Accepted Manuscript

Clostridium difficile colitis a clinical review

Gabie K.B. Ong, Tobi J. Reidy, Matthew D. Huk, Frederick R. Lane

PII: S0002-9610(17)30005-3
DOI: 10.1016/j.amjsurg.2016.10.035
Reference: AJS 12240

To appear in: The American Journal of Surgery

Received Date: 15 August 2016

Revised Date: 16 September 2016
Accepted Date: 14 October 2016

Please cite this article as: Ong GKB, Reidy TJ, Huk MD, Lane FR, Clostridium difficile colitis a clinical
review, The American Journal of Surgery (2017), doi: 10.1016/j.amjsurg.2016.10.035.

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 ACCEPTED MANUSCRIPT

Clostridium Difficile Colitis

A Clinical Review

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Authors:

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Gabie K. B. Ong, MDᵃ

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Tobi J. Reidy, DOᵇ

Matthew D. Huk, MDᵇ

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Frederick R. Lane, MDᵇ
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ᵃSt. Vincent's Hospital, 2001 W. 86th St., Indianapolis, IN 46260
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ᵇKendrick Colon and Rectal Center, 5255 E. Stop 11 Ave., Suite 250, Indianapolis, IN

46237
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Corresponding Author:

Frederick R. Lane, MD. fredl422@aol.com

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This manuscript has been seen and approved by all authors.

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This research did not receive any specific grant from funding agencies in the public,

commercial, or not-for-profit sectors.

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Abstract

Background

Clostridium difficile colitis is an important cause of morbidity and mortality in the

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surgical patient. In recent years, Clostridium difficile infections have shown marked increases in

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frequency, severity, and resistance to standard treatment. With urgent operative interventions

and novel endoscopic approaches, pseudomembranous colitis is being seen more commonly in

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surgical practices.

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Data Sources
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In this paper, we will review a number of papers from the literature. We will discuss the
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epidemiology, evaluation and treatment of Clostridium difficile infection. Fulminant colitis may

require emergency operation. For the surgical endoscopist, fecal microbiota transplantation
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restores the gastrointestinal flora, and has been shown to be effective in more than 80% of
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patients.
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Conclusion
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Clostridium difficile infection is a major cause of healthcare-related diarrhea

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leading to increased morbidity and mortality in surgical patients. Increases in failure rates and

resistance to current treatments are clinical and economic challenges in the healthcare situation.

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Clostridium difficile colitis, originally known as pseudomembranous colitis, was first

described as an etiology of diarrhea from antibiotic use by Bartlett et al in the New England

Journal of Medicine in 1978.(1) In recent years, Clostridium difficile infections (CDI) have

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shown marked increases in frequency, severity and resistance to standard treatment.

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Epidemiology

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The frequency of CDI infection increased from 4.5 CDI cases per 1000 discharges in

2001 to 8.2 in 2010 with a mortality rate of around 7%.(2) A population-based study by Lessa et

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al estimated almost a half million cases in the United States in 2011, with 83,000 recurrences and
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29,300 deaths.(3)

Clostridium difficile infection is triggered by toxin production from the bacteria. Normal
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bacterial flora is disrupted, the colon is colonized with the Clostridium difficile bacteria, and

toxins are released that cause mucosal damage and inflammation.(4) Normal bacterial flora is
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typically disrupted by antibiotic treatment, with clindamycin as the earliest reported cause. The
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disease can be triggered by nearly any antibiotic, but a study by Slimings and Riley ranked

cephalosporins, clindamycin, carbapenems, trimethoprim/sulphonamides, fluoroquinolones and

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penicillin combinations as the most frequent offenders.(5)

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A recent report by Khanna et al(6) found that in Olmsted County, Minnesota, over 40% of
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cases of CDI were community-acquired. These community-acquired CDI patients were less

likely to have severe infection, and had been exposed to antibiotics in only 78% of cases.

