Clostridium difficile

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Clostridium difficile (Greek kloster (κλωστήρ), spindle, and Latin difficile,[1] difficult), also known as "CDF/cdf", or "C. diff", is a species of Gram-positive bacteria of the genus Clostridium. Clostridia are anaerobic, spore-forming rods (bacillus).[2] C. difficile is the most serious cause of antibiotic-associated diarrhea (AAD) and can lead to pseudomembranous colitis, a severe infection of the colon, often resulting from eradication of the normal gut flora by antibiotics.[3] The C. difficile bacteria, which naturally reside in the body, become overpopulated: The overpopulation is harmful because the bacterium releases toxins that can cause bloating, constipation, and diarrhea with abdominal pain, which may become severe. Latent symptoms often mimic some flu-like symptoms. Discontinuation of causative antibiotic treatment is often curative.[2] In more serious cases, oral administration of metronidazole or vancomycin is the treatment of choice. Relapses of C. difficile AAD have been reported in up to 20% of cases.[2]
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[edit] Bacteriology
Individual, drumstick-shaped C. difficile bacilli seen through scanning electron microscopy.
Clostridia are motile bacteria that are ubiquitous in nature and are especially prevalent in soil. Under the microscope, clostridia appear as long, irregularly (often "drumstick" or "spindle") shaped cells with a bulge at their terminal ends. Under Gram staining, Clostridium difficile cells are Gram-positive and show optimum growth on blood agar at human body temperatures in the absence of oxygen. When stressed, the bacteria produce spores, which tolerate extreme conditions that the active bacteria cannot tolerate.[2]
C. difficile is a commensal bacterium of the human intestine in 2-5% of the population.[2] Long-term hospitalization or residence in a nursing home within the previous year are independent risk factors for increased colonization.[4] In small numbers, C. difficile does not result in significant disease. Antibiotics, especially those with a broad spectrum of activity, cause disruption of normal intestinal flora, leading to an overgrowth of C. difficile, which flourishes under these conditions. This can lead to pseudomembranous colitis (PMC), the generalized inflammation of the colon and the development of pseudomembrane, a viscous collection of inflammatory cells, fibrin, and necrotic cells.[2] Pathogenic C. difficile strains produce several known toxins. The most well-characterized are enterotoxin (toxin A) and cytotoxin (toxin B), both of which are responsible for the diarrhea and inflammation seen in infected patients, although their relative contributions have been debated.[2] Toxins A and B are glucosyltransferases that target and inactivate the Rho family of GTPases. Another toxin, binary toxin, has also been described, but its role in disease is not yet fully understood.[5]
Antibiotic treatment of C. difficile infections can be difficult, due both to antibiotic resistance as well as physiological factors of the bacteria itself (spore formation, protective effects of the pseudomembrane).[2] C. difficile is transmitted from person to person by the fecal-oral route. Because the organism forms heat-resistant spores, it can remain in the hospital or nursing home environment for long periods of time. It can be cultured from almost any surface in the hospital. Once spores are ingested, they pass through the stomach unscathed because of their acid-resistance. They change to their active form in the colon and multiply. Pseudomembranous colitis caused by C. difficile is treated with specific antibiotics, for example, vancomycin, metronidazole, bacitracin or fusidic acid.
Several disinfectants commonly used in hospitals may be ineffective against C. difficile spores, and may actually promote spore formation. However, disinfectants containing bleach are effective in killing the organisms.[6]
Initially named bacillus difficilis by Hall and O'Toole in 1935 because it was resistant to early attempts at isolation and grew very slowly in culture, it was renamed in 1970.[7]
[edit] Role in disease

With the introduction of broad-spectrum antibiotics and chemotherapeutic antineoplastic drugs[citation needed] in the latter half of the twentieth century, antibiotic (and chemotherapy) associated diarrhea became more common. Pseudomembranous colitis was first described as a complication of C. difficile infection in 1978,[8] when a toxin was isolated from patients suffering from pseudomembranous colitis and Koch's postulates were met.
C. difficile infection (CDI) can range in severity from asymptomatic to severe and life-threatening, especially among the elderly. People are most often nosocomially infected in hospitals, nursing homes, or institutions, although C. difficile infection in the community, outpatient setting is increasing. The rate of C. difficile acquisition is estimated to be 13% in patients with hospital stays of up to 2 weeks, and 50% in those with hospital stays longer than 4 weeks.[citation needed] C. difficile-associated diarrhea (aka CDAD) is most strongly associated with fluoroquinolones. Fluoroquinolones are more strongly associated with C difficile infections than other antibiotics including clindamycin, 3rd generation cephalosporins and beta-lactamase inhibitors. One study found that fluoroquinolones were responsible for 55% of C difficile infections.[9] The European Center for Disease Prevention and Control recommend that fluoroquinolones and the antibiotic clindamycin be avoided in clinical practice due to their high association with clostridium difficile.[10] Frequency and severity of C. difficile colitis remains high and seems to be associated with increased death rates.[citation needed] Immunocompromised status and delayed diagnosis appear to result in elevated risk of death. Early intervention and aggressive management are key factors to recovery.
Increasing rates of community-acquired C. difficile-associated infection/disease have also been linked to the use of medication to suppress gastric acid production: H2-receptor antagonists increased the risk twofold, and proton pump inhibitors threefold, mainly in the elderly. It is presumed that increased gastric pH, (alkalinity), leads to decreased destruction of spores.[11]
The emergence of a new, highly toxic strain of C. difficile, resistant to fluoroquinolone antibiotics, such as Cipro (ciprofloxacin) and Levaquin (levofloxacin), said to be causing geographically dispersed outbreaks in North America was reported in 2005.[12] The Centers for Disease Control in Atlanta has also warned of the emergence of an epidemic strain with increased virulence, antibiotic resistance, or both.[13]

