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Clostridium difficile infection

Overview

Diagnostic Criteria

Classification of Disease Severity

Risk Factors

Complete Diagnostic Approach

Management

Dos and Don'ts

Guidelines

Main article: Clostridium difficile infection

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Clostridium difficile infection is the leading cause to nosocomial diarrhea. Clinical presentation ranges across a broad spectrum from asymptomatic carriage, to diarrheal illness, to complicated disease hallmarked by pseudomembranous colitis, toxic megacolon, or bowel perforation. Diagnosis is established by the presence of diarrheal symptoms coupled with positive stool tests or endoscopic findings. Therapeutic approach and antibiotic choice should be stratified according to severity of disease and risk of recurrence.

Diagnostic Criteria

Infectious Disease Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)

The diagnosis of C. difficile infection should be based on a combination of clinical and laboratory findings. A case definition for the usual presentation includes the following findings:

• The presence of diarrhea, defined as passage of 3 or more unformed stools in 24 or fewer consecutive hours AND
• A stool test result positive for the presence of toxigenic C. difficile or its toxins OR colonoscopic or histopathologic findings demonstrating pseudomembranous colitis.

The same criteria should be used to diagnose recurrent C. difficile infection.

European Society of Clinical Microbiology and Infectious Diseases (ESCMID)

Diagnosis of C. difficile infection is based on the following criteria:

• A combination of signs and symptoms, confirmed by microbiological evidence of C. difficile in stools, in the absence of another cause
  OR
• Colonoscopic or histopathological findings demonstrating pseudomembranous colitis

Diagnostic tests for C. difficile infection include:

• Enzyme immunoassay (EIA): glutamate dehydrogenase (GDH), toxins A and B
• Nucleic acid amplification tests (NAAT): 16S ribosomal RNA, GDH genes, toxin genes
• Cell culture cytoxicity assay (CCA)
• Culture of toxigenic C. difficile

Classification of Disease Severity

Infectious Disease Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)

Initial episode of C. difficile infection may be stratified by disease severity as follows:

• Mild-to-moderate disease

Leukocytosis with WBC < 15,000 cells/mL AND serum creatinine < 1.5 times the premorbid level

• Severe disease

Leukocytosis with WBC ≥ 15,000 cells/mL OR serum creatinine ≥ 1.5 times the premorbid level

• Severe, complicated disease

Hypotension or shock, ileus, megacolon

European Society of Clinical Microbiology and Infectious Diseases (ESCMID)

Severe disease is defined as an episode of C. difficile infection with:

• One or more specific signs and symptoms of severe colitis
  OR
• A complicated course of disease, with significant systemic toxin effects and shock, resulting in need for intensive care unit admission, colectomy, or death.

Characteristics that correlate with severity of colitis:

• Physical examination

Fever (core body temperature > 38.5°C)

Rigors (uncontrollable shaking and a feeling of cold followed by a rise in body temperature)

Hemodynamic instability including signs of distributive shock

Respiratory failure requiring mechanical ventilation

Signs and symptoms of peritonitis

Signs and symptoms of colonic ileus

• Laboratory investigations

Marked leukocytosis (leukocyte count > 15,000 cells/mL)

Marked left shift (band neutrophils > 20% of leukocytes)

Rise in serum creatinine (> 50% above the baseline)

Elevated serum lactate (≥ 5 mmol/L)

Markedly reduced serum albumin (< 3 mg/dl)

• Colonoscopy or sigmoidoscopy

Pseudomembranous colitis

• Imaging

Distention of large intestine (> 6 cm in transverse width of colon)

Colonic wall thickening including low-attenuation mural thickening

Pericolonic fat stranding

Ascites not explained by other causes

American College of Gastroenterology (ACG)

Classification of disease severity:

• Mild disease

Diarrhea as the only symptom

• Moderate disease

Diarrhea but without additional symptoms/signs meeting the definition of severe or complicated disease

• Severe disease

Hypoalbuminemia (serum albumin < 3 g/dl) AND

WBC ≥ 15,000 cells/mL OR abdominal tenderness without criteria of complicated disease

• Complicated disease

Any of the following attributable to C. difficile infection:

Admission to intensive care unit

Hypotension with or without required use of vasopressors

Fever ≥ 38.5°C

Ileus (acute nausea, emesis, sudden cessation of diarrhea, significant abdominal distention, or radiological signs consistent with disturbed intestinal transit)

Mental status changes

WBC ≥ 35,000 cells/mL or < 2,000 cells/mL

Serum lactate levels > 2.2 mmol/l

Any evidence of end organ failure

• Recurrent disease

Recurrence within 8 weeks of completion of therapy

Risk Factors

The most important risk factor remains antibiotic use. Other established risk factors include:

• Advanced age
• Chemotherapy
• Chronic kidney disease
• Consumption of processed meat
• Contact with active carriers
• Cystic fibrosis
• Diabetes mellitus
• Hypoalbuminemia
• Immunosuppression, immunodeficiency, or human immunodeficiency virus
• Increased risk with prolonged use or multiple antibiotics
• Inflammatory bowel disease
• Liver cirrhosis
• Malignancy
• Malnutrition
• Nursing home or long-term care facility residence
• Presence of comorbid conditions
• Presence of gastrostomy or jejunostomy tube
• Previous gastrointestinal surgery or endoscopic procedure
• Previous hospitalization and prolonged length of hospital stay
• Solid organ or hematopoietic stem cell transplantation
• Use of proton pump inhibitors

Use of the following antibiotics has been associated with C. difficile infection:

• Very common

Clindamycin

Ampicillin

Amoxicillin

Cephalosporins

Fluoroquinolones

• Somewhat common

Penicillins

Sulfonamides

Trimethoprim

Trimethoprim-Sulfamethoxazole

Macrolides

• Uncommon

Aminoglycosides

Bacitracin

Metronidazole

Teicoplanin

Rifampin

Chloramphenicol

Tetracyclines

Carbapenems

Daptomycin

Tigecycline

Complete Diagnostic Approach

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; DC, differential count; EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; NAAT, nucleic acid amplification test; PCR, polymerase chain reaction; SMA-7, sequential multiple analysis-7.