More than 300 toxigenic strains of Clostridium difficile have been discovered in North

America. The virulence of the disease is primarily from exotoxins A and B. Some strains also

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produce a third toxin, which is present among NAP1/BI/027 strains, the most resistant or virulent

toxin.(7) (8)

Diagnosis

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Diagnosis of CDI requires the presence of diarrhea (at least 3 unformed stools in 24

hours) or radiographic evidence of ileus or toxic megacolon, in addition to positive stool testing

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for Clostridium difficile toxin or colonoscopic or pathologic findings showing

pseudomembranes.(9)

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Pseudomembranes are pathognomonic of the disease, but are present in only about 50%

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of patients who are toxin-assay positive. As many as 70% of patients may present with rectal
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sparing, and 10% may have pseudomembranes above the reach of a flexible sigmoidoscope.(10)

It is important to limit stool testing to patients with significant diarrhea, since

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colonization with Clostridium difficile is relatively common.(11) Many facilities will test only

loose or liquid stool for CDI.

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Several different assays are available for testing. Cytotoxicity assays were once believed
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to be the gold standard, but they may take up to 72 hours and are rarely performed today.

Enzyme immunoassays (EIA) are widely used, which test for both toxins A and B, but sensitivity
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averages only around 60%.(12) Immunoassays with glutamate dehydrogenase (GDH) have
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sensitivities in the 75-90% range.

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Molecular tests have been available in the United States since 2010. Most are based on

polymerase chain reaction technology (PCR). These tests tend to have very good specificity (91-

100%) and sensitivity (73-100%) for CDI and can be used as a stand-alone test in patients with

diarrhea.(13) Multistep algorithms using some combination of EIA with GDH and PCR (as a

confirmatory test) have been developed which increase accuracy of diagnosis of CDI.( 14)

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Clinical Features

The signs and symptoms of CDI range from self-limited diarrhea to a combination of

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symptoms which may include fever, elevated white blood cell count, abdominal pain and/or

distention, and tachycardia. With worsening disease, patients may progress to renal failure,

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shock, intensive care unit admission, and an acute surgical abdomen. Several grading scales

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have been published to enable the clinician to identify the appropriate therapy for a patient with

active infection. (See Tables 1 and 2)

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Medical Management
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Treatment of Clostridium difficile infection involves discontinuation of the offending

antibiotic, whenever possible. Antiperistaltic agents should be avoided, at least until antibiotic
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therapy is well underway. Resuscitation should be initiated for patients with more advanced
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disease.
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Metronidazole is the drug of choice for mild infection (500 mg by mouth three times a

day for 10-14 days), while vancomycin should be used for more severe episodes (125 mg by
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mouth four times daily for 10-14 days).9 Recurrence rates over 30 per cent have been reported in

some studies for both regimens.(15)

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A randomized, double-blind, placebo-controlled study showed that clinical cure rates

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were similar for both vancomycin and metronidazole for mild to moderate disease. In severe

disease, vancomycin proved superior (97% vs. 76%).(16) In patients who fail to respond to

metronidazole within 5-7 days, a change to vancomycin should be considered.(17)

Patients with severe/complicated disease should be treated with a combination of

vancomycin 125 mg orally four times daily and metronidazole 500 mg intravenously every eight

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hours. Supportive care is important with fluid resuscitation and electrolyte replacement. CT

scanning is recommended, and surgical consultation should be obtained.17

Fidaxomicin is a macrocyclic antibiotic which is more active against NAP1/BI/027

strains than vancomycin. Released in 2011, it also achieves higher fecal concentration than

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vancomycin, has minimal systemic absorption, and has limited activity against normal

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gastrointestinal flora.(18)

Recurrence may be treated with metronidazole, vancomycin or fidaxomicin, but

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subsequent recurrences should rely on vancomycin or fidaxomicin. Pulsing or tapering may be

used with vancomycin for recurrent disease, but the data remains limited for this approach.9 Oral

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fidaxomicin has been shown to have a lower recurrence rate (19.7%) than vancomycin (35.5%)
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after the first recurrence of CDI in a pair of phase III trials.(19)

For patients unable to tolerate oral medication, metronidazole 500 mg intravenously is

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recommended for patients with mild to moderate disease. Vancomycin retention enemas (500
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mg in 100 ml of normal saline) four times daily, or nasogastric or orogastric instillation of 500
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mg of vancomycin four times daily may be combined with intravenous metronidazole for more

severe cases.9
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The role of probiotics in prevention and treatment of Clostridium difficile infection is

not clear. A 2003 Cochran review by Goldenberg et al suggested that probiotics may decrease
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the risk of developing CDI by 64% in nearly 4500 patients being treated with antibiotics.(20)
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A recent meta-analysis reviewed 20 randomized, controlled trials (RCTs) that included

over 3800 patients. Johnston and associates(21) found that probiotics reduced incidence of CDI

by 66%, preventing an estimated 33 episodes per 1000 patients. Another review by Hempel et

al(22) looked at 63 RCTs. While most individual studies did not show a statistically significant

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difference, the combination of studies which included nearly 12,000 patients found a

significantly lower rate of antibiotic-associated diarrhea in patients who received probiotics

during their course of antibiotics.

