ileus.

Toxic megacolon is a clinical diagnosis based on severe systemic toxicity and radiological findings (see below) while bowel perforation presents as acute abdomen with abdominal rigidity and septic shock.

B. History Part 2: Prevalence and risk factors:

In the United States, CDI is the most common healthcare-associated infection and elderly hospitalized patients are especially prone.

Risk factors include recent antibiotic use, advanced age (CDI is ten times more common in the elderly), immunosuppression and chemotherapy, inflammatory bowel disease (8% are carriers even in the absence of antibiotics in contrast to 1% in the normal population), nursing home residency (50% are asymptomatic carriers), and recent hospitalization (up to 20% are carriers).

Antibiotic use is the most widely recognized and modifiable risk factor for C. difficile infection. The most common antimicrobials that predispose to CDI are clindamycin, broad-spectrum penicillins, cephalosporins and fluroquinolones but virtually every antibiotic has been implicated in this disease.

The BI/NAP1/027 strain is characterized by high-level fluoroquinolone resistance, efficient sporulation, high toxin production, and a mortality rate three times as high as that associated with less virulent strains.

C. History Part 3: Competing diagnoses that can mimic CDI.

C. difficile is the major infectious etiology of antibiotic-associated diarrhea. Other pathogens that can cause similar symptoms rarely are Klebsiella oxytoca, Clostridium perfringens, and other enteric pathogens. Klebsiella oxytoca can cause pseudomembranous and hemorrhagic colitis.

The differential diagnosis should include non-infectious etiologies like postinfectious irritable bowel syndrome and osmotic diarrhea, though the latter usually resolves with fasting. Postinfectious irritable bowel syndrome in a C. difficile carrier can be clinically indistinguishable from a relapse of C. difficile infection, though there should be an improving or normal white count and normal temperature curve.

D. Physical Examination Findings.

On physical exam, there are often non-specific findings, including lower abdominal tenderness. However, in the setting of fulminant colitis, systemic toxic signs such as abdominal distension, decreased or absent bowel sounds, hypovolemia, and signs of septic shock are present. Toxic megacolon can lead to bowel perforation which presents with signs of acute abdomen such as rebound tenderness, rigidity and involuntary guarding.

E. What diagnostic tests should be performed?

Diagnostic tests for C. difficile should be performed only if a patient has clinically significant diarrhea, defined as three or more watery stools for two days or when associated with fever or in the case of a patient with ileus with a high suspicion of CDI. The diagnosis is usually made by the detection of toxins by enzyme immunoassay or detection of toxin genes by DNA-based tests. There is no role for diagnostic testing in an asymptomatic patient or for test of cure after therapy and clinical resolution.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There are two main types of tests: toxin assays (to detect the presence of toxin) and organism detection assays (which evaluate the presence of the organism).

Toxin assays

  1. Cell cytotoxicity assay: This is one of the gold standards for diagnosis of CDI. The sensitivity is 77-86% and the specificity is 97-99%.

  2. Enzyme immunoassay (EIA): This is a rapid test with a quick turnaround time within 24hrs. It directly detects both toxins A and B from stool filtrate. The sensitivity is 60-80% and the specificity is 93-99%. Checking three consecutive stool samples can improve the sensitivity by 10%, which is still a high false negative rate as a single test.

  3. DNA-based tests, such as polymerase chain reaction (PCR) or loop-mediated isothermal amplification (LAMP): The PCR was approved in 2009, and is a rapid and accurate toxin B detection test with a high sensitivity and specificity of 97 and 93% respectively. It is especially useful in detecting the presence of the BI/NAP1/027 strain. This test is slowly becoming the primary diagnostic test.

Organism detection assays

  1. EIA for glutamate dehydrogenase (GDH): This is an enzyme immunoassay for the detection of GDH which is an essential enzyme (somatic antigen) produced by all C. difficile strains, whether they are pathogenic or not. The sensitivity is 71-100% and the specificity is 67-99%.

  2. Toxigenic stool culture: The other gold standard with a sensitivity of 95-100% and specificity of 96-100%. This is the most sensitive test however it is cumbersome and the results take about 3 days and it still cannot distinguish between toxin producing and non-toxin producing strains. It is used for epidemiological surveillance.

Because the pathogen and its toxins can be readily detected with most of the available tests, detection of C. difficile in the absence of symptoms does not meet the criteria for a diagnosis of CDI.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Abdominal imaging should be performed in the presence of acute abdomen. Remember to obtain an urgent surgical evaluation if patient has any signs of acute abdomen like rebound, rigidity or lack of bowel sounds.

Kidneys, ureter and bladder (KUB) abdominal series: signs of ileus with small bowel dilatation and air fluid levels. Transverse colon dilatation greater than 6 cm (centimeters) and "thumb printing" (scalloping of bowel wall) due to submucosal edema are cardinal features of toxic megacolon. Free abdominal air will be present in cases of bowel perforation.

