Current Treatment Options in Gastroenterology DOI 10.1007/s11938-014-0038-3

Colon (C Burke, Section Editor)

Clostridium Difficile Infection: Risk Factors, Diagnosis and Management Christina M. Surawicz, MD Address Department of Medicine, Division of Gastroenterology, University of Washington, 325 9th Ave.Box 359773, Seattle, WA 98104, USA Email: [email protected]

* Springer Science+Business Media, LLC 2015

This article is part of the Topical Collection on Colon Keywords Fecal microbiota transplant I Antibiotic associated diarrhea I Vancomycin I Metronidazole I Fidaxomicin I Recurrent C. difficile infection I Clostridium difficile infection

Opinion statement Clostridium difficile infection (CDI) is the leading cause of death due to gastrointestinal infections in the US and is the most common cause of nosocomial diarrhea. The emergence of a hypervirulent strain in the early 2000s has been associated with a dramatic increase in the number and severity of cases in the US, Canada, and several other countries. Most cases are related to antibiotic use, but sporadic cases occur in otherwise healthy individuals with no risk factors. Morbidity and mortality are highest in the elderly. Diagnosis is confirmed by detection of C. difficile toxin in the stools. Treatment should be stratified by severity of disease, with metronidazole use for mild disease cases and vancomycin for severe disease. Recurrent CDI occurs in 10-20 % of cases. A first recurrence can be treated with a ten-day regimen of metronidazole or vancomycin; a second recurrence is best treated by a pulsed regimen of vancomycin. In patients with multiple (three or more) recurrences, fecal microbiota transplant has a high rate of success. The most important methods of prevention are wise antibiotic policies, hand hygiene, isolation, and barrier methods in hospital and long-term care facilities (LCTF) settings.

Introduction Research and interest in C. difficile infection (CDI) have ramatically increased in the last 15 years, in part due to a marked increase in numbers and severity of cases in the US, Canada, and Europe. Moreover, research on the intestinal microbiome has also exploded. As C. difficile is a classic example of a disease that is due to an altered

microbiota, there is synergy in the research in these two areas. CDI now leads as the cause of death due to gastrointestinal infection in the US and is the most common cause of nosocomial diarrhea. As CDI is common in hospitals and long-term care facilities (LTCF), many

Colon (C Burke, Section Editor) patients have extended hospital stays, and the financial cost to the health care system is substantial; recently estimated to have increased fourfold for patients compared to matched hospitalized patients and to cost the US more than $1 billion per year [1]. C. difficile is a gram-positive, spore-forming bacterium that produces two toxins, A and B, that cause disease. The spread is fecal-oral. The emergence of a hypervirulent strain (Nap I/B1/027) has led to epidemics with high mortality in many hospitals in the US, Canada, and Europe [2]. This

strain produces 16 times more Toxin A and 23 times more Toxin B in vitro and has a high rate of fluroquinolone resistance [3]. It is postulated that these characteristics have contributed to the epidemics and disease severity. The spectrum of disease ranges from mild diarrhea to severe colitis with pseudomembranes (pseudomembranous colitis) that can lead to death. This paper will review risk factors, diagnosis, and management and include recommendations from recent guidelines [4••, 5, 6••].

Risk factors Rates of CDI have been increasing since the year 2000, with the highest rates in the elderly, in whom the disease is more likely to be fatal. While rates have been highest in hospitals and LTCF, recently there are more cases in outpatients and even in healthy individuals with no risk factors. The major risk factors for acquiring CDI are antibiotic exposure, severe underlying disease, older age, and immune suppression. The antibiotics associated with the highest risk of CDI are clindamycin, cephalosporins, and fluroquinolones. In a recent meta-analysis, clindamycin and third-generation cephalosporins continue to be the highest risk antibiotics [7]. Fluoroquinolones continue to be an important risk factor for the Nap I/B1/027 fluoroquinolone-resistant strains. Higher rates of CDI have been seen with patients with inflammatory bowel disease (IBD), and postsolid organ transplant. However, healthy individuals can acquire CDI, even in the absence of prior antibiotics. Decreased gastric acid suppression increases the risk of gastrointestinal infection. While data on the association of C. difficile has both supported and refuted proton pump inhibitors (PPIs) as a risk factor for CDI, more recent studies support them as an independent risk factor for acquiring CDI but they may not be a risk factor for recurrent CDI [8–11]. Patients with IBD are at increased risk of CDI; risk factors include immune suppression and colonic disease. Stools should be tested for C. difficile in all patients with IBD flares. These patients have a higher morbidity and mortality than patients with IBD alone or CDI alone [12, 13].