Potentially on the horizon, a mixture of bacterial spores (SER-109), produced clinical

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cure in 29 of 30 patients with recurrent CDI at 8 weeks in an open label single arm phase I/II

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trial.(23) Sanofi and Pfizer are both actively pursuing a Clostridium difficile vaccine, while at

least three companies are actively developing other antibiotics targeting CDI.(24)

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Fecal Microbiota Transplantation

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A form of fecal microbiota transplantation (FMT) has been used in Chinese medicine for
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at least 1700 years for the treatment of various gastrointestinal ailments.(25) More recently,

Eiseman, in 1958, described the use of fecal enemas in the treatment of four patients with
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Clostridium difficile colitis.(26) Since that time, there have been sporadic reports in the literature,

with a marked increase in the number of publications in the last several years, as seen in the NIH
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clinical trials registry. (Figure 1)(27)

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In patients with recurrent CDI, bacterial diversity has been found to be decreased

markedly. Successful fecal transplantation restores the gastrointestinal flora to that of the
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donor.(28)
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A recent publication from the University of Michigan used 16S rRNA-encoding gene
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sequence analysis to examine fecal microbial diversity. Seekatz et al(29) found that fecal

microbiota at initial diagnosis in patients with recurrence trended toward lower diversity when

compared with patients who did not recur. Samples from patients with severe disease at

diagnosis had significantly lower diversity than those in patients with milder disease.

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There may also be differences in microbial diversity in different age cohorts. Girotra et

al(30) found promising results utilizing FMT in patients older than 65, with no recurrence in 29

geriatric patients after long-term follow up. Genomic analysis showed that while microbial

diversity increased in elderly patients after transplantation, the response was less robust in

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comparison to a younger group of patients.

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In attempts to further understand the efficacy of FMT, Millan et al studied the profile of

antibiotic resistant (ABR) genes in 20 patients with recurrent CDI compared to healthy controls.

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They found that CDI patients had a greater number and diversity of ABR genes, with the group

responding to a single FMT having the highest number of these genes. Following successful

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FMT, the number of ABR genes decreased significantly.(31)
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Fecal microbiota transplantation has typically been reserved for patients who have

refractory Clostridium difficile colitis. FMT involves the infusion of stool from an uninfected
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donor into the intestinal tract of the involved recipient. These transplants have most commonly
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been performed into the colon by colonoscopy(32), although the procedure has been described
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through a nasogastric or nasoduodenal tube, gastroscope, retention enema, or even by self-

administered enemas ("home remedy").(33)

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The donor may be a family member, partner or even a close friend. For patients without

an available donor, healthy donors, who have been appropriately screened, can be used. Some
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hospitals have developed their own banks of healthy donors, while a non-profit company (Open
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Biome) started at the Massachusetts Institute of Technology offers pre-screened, ready to

administer preparations.(34)

Similar to blood donation programs, donors are tested for infectious diseases, such as

hepatitis A, B and C, syphilis, and HIV. Stool is checked to rule out bacterial infection, ova and

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parasites as well as Clostridium difficile. Donor exclusions may also include prior

gastrointestinal neoplasia, imprisonment, high risk sexual practices, tattoos or body piercings, or

recent travel to diarrhea-endemic areas. Other considerations which may affect the transplant are

the use of antibiotics by the donor within the previous few months, immunosuppressive

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medications, and dietary intake of recipient allergens by the donor.(35) (36)

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No standard technique exists for preparation of the stool sample. The stool is usually

collected within six hours of transplantation. Many protocols recommend a mild laxative for the

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donor to ensure production of a sample. The specimen is then mixed with saline or water and

filtered through a gauze or cheesecloth to produce a sample thin enough to be administered

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through the injection channel of a colonoscope. Recipients should stop their antibiotic(s) a day
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or two prior the procedure and cleanse the bowel as for a standard colonoscopy. Ideally, the

transplant is instilled into the distal ileum or cecum with a bolus, but may also be injected in a
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gradual fashion throughout the large intestine.(37) Loperamide may be given to maximize
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retention of the infusate. Antibiotics should be stopped, and stool should be tested only for
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recurrent symptoms.

