Clostridium difficile, also known as "CDF/cdf", or "C. diff", is a species of Gram-positive bacteria of the genus Clostridium that causes severe diarrhea and other intestinal disease when competing bacteria in the gut flora have been wiped out by antibiotics. Clostridia are anaerobic, spore-forming rods. C. difficile is the most serious cause of antibiotic-associated diarrhea (AAD) and can lead to pseudomembranous colitis, a severe inflammation of the colon, often resulting from eradication of the normal gut flora by antibiotics. In a very small percentage of the adult population, C. difficile bacteria naturally reside in the gut. Other people accidentally ingest spores of the bacteria while they are patients in a hospital, nursing home, or similar facility. When the bacteria are in a colon in which the normal gut flora has been destroyed (usually after a broad-spectrum antibiotic such as clindamycin has been used), the gut becomes overrun with C. difficile. This overpopulation is harmful because the bacteria release toxins that can cause bloating and diarrhea, with abdominal pain, which may become severe. C. difficile infections are the most common cause of pseudomembranous colitis, and in rare cases this can progress to toxic megacolon, which can be life-threatening. Latent symptoms of C. difficile infection often mimic some flu-like symptoms and can mimic disease flare in patients with inflammatory bowel disease-associated colitis.[4] Mild cases of C. difficile infection can often be cured by discontinuing the antibiotics responsible.[2] In more serious cases, oral administration of, first, oral metronidazole and - if that fails - then, second, vancomycin and if unsuccessful again, intravenous metronidazole can be used. Relapses of C. difficile AAD have been reported in up to 20% of cases. With the introduction of broad-spectrum antibiotics and chemotherapeutic antineoplastic drugs[citation needed] in the second 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,[6] when a toxin was isolated from patients suffering from pseudomembranous colitis and Koch's postulates were met. The many spores formed by C. difficile are resistant to most routine cleaning methods that are used on surfaces (except for diluted bleach).[citation needed] Spores of these bacteria can remain viable outside of the human body for very long periods of time, and this means that patients in a medical facility are often exposed to situations where they end up accidentally ingesting spores.[citation needed] Extremely rigorous infection protocols are required in order to decrease or eliminate this risk.[7] 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 other medical 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.[8] 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] In addition to previous use of antimicrobials, use of proton pump inhibitors [PPIs] is associated with a 2-fold increase in risk for C. difficile infection.[10] 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 subsequent Clostridium difficile infections.[11] 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 infection are associated with the use of medication that suppress gastric acid production: H2-receptor antagonists increased the risk 1.5 fold, and proton pump inhibitors by 1.7 with once daily use and 2.4 with more than once daily use.[12] The emergence of a new, highly toxic strain of C. difficile, resistant to fluoroquinolone antibiotics, such as ciprofloxacin (Cipro) and levofloxacin (Levaquin), said to be causing geographically dispersed outbreaks in North America was reported in 2005.[13] The Centers for Disease Control in Atlanta has also warned of the emergence of an epidemic strain with increased virulence, antibiotic resistance, or both.[14] In 2005, molecular analysis led to the identification of the C. difficile strain type that was characterized as group BI by restriction endo nuclease analysis (REA), as North American pulse-field-type NAP1 by pulse-field gel electrophoresis (PFGE) and as ribotype 027; the differing terminology reflects the predominant techniques that were used for epidemiological typing and this strain is referred to as C. difficile BI/NAP1/027.[15] Some recent research suggests that the overuse of antibiotics in the raising of livestock for meat consumption is contributing to outbreaks of bacterial infections such as C. difficile. 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.[21] Assessment of the A and B toxins by enzyme-linked immunosorbent 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%.[citation needed] Previously, experts recommended sending as many as three stool samples to rule out disease if initial tests are negative. However, recent evidence suggests that repeat testing during the same episode of diarrhea is of limited value and should be discouraged.[22]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.[23][24] Not testing for both may contribute to a delay in obtaining laboratory results, which is often the cause of prolonged illness and poor outcomes. Stool leukocyte measurements and stool lactoferrin levels have also been proposed as diagnostic tests, but may have limited diagnostic accuracy.[25] In a recent study, a patient who received a diagnosis of Clostridium difficile colitis (CDC) on the basis of computed tomography (CT scan) had an 88% probability of testing positive on stool assay.[26] 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 with CT findings diagnostic of CDC merit consideration for treatment on that basis. By the end of 2009, 3 different Real-Time PCR tests had achieved 510(k) clearance from the FDA.[citation needed] Cepheid's GeneXpert is by far the fastest and easiest of the three, but it is also the most expensive. Cepheid uses a cartridge-based kit that is tailored for small hospitals or labs without the ability to batch large numbers of samples together. In fact, batching is not required since the extraction occurs in the same vial as amplification of the target, positive, and negative controls. The reported time from sample to result is ~45 minutes. Prodesse offers another kit-based IVD Real-Time PCR test (ProGastro Cd), which uses an external extraction and purification on the Roche MagnaPure. Prodesse (Gen-Probe) tech support claims that this external separation produces higher yields than the BD GeneOhm. The Prodesse technique is similar in price to the BD GeneOhm technique after one includes the price of the extraction and takes about three hours from sample to result. The final IVD Clostridium difficile Real Time PCR test on the market since 2009 is from BD GeneOhm. The protocol uses a glass-bead lysis rather than an extraction, but results are reported to be good and the method shaves a little over an hour off the protocol time (about 1 hour 45 minutes from sample to result). Total costs for the Prodesse and BD GeneOhm tests are approximately the same. For each test, sensitivities are generally reported as 88-91% and specificities as 96-97%, depending on the tests, prevalence of the disease and the size of the patient pool.[