Diagnosis The diagnosis of CDI rests on detection of toxin in the stools, although toxigenic culture is used in evaluating epidemics. Only diarrheal stools should be tested because 5 % to 15 % of healthy individuals may be carriers [14]. A single sample should be adequate. Submitting multiple specimens has a low yield [15]. However, some experts suggest that multiple stool samples should be tested in patients with flares of their inflammatory bowel disease [6••].

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Glutamate dehydrogenase (GDH) is an enzyme produced by Clostridia but is not specific for C. difficile. It is often used as a screen because it is sensitive and inexpensive; however, a confirmatory test is necessary because it is not specific for C. difficile [16]. Enzyme immune assay tests for Toxins A and B were more widely used in the past but have relatively poor sensitivity and specificity. The most sensitive and specific tests are nucleic acid amplification tests like the polymerase chain reaction (PCR) test that detects the gene for Toxin B [17]. While these tests are more expensive than enzyme immune assay tests for Toxin A and B, they may be more cost-effective in the long run, with improved accuracy, earlier detection, and therapy. However, even PCR can be negative in patients with CDI, so a negative test should not preclude therapy in a sick patient in whom CDI is suspected.

Treatment of CDI Therapy should be based on disease severity with the following classification: mild to moderate, severe, or severe and complicated [6••]. Patients with mild to moderate disease have diarrhea, but no signs of severe or complicated disease. They should be treated with metronidazole (500 mg orally three times a day for ten days) unless there is a contraindication to metronidazole such as early pregnancy when there is placental transmission and case reports of facial anomalies, as well as during breast-feeding, or in those who are intolerant. In these cases vancomycin should be given (125 mg orally four times a day for ten days). Fidaxomicin (200 mg orally twice a day for ten days) is an alternate antibiotic; its use has been limited by its high cost. Intercurrent antibiotics should be discontinued if possible. Antiperistaltics should not be used as they may pose a risk of toxic colitis and interfere with evaluation of symptoms. Patients will typically improve in 3-5 days and resolve by the end of the ten-day treatment. If the patient is not better in 3-5 days, a switch to vancomycin (125 mg orally, four times a day) should be considered. Severe CDI is defined as a patient with CDI who has hypoalbuminemia (albuminG3) and abdominal distension or tenderness and/or an elevated white blood cell count (915,000) [6••, 18••]. These patients should be given vancomycin (125 mg orally, four times a day). If they do not get better quickly, consider increasing the vancomycin to 1-2 grams/day. Patients with severe and complicated CDI have criteria for severe CDI and one or more of the following: admission to the intensive care unit, hypotension, fever (938.5o centigrade), ileus, white blood cell count over 35,000 or less than 2,000, a serum lactate 92,2 mmol/L, and/or evidence of end organ failure, especially renal or pulmonary [5, 6••]. They should be treated with vancomycin (500 mg orally, four times a day) and metronidazole (500 mg intravenously every 8 hours). Vancomycin enemas (500 mg of liquid vancomycin in 100 ml of normal saline) may be a useful adjunct, especially in the setting of ileus or toxic colon. There is enthusiasm for the use of fecal microbiota transplant (FMT), or “stool transplant” (see RCDI section for details) for treatment of severe refractory CDI that is not responding to standard treatment, with case reports showing efficacy. However, experience is limited, and in such severely ill patients, it may be best to use the traditional surgical approach until there is better evidence to support a role for FMT. There is a small series of patients with

