Clostridia Difficile Diarrhea

Clostridia difficile is a gram positive, spore forming anaerobic bacilli1 Infection occurs when the organism is ingested. Though initially thought of as a nosocomial infection, community acquired clostridia difficile infection is increasingly recognized.2 Clostridia Difficile produces a variety of toxins, toxin A (enterotoxin) and B (cytotoxin) are the toxins most frequently linked to disease. They cause inflammation and disrupt cell cytoskeleton synthesis leading to colonic cell disruption.3,4,5 A new strain, termed NAP1 or BI or 027 (depending on the technique used to identify it) was identified in the early 2000s the cause of selected outbreaks. This strain of clostridia difficile is associated with clinically more severe disease, innate resistance to quinolones and higher amounts of toxin production.6


Introduction
The term antibiotic associated diarrhea is usually reserved for diarrhea caused by infection with the organism Clostridia Difficile.Infection is thought to take place after the normal intestinal flora is altered by antibiotic use allowing for proliferation of Clostridia Difficile.Worryingly, the incidence and severity of illness caused by Clostridia Difficile is on the increase.

Pathophysiology
Clostridia difficile is a gram positive, spore forming anaerobic bacilli 1 Infection occurs when the organism is ingested.Though initially thought of as a nosocomial infection, community acquired clostridia difficile infection is increasingly recognized. 2 Clostridia Difficile produces a variety of toxins, toxin A (enterotoxin) and B (cytotoxin) are the toxins most frequently linked to disease.They cause inflammation and disrupt cell cytoskeleton synthesis leading to colonic cell disruption. 3,4,5A new strain, termed NAP1 or BI or 027 (depending on the technique used to identify it) was identified in the early 2000s the cause of selected outbreaks.This strain of clostridia difficile is associated with clinically more severe disease, innate resistance to quinolones and higher amounts of toxin production. 6

Epidemiology
Clostridia difficile infection was linked to the development of pseudomembranous colitis in the 70's. 7Initial cases were mostly linked to clindamycin but since then the range antibiotics linked with development of Clostridia Difficile has widened and cephalosporins and floroquinolones are thought to be the major causes. 8hough less often thought of as a cause of diarrhea in developing countries, pathogenic C. Difficile has been noted in South Africa 9 and India. 10he incidence rate of C. Difficile infection in the US was about 30 to 40 cases per hundred thousand. 11ne research group noted an increasing rate of colectomies following C. Difficile infection. 12anadian authors noted a four fold increase in background prevalence of C. Difficile between when the period before 2002 was compared to 2003. 13

Clinical presentation
Presentation may range from asymptomatic carrier state 14 to fulminant colitis. 15ymptomatic patients typically present with watery diarrhea and lower abdominal pain. 16evere diarrhea with leucocytosis, fever, abdominal pain and distention occurs in the severely ill 16,17 .Surgical management with colectomy may be required in severe cases 18 .C. Difficile colitis was increasingly listed as the cause of death in an English population. 19ises in white cell count to above 30,000 or a doubling of serum creatinine have been suggested as harbingers complicated disease. 20

Diagnosis
C. Difficile diagnosis is usually done with laboratory testing in a patient suspected to be having the infection.One of the most sensitive and specific tests available is the cell cytotoxycity assay, which had a sensitivity of 98% and specificity of 99% when compared to clinical and laboratory criteria. 21This test is unfortunately technically demanding and may not be the first choice of many laboratories.Many laboratories will use EIAs for detection of toxin A and B. These tests are insensitive when compared to cell culture or cytotoxicity assay but they are cheaper and produce results in hours rather than days. 22Due to the lower positive predictive value of these tests a 2 step approach with a sensitive screening test followed by confirmation by culture or cell cytotoxicity may be appropriate. 23esting for glutamate dehydrogenase, an enzyme produced by C. Difficile is sensitive (96 to 100%) 24 , cheap, and rapid but it only detects presence of organism rather than toxin production.Though its usually unnecessary, direct visualization of colitis by endoscopy is virtually diagnostic as they are few other infections that would cause pseudomembrane formation. 25ndoscopy carries the risk of perforation in fulminant colitis.

Treatment
First line therapy for C. Difficile infection has long been considered to be a choice between metronidazole or vancomycin.Resolution of disease was seen in over 90% of patients taking a 10 day course of either therapy. 26ore recently, metronidazole has been associated with therapeutic failure rates as high as 50 percent if persistence of disease and recurrence are conbined. 27That said, oral metronidazole at a dose of 500mg, three times daily for ten to fourteen days remains the initial recommended therapy for mild disease. 28Oral or rectal vancomycin (500mg four times a day) is recommended for more severe disease. 28Patients who cannot tolerate oral therapy may be treated with intravenous metronidazole. 29p to 25% of patients may have recurrent infection 16 believed to occur because of germination of spores or ingestion of new spores.Many approaches have been taken to recurrent symptomatic C Difficile infection.A tapered or pulsed course of oral vancomycin may reduce recurrence rates 30 .
Other approaches include fecal transplants 31 , immunization against C difficile toxins 32 , cholestyramine 33 , rifampin 34 or probiotics 35 .There isn't sufficient data to recommend any of these approaches.Recently fidaxomicin (200 mg oral, twice daily for ten days), a macrolide antibiotic, was shown to be non inferior to vancomycin. 36During the trial referenced, patients were noted to have a lower recurrence rate when they were treated using fidaxomicin rather than vancomycin (13.3% vs. 24.0%)

Prevention
Judicious use of antibiotics has been shown to reduce the rates of C. difficile infection. 37,38 shing hands with soap and water, using gloves when touching patients and use of disposable thermometers have been recommended as control measures with good quality evidence of efficacy. 39Alcohol hand washing gels are not effective in preventing disease spread. 40