Clostridium difficile infection

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EIA: enzyme immunoassay; GDH: glutamate dehydrogenase; ToxAB: toxins A and B." ] ] ] "textoCompleto" => "IntroductionClostridium difficile was first described by Hall and O’Toole<a class="elsevierStyleCrossRef" href="#bib0305">1</a> in 1935 as a strict sporulating anaerobic bacteria colonizing the intestinal mucosa of healthy neonates. Initially called Bacillus difficilis, it was soon found that certain variants produced toxins with pathogenic properties in humans.<a class="elsevierStyleCrossRef" href="#bib0310">2</a> Since then, there has been increasing evidence of the importance of infections caused by this microorganism to the point of becoming the leading cause of nosocomial infection in many first-world countries.PathogenicityAs with other Clostridium species, the main virulence factors of C. difficile are protein toxins. The major C. difficile toxins are TcdA, toxin A or enterotoxin (308kDa), and TcdB, toxin B or cytotoxin (270kDa).<a class="elsevierStyleCrossRef" href="#bib0315">3</a> Both toxins belong to the large group of Clostridium toxins, including also the TcsH and TcsL toxins of C. sordellii and toxin Tcnα of C. novyi, all characterized by a molecular weight close to 300 KDa.<a class="elsevierStyleCrossRef" href="#bib0320">4</a> The genes encoding toxin A (tcdA) and toxin B (tcdB) are located in a pathogenicity locus of the C. difficile chromosome about 19.6kb size (PaLoc) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0325">5,6</a> Within this pathogenicity locus there are 3 other genes that, in one way or another, are related to the expression of these toxins: the tcdC gene, which behaves as a negative regulator of toxin A and B production, with maximal expression in the early exponential phase, and dropping as the bacteria approaches the stationary phase; The tcdD gene, a positive regulator of toxin expression and reaching its maximal expression in the stationary phase of C. difficile growth; And finally the tcdE gene, which appears to encode for proteins called holins, present in the cell wall of some bacteria, which let toxins A and B out of the cell.<a class="elsevierStyleCrossRef" href="#bib0335">7</a> Alteration in the tcdC gene may lead to toxin overproduction, as in the case with ribotype 027 hypervirulent strains, which have an 18-base pair deletion and a point mutation at nucleotide 117 of this gene. Recently it has been proven that there is a regulatory system for the production of toxins A and B, called agr1 locus.<a class="elsevierStyleCrossRef" href="#bib0340">8</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>There is a third toxin, called binary toxin, which is encoded by the cdtA and cdtB genes, located outside the pathogenicity region, and whose pathogenic role remains to be elucidated, since there are discrepancies in correlating the severity of the infection by C. difficile (CDI) with the presence of these toxins in C. difficile strains.<a class="elsevierStyleCrossRefs" href="#bib0345">9,10</a>The mechanisms of action of toxins A and B in human intestinal cells are not entirely known. Toxins enter colon cells by endocytosis from disaccharide receptors for toxin A and of unknown nature for toxin B. These receptors are low in number or are not present in children under 2 years of age, reason why this group of population does not usually develop the disease in spite of its high rate of colonization by toxigenic C. difficile. Once inside the intestinal cells these toxins irreversibly inactivate the GTPases, Rho, Rac and Cdc-42 through glycosylation, resulting in an interruption of certain vital cellular mechanisms, such as cytoskeletal chitin regulation, cell binding, cell motility and cell migration, in addition to promoting certain inflammatory processes, the production of cytokines and chemokines or the infiltration of neutrophils in the intestinal lumen. All these mechanisms induced by toxins A and B lead to lysis of the intestinal cell and typical symptoms of CDI.<a class="elsevierStyleCrossRef" href="#bib0320">4</a>EpidemiologyC. difficile is isolated in feces from 3% healthy individuals, 20% from hospitalized patients and up to 80% from children under 1 year of age, a significant number of these strains being toxigenic. The main international guidelines define healthcare-associated CDI (HA-CDI) as the infection with symptoms beginning 48h after the patient's admission to a health center (HC), or when symptoms begin in the community within the first 4 weeks after discharge from a HC. In contrast, community-based CDI is defined as symptoms beginning in the community or within the first 48 hours after admission to a HC, if the patient has not been discharged from a HC within the 12 previous weeks. Finally, CDI is considered as indeterminate or uncertain when the patient is discharged from a HC 4–12 weeks before the onset of symptoms (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>The main risk factors for acquiring a HA-CDI are previous antibiotic intake (60–90% of cases), prolonged hospital stay and advanced age<a class="elsevierStyleCrossRefs" href="#bib0355">11–19</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Studies assessing risk factors for community-based CDI emphasize on important differences regarding the typical risk factors for HC-CDI. Thus, in an analysis by Kuntz et al. in 2011 it was found that 27% of patients with community-based CDI had not received antibiotics during the last 180 days prior to the episode and 17% had no typical risk factors for nosocomial CDI.<a class="elsevierStyleCrossRef" href="#bib0400">20</a> This significant number of patients with CDI without any typical risk factor may lead to an underdiagnosis of CDI, as proven in a Spanish study conducted in 2013. In this study, one in 2 CDI episodes was not diagnosed because of a lack of clinical suspicion, especially in subjects aged under 65 years, patients not hospitalized or patients hospitalized less than 3 days.<a class="elsevierStyleCrossRef" href="#bib0405">21</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The incidence of CDI experienced a dramatic increase at the beginning of this century in North America and northern Europe due to the eruption of C. difficile strain NAP1/BI/027.<a class="elsevierStyleCrossRef" href="#bib0410">22</a> This strain, whose first outbreaks occurred in Quebec (Canada) and USA, appeared to be more virulent and more refractory to treatment than other circulating strains, especially in patients aged over 65.<a class="elsevierStyleCrossRef" href="#bib0415">23</a> In Europe, this strain was introduced by the United Kingdom and, little by little, was transmitted to the countries of central and southern Europe.<a class="elsevierStyleCrossRef" href="#bib0420">24</a> In Spain, the first episode was described in 2007 in a patient from England, while the second was an employee in the Microbiology laboratory who was manipulating the index case strain.<a class="elsevierStyleCrossRef" href="#bib0425">25</a> Following the subsequent description in Spain of a few specific cases, a large outbreak of this ribotype occurred in late 2014 in the Community of Madrid, on a single institution in which there were over 100 cases in a few months.<a class="elsevierStyleCrossRef" href="#bib0430">26</a>In a European multi-center (482 laboratories) and multinational (20 countries) study in 2013 it was estimated a global nosocomial CDI incidence of 18 cases per 10,000 hospital stays. The ribotypes most frequently causing disease were: 027 (19%), 001/072 (11%) and 014/020 (10%). Ribotype 027 was more prevalent in Central European countries such as Romania, Hungary, Poland or Germany, coinciding with a higher incidence of CDI in these countries.<a class="elsevierStyleCrossRef" href="#bib0435">27</a> In Spain, the HA-CDI incidence was estimated in a study based on 2 prevalence cut points in 6.5 episodes per 10,000 hospital stays, although this value cannot be compared with the European multicenter study because of the different methods used. The distribution of the most prevalent ribotypes was: 078/126 (16%), 014/020 (13%) and 001/072 (12%), whereas there was only 3% ribotype 027 strains.