CLOSTRIDIUM DIFFICILE INFECTION

Darren S. Bryan, MD • James R. Yon, MD

 BASICS

DESCRIPTION

•  A gram-positive, spore-forming anaerobic bacillus that releases toxins to produce clinical disease

•  Infection caused by Clostridium difficile is frequently associated with antibiotic use, hospitalization, and age.

•  Severity of infection can range from diarrhea to pancolitis, perforation, and death.

•  System(s) affected: gastrointestinal

•  Synonyms(s): C. difficile–associated disease or diarrhea (CDAD); C. difficile colitis; C. difficile

EPIDEMIOLOGY

Incidence

•  C. difficile infection is among the most common hospital-acquired infections. The incidence is rising (1).

•  There are ~15 new cases per 1,000 clinical discharges. Higher with increased age (2)

•  Rates of complications are also increasing (1).

Prevalence

•  C. difficile causes ∼25% of all cases of antibiotic-associated diarrhea.

•  Prevalence of community-acquired C. difficile infection is increasing. Up to 40% of patients require hospitalization (2).

•  C. difficile is a commensurate organism in 2–5% of the adult U.S. population.

ETIOLOGY AND PATHOPHYSIOLOGY

•  C. difficile are motile bacteria existing in vegetative and spore forms. Spores can survive for months in harsh conditions and outside of the body.

•  Spread by fecal–oral contact. Acid-resistant spores pass through stomach to reside predominantly in the colon.

•  Colonic colonization causes disruptions in barrier functions of the normal microbiome (2).

•  C. difficile is noninvasive. Toxins mediate disease:

–  Toxins A (enterotoxin) and B (cytotoxin) attract neutrophils and monocytes, degrading colonic epithelial cells and causing clinical disease.

•  BI/NAP1/027 strain of C. difficile has been shown to produce a much more virulent form of disease, with increased endotoxin concentrations. It is associated with increased rates of colectomy and death.

Genetics

No known genetic factors

RISK FACTORS

•  Host risk factors

–  Age >65 years

–  Hospitalization or stay in long-term health care facility. The length of stay is directly correlated with the risk for C. difficile infection.

–  Comorbidities, including inflammatory bowel disease, immunosuppression, tube feeding, chronic liver disease, and end-stage renal disease

–  Previous C. difficile infection

•  Factors that disrupt normal colonic microbiota:

–  Exposure to many antibiotics (including perioperative prophylaxis) is associated with an increased risk for C. difficile infection.

–  Most commonly implicated antibiotics include: ampicillin, amoxicillin, clindamycin, cephalosporins, and fluoroquinolones

•  Recurrence from prior infection

–  Recurrence rates approximately 20% after initial episode. Recurrence more likely with each additional episode (2)

•  Can colonize ileum in patients with prior colectomy

•  Community-acquired C. difficile infections (no overnight admission in >12 weeks) are more frequent in patients without other risk factors (younger, no recent antibiotic exposure).

Geriatric Considerations

C. difficile is the most common cause of acute diarrheal illness in long-term care facilities. Elderly patients also commonly have multiple other risk factors (comorbid disease, antibiotic exposure, medication use).

Pediatric Considerations

•  Neonates have a higher rate of C. difficile colonization (25–80%) but are generally less symptomatic than adults (possibly due to immature toxin receptors).

•  Frequently serve as carrier for infection in adults

GENERAL PREVENTION

•  A comprehensive infection control program decreases the incidence of C. difficile infection.

•  2010 Society for Healthcare Epidemiology of America (SHEA)/Infectious Diseases Society of America (IDSA) guidelines:

–  For health care workers, patients, and visitors:

  Contact precautions, including gloves and gowns, on entry to room

  Alcohol-based hand sanitizers not effective. Hand hygiene with soap and water before and after patient interaction

  Accommodate patients with C. difficile infection in private rooms, if possible.

–  Environmental cleaning and disinfection

  Disinfection with hypochlorite solution or other spore-killing solutions

  Identification and reduction of environmental sources of C. difficile, including the use of nondisposable rectal thermometers

–  Antimicrobial use restrictions

  Minimize the frequency and duration of antibiotic therapy. Use particular care when prescribing commonly implicated antibiotics.

