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  © 2016 Hellenic Society of Gastroenterology www.annalsgastro.gr  Annals of Gastroenterology (2016)  29, 147-154 REVIEW ARTICLE Clostridium difficile  infection: a review of current and emerging therapies Andrew Ofosu Jefferson Medical College, USA Introduction Clostridium difficile  ( C. difficile ) is now widely recognized as the leading cause o nosocomial diarrhea worldwide with associated substantial morbidity and mortality [1,2]. Recent data suggest an increase in both the incidence and severity o C. difficile  inection (CDI) [3]. Over 250,000 people need hospital care and at least 14,000 people die rom CDI in the United States each year based on statistics rom the Centers o Disease Control and Prevention [4].Te recent increase in incidence and severity is due to the emergence o the hypervirulent strain, NAP1/BI/ribotype 027 that is more resistant to antibiotics and produces more toxin [5-7]. CDI is most requently caused by exposure to antibiotics, which alters the natural flora o the intestines [8]. Depletion o gut flora allows endogenous or environmental C. difficile  to prolierate in the colon and produce toxins. Meta-analyses o current data implicate clindamycin, cephalosporins, and fluoroquinolone antibiotics as the highest risk antibiotics [9-11]. CDI occurs particularly during the use o the antibiotic and within the first month afer antibiotic use, but the risk persists or up to 90 days [12]. However, in community-acquired CDI patients, proton pump inhibitor exposure has been observed in about 31% o patients with CDI, with no exposure to antibiotics [13]. Tis review discusses the clinical eatures o CDI, diagnosis o C. difficile  and highlights current and new emerging therapies or CDI. Microbiology C. difficile  is an anaerobic toxin-producing gram-positive spore orming bacterium. ransmission is via the ecal-oral route. Colitis and diarrhea is mediated through the release o two exotoxins by C. difficile : toxin A (“enterotoxin”) and toxin B (“cytotoxin”). oxin A, causes increased intestinal permeability and fluid secretion. oxin B, leads to intense colonic inflammation. oxins bound to receptors gain intracellular entry by modification o Rho proteins-small glutamyl transpeptidase-binding proteins. Tese proteins are involved in actin polymerization, cytoskeletal architecture, and cell movement. Te resultant effect is the loss o intercellular tight Department o Medicine, Jefferson Medical College, Philadelphia, USAConflict o Interest: NoneCorrespondence to: Andrew Oosu, MD, Jefferson Medical College, 211 S 9 th  St #210, Philadelphia, PA 19107, USA, el.: +1 215 955 1533, e-mail: Andrew.oosu@jefferson.eduReceived 4 November 2015; accepted 29 December 2015DOI: http://dx.doi.org/10.20524/aog.2016.0006 Clostridium difficile  ( C. difficile ) inection (CDI) is the most common cause o healthcare-associated inections in US hospitals. Te epidemic strain NAP1/BI/ribotype 027 accounts or outbreaks worldwide, with increasing mortality and severity. CDI is acquired rom an endogenous source or rom spores in the environment, most easily acquired during the hospital stay. Te use o antimicrobials disrupts the intestinal microflora enabling C. difficile  to prolierate in the colon and produce toxins. Clinical diagnosis in symptomatic patients requires toxin detection rom stool specimens and rarely in combination with stool culture to increase sensitivity. However, stool culture is essential or epidemiological studies. Oral metronidazole is the recommended therapy or milder cases o CDI and oral vancomycin or fidaxomicin or more severe cases. reatment o first recurrence involves the use o the same therapy used in the initial CDI. In the event o a second recurrence oral vancomycin ofen given in a tapered dose or intermittently, or fidaxomicin may be used. Fecal transplantation is playing an immense role in therapy o recurrent CDI with remarkable results. Fulminant colitis and toxic megacolon warrant surgical intervention. Novel approaches