<a class="elsevierStyleCrossRef" href="#bib0405">21</a>Clinical manifestationsThe clinical manifestations of CDI are very varied and range from an asymptomatic carrier state to fulminant colitis<a class="elsevierStyleCrossRef" href="#bib0440">28</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The severity of the disease depends on two factors: first, the characteristics of the host, mainly their immune status, and, second, the characteristics of the CDI-producing strain, especially its invasive capacity and ability to produce toxins. The most frequent presentation of CDI is moderate diarrhea similar to that caused by other enteropathogenic bacteria and that, sometimes, it ceases simply with the withdrawal of the inducing antibiotic. The main symptoms are general malaise, abdominal pain, nausea, vomiting, liquid or semi-liquid stools, fever and leukocytosis.<a class="elsevierStyleCrossRef" href="#bib0445">29</a> In a small number of patients with CDI, we can easily observe in a colonoscopy pseudomembranes consisting of yellowish-white plaques 2–20mm in diameter in the lumen of the colon.<a class="elsevierStyleCrossRef" href="#bib0440">28</a> One of the most serious clinical presentations of CDI is fulminant colitis accompanied by a sudden increase in the white blood cell count by up to 50,000 leukocytes/μl known as the leukemoid reaction.<a class="elsevierStyleCrossRef" href="#bib0450">30</a> It is estimated that severe CDI accompanied by a leukemoid reaction, although rare, has a mortality rate close to 50%.<a class="elsevierStyleCrossRef" href="#bib0455">31</a> Another serious CDI is paralytic ileus, which occurs without diarrhea and may evolve to toxic megacolon with intestinal perforation and peritonitis and with a high mortality rate. One of the major complications of CDI is recurrences, defined as the occurrence of a new episode of CDI within 8 weeks of a first episode that has been treated and whose symptoms have been initially resolved. Recurrences are reported in approximately 15–25% of episodes and may be due to either a new episode caused by the same strain (relapse) or a new infection caused by a different strain (reinfection). After a first recurrence, the patient has a 35–50% chance of having new relapses and this number remains as the risk of subsequent recurrences.<a class="elsevierStyleCrossRefs" href="#bib0460">32–34</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>C. difficile is isolated only rarely in extraintestinal samples. It may appear as part of the microbiota of abscesses or peritoneal collections, in patients with colonic disease and with previous perforations. Its presence is a lot more rare and dubiously significant in pyogenic infections located far from the peritoneum (brain abscess, etc.), and even in some cases, in blood cultures. This presence should be interpreted very cautiously, since it probably reflects the intestinal origin of the process. Therefore, the treatment to be applied is the same as with the presence of any other clostridium in the same circumstances.<a class="elsevierStyleCrossRef" href="#bib0475">35</a>DiagnosisThe diagnosis of CDI requires meeting two conditions: (a) the existence, of symptoms compatible with the infection, ruling out any other potential cause, generally the presence of diarrhea (3 or more unformed stools in the last 24h); (b) the detection of toxins A and/or B or toxigenic C. difficile in the sample, or the detection of pseudomembranes in the patient's colon through endoscopy, in the stump of a colostomy or ileostomy or at autopsy. Since the presence of pseudomembranes is evidenced in a relatively low number of CDI cases, and is not pathognomonic<a class="elsevierStyleCrossRef" href="#bib0480">36</a> the toxin demonstration or the isolation of toxigenic C. difficile have become the main methods used for the diagnosis of CDI. From the definition above we can conclude that the diagnosis should only be made in symptomatic patients and unformed stool samples, except when the patient's special conditions (paralytic ileus or toxic megacolon) prevent the presence of diarrhea.<a class="elsevierStyleCrossRefs" href="#bib0460">32,37</a>There are different laboratory assays used to diagnose CDI. The most widely used are those based on enzyme immunoassay (EIA), usually immunochromatographic assays, for the detection of toxins A and B. These are very simple and fast assays which, in addition, have the advantage of being cheap.<a class="elsevierStyleCrossRef" href="#bib0490">38</a> The main problem is their lack of sensitivity, since most assays have values close to 50%. On the other hand, its specificity is 95–98%, so that in a stool sample population of a standard laboratory in which the number of positives barely reaches 10%, the positive predictive value of these assays is 40–60%.<a class="elsevierStyleCrossRefs" href="#bib0495">39–42</a>Another group of EIA techniques widely used in laboratories are those that detect glutamate dehydrogenase (GDH), an enzyme present in both toxigenic and non-toxigenic C. difficile. Most of these techniques are immunochromatographic assays, low cost, very fast and easy to use. In addition, they have a high sensitivity – close to 90% – compared to the toxigenic culture, although they have low specificity because they also detect the C. difficile non-toxigenic strains.<a class="elsevierStyleCrossRefs" href="#bib0515">43–47</a>In a third group of rapid diagnostic assays we would include the molecular assays that detect the toxin A or B gene of C. difficile. These assays have undergone significant development in recent years. They are automated or semiautomated commercial systems capable of detecting these genes in a few hours (some of them in less than an hour) and are based on various amplification assays, such as real-time PCR or isothermal amplification.<a class="elsevierStyleCrossRef" href="#bib0540">48</a> The sensitivity and specificity of these techniques are very high, some of them close to those obtained by the toxigenic culture. Its main drawback is that they are still expensive assays, which prevents their widespread use in most of the Microbiology laboratories.The cell cytotoxicity assay, the first system used for the diagnosis of CDI since the late 1970s, consists in detecting the cytotoxic activity of the stool sample in a cell monolayer by observing cell lysis and neutralization of this activity through specific antitoxins.<a class="elsevierStyleCrossRef" href="#bib0545">49</a> The high correlation between the cytotoxic activity of the sample and the presence of disease in the patient made this assay appear as a reference in the diagnosis of CDI for many years. Its main drawbacks are its low sensitivity, close to 60%; and requiring the use of cell cultures, which leads to significant diagnostic delay (24–48h) after sample reception.<a class="elsevierStyleCrossRefs" href="#bib0550">50,51</a>Almost simultaneously with the cytotoxicity assay, the toxigenic culture was developed, consisting of the sample culture in a medium selective for C. difficile and the subsequent detection of toxins A and B of C. difficile from the isolates obtained in the culture. This is a very sensitive and specific method very accessible to most laboratories and has therefore been considered as the reference assay for the diagnosis of CDI. Its main drawback is that the procedure requires a period of time of 24–96h.<a class="elsevierStyleCrossRef" href="#bib0560">52</a>Clearly, none of the diagnostic methods described can be used as a single procedure for diagnosing CDI either because of lack of internal validity (sensitivity and specificity), or because of the diagnostic speed or price of every test. For this reason, a series of algorithms for diagnosing CDI have been developed during the last years, recommended by the main national and international guidelines (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>)<a class="elsevierStyleCrossRefs" href="#bib0460">32,53</a> (<a href="http://www.asm.org/images/pdf/Clinical/clostridiumdifficile9-21.pdf">http://www.asm.org/images/pdf/Clinical/clostridiumdifficile9-21.pdf</a>). These algorithms are based on the detection of GDH as a screening test due to its high sensitivity and low cost, and a molecular assay that detects toxin A or B genes as a confirmatory test of positive results (2-step algorithm). In some cases the detection of toxins between both steps is included as the first method to confirm the positive results of the GDH detection, leaving the molecular method for the discordant results between the GDH and toxin detection (3-step-algorithm and multipass). In several studies evaluating these algorithms it has been proven that their sensitivity values range from 90% to 95% (sensitivity limited by the detection of GDH) and specificity values close to 100%, with a final price not much higher than the EIA-based techniques.