Clostridium difficile Infection Diarrhea (passage of 3 or more unformed stools in ≤ 24 hours) with microbiological evidence of C. difficile Colonoscopic or histopathological findings demonstrating pseudomembranous colitis
Focused History Characterize the symptoms: Abdominal discomfort Poor appetite Diarrhea Nausea Vomiting Bloating Belching Flatulence Constipation or obstipation Other relevant history: Risk factors (details) Comorbidities Recent sick contacts Recent hospitalizations Prior use of antibiotics Immunosuppressive state Travel history
Physical Examination Vital signs (body temperature, pulse rate, respiration rate, blood pressure) Signs of ileus (distended and tympanic abdomen with tenderness, hypoactive bowel sounds) Signs of peritonitis (rebound tenderness, abdominal guarding, hypoactive bowel sounds) Signs of dehydration (delayed capillary refill, decreased skin turgor, abnormal respiratory pattern) Signs of respiratory distress (tachypnea, tachycardia, abnormal breath sounds) Signs of multiple organ failure (cold and clammy skin, tissue hypoperfusion)
Laboratory Workup and Imaging Study Complete blood count with differential Basic metabolic panel including urea nitrogen and creatinine AST, ALT, bilirubin, alkaline phosphatase, albumin, lactate Consider abdominal CT scan or colonoscopy in severe disease or concurrent inflammatory bowel disease
Other Investigation Positive results of either EIA or NAAT should prompt treatment. GDH (high sensitivity, low specificity): screening test EIA for toxins (low sensitivity, high specificity): confirmatory test NAAT (high sensitivity, high specificity): standard diagnostic test

Management

Asymptomatic carrier

• No treatment indicated

Mild disease

• Predisposing antibiotic cessation
• Hydration
• Monitoring of clinical status
• Administration of metronidazole (500 mg three times per day)
  OR

Close outpatient monitoring without the administration of antibiotics

Moderate disease

• Consideration of hospitalization
• Cessation of predisposing antibiotics
• Hydration
• Monitoring of clinical status
• Administration of metronidazole (500 mg three times per day)
  OR

Administration of vancomycin (125 mg orally four times per day for 14 days)

Severe disease

• Hospitalization
• Oral or nasogastric vancomycin (500 mg four times per day) with or without intravenous metronidazole (500 mg three times per day)
  OR

Oral fidaxomicin (200 mg twice a day for 10 days) if the risk of recurrence is high

Complicated disease

• Antibiotics as for severe infection
• Surgical consultation for subtotal colectomy or a diverting ileostomy with vancomycin colonic lavage
• Consideration of fecal microbial transplantation or additional antibiotics

First recurrence

• Oral vancomycin (125 mg four times per day for 14 days)
  OR

Oral fidaxomicin (200 mg twice a day for 10 days)

Second or further recurrence

• Vancomycin in a tapered and pulsed regimen
  OR
• Fecal microbial transplantation
  OR
• Fidaxomicin (200 mg twice a day for 10 days)

Dos and Don'ts

Dos

• Inform the laboratory when testing for Clostridium difficile from formed stools in a patient with ileus.
• Initiate empiric antibiotics regardless of the laboratory results when there is a high index of suspicion for C. difficile infection.
• Vancomycin should be delivered via enema to treat patients in whom oral antibiotics cannot reach a segment of the colon as in Hartmann's pouch, ileostomy, or colonic diversion.
• Test for C. difficile among patients with diarrhea in the context of malignancy, chemotherapy, immunosuppressive therapy, organ transplantation, cirrhosis, inflammatory bowel disease, or pregnancy.

Don'ts

• Do NOT test for C. difficile in a patient without diarrhea.
• Do NOT repeat test if the results are negative.
• Do NOT perform test of microbiological cure.
• Do NOT treat asymptomatic carriage.
• Do NOT administer antiperistaltic agents to patients with suspected or confirmed C. difficile infection.

Guidelines

Infectious Disease Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)

• Strategies to Prevent Clostridium difficile Infections in Acute Care Hospitals (2014)
• Clinical Practice Guidelines for Clostridium difficile Infection in Adults (2010)

American College of Gastroenterology (ACG)

• Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections (2013)

Association for Professionals in Infection Control and Epidemiology (APIC)

• Preventing Clostridium difficile infections (2011)

Eastern Association for the Surgery of Trauma (EAST)

• Timing and type of surgical treatment of Clostridium difficile-associated disease (2014)

American Society of Colon and Rectal Surgeons (ASCRS)

• Practice Parameters for the Management of Clostridium difficile Infection (2015)

European Society of Clinical Microbiology and Infectious Diseases (ESCMID)

• Update of the Treatment Guidance Document for Clostridium difficile Infection (2014)

American Academy of Pediatrics (AAP)

• Policy Statement: Clostridium difficile Infection in Infants and Children (2013)

References