COMMONLY ASSOCIATED CONDITIONS

Pseudomembranous colitis, toxic megacolon, sepsis, colonic perforation

 DIAGNOSIS

HISTORY

•  Age and underlying comorbidities

•  Recent antibiotic use

•  Diarrhea (defined as >3 stools in 24 hours) that is watery, foul-smelling, and sometimes bloody (1)

•  Fever (<10%), anorexia, nausea

•  Recent hospitalization or stay at nursing facility

PHYSICAL EXAM

Physical exam findings range from mild abdominal pain to peritonitis and shock:

•  Mild or moderate disease: mild (cramping) lower abdominal pain

•  Severe disease: fever, nausea/vomiting, dehydration

•  Severe, complicated disease: shock, peritonitis, ileus

DIFFERENTIAL DIAGNOSIS

•  Antibiotic-associated diarrhea

•  Inflammatory bowel disease

•  Enteric infections

•  Foodborne illness

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

•  Polymerase chain reaction (PCR)-based testing is preferred for identification of C. difficile. Rapid, highly sensitive, and highly specific (2)[B]

•  Alternative to PCR: screening and confirmatory testing. C. difficile common antigen tests: tests for glutamate dehydrogenase (GDH), found in both toxic and nontoxic strains of C. difficile (sensitivity, 85–95%; specificity, 89–99%)

•  Confirmatory: enzyme immunoassay for toxins (A/B or A); rapid results, inexpensive, easy to use (sensitivity 63–94%)

•  Stool culture is the most sensitive test; however, non–toxin-producing strains are also detected.

•  Repeat testing during the same episode of diarrhea is not recommended. Stool carriage persists for 3 to 6 weeks after successful treatment (2)[A].

•  Routine radiologic examination is not recommended in the absence of signs of systemic disease or clinical suspicion for complicated/severe disease

•  Plain films may show thumbprinting and colonic distension.

•  CT may show mucosal thickening, colonic wall thickening, pericolonic inflammation, or signs of complicated infection in severe cases (i.e., extra-luminal air).

Diagnostic Procedures/Other

•  Endoscopy can evaluate for presence of pseudomembranes and exclude other conditions.

–  While not all patients with C. difficile infection have pseudomembranes, their presence is pathognomonic for C. difficile.

•  Flexible sigmoidoscopy may miss 15–20% of pseudomembranes (present in the proximal colon).

•  Colonoscopy evaluates the entire colon: Use when diagnosis is in doubt or severity demands rapid diagnosis.

Test Interpretation

SHEA/IDSA guidelines (2)

•  Mild or moderate disease: leukocytosis with white blood cell (WBC) count <15,000 cells/μL and a serum creatinine level <1.5× the premorbid level

•  Severe, uncomplicated disease: leukocytosis with WBC count >15,000 cells/μL or a serum creatinine level >1.5× the premorbid level

•  Severe, complicated disease: hypotension, sepsis, markedly elevated WBC count, and imaging findings of complicated disease

 TREATMENT

GENERAL MEASURES

•  Antimotility agents are contraindicated.

•  Avoid indiscriminate use of antibiotics.

•  Proton pump inhibitors associated with recurrent infection but have not been shown to be causal

•  Discontinue offending antibiotic, if possible.

MEDICATION

First Line

•  Mild or moderate infection (3)[A]

–  Oral metronidazole is the drug of choice for mild to moderate C. difficile infection:

  500 mg PO three times daily for 10 to 14 days

  If patient is unable to take oral medications, then intravenous (IV) metronidazole or intraluminal (oral) vancomycin can be used.

•  Severe infection (3)[A]

–  Enteral vancomycin is first-line therapy in patients with severe or fulminant C. difficile infection:

  125 mg PO four times daily for 10 to 14 days

  Vancomycin retention enema if unable to take PO or if there is evidence of poor gastrointestinal motility

•  Severe, complicated infection—consider surgical and critical care consultation (3)[A]

–  Vancomycin: 500 mg PO four times daily and metronidazole 500 mg PO three times daily. Consider vancomycin retention enemas.

•  First recurrence

–  Treat the same as first episode.

•  Second recurrence

–  Vancomycin taper and/or pulse: vancomycin 125 mg PO QID for 10 to 14 days, then 125 mg PO BID for 7 days, then 125 mg PO once daily for 7 days, then 125 mg PO every 2 to 3 days for 2 to 8 weeks:

  Pulse dosing every 2 to 3 days allows spores to germinate and then be killed.