<a class="elsevierStyleCrossRefs" href="#bib0515">43–47</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Despite the existence and widespread recommendation of the use of such cost-effective algorithms, laboratories still use non-sensitive methods such as EIAs that detect toxins as the only diagnostic procedures. In a study conducted in 2013, in 111 Spanish laboratories, it was verified that almost half of these still belonged to this group. Therefore, the overall diagnostic sensitivity estimate of the laboratories participating in the study was 80.0%, finally resulting in a 15.5% underdiagnosis of the total CDI cases.<a class="elsevierStyleCrossRef" href="#bib0405">21</a>The description in the scientific literature of CDI episodes caused by ribotype 027 shows that these strains produce more transmissible, aggressive and recurrent episodes than the rest of the ribotypes. This is why the national guidelines for diagnosis of CDI recommend the early detection through molecular assays of these episodes in environments suffering from an epidemic caused by this ribotype or in which there is a high suspicion of its occurrence (increased cases of severe CDI, occurrence of CDI cases produced by this ribotype in nearby areas, detection of isolated cases in the institution, etc.). Early detection of these episodes makes it possible to take measures that help prevent their transmission to other patients and the use of a proper treatment aimed at improving the prognosis of the episode and to minimize the potential recurrences.<a class="elsevierStyleCrossRef" href="#bib0565">53</a>It has been shown that there is a positive correlation between the low number of molecular amplifications of the toxin B gene (marker of high toxigenic burden of C. difficile in the stool sample) and poor evolution (severe episodes, increased severity of disease or recurrences) of patients with CDI. Therefore, this system might be a good early predictor of poor outcome in patients with CDI that would facilitate the use of optimal treatments to improve the prognosis of this group of patients.<a class="elsevierStyleCrossRef" href="#bib0370">14</a>TreatmentIt depends on factors of both, patient and type of infection. For this reason, in the therapeutic guidelines of the ESCMID, the CDIs are grouped into 5 therapeutic groups: initial non-severe CDI, initial severe CDI, CDI with first recurrence (or risk of recurrence), CDI with multiple recurrences and CDI in patients with no possibility of oral treatment (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRef" href="#bib0460">32</a><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>In mild-moderate CDI episodes (not severe) in nonepidemic environments and whose infection has been clearly induced by antibiotics, the first-line therapy is, where possible, the withdrawal of the antibiotic inducing infection and observation of clinical response during 48h, adding specific therapy in case of clinical worsening.<a class="elsevierStyleCrossRef" href="#bib0570">54</a> Almost one in four episodes can be resolved with this simple measure. When necessary, the antibiotic treatment of choice for non-severe episodes is metronidazole (500mg/8h/10 days) orally.In the presence of a first recurrence or in case of a well-founded suspicion that the patient might present relapses or does not respond well to metronidazole, due to its risk factors, the treatment of choice is oral vancomycin (125mg/6mg/10 days) or oral fidaxomicin (200mg/12h/10 days). In case of a second recurrence the treatment proved to be most effective is fecal transplantation, after preparation for a few days with oral vancomycin. Fecal transplantation is transferring a fecal sample from a healthy donor to the patient's colon through colonoscopy, nasoduodenal tube, or encapsulated fecal material. Colon colonization with transplanted bacteria helps eliminate C. difficile and thus prevent new episodes. In a recent meta-analysis of over 600 patients with fecal transplantation, the efficacy of this long-term therapeutic method (≥90 days) was 94.5%.<a class="elsevierStyleCrossRef" href="#bib0575">55</a> An alternative to transplantation is the use of oral vancomycin in higher doses (2g/day initially) in a progressively decreasing regimen up to 4 or more weeks of treatment, ending with intermittent doses to promote the elimination of C. difficile in the bowel in both its vegetative and sporulated forms. The main drawback of this treatment is that it can induce the appearance of vancomycin-resistant enterococcus strains.In severe patients or suspected to evolve to a severe form the treatment of choice is oral vancomycin or fidaxomicin. The use of this latter drug has been relegated to the alternative position in many clinical guidelines, exclusively for reasons of price, but it has been shown to be better than vancomycin in preventing recurrences. Immunotherapy is undoubtedly part of the future in the treatment of severe CDI. Studies using monoclonal antibodies against C. difficile toxin B have been proven effective on severe CDI and recurrences.<a class="elsevierStyleCrossRef" href="#bib0580">56</a>Finally, when the patient cannot take any antibiotics orally, intravenous metronidazole (500mg/8h/10 days) is recommended with the addition of enteral vancomycin (500mg/6h/10 days) through nasogastric tube or enemas. Vancomycin is not effective for CDI through intravenous route because it reaches very low concentrations in the colon lumen.<a class="elsevierStyleCrossRef" href="#bib0585">57</a> An alternative to these treatments is iv tigecycline (50mg/12h/14 days), although with a low strength of recommendation, type C.ProphylaxisThe preventive measures of the CDI should be aimed at preventing both colonization of patients with C. difficile and subsequent microorganism overgrowth in the colon lumen of the colonized patient, factors usually necessary for a new case of CDI. Regarding prevention of colonization, it is essential to prevent the spore dissemination from patients with CDI. To this purpose, a rapid and effective diagnosis of CDI is important, in addition to rapid transmission by the laboratory of the positive results (and ideally of the negative ones) to initiate appropriate treatment of the episode as soon as possible and effective patient isolation measures. It should be a contact isolation, always trying that the patient be in a single room and, if this is not possible, shared with some other patients with CDI. On the other hand, all health and non-health personnel, who are in contact with the patient should wear gloves and gowns and dispose of them after contact, as well as wash their hands with soap and water (alcoholic solutions are not sporicidal). It is recommended that any material used with the patient be disposable and, if this is not possible, it should be disinfected prior to use with another patient. The use of rectal thermometers is not recommended. The use of sodium hypochlorite (1000ppm) is recommended for cleaning rooms and hospital equipment. We also recommend the use of specific and exclusive cleaning material for rooms with CDI patients. The rooms for patients with CDI should be cleaned thoroughly through reinforcing hygiene in toilets, devices surrounding the patient and the surfaces frequently used by the staff, always cleaning deeply after patient's discharge.<a class="elsevierStyleCrossRef" href="#bib0590">58</a> Certain procedures that allow more terminal decontamination, such as hydrogen peroxide vaporizers or those based on ultraviolet light, appear to be more effective in reducing the risk of acquiring C. difficile in patients who occupy a room previously occupied by a patient with CDI. For preventing C. difficile overgrowth in colonized patients, it is essential to prevent any unnecessary antimicrobial treatment by implementing programs for the rational use of antibiotics.