Colon (C Burke, Section Editor) severe CDI who were treated with intravenous immune globulin; the study authors concluded that there was not enough evidence of efficacy to adopt IVIG as routine treatment for severe CDI [19]. It is important to recognize that C. difficile can infect the ileal pouch in patients who had a total proctocolectomy. Pouchitis (inflammation of the pouch) is a common complication after IPAA surgery, and C. difficile infection may account for 10 % of cases. Thus, it should be tested for in all patients with flares [20, 21]. Vancomycin enemas should be the first-line therapy. There are a few case reports of C. difficile infection involving the distal ileum. A retrospective series of patients with fulminant (severe and complicated) CDI in Quebec during the years 2003-2005 (during the height of their epidemic) compared mortality in those who underwent surgery (overall mortality was 34 %) compared to those treated medically (overall mortality was 58 %) [22]. Predictors of 30-day mortality were elevated serum lactate (95), elevated white blood cell count (920,000), being in shock or on pressors, and being 75 years of age or older. Patients with one or more of these features should be considered for earlier surgical intervention. Indications for surgery vary with each patient but should be considered in the patient with severe and complicated CDI who does not respond to maximal medical therapy, or who develops sepsis, lactic acidosis, and/or multiorgan failure. Such patients undergoing subtotal colectomy have a high morbidity (30-60 %). An alternative to subtotal colectomy is creating a loop ileostomy and leaving the colon in place, then using the loop to lavage the colon with a PEG solution and vancomycin directly. In one series, mortality was 19 % compared to 50 % in their historical controls who underwent subtotal colectomy. In many of those patients, their colons were successfully reanastomosed later [23•].

Recurrent C. Difficile Infection (RCDI) RCDI is an episode of CDI that occurs within eight weeks of a previous episode. One recurrence occurs in 10-20 % of patients, but after one recurrence, the rate of further recurrences goes up to 40-65 % [24]. The first recurrence can be treated with the same antibiotic, although if the recurrence is severe, vancomycin is recommended. A second recurrence should be treated with a pulsed vancomycin regimen as follows: vancomycin (125 mg orally, four times a day for ten days), followed by a single dose of 125 mg every three days for ten more doses. While this is empiric, it is simpler than other tapering and pulsing regimens, and this author and others have seen it be successful in many cases (Scott Curry, Personal Communication). If this fails, fecal microbiota transplant (FMT) should be considered [25]. This involves putting stool from a healthy donor into the colon of the patient with RCDI by one of several methods: enema, colonoscopy, or nasoduodenal infusion. The introduction of normal microbiota is correlated with reappearance of Firmicutes, Bacteroidetes, and with resolution of CDI. It is likely that the normal microbiota is able to inhibit the growth of C. difficile allowing resolution of the infection. The first randomized controlled trial of FMT for RCDI showed statistically significant resolution of RCDI compared to

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therapy with vancomycin or vancomycin and gut lavage (81 % vs. 31 %, pG0.001) after one infusion and 93.8 % after a second infusion [26]. Meta-analyses of case reports and a series of FMT for treatment of RCDI show efficacy of 90 % [27, 28]; this is far better than any other therapy. There is evidence that fresh, frozen, and thawed stools have a similar efficacy. One series used standardized frozen stool from patient-identified donors or volunteer donors with excellent results [29]. A novel approach used a stool substitute preparation made from purified intestinal bacterial cultures from a healthy donor to treat successfully two patients with RCDI [30]. A costeffectiveness study of strategies for management of RCDI showed FMT via colonoscopy to be the most cost-effective, compared to metronidazole, vancomycin, or fidaxomicin [31]. There are many unanswered questions about FMT. They include: why does it work, what is the best method of delivery, how are donors selected, what is appropriate screening of donor and recipient, the use of pre-screened donors, and the long-term safety. FMT must be performed by clinicians with expertise in the procedure [32, 33]. It is very important to treat the appropriate patients who have clearly defined RCDI and not those who may have symptoms from other diseases like post-infection irritable bowel syndrome. The donor must be screened to exclude a variety of diseases including cancer, metabolic syndrome, autoimmune diseases, and high-risk behaviors. Once an appropriate donor is selected, their blood and stool must be screened for pathogens including but not limited to serology for HIV, hepatitis A, B, C, and syphilis and stools for enteric pathogens and parasites, among others. Stool banks using standardized donors are being developed which will eliminate this costly screening [33]. Moreover, the recipient must get baseline blood testing for HIV types I and II, syphilis, and hepatitis A, B, and C. Most practitioners use freshly passed stool mixed with nonbacteroistatic saline and infused directly into the colon or via the upper GI tract. There are few reported risks: two patients contracted norovirus from their asymptomatic donors [34]. One patient had a flare of previously quiescent ulcerative colitis following FMT [35]. There are little data on long-term follow-up. In one study, patients treated at five different centers submitted follow-up data (follow-up ranged from 3-68 months). Of 77 patients, four developed new conditions: peripheral neuropathy, rheumatoid arthritis, Sjogren’s syndrome, and idiopathic thrombocytopenic purpura [36]. FMT appears to be safe in immune compromised patients. A large series collected data retrospectively from 80 such patients from 16 centers [37]. Most were adults, although a few children were included. The most common indication for treatment was recurrent CDI but some patients had refractory (12 %) or severe and complicated CDI (32 %). The efficacy of FMT was high—78 % for the first treatment and an additional eight of 12 responded to a repeat FMT with an overall 89 % cure rate. Significant adverse events were reported in 12 patients within the first 12 weeks post-FMT; of the 12 patients with SAEs, ten were hospitalized. Four episodes were felt related to FMT, five possibly related, and three unrelated. Related SAEs were patients with self-limited abdominal pain and diarrhea. Five patients had flares of inflammatory bowel disease. Two patients died; one from worsening pneumonia and one from aspiration from sedation administered during the colonoscopy. This patient had advanced