Abdominal computed tomography (CT) shows pronounced thickening of colonic wall in pseudomembranous colitis.

Sigmoidoscopy or colonoscopy is indicated as an adjunct diagnostic tool in cases of the following:

- High suspicion for C. difficile but negative toxin assays or inability to obtain stool samples.

- Need for prompt diagnosis of C. difficile before laboratory tests can be obtained as in fulminant colitis (care should be taken to introduce minimal air for risk of perforation).

- Failure of response to antibiotic therapy.

- Atypical presentation to evaluate for evidence of CDI and to exclude other etiologies.

The endoscopic findings range from bowel edema with patchy erythema to friability to pseudomembrane formation. The toxin produced disrupts the intestinal cytoskeleton, forming shallow ulcers, which allow loss of serum proteins, mucus and inflammatory cells, which together form yellowish plaques called pseudomembranes, which in their most severe form expand from scattered lesions to covering the entire colonic mucosa.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Do not repeat stool testing during the same episode of diarrhea as it is of limited value and should be discouraged.

Do not send repeat stool assays following treatment as up to 50% of patients have positive stool assays for several weeks after the completion of therapy.

III. Default Management.

Treatment is indicated if a patient has typical manifestations of C. difficile infection and a positive toxin assay. Empiric therapy may be initiated in cases of severe symptoms or high suspicion, pending diagnostic testing. There is no role of treatment of an asymptomatic carrier with a positive toxin assay.

Treatment depends on severity and number of episodes.

A. Immediate management.

The initial steps when C. difficile infection is identified include the following:

- Discontinuation of inciting antibiotic as soon as possible. If ongoing treatment of the primary infection is needed, consider switch to alternatives to clindamycin, beta-lactams and fluoroquinolones.

- Implementation of contact precautions for all suspected and proven cases of CDI until the patient’s diarrhea resolves. Hand hygiene should include washing with soap and water, not alcohol based gels, as the latter do not kill the C. difficile spores.

- Avoid the use of anti-motility agents, which can obscure symptoms and precipitate toxic megacolon.

Antibiotic therapy

- Non-severe disease: oral metronidazole 500 mg (milligrams) 3 times daily for 10-14 days.

- Severe disease: oral vancomycin 125 mg 4 times daily for 10-14 days.

- Severe, complicated disease: high dose oral vancomycin 500 mg q6h plus intravenous metronidazole 500 mg q8h for at least 14 days. In cases of oral intolerance, administer vancomycin via nasogastric route or in case of ileus, consider adding retention vancomycin enema 500 mg in 100 ml (milliliters) of saline per rectum every 6 hours.

- First recurrence of CDI: can be treated as first episode with oral vancomycin or metronidazole in non-severe cases and oral vancomycin for severe cases. Vancomycin may be more effective in bacteriological cure than metronidazole in recurrent CDI. Fidaxomicin 200 mg twice a day for 10 days should be considered over vancomycin in non-NAP1 strains and when the risk of recurrent is high (age >65 years, continued use of non-CDI antibiotics, severe underlying disease or renal failure, previous severe CDI).

- Second or further recurrence: vancomycin taper, fidaxomicin or fecal microbiota transplantation.

Example of vancomycin taper: 125 mg four times a day for 2 weeks, 125 mg three times a day for 1 week, 125 mg twice a day for 1 week, 125 mg daily for 1 week, 125 mg every other day for 1 week and 125 mg every 3 days for 1 week.

B. Physical Examination Tips to Guide Management.

Surgery should be considered if the patient’s clinical status fails to improve in 48 hours of medical treatment or in case of physical signs such as abdominal distension or acute abdomen with peritoneal signs concerning for perforation, ileus or toxic megacolon.

If surgery is necessary, perform subtotal colectomy with preservation of rectum and diverting ileostomy. A diverting ileostomy with vancomycin colonic lavage could be an effective alternative.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Daily cell count to monitor leukocytosis, serial creatinine and lactate levels should be done to follow the patient’s response to therapy.

Rising leukocytosis to 50,000 cells/microliter or serum lactate to 5 millimoles/liter are associated with high perioperative mortality.

D. Long-term management.

Twenty five percent of cases treated initially with either metronidazole or vancomycin recur. After the initial recurrence, the rate increases to a 45 to 65% chance of additional episodes. Risk factors for recurrence include age greater than 65 years, underlying medical disorders and the need for ongoing antimicrobial therapy for primary infection.

Because a positive stool toxin assay does not exclude asymptomatic carriage, other infectious pathogens and non-infectious etiologies like postinfectious irritable bowel syndrome and inflammatory bowel disease should be considered. Colonoscopy may be considered.

Whan a vancomycin taper is used, the rationale is to allow the germination of the dormant C. difficile spores in the gut into the toxin-producing vegetative form which can then be killed by the antibiotics. Do not use metronidazole for prolonged treatment or after the first recurrence to avoid the cumulative peripheral neurotoxic effect.