[edit] Diagnosis
[edit] Symptoms and signs
In adults, a clinical prediction rule found the best signs to be: significant diarrhea ("new onset of > 3 partially formed or watery stools per 24 hour period"); recent antibiotic exposure; colitis (abdominal pain); and foul stool odour. The presence of any one of these findings has a sensitivity of 86% and a specificity of 45%.[14] In this study of hospitalized patients with a prevalence of positive cytotoxin assays of 14%, the positive predictive value was 20% and the negative predictive value was 95%.
[edit] Cytotoxicity assay
C. difficile toxins have a cytopathic effect in cell culture, and neutralized with specific anti-sera is the practical gold standard for studies investigating new CDAD diagnostic techniques.[2] Toxigenic culture, in which organisms are cultured on selective medium and tested for toxin production, remains the gold standard and is the most sensitive and specific test, although it is slow and labour-intensive.[15]
[edit] Toxin ELISA
Assessment of the A and B toxins by enzyme-linked immunoabsorbant assay (ELISA) for toxin A or B (or both) has a sensitivity of 63–99% and a specificity of 93–100%: at a prevalence of 15%, this leads to a positive predictive value (PPV) of 73% and a negative predictive value (NPV) of 96%.
Experts recommend sending as many as three samples to rule-out disease if initial tests are negative. C. difficile toxin should clear from the stool of previously infected patients if treatment is effective. However, many hospitals test only for the prevalent toxin A. Strains that express only the B toxin are now present in many hospitals, and ordering both toxins should occur.[16] Not testing for both may contribute to a delay in obtaining laboratory results, which is often the cause of prolonged illness and poor outcomes.
[edit] Other stool tests
Stool leukocyte measurements and stool lactoferrin levels have also been proposed as diagnostic tests, but may have limited diagnostic accuracy.[17]
[edit] Computed tomography
In a recent study, a patient who received a diagnosis of CDC on the basis of computed tomography (CT scan) had an 88% probability of testing positive on stool assay.[18] Wall thickening is the key CT finding in this disease. Once colon wall thickening is identified as being >4 mm, the best ancillary findings were pericolonic stranding, ascites, and colon wall nodularity. The presence of wall thickness plus any one of these ancillary findings is 70% sensitive and 93% specific.
Using criteria of ≥10 mm or a wall thickness of >4 mm and any of the more-specific findings does not add significantly to the diagnosis but gives equally satisfactory results. In this study with a prevalence of positive C. difficile toxin of 54%, the PPV was 88%. Patients who have antibiotic-associated diarrhea who have CT findings diagnostic of CDC merit consideration for treatment on that basis. A weakness of this study was the lack of comparison with the accepted cytotoxicity assay.

[edit] Treatment
Asymptomatic colonization with C. difficile is common. Treatment in asymptomatic patients is controversial, also leading into the debate of clinical surveillance and how it intersects with public health policy. Mild cases generally do not require specific treatment.[2][19]
Patients should be treated as soon as possible when the diagnosis of Clostridium difficile colitis (CDC) is made to avoid frank sepsis or bowel perforation. To reduce complications, physicians often begin treatment based on clinical presentation before definitive results are available. Knowledge of the local epidemiology of intestinal flora of a particular institution can guide therapy.