<a class="elsevierStyleCrossRef" href="#bib0595">59</a>Several CDI vaccines are currently being developed, including some vaccines inactivated with various substances such as formaldehyde, and other alive substances that express, to a greater or lesser extent, attenuated forms of toxin A and/or toxin B. However, there is still no marketed vaccine that can be used selectively in at-risk groups.<a class="elsevierStyleCrossRef" href="#bib0600">60</a>ConclusionsCDI is the leading cause of nosocomial diarrhea in the first-world countries and an increasingly common cause of community diarrhea. The infection is caused by 2 types of toxins, toxin A and toxin B, while a third toxin, the binary toxin, has a little known role that still has to be elucidated. The arrival in Canada of a new hypervirulent clone belonging to ribotype 027 and its spread to USA and most part of Europe at the beginning of this century greatly increased both the CDI incidence and its associated mortality. The main risk factors for CDI are broad-spectrum antibiotics, hospitalization and advanced age, although there is a significant number of cases without any of these factors leading to a significant underdiagnosis of the disease. Thus, in Spain, one in two episodes of CDI is not diagnosed because there was no clinical suspicion, especially in young and non-hospitalized patients, or because of poor sensitivity of the diagnostic methods. Although it usually occurs in the form of mild diarrhea, CDI can lead to severe forms that can become life-threatening. The emergence of methods of gene amplification of C. difficile toxins has led to a revolution in the diagnosis of this infection, since they allow rapid and effective diagnosis of the disease when used as confirmatory methods in algorithms with screening systems based on GDH detection. The treatment recommended depends on the type of infection and the patient's characteristics, being metronidazole, vancomycin, fidaxomycin and fecal transplantation the main treatments recommended by international guidelines, which will soon be complemented with the use of monoclonal antitoxin antibodies.Conflict of interestsThe authors report no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres851024" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec845663" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres851023" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec845662" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Pathogenicity" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Epidemiology" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Clinical manifestations" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Diagnosis" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Treatment" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Prophylaxis" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Conclusions" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflict of interests" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-12-03" "fechaAceptado" => "2017-01-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec845663" "palabras" => array:6 [ 0 => "Clostridium difficile" 1 => "Pseudomembranous colitis" 2 => "Metronidazole" 3 => "Vancomycin" 4 => "Fidaxomicine" 5 => "Recurrence" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec845662" "palabras" => array:6 [ 0 => "Clostridium difficile" 1 => "Colitis pseudomembranosa" 2 => "Metronidazol" 3 => "Vancomicina" 4 => "Fidaxomicina" 5 => "Recurrencia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Clostridium difficile infection (CDI) is the main cause of nosocomial diarrhea in industrialized countries and the source of a growing number of cases of diarrhea in the community. The outbreak of the hypervirulent strain belonging to ribotype 027 has increased the incidence and severity of CDI in some countries. Although CDI usually courses as a mild diarrhea it can lead to severe forms such as toxic megacolon or septic shock. One of every 2 episodes of CDI is not diagnosed in Spanish hospitals due to a lack of clinical suspicion or the use of insensitive diagnostic methods. The diagnostic techniques of choice are algorithms based on the detection of glutamate dehydrogenase and molecular detection of the genes of the toxins with or without the direct detection of the toxins. The recommended treatment for CDI depends on the type of infection and the characteristics of the patient." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La infección por Clostridium difficile (ICD) es la principal causa de diarrea nosocomial en países industrializados y el origen de un número de casos cada vez mayor de diarrea en la comunidad. La irrupción de la cepa del ribotipo 027 ha incrementado en algunos países la incidencia y la gravedad de la ICD. Aunque suele cursar como una diarrea leve/moderada, puede dar lugar a formas graves, como megacolon tóxico y shock séptico. Uno de cada 2 episodios de ICD no es diagnosticado en los hospitales españoles por falta de sospecha clínica o por el uso de métodos diagnósticos poco sensibles. Se recomiendan algoritmos diagnósticos basados en la detección de glutamato deshidrogenasa y en la detección molecular de los genes de las toxinas con o sin la detección directa de las toxinas. El tratamiento recomendado de la ICD depende del tipo de infección y las características del paciente." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Alcalá Hernández L, Reigadas Ramírez E, Bouza Santiago E. Infección por Clostridium difficile. Med Clin (Barc). 2017;148:456–463." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 635 "Ancho" => 2514 "Tamanyo" => 81277 ] ] "descripcion" => array:1 [ "en" => "Pathogenicity locus (PaLoc) in which the genes of Clostridium difficile for toxins A and B and their regulatory genes are located." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 970 "Ancho" => 3183 "Tamanyo" => 154908 ] ] "descripcion" => array:1 [ "en" => "Epidemiological classification of Clostridium difficile infection." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2120 "Ancho" => 3336 "Tamanyo" => 356508 ] ] "descripcion" => array:1 [ "en" => "Diagnostic algorithms for Clostridium difficile infection. EIA: enzyme immunoassay; GDH: glutamate dehydrogenase; ToxAB: toxins A and B." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "CDI: Clostridium difficile infection; HIV: human immunodeficiency virus." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of episode \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk factors \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="8" align="left" valign="top">First episode</td><td class="td" title="table-entry " align="left" valign="top">Antibiotics (clindamycin, beta-lactams, fluoroquinolones and others) for 6–8 previous weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Prolonged hospital stay \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Advanced age, consequence of higher number of underlying diseases and low level of protective antibodies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oncological diseases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">immunosuppression \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Malnutrition \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Solid organ transplantation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HIV infection. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="7" align="left" valign="top">Recurrence</td><td class="td" title="table-entry " align="left" valign="top">Advanced age \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antimicrobial maintenance after CDI episode \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Low albumin levels \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Prolonged hospital stay \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Admission to an intensive care unit \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Severe underlying disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">High toxin burden in feces \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1436577.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Major risk factors for health center-associated Clostridium difficile infection." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Modified from Cohen et al.<a class="elsevierStyleCrossRef" href="#bib0485">37</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of Clostridium difficile infection \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical or laboratory characteristics \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mild/moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Leukocytosis<15,000cells/μl or serum creatinine <1.5 times baseline \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Serious \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Leukocytosis≥15,000cells/μl or serum creatinine≥1.5 times baseline \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Serious-complicated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypotension or shock, ileus, megacolon \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1436576.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Classification of Clostridium difficile infection depending on its severity." ] ] 5 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Degree of strength of recommendation: A, strongly recommends its use; B, moderately recommends its use; C, recommends its use marginally; D, recommends non-use. Quality of Evidence: I, evidence of at least one randomized, correctly designed, controlled clinical trial; II, evidence of at least one well-designed non-randomized clinical trial, from analytical cohort or case-control studies (preferably more than one-center), multiple time series, or irrefutable results from uncontrolled experimental studies; III, evidence of expert opinions based on their clinical experience, descriptive case studies, or expert committee reports.Modified from Debast et al.<a class="elsevierStyleCrossRef" href="#bib0460">32</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of infection \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of therapy \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="7" align="left" valign="top">Non-serious disease</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Oral antibiotic therapy</td><td class="td" title="table-entry " align="left" valign="top">Oral metronidazole 500mg/8h/10 days (A-I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Vancomycin 125mg/6h/10 days (B-I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Fidaxomycin 200mg/12h/10 days (B-I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">Without antibiotic therapy</td><td class="td" title="table-entry " align="left" valign="top">Withdrawal of inducing antibiotics+clinical observation 48h (C-II) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Immunotherapy with human monoclonal antibodies (C-I) or immune serum (C-II) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Probiotics (D-I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Toxin binding (D-I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">First recurrence or risk of recurrence</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Oral antibiotic therapy</td><td class="td" title="table-entry " align="left" valign="top">Oral Vancomycin 125mg/6h/10 days (B-I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Fidaxomycin 200mg/12h/10 days (B-I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral metronidazole 500mg/8h/10 days (C-I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="7" align="left" valign="top">Multiple recurrences</td><td class="td" title="table-entry " rowspan="4" align="left" valign="top">Oral antibiotic therapy</td><td class="td" title="table-entry " align="left" valign="top">Oral vancomycin in a gradual reduction and/or in discontinued doses (B-II) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Fidaxomycin 200mg/12h/10 days (B-II) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Vancomycin 500mg/6h/10 days (C-II) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Vancomycin 500mg/8h/10 days (D-II) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Without antibiotic therapy</td><td class="td" title="table-entry " align="left" valign="top">Fecal transplantation (combined with oral antibiotic therapy) (A-I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Probiotics (D-I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Passive Immune therapy with immune serum (D-I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Severe disease or complicated course</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Oral antibiotic therapy</td><td class="td" title="table-entry " align="left" valign="top">Oral vancomycin 125mg/6h/10 days (A-I) or oral vancomycin 500mg/6h/10 days (B-III) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Fidaxomycin 200mg/12h/10 days (B-I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Metronidazole 500mg/8h/10 days (D-II) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">No possibility of oral therapy</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral Metronidazole 500mg/8h/10 days (A-II) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Metronidazole iv 500mg/8h/10 days (A-II)+enteral vancomycin 500mg/6h/10 days (severe disease) (B-III) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tigecycline iv 50mg/12h/14 days (severe disease) (C-III) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1436578.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Treatment of Clostridium difficile infection." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:60 [ 0 => array:3 [ "identificador" => "bib0305" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intestinal flora in newborn infants with a description of a new pathogenic anaerobe, Bacillus difficilis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "I.C. 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Clostridium difficile infection

Infección por Clostridium difficile

Luis Alcalá Hernándeza,b,c,

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luisalcala@efd.net

Corresponding author.

, Elena Reigadas Ramíreza,c, Emilio Bouza Santiagoa,b,c,d

a Servicio de Microbiología y Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón, Madrid, Spain

b Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES CD06/06/0058), Madrid, Spain

c Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain

d Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain

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the main virulence factors of <span class="elsevierStyleItalic">C&#46; difficile</span> are protein toxins&#46; The major <span class="elsevierStyleItalic">C&#46; difficile</span> toxins are TcdA&#44; toxin A or enterotoxin &#40;308<span class="elsevierStyleHsp" style=""></span>kDa&#41;&#44; and TcdB&#44; toxin B or cytotoxin &#40;270<span class="elsevierStyleHsp" style=""></span>kDa&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">3</span></a> Both toxins belong to the large group of <span class="elsevierStyleItalic">Clostridium</span> toxins&#44; including also the TcsH and TcsL toxins of <span class="elsevierStyleItalic">C&#46; sordellii</span> and toxin Tcn&#945; of <span class="elsevierStyleItalic">C&#46; novyi</span>&#44; all characterized by a molecular weight close to 300<span class="elsevierStyleHsp" style=""></span> KDa&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">4</span></a> The genes encoding toxin A &#40;tcdA&#41; and toxin B &#40;tcdB&#41; are located in a pathogenicity locus of the <span class="elsevierStyleItalic">C&#46; difficile</span> chromosome about 19&#46;6<span class="elsevierStyleHsp" style=""></span>kb size &#40;PaLoc&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">5&#44;6</span></a> Within this pathogenicity locus there are 3 other genes that&#44; in one way or another&#44; are related to the expression of these toxins&#58; the tcdC gene&#44; which behaves as a negative regulator of toxin A and B production&#44; with maximal expression in the early exponential phase&#44; and dropping as the bacteria approaches the stationary phase&#59; The tcdD gene&#44; a positive regulator of toxin expression and reaching its maximal expression in the stationary phase of <span class="elsevierStyleItalic">C&#46; difficile</span> growth&#59; And finally the tcdE gene&#44; which appears to encode for proteins called holins&#44; present in the cell wall of some bacteria&#44; which let toxins A and B out of the