E. Common Pitfalls and Side-Effects of Management.

The limitations to the use of metronidazole are oral intolerance due to nausea and metallic taste and dose-dependent peripheral neurotoxicity. Hence, the use of metronidazole beyond a first recurrence is not recommended.

In case of ileus or per os (PO) intolerance, use vancomycin enema and not intravenous vancomycin because the antibiotic is not secreted in the colon.

The in vitro efficacy, risk of relapse and gut colonization with vancomycin-resistant Enterococcus (VRE) is the same with metronidazole and vancomycin. However the former is much less in cost than oral vancomycin.

IV. Management with Co-Morbidities.

Use vancomycin as a first line agent in cases of low serum albumin, critically ill patients or during pregnancy.

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

Consider use of oral vancomycin as first line agent in case of hypoalbuminemia less than 2.5 mg/dl (milligrams/deciliter).

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

Consider empirically initiating C. difficile treatment pending diagnostic test results.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Serial abdominal exams should be carried out to exclude abdominal distension and acute abdomen, which would be suggestive of severe complicated C. difficile infection secondary to ileus, toxic megacolon or perforation. Emergent surgical evaluation and intensive care monitoring would then be required.

Daily white count, creatinine and lactate levels are needed to monitor response to treatment and evaluate for bowel ischemia.

B. Anticipated Length of Stay.

Length of stay is usually 3-5 days unless associated with severe C. difficile infection with multiorgan failure or surgical complications.

C. When is the Patient Ready for Discharge?

The patient is ready to be discharged on resolution of systemic symptoms, when tolerating oral nutrition and medication and when able to maintain input orally to compensate for gastrointestinal losses. Resolution of diarrhea is not a criterion for discharge.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom.

Follow-up should be arranged a couple of weeks after completion of antibiotics with a general medicine clinic.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

None

E. Placement Considerations.

If the patient requires placement for other reasons, it is important to continue contact precautions while the patient is symptomatic.

F. Prognosis and Patient Counseling.

The patient should be advised about home hygiene including the importance of hand washing with soap and water, especially after using the bathroom and before food preparation. Patients with diarrhea should avoid using the same toilet as other family members. In addition, bathroom and kitchen areas may be cleaned with a mixture of bleach (1 part) and water (10 parts) to help prevent the spread of C. difficile.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

Contact precautions with gloves and gowns and hand washing with soap and water instead of alcohol-based gels is a requirement while the patient has diarrhea.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Twenty percent of hospitalized patients and 50% of long-term care facility residents may be asymptomatic carriers of C. difficile. Treatment is not recommended even though they can act as environmental reservoirs.

There is a 25% recurrence after the first course of treatment and 50% after subsequent treatments. The recurrence is due to reingestion of spores or spores remaining in the gastrointestinal tract after therapy. Antibiotic resistance has not been demonstrated.

Administration of currently available probiotics is currently not recommended to prevent C. difficile infection given the limited data to support their use and the potential risk of bloodstream infection. Use of Saccharomyces boulardii has been associated with fungemia in some immunocompromised and debilitated patients.

A vaccination against the two exotoxins is currently being investigated. Vaccination against the toxins offers the possibility of an effective and relatively inexpensive approach to prevention. However, at this point it is unclear whether vaccination will be used for primary or secondary prevention and whether vaccination will prevent or lessen the severity of clinical infection.

Fecal microbiota transplantation has recently emerged as an accepted, safe, and effective treatment for recurrent C. difficile infection. Bacteroidetes and Firmicutes comprise critical components of the material that needs to be transplanted. The oral or rectal transplantation of feces from a healthy, pretested donor has been successful in treating more than 90% of patients with recurrent C. difficile infection.

What’s the evidence?

Cohen, SH, Gerding, DN, Johnson, S. "Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Health Care Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA)". Infect Control Hosp Epidemiol. vol. 31. 2010. pp. 431-455.

Louie, TJ, Miller, MA, Mullane, KM. "Fidaxomicin versus vancomycin for Clostridium difficile infection". N Engl J Med. vol. 364. 2011. pp. 422-431.

Surawicz, CM, Brandt, LJ, Binion, DG. "Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections". Am J Gastroenterol. vol. 108. 2013. pp. 478-498.

Debast, SB, Bauer, MP, Kuijper, EJ. "European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection". Clin Microbiol Infect. vol. 20. 2014. pp. 1-26.

(The two references above are guidelines published in 2013 and 2014 and have more recent evidence about management of C. diff infection.)

Leffler, DA, Lamont, JT. "Clostridium difficile infection". N Engl J Med. vol. 372. 2015. pp. 1539-1548.

(This is a nice review recently published at NEJM. Fidaxomicin has a more prominent role compared to the 2010 SHEA guidelines [which are being updated currently].)

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