As there is no current standardized method of administration, the specimen may also be

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infused through a nasogastric tube or with a gastroscope. In their review, Gough et alError!

Bookmark not defined. showed a trend toward lower success rates with the upper GI route at
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76.4 percent, compared to 88.7 percent for colonoscopic instillation. Enemas and rectal catheters
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were effective in over 95 percent of patients.

A review of the literature by Gough et al(38) in 2011 summarized results of fecal

transplantation in 317 patients treated in 27 case series and reports. This summary showed

disease resolution in 92% of cases. A year later, Kassam et al(39) found 90% success in an

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analysis of 273 patients from 11 studies, while another review published in 2014 by Dodin et

al(40) reviewed over 30 reports published between 2011 and 2013. With 583 patients in total,

success rates were again over 90%. In Dodin's review, higher volume infusions (greater than

500 ml) showed the greatest success.

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In a recent multi-center double-blind, randomized, controlled trial in Canada, 232 patients

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with recurrent CDI were enrolled to receive either fresh or frozen FMT. Antibiotics were

discontinued 24 to 48 hours prior to the procedure, and stool was administered by enema with no

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bowel lavage. Frozen stool was stored for a maximum of 30 days and administered within 24

hours of thawing. Fresh stool was administered within 24 hours of collection. Results showed

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no statistical difference between the groups with clinical resolution in 83.5% of frozen FMT and
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85.1% in the fresh group.(41)

Early results from fecal transplantation are encouraging in treatment of recurrent CDI;
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however, further investigation into recurrence rates, risk factors, and long-term follow up is
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warranted.
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Fischer et al looked at predictors of transplantation failure in over 300 patients in a recent

multicenter study.(42) The authors found an 18.6% early failure rate and a 2.7% late failure rate
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between one and three months after FMT. Predictors of failure included patients with severe or

severe-complicated CDI, inpatient status at FMT and multiple prior CDI-related

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hospitalizations.
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Another study looked at long-term follow up in 94 patients. Although the average

duration of symptoms prior to FMT was 11 months and patients failed an average of five

conventional antimicrobial regimens, 74% of patients resolved their diarrhea within three days.

Brandt et al(43) had a primary cure rate of 91% in 94 patients.

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O'Brien et al(44) presented information from the OpenBiome database at the 2016

Digestive Disease Week. Data was collected from 482 healthcare facilities and 1406 fecal

transplantations. Overall cure rate was 82.4%. FMT by colonoscopy (84.3% cure rate) was

statistically superior to upper endoscopy (69.3%).

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Scattered case reports describe the use of FMT in patients with severe, complicated

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disease, or even toxic megacolon. Gweon et al(45) reported successful treatment of a patient with

numerous comorbidities, initially on dopamine, who was cured with a series of three transplants,

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the first two by colonoscopy in the distal colon and the third by gastroduodenoscopy. Costello et

al reported another patient with toxic megacolon, who was cured with a single FMT

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administered by push enteroscopy after the patient declined subtotal colectomy.(46)
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Fischer and her colleagues reported their series of 29 patients with severe or

severe/complicated CDI treated with fecal transplantation.(47) All patients were refractory to oral
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vancomycin with or without rectal vancomycin and intravenous metronidazole. Their protocol
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consisted of sequential FMT by colonoscopy. Oral vancomycin was resumed 24-48 hours after
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FMT in patients who had pseudomembranes at colonoscopy. Patients who failed to improve

after a minimum of five days of vancomycin were treated with a second FMT. Overall response
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was 93% with a 7% all-cause mortality rate in these very high-risk patients. Nearly 40% of

patients required more than one FMT.

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The authors note that this is the largest reported experience with FMT in this patient
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population, exceeding the combined size of previous reports. They suggest that their success

indicates that their protocol warrants additional study. At this time, surgery remains the gold

standard for these severely ill patients.

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Even patients who are immunocompromised appear to respond to fecal transplantation.

Kelly et al(48) presented data from a multicenter retrospective series. Of 80 immunocompromised

patients treated with FMT, 78% were cured with a single treatment. An additional 12 patients

had a second FMT, with eight successes, yielding an overall cure rate of 89% in this high-risk

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group of patients.