cell&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">7</span></a> Alteration in the tcdC gene may lead to toxin overproduction&#44; as in the case with ribotype 027 hypervirulent strains&#44; which have an 18-base pair deletion and a point mutation at nucleotide 117 of this gene&#46; Recently it has been proven that there is a regulatory system for the production of toxins A and B&#44; called agr1 locus&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">There is a third toxin&#44; called binary toxin&#44; which is encoded by the cdtA and cdtB genes&#44; located outside the pathogenicity region&#44; and whose pathogenic role remains to be elucidated&#44; since there are discrepancies in correlating the severity of the infection by <span class="elsevierStyleItalic">C&#46; difficile</span> &#40;CDI&#41; with the presence of these toxins in <span class="elsevierStyleItalic">C&#46; difficile</span> strains&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">9&#44;10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The mechanisms of action of toxins A and B in human intestinal cells are not entirely known&#46; Toxins enter colon cells by endocytosis from disaccharide receptors for toxin A and of unknown nature for toxin B&#46; These receptors are low in number or are not present in children under 2 years of age&#44; reason why this group of population does not usually develop the disease in spite of its high rate of colonization by toxigenic <span class="elsevierStyleItalic">C&#46; difficile</span>&#46; Once inside the intestinal cells these toxins irreversibly inactivate the GTPases&#44; Rho&#44; Rac and Cdc-42 through glycosylation&#44; resulting in an interruption of certain vital cellular mechanisms&#44; such as cytoskeletal chitin regulation&#44; cell binding&#44; cell motility and cell migration&#44; in addition to promoting certain inflammatory processes&#44; the production of cytokines and chemokines or the infiltration of neutrophils in the intestinal lumen&#46; All these mechanisms induced by toxins A and B lead to lysis of the intestinal cell and typical symptoms of CDI&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Epidemiology</span><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">C&#46; difficile</span> is isolated in feces from 3&#37; healthy individuals&#44; 20&#37; from hospitalized patients and up to 80&#37; from children under 1 year of age&#44; a significant number of these strains being toxigenic&#46; The main international guidelines define healthcare-associated CDI &#40;HA-CDI&#41; as the infection with symptoms beginning 48<span class="elsevierStyleHsp" style=""></span>h after the patient&#39;s admission to a health center &#40;HC&#41;&#44; or when symptoms begin in the community within the first 4 weeks after discharge from a HC&#46; In contrast&#44; community-based CDI is defined as symptoms beginning in the community or within the first 48 hours after admission to a HC&#44; if the patient has not been discharged from a HC within the 12 previous weeks&#46; Finally&#44; CDI is considered as indeterminate or uncertain when the patient is discharged from a HC 4&#8211;12 weeks before the onset of symptoms &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The main risk factors for acquiring a HA-CDI are previous antibiotic intake &#40;60&#8211;90&#37; of cases&#41;&#44; prolonged hospital stay and advanced age<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">11&#8211;19</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Studies assessing risk factors for community-based CDI emphasize on important differences regarding the typical risk factors for HC-CDI&#46; Thus&#44; in an analysis by Kuntz et al&#46; in 2011 it was found that 27&#37; of patients with community-based CDI had not received antibiotics during the last 180 days prior to the episode and 17&#37; had no typical risk factors for nosocomial CDI&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">20</span></a> This significant number of patients with CDI without any typical risk factor may lead to an underdiagnosis of CDI&#44; as proven in a Spanish study conducted in 2013&#46; In this study&#44; one in 2 CDI episodes was not diagnosed because of a lack of clinical suspicion&#44; especially in subjects aged under 65 years&#44; patients not hospitalized or patients hospitalized less than 3 days&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">The incidence of CDI experienced a dramatic increase at the beginning of this century in North America and northern Europe due to the eruption of <span class="elsevierStyleItalic">C&#46; difficile</span> strain NAP1&#47;BI&#47;027&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">22</span></a> This strain&#44; whose first outbreaks occurred in Quebec &#40;Canada&#41; and USA&#44; appeared to be more virulent and more refractory to treatment than other circulating strains&#44; especially in patients aged over 65&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">23</span></a> In Europe&#44; this strain was introduced by the United Kingdom and&#44; little by little&#44; was transmitted to the countries of central and southern Europe&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">24</span></a> In Spain&#44; the first episode was described in 2007 in a patient from England&#44; while the second was an employee in the Microbiology laboratory who was manipulating the index case strain&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a> Following the subsequent description in Spain of a few specific cases&#44; a large outbreak of this ribotype occurred in late 2014 in the Community of Madrid&#44; on a single institution in which there were over 100 cases in a few months&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">26</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In a European multi-center &#40;482 laboratories&#41; and multinational &#40;20 countries&#41; study in 2013 it was estimated a global nosocomial CDI incidence of 18 cases per 10&#44;000 hospital stays&#46; The ribotypes most frequently causing disease were&#58; 027 &#40;19&#37;&#41;&#44; 001&#47;072 &#40;11&#37;&#41; and 014&#47;020 &#40;10&#37;&#41;&#46; Ribotype 027 was more prevalent in Central European countries such as Romania&#44; Hungary&#44; Poland or Germany&#44; coinciding with a higher incidence of CDI in these countries&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">27</span></a> In Spain&#44; the HA-CDI incidence was estimated in a study based on 2 prevalence cut points in 6&#46;5 episodes per 10&#44;000 hospital stays&#44; although this value cannot be compared with the European multicenter study because of the different methods used&#46; The distribution of the most prevalent ribotypes was&#58; 078&#47;126 &#40;16&#37;&#41;&#44; 014&#47;020 &#40;13&#37;&#41; and 001&#47;072 &#40;12&#37;&#41;&#44; whereas there was only 3&#37; ribotype 027 strains&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical manifestations</span><p id="par0045" class="elsevierStylePara elsevierViewall">The clinical manifestations of CDI are very varied and range from an asymptomatic carrier state to fulminant colitis<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">28</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The severity of the disease depends on two factors&#58; first&#44; the characteristics of the host&#44; mainly their immune status&#44; and&#44; second&#44; the characteristics of the CDI-producing strain&#44; especially its invasive capacity and ability to produce toxins&#46; The most frequent presentation of CDI is moderate diarrhea similar to that caused by other enteropathogenic bacteria and that&#44; sometimes&#44; it ceases simply with the withdrawal of the inducing antibiotic&#46; The main symptoms are general malaise&#44; abdominal pain&#44; nausea&#44; vomiting&#44; liquid or semi-liquid stools&#44; fever and leukocytosis&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a> In a small number of patients with CDI&#44; we can easily observe in a colonoscopy pseudomembranes consisting of yellowish-white plaques 2&#8211;20<span class="elsevierStyleHsp" style=""></span>mm in diameter in the lumen of the colon&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">28</span></a> One of the most serious clinical presentations of