[edit] Pharmacotherapy
Three antibiotics are specifically effective against C. difficile in vivo :
Metronidazole (400-500 mg orally three times daily 10-14 days[20]) is the drug of choice, because of lower price and comparable efficacy.[21]
Oral vancomycin (125 mg four times daily) is second-line therapy, but is often avoided due to concerns of converting intestinal flora into vancomycin-resistant organisms.[22][23] Vancomycin is the treatment of choice in the following cases: no response to oral metronidazole; the organism is resistant to metronidazole; the patient is allergic to metronidazole; the patient is either pregnant or younger than 10 years of age. Vancomycin must be administered orally because IV administration does not achieve gut lumen minimum therapeutic concentration.
A more recent study by Zar and others[24] showed no difference between vancomycin and metronidazole in mild disease, but that vancomycin was superior to metronidazole for treating severe disease. In this study, severe disease was defined on a point score: One point each was given for age >60 years, temperature >38.3°C, albumin level <2.5>15,000 cells/mm3 within 48 h of enrollment. Two points were given for endoscopic evidence of pseudomembranous colitis or treatment in the intensive care unit. Severe disease was defined as 2 or more points on this score. The main criticism of this study is that a low, non-standard dose of metronidazole (250 mg) was used instead of (500 mg).
The use of linezolid may be considered, too.
Newer drugs such as ramoplanin and fidaxomicin are in clinical development.
Drugs traditionally used to stop diarrhea frequently worsen the course of C. difficile-related pseudomembranous colitis. Loperamide, diphenoxylate and bismuth compounds are contraindicated: slowing of fecal transit time is thought to result in extended toxin-associated damage. Cholestyramine, a powder drink occasionally used to lower cholesterol, is effective in binding both Toxin A and B, and slows bowel motility and helps prevent dehydration.[25] The dosage can be 4 grams daily, to up to four doses a day: Caution should be exercised to prevent constipation, or drug interactions, most notably the binding of drugs by cholestyramine, preventing their absorption. Powdered banana flakes given twice daily is an alternative to cholestyramine and allow for stool bulking. Treatment with probiotics ("good" intestinal flora) has also been shown effective.[26] Provision of Saccharomyces boulardii (Florastor) or Lactobacillus acidophilus twice daily times 30 days along with antibiotics has been clinically shown to shorten the duration of diarrhoea. A last-resort treatment in immunosuppressed patients is intravenous immunoglobulin (IVIG).[25]
[edit] Colectomy
In those patients that develop systemic symptoms of CDC, colectomy may improve the outcome if performed before the need for vasopressors.
[edit] Fecal bacteriotherapy
Fecal bacteriotherapy, a procedure related to probiotic research, has been suggested as a potential cure for the disease. It involves infusion of bacterial flora acquired from the feces of a healthy donor in an attempt to reverse bacterial imbalance responsible for the recurring nature of the infection. It has a success rate of nearly 95% according to some sources.[27][28][29]

[edit] Recurrence
The evolution of protocols for patients with recurrent C. difficile diarrhea also present a challenge: There is no known proper length of time or universally accepted alternative drugs with which one should be treated. However, re-treatment with metronidazole or vancomycin at the previous dose for 10 to 14 days is generally successful. The addition of rifampin to vancomycin also has been effective. Prophylaxis with competing, nonpathogenic organisms such as Lactobacillus spp. or Saccharomyces boulardii has been found to be helpful in preventing relapse in small numbers of patients (see, for example, Florastor, or Lactinex). It is thought that these organisms, also known as probiotics, help to restore the natural flora in the gut and make patients more resistant to colonization by C. difficile.[26]

[edit] Prevention
The most effective method for preventing CDAD is proper antimicrobial prescribing. In the hospital setting, where CDAD is most common, nearly all patients that develop CDAD are exposed to antimicrobials. Although proper antimicrobial prescribing sounds easy to do, approximately 50% of antimicrobial use is considered inappropriate. This is consistent whether in the hospital, clinic, community, or academic setting. Several studies have demonstrated a decrease in CDAD by limiting antibiotics most strongly associated with CDAD or by limiting unnecessary antimicrobial prescribing in general, both in outbreak and non-outbreak settings. The testing of all hospital inpatients over the age of 65 with diarrhea for CDiff became a compulsory NHS practice in January 2008, when it became evident that many outbreaks were being disguised as Norovirus in the UK, by hospital Risk Managers, who can be sacked by the Department of Health if CDiff infection rates are too high, but cannot be dismissed as a result of a Norovirus outbreak.[citation needed] Patients most at risk are those with a prescription medicine history of broad-range antibiotics such as penicillins, and proton pump inhibitor drugs like omeprazole.
Infection control measures, such as wearing gloves when caring for patients with CDAD, have been proven to be effective at prevention. This works by limiting the spread of C. difficile in the hospital setting. In addition, washing with soap and water will eliminate the spores from contaminated hands, but alcohol-based hand rubs are ineffective.[30]
Treatment with various oral supplements containing live bacteria has been studied in efforts to prevent Clostridium difficile-associated infection/disease. A randomized controlled trial using a probiotic drink containing Lactobacillus casei, L bulgaricus, and Streptococcus thermophilus was reported to have some efficacy. This study was sponsored by the company that produces the drink studied.[31] Although intriguing, several other studies have been unable to demonstrate any benefit of oral supplements of similar bacteria at preventing CDAD.[citation needed] Of note, patients on the antibiotics most strongly associated with CDAD were excluded from this study.
In a limited clinical trial, a C. difficile anti-toxoid vaccine was reported to improve patient outcomes. Further testing will be required to validate this trial.[32]