Definition: CDAD is a unique colon infection acquired almost exclusively in association with antimicrobial use and the consequent disruption of the normal colonic flora. It is the most commonly Dx diarrheal illness acquired in the hospital, resulting from ingestion of spores of C. difficile that vegetate, multiply, and secrete toxins, causing diarrhea and pseudomembranous colitis (PMC).
Etiology and Epidemiology: It is an obligate anaerobic, GPB with spores found widely in nature, particularly in hospitals and chronic-care facilities. Occurs most common in hospitals and NH where the level of antimicrobial use is high and the environment is contaminated by C. difficile spores.
Clindamycin, ampicillin, and cephalosporins were the first ABx associated with CDAD.
2G, 3G cephalosporins: cefotaxime, ceftriaxone, cefuroxime, and ceftazidime, are frequently responsible for this condition.
FQ: ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin are recent drug class implicated in hospital outbreaks.
PCN/beta-lactamase-inhibitor combinations such as ticarcillin/clavulanate and piperacillin/tazobactam pose significantly less risk.
However, all ABx, including vancomycin and metronidazole (agents used to tx CDAD), have been found to carry a risk of subsequent CDAD.
Rare cases are reported in patients without prior ABx exposure.
C. difficile acquistion increases in proportion to length of hospital stay. It is acquired exogenously, most frequently in the hospital and is carried in the stool of sx and Asx Pts. Rate of colonization is often >20% among adult Pts hospitalized for >1 week; in contrast, the rate is 1-3% among community residents.
Risk Factors:
Hands of hospital personnel - who fail to practice good hand hygiene
Older age
Severity of underlying illness
GI surgery
Use of rectal thermometers
Enteral tube feeding
Antacid Tx. Use of PPI may be a risk factor.
Clinical features:
Diarrhea, non-bloody, soft to watery or mucoid in consistency, with a characteristic odor. Pts may have as many as 20 BM a day.
Fever, abdominal pain in 20 - 30% cases and leukocytosis in 50%
Adynamic ileus in ~20% cases can be deceive by cessation of stool passage, leading to misdiagnoses. Look for leukocytois in such case, usually >15,000 cell/uL. Watch for toxic megacolon and sepsis.
C. difficile diarrhea may recur following Tx in ~15-30% of cases. May occur due to relapses due to the same strain or reinfections with a new strain.
Recurrence of clinical CDAD is likely to be a result of continued disruption of the normal fecal flora by ABx used to Tx CDAD.
Dx: made by detection of C. difficile toxin in stool or by C-scopic visualization of pseudomembranes.
The Dx of CDAD is based on a combination of clinical criteria:
Diarrhea >3 or more unformed stools per 24 h for >2 or more days, with no other recognized cause; plus
Toxin A or B detected in stool, toxin-producing C. difficile detected by stool culture, or pseudomembranes seen in colon. PMC is a more advanced from of CDAD and is visualized at endoscopy in only ~50% of patients with diarrhea who have positive stool culture and toxin assay for C. difficile.
No single test for C. difficile has high sensitivity, high specificity, and rapid turn around. However, if cell cultures are examined q4h, the cell cytotoxicity test can be shortened to <24 h. However, observation for 48 h is required for a conclusive test result.
Stool culture for C. difficile: sensitivity >90%, specificity 71-90% (>90% if C. difficile isolate tests +ve for toxin; with clinical data, is dxtic of CDAD.
Cell culture cytotoxin test on stool: sensitivity: 71-90%, specificity: >90%
Enzyme immunoassay for toxin A or toxins A and B in stool: sensitivity: 51-90%; specificity: 71-90%
Enzyme immunoassay for C. difficile common antigen in stool: sensitivity: >90%, specificity: 71-90%
Colonoscopy or simoidoscopy: sensitivity: 50%, specificity: >90%. Highly specific if pseudomembranes are seen.
Tests for cure following treatment is not recommended because many patients continue to harbor the organism and toxin after diarrhea has ceased and test result do not always predict recurrence of CDAD. Thus these results should not be used to restrict placement of patients in long-term care or nursing home facilities.
DDx: Diarrhea directly due to ABx use without C. difficile infection should be first considered, which will resolve with withdrawal of the ABx.
Tx:
Primary CDAD:
Stop any ongoing ABx
IVF hydration
Avoidance of antiperistaltic agents and opiates which may mask symptoms and possibly worsen disease. However, antiperistaltic agents have been used safely with vancomycin or metronidazole for mild to moderate CDAD.