CDI is fulminant colitis accompanied by a sudden increase in the white blood cell count by up to 50&#44;000 leukocytes&#47;&#956;l known as the leukemoid reaction&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">30</span></a> It is estimated that severe CDI accompanied by a leukemoid reaction&#44; although rare&#44; has a mortality rate close to 50&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">31</span></a> Another serious CDI is paralytic ileus&#44; which occurs without diarrhea and may evolve to toxic megacolon with intestinal perforation and peritonitis and with a high mortality rate&#46; One of the major complications of CDI is recurrences&#44; defined as the occurrence of a new episode of CDI within 8 weeks of a first episode that has been treated and whose symptoms have been initially resolved&#46; Recurrences are reported in approximately 15&#8211;25&#37; of episodes and may be due to either a new episode caused by the same strain &#40;relapse&#41; or a new infection caused by a different strain &#40;reinfection&#41;&#46; After a first recurrence&#44; the patient has a 35&#8211;50&#37; chance of having new relapses and this number remains as the risk of subsequent recurrences&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">32&#8211;34</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">C&#46; difficile</span> is isolated only rarely in extraintestinal samples&#46; It may appear as part of the microbiota of abscesses or peritoneal collections&#44; in patients with colonic disease and with previous perforations&#46; Its presence is a lot more rare and dubiously significant in pyogenic infections located far from the peritoneum &#40;brain abscess&#44; etc&#46;&#41;&#44; and even in some cases&#44; in blood cultures&#46; This presence should be interpreted very cautiously&#44; since it probably reflects the intestinal origin of the process&#46; Therefore&#44; the treatment to be applied is the same as with the presence of any other clostridium in the same circumstances&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diagnosis</span><p id="par0055" class="elsevierStylePara elsevierViewall">The diagnosis of CDI requires meeting two conditions&#58; &#40;a&#41; the existence&#44; of symptoms compatible with the infection&#44; ruling out any other potential cause&#44; generally the presence of diarrhea &#40;3 or more unformed stools in the last 24<span class="elsevierStyleHsp" style=""></span>h&#41;&#59; &#40;b&#41; the detection of toxins A and&#47;or B or toxigenic <span class="elsevierStyleItalic">C&#46; difficile</span> in the sample&#44; or the detection of pseudomembranes in the patient&#39;s colon through endoscopy&#44; in the stump of a colostomy or ileostomy or at autopsy&#46; Since the presence of pseudomembranes is evidenced in a relatively low number of CDI cases&#44; and is not pathognomonic<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">36</span></a> the toxin demonstration or the isolation of toxigenic <span class="elsevierStyleItalic">C&#46; difficile</span> have become the main methods used for the diagnosis of CDI&#46; From the definition above we can conclude that the diagnosis should only be made in symptomatic patients and unformed stool samples&#44; except when the patient&#39;s special conditions &#40;paralytic ileus or toxic megacolon&#41; prevent the presence of diarrhea&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">32&#44;37</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">There are different laboratory assays used to diagnose CDI&#46; The most widely used are those based on enzyme immunoassay &#40;EIA&#41;&#44; usually immunochromatographic assays&#44; for the detection of toxins A and B&#46; These are very simple and fast assays which&#44; in addition&#44; have the advantage of being cheap&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">38</span></a> The main problem is their lack of sensitivity&#44; since most assays have values close to 50&#37;&#46; On the other hand&#44; its specificity is 95&#8211;98&#37;&#44; so that in a stool sample population of a standard laboratory in which the number of positives barely reaches 10&#37;&#44; the positive predictive value of these assays is 40&#8211;60&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">39&#8211;42</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Another group of EIA techniques widely used in laboratories are those that detect glutamate dehydrogenase &#40;GDH&#41;&#44; an enzyme present in both toxigenic and non-toxigenic <span class="elsevierStyleItalic">C&#46; difficile</span>&#46; Most of these techniques are immunochromatographic assays&#44; low cost&#44; very fast and easy to use&#46; In addition&#44; they have a high sensitivity &#8211; close to 90&#37; &#8211; compared to the toxigenic culture&#44; although they have low specificity because they also detect the <span class="elsevierStyleItalic">C&#46; difficile</span> non-toxigenic strains&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">43&#8211;47</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In a third group of rapid diagnostic assays we would include the molecular assays that detect the toxin A or B gene of <span class="elsevierStyleItalic">C&#46; difficile</span>&#46; These assays have undergone significant development in recent years&#46; They are automated or semiautomated commercial systems capable of detecting these genes in a few hours &#40;some of them in less than an hour&#41; and are based on various amplification assays&#44; such as real-time PCR or isothermal amplification&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">48</span></a> The sensitivity and specificity of these techniques are very high&#44; some of them close to those obtained by the toxigenic culture&#46; Its main drawback is that they are still expensive assays&#44; which prevents their widespread use in most of the Microbiology laboratories&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The cell cytotoxicity assay&#44; the first system used for the diagnosis of CDI since the late 1970s&#44; consists in detecting the cytotoxic activity of the stool sample in a cell monolayer by observing cell lysis and neutralization of this activity through specific antitoxins&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">49</span></a> The high correlation between the cytotoxic activity of the sample and the presence of disease in the patient made this assay appear as a reference in the diagnosis of CDI for many years&#46; Its main drawbacks are its low sensitivity&#44; close to 60&#37;&#59; and requiring the use of cell cultures&#44; which leads to significant diagnostic delay &#40;24&#8211;48<span class="elsevierStyleHsp" style=""></span>h&#41; after sample reception&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">50&#44;51</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Almost simultaneously with the cytotoxicity assay&#44; the toxigenic culture was developed&#44; consisting of the sample culture in a medium selective for <span class="elsevierStyleItalic">C&#46; difficile</span> and the subsequent detection of toxins A and B of <span class="elsevierStyleItalic">C&#46; difficile</span> from the isolates obtained in the culture&#46; This is a very sensitive and specific method very accessible to most laboratories and has therefore been considered as the reference assay for the diagnosis of CDI&#46; Its main drawback is that the procedure requires a period of time of 24&#8211;96<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Clearly&#44; none of the diagnostic methods described can be used as a single procedure for diagnosing CDI either because of lack of internal validity &#40;sensitivity and specificity&#41;&#44; or because of the diagnostic speed or price of every test&#46; For this reason&#44; a series of algorithms for diagnosing CDI have been developed during the last years&#44; recommended by the main national and international guidelines &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">32&#44;53</span></a> &#40;<a href="http://www.asm.org/images/pdf/Clinical/clostridiumdifficile9-21.pdf">http&#58;&#47;&#47;www&#46;asm&#46;org&#47;images&#47;pdf&#47;Clinical&#47;clostridiumdifficile9-21&#46;pdf</a>&#41;&#46; These algorithms are based on the detection of GDH