including new antibiotics and immunotherapy against CDI or its toxins appear to be o potential value. Keywords Clostridium difficile  inection, ecal microbial transplantation, fidaxomicin, humanized monoclonal antitoxin antibodies, toxic megacolon  Ann Gastroenterol 2016; 29 (2): 147-154 Abstract   Annals of Gastroenterology   29 148 A. Oosu  junctions leading to secretory diarrhea, and an inflammatory response with eventual cell death [14]. Clinical manifestations/diagnosis of CDI Te clinical presentation o CDI ranges rom asymptomatic carriage, to mild or moderate diarrhea, to ulminant colitis [15,16]. Tree or more watery, nonbloody stools per 24-h period is the hallmark o symptomatic illness [17]. Mild disease is characterized by diarrhea in the absence o signs and symptoms o colitis whereas moderate disease is characterized by moderate diarrhea with colitis maniested by ever, abdominal cramps and discomort, usually in the lower quadrants [18]. Severe disease is characterized by white blood cell count o >15,000 cells/μL, serum albumin <3 g/dL, and/or a serum creatinine level ≥1.5 times the premorbid level [19].Te clinical eatures o CDI/ulminant colitis include ever, diarrhea leading to hypovolemia, severe lower quadrant or diffuse abdominal pain, abdominal distention, severe lactic acidosis, hypoalbuminemia, and significant leukocytosis (40,000 white blood cells/μL or higher) [20]. Fulminant colitis can lead to bowel peroration and toxic megacolon. Other complications o C. difficile  include electrolyte imbalance, renal ailure rom severe dehydration, systemic inflammatory response syndromes and sepsis. Bacteremia is rare, with ew case reports o C. difficile  bacteremia [21]. Diagnosis is based on the presentation o signs and symptoms o CDI, with confirmed microbiological evidence o toxin-producing C. difficile  in stools, or colonoscopic or histopathological findings o pseudomembranous colitis (PMC) particularly with the exclusion o other causes o PMC [22]. However, not all patients with CDI have pseudomembranes, particularly patients with mild or partially treated inection. Tere are reports o PMC caused by other organisms such as Salmonella  [23]. Te absence o pseudomembranes does not rule out CDI. Laboratory diagnosis of CDI CDI should only be investigated in patients with diarrhea. Diagnostic tests available include enzyme immunoassays (EIA) or toxins, EIA or C. difficile  glutamate dehydrogenase (GDH) and nucleic acid amplification tests (NAAs, or Polymerase chain reaction (PCR) or C. difficile  toxin genes. Other diagnostic tests include toxigenic cultures, or cell culture neutralization assays (CCNA) [24].One strategy to improve sensitivity is through a two-step method that uses EIA detection o GDH as an initial screen. Antigen-positive specimens or GDH (and negative or toxin(s) i tested) are urther assessed using a NAA or CCNA [25]. oxigenic culture is considered the gold standard, however its use limited in the clinical setting given the duration o time or culture results to become available. NAAs (e.g. PCR) are highly specific (>95%), and highly sensitivity rapid tests or C. difficile  detection. Tis diagnostic test affords a quick and efficient way o detecting CDI [26]. Imaging studies and procedures Radiology  Radiographic findings are neither sensitive nor specific or CDI. Radiographic eatures on abdominal radiography suggestive o CDI include polypoid mucosal thickening, haustral old thickening, or gaseous distention o the colon. Abdominal computed tomography scan findings include low-attenuation colonic mural thickening corresponding to mucosal and sub-mucosal edema, with wall thickening involving the entire colon (pancolitis), peri-colonic at stranding, and ascites [27]. Endoscopy  Endoscopy is indicated when there is a high clinical suspicion or CDI with negative laboratory assay or when other colonic diseases are in the differential diagnosis (e.g. inflammatory bowel disease) [28]. ypically in negative laboratory assay, CDI is suggestive by the direct