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Konijeti et al, in 2014, compared four treatment strategies for treatment of recurrent

Clostridium difficile colitis - metronidazole, vancomycin, fidaxomicin and fecal microbiota

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transplantation with colonoscopy. They found that FMT colonoscopy was the most cost-

effective initial strategy with cure rates of 88.4% and recurrence rates of 14.9%. In clinical

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settings without availability of FMT, oral vancomycin was demonstrated to be more cost
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effective than fidaxomicin.(49)

These findings were supported by a 2016 publication from the University of Toronto - a
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cost analysis of six different treatment strategies expanding on FMT delivery methods. They
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compared metronidazole, vancomycin, fidaxomicin, FMT by enema, FMT by nasogastric tube

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and FMT by colonoscopy. Fecal transplantation by colonoscopy was both cost-saving and more

effective than all the other treatment options. In settings without colonoscopy, FMT by enema
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was cost effective when compared to metronidazole.(50)

Among patients with virulent NAP1/BI/027 strains, FMT colonoscopy has also been
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shown to be favorable to other treatments. In a retrospective review of 70 patients with recurrent

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CDI who underwent transplantation with colonoscopy, Mattila et al found that 12 weeks post

FMT, symptoms resolved in all patients (n=34) who did not have a strain 027. In patients with

the more virulent strain, 32 of 36 (89%) had a favorable response to FMT colonoscopy.(51)

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Other novel techniques for fecal transplantation include self-administration of fecal

enemas. Silverman et al had a 100% success rate in a case series of 7 patients.43 The

Massachusetts General Hospital in Boston completed an open label study of 20 patients using

frozen FMT capsules from prescreened unrelated donors. Fourteen patients had resolution of

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diarrhea with a single ingestion of 15 capsules on 2 consecutive days, while another four had

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resolution of diarrhea with a second treatment.(52)

Another study by Hirsch et al(53) demonstrated similar findings in 19 patients with

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recurrent CDI using frozen FMT capsules. Thirteen patients (68%) had resolution after a single

administration while four more had resolution after a subsequent dose (administered about six

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weeks later) for a cumulative cure rate of 89%. One patient failed to resolve despite four courses
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of treatment. Interestingly, another patient failed to complete the treatment due to anxiety after

ingestion of only six capsules. The authors suggest that this method of delivery may be a less
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invasive alternative in frail patients with major comorbidities.

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Surgical Treatment
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When medical therapy fails to improve patient status, surgical consultation should be

obtained. Unfortunately, in most cases, this is a time of crisis.

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Abdominal colectomy is the treatment of choice for severely ill patients. Patients with
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megacolon, perforation or an acute abdomen should have an emergency colectomy. A review of

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the Nationwide Inpatient Sample from 2001 to 2010 by Halabi et al found a colectomy rate of

hospitalized patients of 0.7% with an overall mortality rate of 30.7% for the first five years of the

study. This mortality rate increased in the second five years by 47% with the rate of colectomy

increasing by 32%.(54) Stewart et al reported a survival advantage in 510 patients with fulminant

CDI who were managed surgically.(55)

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In a review of the early 21st century literature, Seltman found the need for colectomy in

patients with CDI ranged from 0.4%-1.9% with mortality rates between 32 and 57 per cent.(56)

Neal et al described a novel technique, using loop ileostomy (usually laparoscopic) with

colonic lavage as an alternative to colectomy in 42 patients at the University of Pittsburgh

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Medical Center and the VA Pittsburgh Healthcare System. These patients all met diagnostic

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criteria of severe, complicated or "fulminant" CDI. Patients found to have ischemia of the colon

or perforation underwent total abdominal colectomy with end ileostomy.

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In patients suitable for colon preservation, intraoperative lavage with warmed

polyethylene glycol through the ileostomy was followed by antegrade infusion of vancomycin

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(500 mg in 500 mL of Lactated Ringers q8 hours for 10 days) postoperatively through the
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ostomy. Patients also received intravenous metronidazole (500 mg q8 hours) for 10 days. With

this procedure, the authors decreased mortality, compared to historical matched controls, in these
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severely ill patients from 50% to 19%. Colectomy was avoided in 93% of their patients.(57)
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An open approach is the standard of care for severely ill patients. The colon should be
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mobilized carefully to avoid perforation and contamination. The colon can be divided at the

distal sigmoid or rectosigmoid junction. Higher division allows for a mucus fistula, avoiding the
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potential risk of rectal stump blowout. Vancomycin irrigation of the rectal stump can be done,

but data for this is limited.56

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In 2009, Sailhamer et al reported independent predictors of mortality in almost 5000

