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C. difficile

C. difficile infection (cdi)Clostridium difficile infection

Clostridium difficile infection (CDI) is one of the most common hospital-acquired infections (HAI) and the most common cause of diarrhea associated with antibiotic use. CDI (also called C. difficile-associated diarrhea, or CDAD), ranges in severity from uncomplicated diarrhea to severe colitis and life-threatening toxic megacolon. Clostridium difficile (C. difficile or C. diff.) is an anaerobic, gram positive, rod-shaped bacteria that have the capacity to form spores that are resistant to heat and most disinfectants, which makes it difficult to eliminate them from the environment and this contributes to their transmission to humans. Clostridia also have a propensity to produce various toxins that play a major role in the pathogenesis of the diseases that they cause.

C. difficile can be found in the intestine of up to 5% of individuals. Prolonged hospitalization and residence in a long-term care facility increase the likelihood of both colonization as well as the generation of CDI. Broad-spectrum antibiotic usage and other conditions that alter the normal composition of intestinal flora also predispose to the acquisition and overgrowth of C. difficile and to the development of CDI. A vigorous infection control program is essential for hospitals to decrease the incidence of CDI.

Only toxigenic strains of C.difficile cause CDI. Toxigenic strains carry a genetic element in their genomes called the pathogenic locus which encodes a number of genes and other genetic elements that contribute to the development of CDI. The most important genes encode the two toxins, A and B, that are primarily responsible for the intestinal pathology of CDI. Non-toxigenic strains of C. difficile can colonize the intestine, but do not cause disease.

Diagnosis

Accurate diagnosis of C. difficile is essential for physicians to properly manage patients with antibiotic-associated diarrhea and for hospitals to effectively identify and control outbreaks of CDI. C. difficile testing should only be performed on at-risk patients with diarrhea as evidenced by multiple loose stools.

There are many diagnostic methods available to laboratories detect toxigenic C. difficile in the stool of patients suspected of having CDI. Traditionally most tests focused on the detection of C difficile toxins A and B. Cytotoxicity in cell culture that is neutralized by antitoxin-containing antisera (CCNA) is considered the reference method for toxin B detection. Stool culture for C difficile with confirmation of toxin production (toxigenic culture) is considered the gold standard for definitive identification of CDI, but it is generally impractical for clinical diagnosis due to the length of time before a result is generated. Immunoassays for the detection of toxin A and B have been a commonly-used method because of their rapid turn-around time and ease-of-use. All of these toxin immunoassays, however, have been associated with relatively low sensitivity. To address this issue some manufacturers have added immunoassays for the detection of glutamate dehydrogenase (GDH) to their products. GDH is present in all strains of C. difficile, but is not specifically associated with toxigenic strains and as such lacks specificity and so additional testing must be done to confirm the presence of toxigenic C.difficile.

The need for improved accuracy has promoted the development of molecular assays for the detection of pathogenic C. difficile in diarrheal stool samples. These assays are based on DNA amplification techniques that detect various conserved regions of the pathogenicity locus present in all known toxigenic C. difficile strains. Molecular tests generally all have high sensitivity and specificity when compared to toxigenic culture and high percent positive and negative agreement when compared to each other. Many of the molecular tests are based on real-time PCR and are relatively complex and/or expensive. More recently, some FDA-cleared tests that are based on isothermal DNA amplification technologies, such as loop-mediated amplification (LAMP) and helicase-dependent amplification (HDA), have been developed. These tests are less complex and less expensive because they do not require a thermocycler or fluorescent reader. These new isothermal molecular tests offer laboratories that currently are using toxin immunoassays the benefit of the high level of accuracy of a molecular test without having to incur the significantly higher costs associated with complex instruments and a highly trained molecular staff.

Treatment

Proper management of CDI involves supportive care including replenishment of fluid and electrolytes lost due to the diarrhea. The inciting antibiotics should be discontinued unless that is not possible due a severe infection. Patients with mild-to-moderate CDI should be treated with metronidazole 500 mg orally three times per day for 10 days. Patients with severe CDI should be treated with vancomycin 125 mg four times daily for 10 days. Fidaxomicin is a newer antibiotic is available for use in some circumstances. A surgical consult should be obtained in all patients with complicated CDI and surgical therapy should be considered for patients who are deteriorating. Some patients develop recurrent CDI and following treatment may require alternative prophylactic therapies such as probiotics and fecal transplantation to prevent further recurrence.

Recommended Reading

http://www.cdc.gov/HAI/organisms/cdiff/Cdiff_infect.html

Cohen, S.H. et al. Infection Control and Hospital Epidemiology, May 2010, vol. 31, no. 5

Shannon-Lowe, et al. British Medical Journal 2010;340:c1296 doi: 10.1136/bmj.c1296

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