visualization o pseudomembranes on lower gastrointestinal endoscopy (either proctosigmoidoscopy or colonoscopy) or by histopathologic examination [22,29]. Pseudomembranes appear as raised, yellowish white, 2- to 10-mm plaques which overly an erythematous and edematous mucosa (Fig. 1). Management of CDI General principles Te inducing antibiotic(s) or other medications that predispose to CDI should be stopped as soon as possible, is a strong recommendation in the treatment o CDI [30]. Supportive care should include careul fluids and electrolyte Figure 1  Endoscopic view o Clostridium difficile -induced pseudomembranous colitis. Yellow pseudomembranes attached to the colonic mucosa with riable erythematous colonic mucosa Courtesy of Kenolisa Onwueme, MD, PhD   Annals of Gastroenterology   29 Clostridium difficile  inection 149 management. Te use o anti-motility agents or CDI treatment is discouraged. Patients should be placed on contact precautions in all suspected CDI [19]. Hand hygiene with soap and water by healthcare providers, hospital visitors and patients is more potent than alcohol-based hand sanitizers in eliminating C. difficile  spores, due to the inherent resistance o C. difficile  spores to alcohol [31]. One time use o disposable equipment is recommended to prevent transmission o CDI. Sole use o non-disposable medical equipment in a patient with CDI with thorough cleaning afer use is recommended [19]. In the event o a high clinical suspicion or CDI, medical therapy is recommended beore laboratory confirmation [19]. Medical therapy  Te choice o antibiotic therapy should be tailored to the severity o disease presentation. a. Mild-to-moderate disease:  Te antibiotics metronidazole or vancomycin have been the initial treatment options or CDI. Recommended regimen is oral metronidazole 500 mg t.i.d. or 10-14 days. Te use o intravenous metronidazole at a dose o 500 mg t.i.d. can also be used or treatment o CDI in lieu o oral therapy [32]. Oral vancomycin 125 mg q.i.d. or 10-14 days can be as used alternatively or non-severe CDI. Vancomycin is usually preerred in patients who are intolerant/allergic to metronidazole, pregnant and nursing mothers [19]. Failure to respond to metronidazole therapy within 5-7 days requires a change in therapy to standard dose o vancomycin (125 mg orally q.i.d.) [19,32], (able 1). b. Treating severe or complicated CDI:  Prompt initiation o oral vancomycin, 125 mg q.i.d., or severely ill patients is critical. Some clinicians avor a higher dosing o vancomycin, 500 mg q.i.d., or severe disease [33]. Vancomycin may also be administered rectally as a retention enema in the setting o ileus, megacolon, and colonic diversion [34]. Intravenous metronidazole is added as adjunctive therapy or ileus or severe/complicated CDI, typically with vancomycin when administered orally, or as a retention enema [35]. Te use o fidaxomicin (200 mg orally b.i.d.) is a reasonable alternative in patients with severe disease with less clinical response to oral vancomycin. Fidaxomicin and vancomycin, have similar clinical cure rates; the OR (95%CI) was 1.17 (0.82-1.66) however sustained cure rates [1.75 (1.35-2.27)] are significantly higher or fidaxomicin than vancomycin with lower recurrence rate o fidaxomicin compared to vancomycin [0.47 (0.34-0.65)] [36]. Te apparent superiority o fidaxomicin in the treatment o CDI is limited by the cost o therapy. Tere is also some limited data on the use o intravenous tigecycline as a rescue therapy or the treatment o patients with severe CDI, in whom therapy with vancomycin and metronidazole ailed [37]. However, there are no randomized clinical trials to support this evidence. Early surgical consultation is warranted in severe complicated CDI. Surgery is recommended in the presence o peritoneal signs, severe ileus, and toxic megacolon. In a retrospective observational cohort study, immunocompetent patients aged ≥65 years with a white blood cell count ≥20,000 cells/μL and/or a plasma lactate >2.2 mmol/L had good clinical outcomes ollowing colectomy [38]. Recurrence of C. difficile Recurrent CDI is defined by the complete resolution o presenting symptoms on appropriate therapy, with subsequent relapse and return o symptoms within eight weeks o the initial episode completion o treatment [39]. About 10-20% o CDI recur afer an initial episode o C. difficile , but when Table 1 Recommendations rom the ACG [19] and the ESCMID [22] or Clostridium difficile  inection (CDI) treatment, based on the severity o disease CDI severityACG Guidelines (2013) [19]ESCMID Guidelines (2014) [22]Mild-to-moderate diseaseMetronidazole 500 mg PO t.i.d. 10 daysI intolerant to metronidazole o i no improvement in 5-7 days o metronidazole therapy: vancomycin 125 mg PO q.i.d. or 10 daysMetronidazole 500 mg PO t.i.d. 10 daysAlternatives:- Vancomycin 125 mg PO q.i.d. or 10 days- Fidaxomicin 200 mg PO bid 10 daysSevere diseaseVancomycin 125 mg PO q.i.d. or 10 daysVancomycin 125 mg PO q.i.d. or 10 daysAlternative:- Fidaxomicin 200 mg PO b.i.d. 10 daysSevere and complicated diseaseVancomycin 500 mg PO q.i.d. plus metronidazole 500 mg IV t.i.d.I ileus, toxic colon or significant abdominal distention:  vancomycin 500 mg in 500 mL saline per rectum q.i.d.Surgical consultation/management in complicated disease; e.g. subtotal colectomy with ileostomy or diverting loop ileostomy and colonic lavage+antibiotic treatmentVancomycin 125 mg PO q.i.d. or 10 daysAlternative:- Fidaxomicin 200 mg PO bid 10 daysSurgical consultation/management or complicated diseases-e.g. subtotal colectomy with ileostomy or diverting loop ileostomy and colonic lavage+antibiotic treatmentRecurrent disease1 st  recurrence: repeat the same antibiotic used or the initial episode (metronidazole or vancomycin, standard regimen)2 nd  recurrence: pulsed or tapered vancomycin regimen (see text)3 rd  recurrence: ecal microbiota transplant plus vancomycin 1 st  recurrence: vancomycin or fidaxomicin (standard regimen) 2 nd  recurrence: pulsed or tapered vancomycin regimen or fidaxomicin (standard regimen) 3 rd  recurrence: ecal microbiota transplant plus vancomycin Some data Adapted rom: Carmo J, Marques S, et al   [33]   Annals of Gastroenterology   29 150 A. Oosu a patient has had one recurrence, rates o urther recurrences increase to 40-65% [40].Impaired colonization resistance, allowing prolieration o C. difficile  and impaired immune response demonstrated by lower levels o immunoglobulin G antibody to toxin A are thought to contribute to recurrence [41]. Other risk actors or recurrent disease include advanced age, additional courses o antibiotics and/or chemotherapy, use o medications such as proton pump inhibitors, prolonged hospital stay, and prior episodes o recurrent CDI [42]. Tere is evidence to show that a majority o recurrence o CDI is due to relapses o inection with the srcinal strain rather than re-inection [43,44]. Management of initial recurrence Both the Inectious Diseases Society o America (IDSA) and the European Society o Clinical Microbiology and Inectious Diseases (ESCMID) recommend treating the first recurrence o CDI with the same therapeutic agent used in the initial episode [22]. Metronidazole is preerred or the treatment o non-severe initial recurrence. Te use o oral vancomycin should be based the severity o disease at the time o first recurrence rather than its use in prior CDI. Fidaxomicin dosed at 200 mg b.i.d. or 10 days is an alternative agent or treatment o an initial recurrence o CDI [45]. Fidaxomicin has similar efficacy to vancomycin in achieving a clinical response in patients with a first recurrence o CDI, however is exceptional in preventing a second recurrence within 28 days (19.7 versus 35.5%; 95%CI -30 to -0.3%); P=0.045) [46]. Management of subsequent recurrences of CDI  A second recurrence o CDI can be treated with fidaxomicin (200 mg b.i.d. or 10 days) or by a pulsed or tapping dose o oral vancomycin [47]. Intermittent and tapered vancomycin regimens have been evaluated in an observational study in a cohort o 163 with active recurrent CDI. O the 163 cases, 