Empiric treatment of CDAD is strongly suspected on clinical grounds.
Mild episodes: Metronidazole, 500 mg PO (preferred over IV) tid for 10 days - 14 days, and d/c of offending ABx, if possible.
Vancomycin, 125 - 500 mg PO qid x 10 days (IV is not effective), is superior for severe disease or debilitated patients, but is otherwise reserved for refractory disease. Intracolonic vancomycin is sometimes used in severe cases in which gut motility is altered and surgical intervention is imminent.
Endpoint of therapy is cessation of diarrhea: do not retest stool for toxin clearance. Avoid antimotility agents in severe disease.
Treatment is not deemed a failure until the drug is been given for at least 6 days.
Monitor for decrease in fever, abdominal pain, diarrhea, leucocytosis. If leucocytosis >15,000/uL, persists in mild to moderately ill patients, switch to vancomycin 125 mg PO qid, especially if Pt. appears seriously ill.
Nitazoxanide (antiparasitic) 500 mg PO bid x 10 days is as effective as metronidazole, although not approved by FDA for this indication. It is a potential alternative to vancomycin and metronidazole.
Recurrent CDAD:
Recurrence is common (15-30%) either as relapses caused by the original organism or as a reinfection following Tx.
Recurrence is high in Pts >65 yrs old, and patients who stay in the hospital after the initial episode of CDAD. In the first recurrence, re-treatment with metronidazole is comparable to treatment with vancomycin.
Recurrent disease carries higher mortality and morbidity (shock, megacolon, perforation, colectomy, or death within 30 days).
There is no standard treatment for multiple recurrences, but long or repeated metronidazole courses should be avoided because of the potential neurotoxicity.
Approached not approved by FDA: Vancomycin, f/up with yeast Sacchromyces boulardii; vanco f/up with synthetic fecal bacterial enema; and intentional colonization of the patient with nontoxigenic strain of C. difficile.
Other strategies: vanco in tapering doses or pulse dosing qod for 4-6 wks
Vancomycin 125 mg PO qid, f/up with rifaximin 400 mg PO bid x 14 days, IV immunoglobulin, also has been used with some success, presumably provides antibodies to C. difficile toxins.
Second recurrence (33-65%) is high in patients who have had a first recurrence.
Fulminant CDAD: Difficult to treat. Often mimics acute surgical abdomen, and do not have diarrhea. Sepsis, hypotension, fever, tachycardia, leukocytosis may result from severe CDAD. CT with colon wall thickening. Toxic megacolon, acute abdomen, sepsis should include CDAD in DDx, if the patient has received ABx in past 2 months. Cautions sigmoidoscopy or colonscopy to visualize PMC and an abdominal CT examination are the best diagnostic tests in patients without diarrhea. Medical management of CDAD is suboptimal because of the difficulty of delivery metronidazole or vancomycin to the colon by the oral route in presence of ileus. Vancomycin (via NGT and by retention enema) plus IV metronidazole have been used in uncontrolled studies with some success, but surgical colectomy may be life saving, if there is not response to medical management.
Toxin A - enterotoxin, toxin B - cytotoxin, and binary toxin CDT (~6% strains), related to C. perfingens iota toxin. CDT role in the pathogenesis of CDAD has not yet been defined. High level of FQ resistance.
Pts colonized with C. difficle have decreased risk of subsequent CDAD.
Pathogenesis model for hospital-acquired CDAD:
Exposure to ABx
Exposure to nontoxigenic or toxigenic strains of C. difficle
Asx colonization or CDAD, depending on one or more additional events, including an inadequate host anamnestic IgG response to C. difficle toxin A.
Prognosis:
Mortality rate from CDAD is 6.9% in recent outbreaks and is progressively higher with increasing age. Most Pts. recover but recurrences are common.
Prevention and Control:
Prevention of transmission of the organism to the patient
Handwashing is recommended over alcohol gel, as the gel is not sporicidal.
Gloving of personnel.
Elimination of contaminated electronic thermometers
Use of hypochlorite (bleach) solution for environmental decontamination of patient's rooms.
Reducing the risk of CDAD if the organism is transmitted:
Restrict use of specific ABx, such as clindamycin, and second- and third-generation cephalosporins. Outbreaks of CDAD due to clindamycin-resistant strains have resolved promptly when clindamycin use was restricted.