ALERT

When using vancomycin for treatment of C. difficile infection, oral or rectal formulations must be used. IV formulations are not excreted into the colonic lumen.

Second Line

•  Vancomycin: indicated for patients who cannot tolerate or have failed metronidazole therapy and for those who are pregnant

•  Fidaxomicin 200 mg PO BID. Similar cure rates to vancomycin with lower recurrence rates, however, potentially cost prohibitive

•  Fidaxomicin bactericidal against C. difficile. Fidaxomicin has a narrow antimicrobial spectrum and helps preserve normal anaerobic flora. Should be considered in recurrent disease

•  Fecal transplant: stool from healthy, screened donor. Administered via either rectal or oral route. Highly effective treatment for recurrent infections (80–90% cure rate) when offending antibiotic stopped. Recipient gut flora transformed in as few as 3 days following fecal transplantation (4)[A].

SURGERY/OTHER PROCEDURES

•  Most patients improve with conservative management and oral antibiotics.

•  Patients with severe fulminant colitis develop paralytic ileus, leading to distention (megacolon) and potential perforation.

•  Severe abdominal pain or signs of hemodynamic instability in the setting of known infection should prompt surgical and critical care consultation.

ALERT

BI/NAP1/027 strain associated with fulminant colitis, often requiring surgical intervention. More common in younger patients with severe disease

COMPLEMENTARY & ALTERNATIVE MEDICINE

•  Adjunctive therapy with intravenous immunoglobulin (IVIG) has shown promise, but more data are required before routine clinical use.

•  Probiotics have an (strain-specific) inhibitory effect on C. difficile and may play a role in prevention.

•  Other investigational treatment options:

–  New antibiotics (Rifalazil, Tolevamer, and Ramoplanin)

–  Monoclonal antibodies to modulate toxin effects

–  Vaccine form of C. difficile antitoxin antibody

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

•  Admission criteria/initial stabilization

–  Hypovolemia

–  Inability to keep up with enteric losses

–  Hematochezia

–  Electrolyte disturbances

•  IV fluids to maintain volume status

•  Discharge criteria

–  Decreased diarrhea severity and frequency

–  Tolerating oral diet and medications

–  Do not repeat testing for toxins, as they may shed for weeks following an acute infection.

 ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Many patients can be treated as outpatients.

Patient Monitoring

•  Relapses of colitis occur in 15–30%.

•  Relapses typically occur 2 to 10 days after discontinuing antibiotics.

DIET

Regular diet. NPO if severe and surgical evaluation required

PATIENT EDUCATION

Educate patients about C. difficile transmission, the importance of hand washing, and the appropriate use of antibiotics.

ALERT

Alcohol-based hand sanitizers are not effective against C. difficile. Wash with soap and water.

PROGNOSIS

•  Most patients improve with conservative management and oral antibiotics.

•  1–3% of patients develop severe/fulminant colitis requiring emergency colectomy.

REFERENCES

1.  Khanna S, Pardi DS. Clostridium difficile infection: management strategies for a difficult disease. Therap Adv Gastroenterol. 2014;7(2):72–86.

2.  Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015;372(16):1539–1548.

3.  Debast SB, Bauer MP, Kuijper EJ; for the European Society of Clinical Microbiology and Infectious Diseases. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014;20(Suppl 2):1–26.

4.  Shankar V, Hamilton MJ, Khoruts A, et al. Species and genus level resolution analysis of gut microbiota in Clostridium difficile patients following fecal microbiota transplantation. Microbiome. 2014;2:13.

ADDITIONAL READING

•  Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431–455.

•  Kassam Z, Lee CH, Yuan Y, et al. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108(4):500–508.

•  McCollum DL, Rodriguez JM. Detection, treatment, and prevention of Clostridium difficile infection. Clin Gastroenterol Hepatol. 2012;10(6):581–592.

 CODES

ICD10

A04.7 Enterocolitis due to Clostridium difficile

CLINICAL PEARLS

•  C. difficile is spread by fecal–oral contact.

•  Alcohol-based hand sanitizers are ineffective against C. difficile. Wash hands with soap and water.

•  Testing and treatment of asymptomatic patients is not recommended.

•  PCR is the preferred initial test for diagnosis.

•  Patients may shed organism or toxin for weeks after treatment. Repeat toxin assays following treatment are not helpful.

•  Metronidazole remains the drug of choice for mild to moderate disease.