44.8% had a recurrence o CDI. A tapering course o vancomycin yielded ewer recurrences (31%, P=0.01) as did pulsed dosing o vancomycin (14.3%, P=0.02) compared with a recurrence rate o 45% in patients on other regimens [40]. Te data shows that tapered or pulsed dosing regimens o vancomycin leads to an apparent better cure o recurrent CDI. Bacteriotherapy  Fecal microbiota transplantation (FM) reers to the inusion o ecal suspension rom a healthy donor with the aim o reinstating the gut microbiota o the recipient or curative purposes. Te continuous use o antibiotics leads to the suppression o the host gut microbiota leading to a deficiency in microbes, which generally dominate within the gut microbiota and a decrease in the overall microbiome diversity [48]. Less diversity in colonic microbiota in patients with recurrent CDI compared to healthy individuals has also been demonstrated in some studies [49]. Te resultant effect allows the overgrowth o C. difficile  and the production o toxins leading to CDI and recurrent CDI. Essentially, the role o ecal transplantation o stool rom healthy individuals is to reestablish the diverse, “normal” gut microbiome within the colon breaking the cycle o recurrence. Multiple studies support the saety and efficacy o FM in the treatment o C. difficile -associated diarrhea in patients with recurrent disease afer initial antibiotic therapy [50]. Tere is also mounting evidence in the efficacy o FM in severe C. difficile - associated diarrhea [51]. Te Food and Drug Administration has approved FM as an investigational new drug or use in reractory or re-current CDI afer ailure o standard treatment regimens [52]. Surawicz et al   recommend FM in recurrent or relapsing CDI characterized by at least three episodes o mild-to-moderate CDI with lack o clinical response to a 6-8 week taper with vancomycin with or without an alternative antibiotic [19]. Additionally, Bakken et al have proposed the use o FM in moderate CDI not responding to standard therapy (vancomycin) or at least a week and severe CDI with no response to standard therapy afer 48 h [53] (able 2). Donor screening and selection Te majority o reported FM procedures were perormed with the instillation o resh stool suspensions rom related donors. Te ideal route o administration is yet to be determined. Administration o ecal suspensions by gastroscopy, nasogastric tube, or nasojejunal tube were marginally less effective than other routes o administration such as rectal tube/enema, or colonoscopy in a conducted systematic review. Colonoscopic FM has a slightly higher cure rate than nasogastric FM [54].Donor screening protocols are essential to minimize the risk o transmitted inection. Screening o donors include ull blood count, liver unction tests, screening or hepatitis A, B and C, human immunodeficiency virus I and II, human -cell lymphotrophic virus, Cytomegalovirus, Epstein-Barr  virus, syphilis, stool tests or C. difficile  toxin A and B, stool microscopy or ova cysts and parasites and selective stool culture (e.g., or Salmonella , Shigella , Escherichia coli  O157:H7 and Yersinia ) [55]. In addition to lab testing, a medical history is taken to exclude people with high risk sexual behaviors, use o antibiotics within the preceding 3 months, history o gastrointestinal comorbidities such as irritable bowel syndrome, inflammatory bowel disease, and chronic diarrhea [53].Historically, donors have been amily members, intimate partners, however, Hamilton et al   demonstrated that there Table 2 Proposed indications or ecal microbiota transplantation [19,52] Tree or more episodes o recurrent mild to moderate CDI with ailure to respond to a 6-8 week taper with vancomycin with the inclusion or exclusion o an alternative antibioticModerate CDI with no clinical response to standard therapy or at least 1 week wo or more episodes o severe CDI requiring hospitalizationSevere CDI with no response to standard therapy afer 48 h CDI, Clostridium difficile infection
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