Clostridium difficile-associated disease

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Etiology/Bacteriology

Taxonomy

Domain: Bacteria
Phylum: Firmicutes
Class: Clostridia
Order: Clostridiales
Family: Clostridiaceae
Genus: Clostridium
Species: Clostridium difficile

NCBI Taxonomy link: http://www.ncbi.nlm.nih.gov/genome/?term=clostridium+difficile

Description

Clostridium difficile causes pseudomembranous colitis, toxic megacolon, perforations of the colon, sepsis, and (rarely) death. It is a Gram positive, spore-forming rod that is an obligate anaerobe. It can be found in soil, water, feces, and the human gut. C. difficile is a normal inhabitant of the gut microbial community of about 1-3% of adults. The pathogenic form of C. difficile is transferred via the fecal-oral route as well as through spore dispersal. Clostridium difficile-associated disease (CDAD) was initially reported about 30 years ago and the CDC first recorded infections from a hyper-virulent strain in 2000 along with a marked increase in the number of CDAD infections. C. difficile causes disease by producing the toxins TcdA and TcdB that function to disrupt protein synthesis within the host cell. The toxins are responsible for producing symptoms such as watery diarrhea, fever, loss of appetite, nausea, and severe abdominal pain (1). Although C. difficile only causes about 20% of antibiotic associated colitis, standard treatments fail in about 25% of CDAD cases. Patients treated promptly typically recover. However, CDAD is notorious for recurrence after initial antibiotic treatment. 33% of patients with an infection will have a recurrence with 64% of those being within 30 days of the initial infection (2). Complications typically develop in about 11% of patients in the first recurrence. This likely promotes the growth of antibiotic resistant strains that are able to perform horizontal gene transfer between recurrences. In about 20% of patients the infection will resolve itself in 2-3 of discontinuing the inciting antibiotic. Most infections that persist are treated with a 10-14 day course of antibiotics like metronidazole, vancomycin, and rehydration therapy. In more serious cases fecal transplants and surgery can be performed (3). Patients at risk for developing CDAD include those taking antibiotics (especially broad spectrum), those taking proton pump inhibitors, GI manipulation or surgery, long term stays in hospital or clinical settings, immunocompromising conditions, and old age. The best practices for preventing infection include judicious administration of antibiotics, quarantine, hand hygiene, and the use of EPA-registered disinfectants with a sporicide (especially hypochlorite based disinfectants).

Pathogenesis

Transmission

Clostridium difficile is shed in feces, and therefore transmitted by the fecal-oral route. The spores can survive on almost any surface for months to years, making the pathogen very difficult to get rid of once established.

Infectious dose, incubation, and colonization

Because it is an opportunistic pathogen, the infectious dose and incubation period is unknown and widely debated. Exposure to broad spectrum antibiotics prior to infection is crucial to the pathogenesis, as C. difficile has a difficult time colonizing on its own, but it can be found as part of the normal gut microbiota of approximately 2-3% of the population.

Clinical features

Colonization of the intestine by Clostridium difficile can occur without symptoms, but infection causes symptoms ranging from trivial diarrhea to serious manifestations of disease. General symptoms of CDAD include watery diarrhea, fever, loss of appetite, nausea, and abdominal pain/tenderness, but grossly bloody stools are unusual. Signs of more advanced disease include pseudomembranous colitis, toxic megacolon (also known as colonic distention), perforations of the colon, sepsis, and sometimes death.

One of the most well recognized manifestations of the disease, pseudomembranous colitis was first described in 1893 and is the formation of lesions within the colon that are made of a pseudomembrane of immune cells, mucus, and necrotic tissue (4). For 20% of patients with advanced CDAD: diarrhea and fluid loss are minimal, and instead, abdominal distention and bowel obstruction can lead to misdiagnosis. For other patients, signs of systemic toxicity and systemic inflammatory syndrome, including leukocytosis, rising serum lactate levels, hypotension, acute renal failure, and respiratory distress, lead to poor prognosis and high mortality rates. Fulminant colitis can lead to the need for a total colectomy, but even with this procedure, the average mortality rate at this stage of the disease is 67%, and the progression from inital symptoms to this stage can occur in as little as hours to as much as weeks.

Treatment

Non-severe cases

For non-severe cases, the first step in treatment is the cessation of the inciting antibiotic as soon as possible and only continuing concomitant antibiotics if they are prudent to the treatment of the initial infection. Oral metronidazole or vancomycin are typically administered. However, some literature points to vancomycin having increased efficacy over metronidazole (4).

Moderate to severe cases

Antibiotics:
For more severe cases higher, more frequent doses of vancomycin (either oral or rectal) are administered. However, rectal doses have a higher risk of producing colonic perforations and should only be administered when oral preparations are impossible for the patient.
Fecal Transplantation:
Another method of treatment is the infusion of a purified stool substitute preparation from a healthy donor. Generally, fecal transplantation is used in cases where the patient has had multiple recurrent infection and both metronidazole and vancomycin fail. It is reasonably successful in repopulating the gut with commensal bacteria and combating antibiotic resistant CDAD (5).
Probiotics:
Antibiotics function to alter the intestinal flora in order to produce and unfavorable environment for C. difficile. Some Lactobacilli and in particular S. boulardii have been shown to suppress C. difficile growth in hamsters. Furthermore, temporarily populating the gut with particular Lactobacilli can lower the pH of the surrounding environment and secrete degradation enzymes like proteases that place stress on the C. difficile population. Finally, some strains of beneficial bacteria may have the ability to protect the intestinal barrier by interfering TcdA and TcdB binding to the host gut epithelium (6).
Immunomodulation:
New research suggests that the supplementation of laboratory-derived monoclonal antibodies may have the ability to inhibit C. difficile colonization by stimulating toll-like receptors and upregulating expression of dendritic cells and peripheral blood monocytes (7).
Surgery:
Some severely ill patients with CDAD may require surgical intervention as a result of toxic megacolon, colonic perforations, necrotizing colitis, or infections producing systemic inflammatory responses that could potentially lead to organ failure. In these cases, diseased portions of the gastrointestinal tract are removed.

References

Created by Laura Boucher, Marrett Hild, and Lillian Flannigan, students of Tyrrell Conway at the University of Oklahoma