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patients with CDI. These predictors were patient age 70 or older, severe leukocytosis (>35,000)

or leukopenia (<4,000) or bandemia (>10%), and cardiorespiratory failure (intubation or

pressors). When all factors were present, mortality was reported at 57.1%, while if all predictors

were absent, mortality rate was 0%.(58)

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A review by Osman et al recommended surgical evaluation for patients who failed

maximum medical therapy and developed abdominal pain, distention, localized tenderness, fever

(over 38 degrees Celsius) and/or tachycardia (over 100 beats per minute). Other preoperative

risk factors included elevated lactate, hypotension, low serum albumin, and a CT scan showing

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severe colitis. Preoperative thrombocytopenia, vasopressor requirement, mental status changes,

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renal insufficiency and chronic obstructive pulmonary disease have been associated with higher

surgical mortality rates.(59) (60)

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Clostridium difficile Infection in Inflammatory Bowel Disease

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Clostridium difficile infections have a marked significance in the population with
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coincidental diagnosis of inflammatory bowel disease (IBD). Review of isolated case studies

collected over several decades has concluded that CDI negatively impacts the natural course of
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IBD. This includes increased disease flares, increased morbidity, and increased length of

hospitalization.(61) Unfortunately, the nature of immunosuppressive therapy often makes the

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diagnosis of CDI difficult in this population, as the presentation may be indistinguishable from
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an acute disease flare. The classic pseudomembranes seen at endoscopy are frequently absent.(62)
(63)
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The incidence of CDI has been increasing at a greater rate in the IBD population than in
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the non-IBD group, possibly because providers are more likely to test for CDI when an IBD
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patient is admitted for diarrhea. Moreover, growing evidence suggests that large intestinal

involvement is important, as the rate is climbing faster in the ulcerative colitis (UC) population

than in Crohn’s disease.(64) Similarly, Crohn’s disease patients with large intestinal involvement

have an increased prevalence compared to patients with disease limited to the small bowel.(65)

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The RECIDIVISM study, published in 2016 by Razik et al(66), focused primarily on the

recurrence rate of CDI. This study showed that IBD patients are 33% more likely to experience

recurrent CDI than non-IBD patients. Significant risk factors included non-ileal Crohn’s disease

and recent 5-ASA use. Patients were also more likely to report recent antibiotic, steroid and

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biologic therapy use.

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The well-established link between antibiotic use and CDI has become a popular topic of

research in the IBD patient population. Complications such as fistulae lead to the use of

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antibiotics, many times in a chronic manner. Interestingly, a recent study demonstrated that only

2% of patients on chronic antibiotic therapy for Crohn's disease developed CDI, compared to

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patients on chronic antibiotics for other indications (12.5% for left ventricular assist device
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infections and 22.2% for orthopedic prosthesis infections).(67) The combined use of biologic

agents and antibiotics led to a 10-fold increase in the CDI rate.(68)

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The impact of CDI in the IBD patient is best appreciated by noting an increased need for
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surgery. In a 2015 meta-analysis, Peng et al demonstrated that ulcerative colitis patients with
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CDI had a significantly higher rate of surgery compared to patients with UC alone (41% vs.

31%).(69) Another outcomes study showed a similar increase in surgery rate for Crohn’s patients
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(38.8% vs. 24.9%). The study also showed an increased rate of active Crohn’s disease at 2-year

follow up after successful management of CDI,68 suggesting increased long-term morbidity.

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Short term morbidity was also significant. An operative mortality up to 25% was observed for
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UC patients undergoing surgery during episodes of CDI, even at highly skilled centers.65 These

findings highlight the significance of CDI in these patients.