Colon (C Burke, Section Editor) esophageal cancer. This death was felt to be related to the FMT procedure. There were no infections related to FMT. While this short-term study is encouraging, long-term safety data needs to be prospectively collected. While some insurance companies consider FMT investigational, it offers an effective and enduring cure for most of these patients for whom there are limited treatment options. Bile salt binders such as cholestyramine do not bind C. difficile toxin and have no role in treatment of RCDI. Fidaxomicin was not studied in RCDI, although it had lower recurrence rates in patients with first infections compared to vancomycin [38]. Cases of treatment with intravenous immune globulin have been reported but this author cannot recommend it [39]. Some patients have responded to sequential therapy with vancomycin and rifaximin, but RCT are lacking [40–42]. There is moderate evidence for the efficacy of Lactobacillus GG and Saccharomyces boulardii to prevent antibiotic associated diarrhea [43, 44] but no convincing evidence that probiotics prevent CDI. There is no role for probiotics in the treatment of CDI. In patients with RCDI, S. boulardii (500 mg orally twice a day continued for two weeks after the treating antibiotic has finished) as an adjunct to antibiotics has been shown to decrease recurrences modestly [45]; in one study, the efficacy was only when given in conjunction with high dose vancomycin (2 grams/day) [24].

Prevention In the hospital and LTCF settings, an infection control program can decrease the incidence of CDI. The basics include early contact isolation of patients, hand hygiene, strict barrier precautions, environmental cleaning, dedicated equipment, and antimicrobial stewardship [46]. Hospitals should use an EPA-approved sporicidal cleaner (containing 5000 ppm chlorine). In the home, one can use a spray bottle containing a mixture based on 1 cup of bleach and 9 cups of water, spraying surfaces and rinsing off ten minutes later. A recent systematic review and meta-analysis concluded that probiotics prevent C. difficile diarrhea with moderate quality evidence [47]. In that paper, 20 RCTs were included for analysis. Moderate quality evidence supported their conclusion that probiotics (Bifidobacterium, Lactobacillus, Saccharomyces, or Streptococcus species) decreased AAD and CDI. However, given the heterogeneity of the probiotics studied, it is hard to know if all are equally effective, and in what doses, among other questions. Moreover, a recent large study showed no benefit from a mixture of Lactobacilli and Bifidobacteria in prevention of antibiotic associated diarrhea and C. difficile infection in older hospitalized patients [48]. In this study of 2,981 patients randomized to placebo or probiotic, AAD was common in both arms (RR1, 04). Of the 312 patients with AAD, stool samples were obtained in some patients. C. difficile was found in 17 (1.2 %) of controls and 12 (0.8 %) of probiotic-treated patients. Thus, this author’s opinion is that better data are needed before recommending the widespread use of probiotics in hospitalized patients receiving antibiotics. Probiotics are generally safe but can cause blood stream infection in immune suppressed individuals.

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Compliance with Ethics Guidelines Conflict of Interest Christina M. Surawicz declares that she has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

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Clostridium difficile infection: risk factors, diagnosis and management.

Clostridium difficile infection (CDI) is the leading cause of death due to gastrointestinal infections in the US and is the most common cause of nosoc...
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