Etiology

C. difficile causes a spectrum of enteric complications of antibiotic use ranging from nuisance diarrhea to severe and sometimes life-threatening pseudomembranous colitis. There are occasional cases of antibiotic-associated colitis due to other pathogens (Staphylococcus aureus, Klebsiella oxytoca, enterotoxin-producing strains of Clostridium perfringens or Salmonella), but most cases are either due to C. difficile or are enigmatic.²

Pathophysiology

There are six relevant issues:

1 Colonization with C. difficile: this organism is found in the colonic flora of 2% to 3% of healthy adults and 20% to 30% of hospitalized patients.³

2 Toxin production: C. difficile produces two toxins, designated toxin A and toxin B.⁵ Early studies implicated toxin A as the major cause of enteric toxin based on animal studies that showed florid colitis with injection of toxin A into bowel loops, but more recent studies establish that toxin B is critical for clinical expression.⁵ Most strains of C. difficile produce both toxins, but about 1% to 2% produce only toxin B.⁶

3 Antibiotic exposure: this is the most important identifiable risk and presumably reflects the impact of the inducing agent on the colonic flora, establishing the opportunity for C. difficile to convert from the spore form to the vegetative form, with replication and toxin production. Virtually every antibiotic with an antibacterial spectrum has been implicated, but the most frequent are clindamycin and broad-spectrum cephalosporins. In current practice, fluoroquinolones account for the majority of cases, presumably reflecting their enormous usage rates.⁴ Particularly important in recent years is the NAP-1 strain which is associated with fluoroquinolone use (see 5 below).

4 Epidemiology: C. difficile is relatively infrequent in ambulatory persons, but rates of colonization and disease are much higher as a result of exposure to the hospital environment.³ C. difficile now represents an important and potentially lethal nosocomial pathogen. Nursing homes are another setting in which there is clustering of vulnerable patients with high rates of antibiotic use where C. difficile may be endemic or epidemic.⁶ In the period 2001-2006, the NAP-1 strain emerged as an important epidemic agent of C. difficile in Canada, the United States, and Europe.^4,⁶ This strain appears to be particularly virulent, with increased toxin production, mortality, treatment failure, and relapses.

5 Age: there is increasing susceptibility to the development of C. difficile colitis with age, possibly due to immunosenescence.

6 Immunologic susceptibility: many patients harbor toxigenic strains of C. difficile, with no clinical expression despite extensive antibiotic exposure. One reason for this paradox is the apparent immune protection due to the presence of neutralizing antibody to toxins A and B. This observation accounts for the increasing interest in monoclonal antibodies to toxins A and B for treatment and vaccines for prevention.⁷

Clinical Signs and Symptoms

The typical presentation of Clostridium difficile infection (CDI) is watery diarrhea associated with cramps.² Other common features are fecal leukocytes, endoscopy showing PMC or colitis, characteristic changes on computed tomography (CT) (thickened bowel restricted to the colon, often associated with ascites), fever, hypoalbuminemia, and leukocytosis, sometimes with a leukemoid reaction. Nearly all cases of CDI are associated with diarrhea, but occasional postoperative patients will not have this owing to ileus. The laboratory clue that best predicts this diagnosis and its severity is the white blood cell (WBC) count. The average is about 15,000 cells/mL, but it may be much higher with counts over 20,000 or even 50,000 cells/mL. This strongly supports the CDI diagnosis and predicts severe disease.⁸

Diagnosis

The diagnosis is based on detection of the C. difficile (culture, EIA for glutamine dehydrogenase or polymerase chain reaction [PCR] for toxigenic C. difficile) or its toxins, designated toxin A and toxin B (enzyme immunoassay [EIA] for toxins A + B, or cytotoxin assay). Relative merits are shown in Table 146-1.

TABLE 146-1 Diagnostic Tests for Clostridium difficile Infection

Treatment

Most important to treatment of CDI is discontinuing the implicated antibiotic. If there is a need for antibiotic treatment, select a drug that is unlikely to cause CDI (narrow-spectrum β-lactams, macrolides, aminoglycosides, antistaphylococcal drugs, tetracyclines; Table 146-2). The two favored drugs for treatment of CDI are metronidazole and vancomycin, both given by mouth.^1,^6,⁷ Metronidazole is often preferred because it is less expensive. Earlier studies showed it to work as well as vancomycin, but more recent trials show oral vancomycin is superior to metronidazole in seriously ill patients,⁸ defined as having a WBC over 15,000 cells/mL or elevated creatinine to 1.5 × baseline.⁶ Other markers of serious disease are albumin less than 2 mg/dL, admission to the ICU for CDI, pseudomembranous colitis (PMC) on endoscopy, or pancolitis on CT scan.⁹ Vancomycin is superior to metronidazole owing to pharmacology.⁸ All C. difficile are in the colon, so the challenge is getting an active drug to the colonic lumen. Vancomycin is not absorbed, so it all goes to the colon when given orally; metronidazole given orally is nearly completely absorbed, so it gets to the colon primarily through an inflamed colonic mucosa. Most patients improve with resolution of diarrhea in 3 to 5 days.^1,⁷ Patients who are seriously ill (megacolon, septic shock, WBC >30,000/mL, lactate >5) and fail to respond to standard treatment should be considered for colectomy.⁹ The major indications are failure to respond to standard medical management and colonic perforation.

TABLE 146-2 Treatment of Clostridium difficile Infection

Category	Characteristics	Treatment Recommendations
Mild-moderate	WBC ≤ 15,000/mL and creatinine < 1.5 × baseline	Metronidazole 500 mg PO 3×/d × 10-14 days
Severe	WBC > 15,000/mL or creatinine > 1.5 × baseline	Vancomycin, 125 mg 4×/d PO × 10-12 days
Severe and complicated	Hypotension, shock, ileus or megacolon	Vancomycin, 500 mg PO 4×/d by NG tube or by rectum, plus Metronidazole 500 mg IV q 8 h
First relapse Second relapse		As above Vancomycin, standard dose, then taper and/or pulse

PO, per os (orally); NG, nasogastric; WBC, white blood cell.

Adapted from Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG 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;31:431-55.

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