Another consideration in the inflammatory bowel disease patient is the phenomenon of

small bowel Clostridium difficile enteritis (CDE). Fewer than 100 cases have been reported in

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the literature.(70) (71) Cases of CDE have been observed as late as nine years following

proctocolectomy.(72) Moreover, delay in diagnosis often leads to complications and contributes

to an elevated mortality rate of up to 83%.(73) (74) (75)

Approximately half of the cases of small bowel CDE reported have been in patients with

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IBD.(76) Several of these patients had undergone total proctocolectomy with ileal pouch anal

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anastomosis or had undergone total colectomy for another reason. Another noteworthy number

of patients underwent segmental colectomy, with small bowel CDE seen more frequently in right

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colectomies than left. Neither mechanical nor oral antibiotic bowel prep had an effect on CDE

rates after colectomy.(77)

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The optimal treatment strategy for CDI in the IBD population has yet to be revealed.
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Most authors take the approach outlined for severe CDI regardless of the patient’s clinical

picture. In several studies, vancomycin has been shown to be more effective than metronidazole
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at reducing readmissions and decreasing length of stay for non-severe cases of CDI. Early
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surgical consultation is also recommended, given the higher likelihood of surgical

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intervention.(78) (79)

The future of CDI treatment in IBD patients will likely parallel the advances in treatment
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in non-IBD patients. Research showing that patients with UC and CDI have lower toxin IgA

levels and a lessened antitoxin IgG response have opened the door to new potential therapeutic
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modalities.(80) Other modalities such as vaccines and bile salts are also currently being
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investigated.(81)

Interestingly, FMT has not had the same stunning results in the IBD population. Khoruts

et al. found that FMT had a reduced efficacy (74.4% vs. 92.1%) in patients with IBD, and

approximately 25% of these patients experienced a significant flare following FMT therapy.(82)

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The reason for the decreased efficacy of FMT is not clear, but it does underscore the difficulty

that CDI presents in the IBD population. The fecal microbiota pattern among patients with IBD

and CDI seems to be similar to that of non-IBD patients.(83)

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Conclusion

Clostridium difficile infection is a major cause of healthcare-related diarrhea leading to

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increased morbidity and mortality in surgical patients. Increases in failure rates and resistance to

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current treatments have been clinical and economical challenges in the healthcare setting. New

developments in pharmacologic agents, surgical management and other strategies have been

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developed to improve management of CDI.
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Medical management of CDI is dependent on the severity of the infection.

Metronidazole is usually the first line treatment in mild disease with vancomycin reserved for
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more severe disease. Failure of these regimens or recurrence are common and may be treated

with other agents such as fidaxomicin, which has been shown to be more active against
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NAP1/BI/027 resistant strains. New trials are currently underway studying vaccinations, other
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antibiotic treatments, and bacterial spores such as SER-109.

The use of fecal microbial transplantation in recurrent CDI has gained increasing
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popularity over the past few years. Early reports have shown favorable results with high success
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rates even in geriatric and immunocompromised patients. Studies looking at biodiversity of gut
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microflora have shed light on at-risk cohorts that are susceptible to recurrence and failure of

treatment.

Surgical treatment has classically consisted of emergency total abdominal colectomy with

end ileostomy, but mortality in this population is high. A novel technique using laparoscopic

loop ileostomy and colonic lavage as an alternative has been described with good results.

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Lastly, the relationship between Clostridium difficile and IBD is complex. Evidence

seems to suggest that CDI compounds the severity of IBD, with increased disease flares, higher

recurrence rates and morbidity. Patients with IBD also have higher rates of surgical intervention.

Small bowel Clostridium difficile enteritis is infrequently reported in patients who have

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undergone total proctocolectomy for ulcerative colitis.

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After our review of current treatment modalities, it is clear that additional and larger

randomized studies are necessary to further elucidate all aspects of CDI management.

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Table 1 - Severity Grading Scale - Infectious Disease Society of America9

Mild/Moderate Severe Severe, Complicated

WBC <15,000 cells/µL >15,000 cells/µL >15,000 cells/µL

Serum Cr <1.5x premorbid base >1.5x premorbid base >1.5x premorbid base

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Additional Findings Hypotension, ileus or
megacolon present

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Table 2 - Severity Grading Scale - American College of Gastroenterology17

Mild Moderate Severe Complicated

Diarrhea only Diarrhea Diarrhea Any of the following:
Any additional sign or WBC>15,000 Hypotension (with or
symptom not meeting cells/µL without vasopressor
Severe or use)

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Complicated criteria
Serum albumin End organ failure
<3g/dL

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Abdominal Altered mental status
tenderness
Fever >38.5º

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Ileus or abdominal
distention or tenderness
WBC>35,000 cells/µL
Serum lactate >2.2

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mmol/L
Admission to the ICU
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Figure 1. The number of clinical trials for Clostridium difficile therapies and interventions

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initiated by treatment area from 2002-2015.27
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