Antibiotics
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[citation needed] 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. There is some evidence that probiotics may be useful to prevent infection and recurrence. C diff infected mice treated with viable Streptococcus salivarius subsp. thermophilus exhibited 46% less weight loss compared with untreated controls. Less pathology, diarrhea, and lower detectable toxin levels were noted in cecal contents of the mice as as well.[28] Treatment with S boulardii in non-immunocompromised patients with C Diff may also be useful.[29] [30] In 2010 the Infectious Diseases Society of America recommended against their use due to the risk of complications. [29] However, more recent publications have suggested the use of probiotics for the management of infectious bacterial diseases like C diff.[31] In Britain, the testing of all hospital inpatients over the age of 65 with diarrhea for C. difficile became a compulsory NHS practice in January 2008, when it became evident that many UK outbreaks were being disguised as Norovirus by hospital risk managers. Risk managers can be dismissed by the Department of Health if C. difficile infection rates are too high, but they cannot be dismissed as a result of a Norovirus outbreak.[citation needed] Patients most at risk are those with recent broad-spectrum antibiotic or proton-pump inhibitor treatments. 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.[32] Bleach wipes containing 0.55 percent sodium hypochlorite have been shown to kill the spores and prevent transmission between patients.[33] Hydrogen peroxide vapor (HPV) systems used to sterilize a patient room post discharge has been shown to reduce infection rates and to reduce risk of infection to subsequent patients. One study (Boyce et al. 2008) showed that incidence of CDAD was reduced by 53% though use of HPV. A second study (Manian et al. 2010) showed a 42% reduction in CDAD rates through use of HPV. In a limited clinical trial, a C. difficile anti-toxoid vaccine was reported to improve peoples outcomes. Further testing will be required to validate this trial. 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. In general, mild cases do not require specific treatment.[2][35] 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. In addition, oral rehydration therapy (ORT) is useful in retaining fluids during the duration of diarrhea. Three antibiotics are specifically effective against C. difficile. With the available agents more or less equally effective.[36]
Metronidazole is the drug of choice, because of lower price and comparable efficacy.[29] Oral vancomycin is second line for mild to moderate cases and is recommended first line for severe disease.[29] 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, breastfeeding, or younger than 10 years of age. Vancomycin must be administered orally because intravenous administration does not achieve gut lumen minimum therapeutic concentration. Patients unresponsive to Metronidazole can be placed on 14 days of Vancomycin followed by Rifaximin for another 14 days. A more recent study by Zar and others[37] 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 mg/dL, or peripheral WBC count >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). Fidaxomicin has been found to be equally effective as vancomycin[38] A study[39] showed that the enduring treatment success of Fidaxomicin is better than the previous medication. Its tolerability is as good as vancomycin.[40] Drugs 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 (an ion exchange resin), which is occasionally used to lower cholesterol, is effective in binding both Toxin A and B, slowing bowel motility and helping prevent dehydration.[41] The dosage can be 4 grams daily, to up to four doses a day; however caution should be exercised to prevent constipation, or drug interactions, most notably the binding of drugs by cholestyramine, preventing their absorption. Cholestyramine is not an anti-infective; it dramatically reduces many of the symptoms of a C. difficile infection, but it is not appropriate to use by itself, as it does not change the infection status. Cholestyramine is usually used in concert with vancomycin. Powdered banana flakes given twice daily are an alternative to cholestyramine, and allow for stool bulking. There is insufficient evidence to support the use of probiotics in the treatment of active disease.[42][29] and thus in this situation they are neither recommended as an adjunct to standard therapy or for use alone.[43] However, S Boulardii in conjunction with standard antibiotics or high dose vancomycin has been studied to reduce rates of relapses and recurrence without notable side effect in non-immunocompromised patients. [44][45]
A last-resort treatment in immunosuppressed patients is intravenous immunoglobulin (IVIG).[41] Fecal bacteriotherapy, known in colloquial terms as stool transplant, a procedure related to probiotic research, has preliminarily been shown to cure the disease. It involves infusion of bacterial flora acquired from the feces of a healthy donor to reverse the bacterial imbalance responsible for the recurring nature of the infection. In fecal transplantation, donor stool is collected from a close relative who has been tested for a wide array of bacterial, viral, and parasitic pathogens. The stool is often mixed with saline or milk to achieve the desired consistency, then delivered through a colonoscope or retention enema, or through a nasogastric or nasoduodenal tube. The procedure replaces normal, healthy colonic flora that had been wiped out by antibiotics, and reestablishes the patient's resistance to colonization by Clostridium difficile. However, there is often patient resistance due to the perceived unpleasantness of the procedure that must be overcome first before proceeding with this often-effective treatment. There are currently over 150 published reports dating back to 1958, though many more have been performed. It has a success rate of about 90%.[46][47][48][49] A guide was released in 2010 for home fecal transplantation.[50] In those patients that develop systemic symptoms of CDC, colectomy may improve the outcome if performed before the need for vasopressors. 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.