as a screening test due to its high sensitivity and low cost&#44; and a molecular assay that detects toxin A or B genes as a confirmatory test of positive results &#40;2-step algorithm&#41;&#46; In some cases the detection of toxins between both steps is included as the first method to confirm the positive results of the GDH detection&#44; leaving the molecular method for the discordant results between the GDH and toxin detection &#40;3-step-algorithm and multipass&#41;&#46; In several studies evaluating these algorithms it has been proven that their sensitivity values range from 90&#37; to 95&#37; &#40;sensitivity limited by the detection of GDH&#41; and specificity values close to 100&#37;&#44; with a final price not much higher than the EIA-based techniques&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">43&#8211;47</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Despite the existence and widespread recommendation of the use of such cost-effective algorithms&#44; laboratories still use non-sensitive methods such as EIAs that detect toxins as the only diagnostic procedures&#46; In a study conducted in 2013&#44; in 111 Spanish laboratories&#44; it was verified that almost half of these still belonged to this group&#46; Therefore&#44; the overall diagnostic sensitivity estimate of the laboratories participating in the study was 80&#46;0&#37;&#44; finally resulting in a 15&#46;5&#37; underdiagnosis of the total CDI cases&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">The description in the scientific literature of CDI episodes caused by ribotype 027 shows that these strains produce more transmissible&#44; aggressive and recurrent episodes than the rest of the ribotypes&#46; This is why the national guidelines for diagnosis of CDI recommend the early detection through molecular assays of these episodes in environments suffering from an epidemic caused by this ribotype or in which there is a high suspicion of its occurrence &#40;increased cases of severe CDI&#44; occurrence of CDI cases produced by this ribotype in nearby areas&#44; detection of isolated cases in the institution&#44; etc&#46;&#41;&#46; Early detection of these episodes makes it possible to take measures that help prevent their transmission to other patients and the use of a proper treatment aimed at improving the prognosis of the episode and to minimize the potential recurrences&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">53</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">It has been shown that there is a positive correlation between the low number of molecular amplifications of the toxin B gene &#40;marker of high toxigenic burden of <span class="elsevierStyleItalic">C&#46; difficile</span> in the stool sample&#41; and poor evolution &#40;severe episodes&#44; increased severity of disease or recurrences&#41; of patients with CDI&#46; Therefore&#44; this system might be a good early predictor of poor outcome in patients with CDI that would facilitate the use of optimal treatments to improve the prognosis of this group of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Treatment</span><p id="par0105" class="elsevierStylePara elsevierViewall">It depends on factors of both&#44; patient and type of infection&#46; For this reason&#44; in the therapeutic guidelines of the ESCMID&#44; the CDIs are grouped into 5 therapeutic groups&#58; initial non-severe CDI&#44; initial severe CDI&#44; CDI with first recurrence &#40;or risk of recurrence&#41;&#44; CDI with multiple recurrences and CDI in patients with no possibility of oral treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">In mild-moderate CDI episodes &#40;not severe&#41; in nonepidemic environments and whose infection has been clearly induced by antibiotics&#44; the first-line therapy is&#44; where possible&#44; the withdrawal of the antibiotic inducing infection and observation of clinical response during 48<span class="elsevierStyleHsp" style=""></span>h&#44; adding specific therapy in case of clinical worsening&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a> Almost one in four episodes can be resolved with this simple measure&#46; When necessary&#44; the antibiotic treatment of choice for non-severe episodes is metronidazole &#40;500<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&#47;10 days&#41; orally&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In the presence of a first recurrence or in case of a well-founded suspicion that the patient might present relapses or does not respond well to metronidazole&#44; due to its risk factors&#44; the treatment of choice is oral vancomycin &#40;125<span class="elsevierStyleHsp" style=""></span>mg&#47;6<span class="elsevierStyleHsp" style=""></span>mg&#47;10 days&#41; or oral fidaxomicin &#40;200<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#47;10 days&#41;&#46; In case of a second recurrence the treatment proved to be most effective is fecal transplantation&#44; after preparation for a few days with oral vancomycin&#46; Fecal transplantation is transferring a fecal sample from a healthy donor to the patient&#39;s colon through colonoscopy&#44; nasoduodenal tube&#44; or encapsulated fecal material&#46; Colon colonization with transplanted bacteria helps eliminate <span class="elsevierStyleItalic">C&#46; difficile</span> and thus prevent new episodes&#46; In a recent meta-analysis of over 600 patients with fecal transplantation&#44; the efficacy of this long-term therapeutic method &#40;&#8805;90 days&#41; was 94&#46;5&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">55</span></a> An alternative to transplantation is the use of oral vancomycin in higher doses &#40;2<span class="elsevierStyleHsp" style=""></span>g&#47;day initially&#41; in a progressively decreasing regimen up to 4 or more weeks of treatment&#44; ending with intermittent doses to promote the elimination of <span class="elsevierStyleItalic">C&#46; difficile</span> in the bowel in both its vegetative and sporulated forms&#46; The main drawback of this treatment is that it can induce the appearance of vancomycin-resistant enterococcus strains&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">In severe patients or suspected to evolve to a severe form the treatment of choice is oral vancomycin or fidaxomicin&#46; The use of this latter drug has been relegated to the alternative position in many clinical guidelines&#44; exclusively for reasons of price&#44; but it has been shown to be better than vancomycin in preventing recurrences&#46; Immunotherapy is undoubtedly part of the future in the treatment of severe CDI&#46; Studies using monoclonal antibodies against <span class="elsevierStyleItalic">C&#46; difficile</span> toxin B have been proven effective on severe CDI and recurrences&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">56</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Finally&#44; when the patient cannot take any antibiotics orally&#44; intravenous metronidazole &#40;500<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&#47;10 days&#41; is recommended with the addition of enteral vancomycin &#40;500<span class="elsevierStyleHsp" style=""></span>mg&#47;6<span class="elsevierStyleHsp" style=""></span>h&#47;10 days&#41; through nasogastric tube or enemas&#46; Vancomycin is not effective for CDI through intravenous route because it reaches very low concentrations in the colon lumen&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">57</span></a> An alternative to these treatments is iv tigecycline &#40;50<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#47;14 days&#41;&#44; although with a low strength of recommendation&#44; type C&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Prophylaxis</span><p id="par0130" class="elsevierStylePara elsevierViewall">The preventive measures of the CDI should be aimed at preventing both colonization of patients with <span class="elsevierStyleItalic">C&#46; difficile</span> and subsequent microorganism overgrowth in the colon lumen of the colonized patient&#44; factors usually necessary for a new case of CDI&#46; Regarding prevention of colonization&#44; it is essential to prevent the spore dissemination from patients with CDI&#46; To this purpose&#44; a rapid and effective diagnosis of CDI is important&#44; in addition to rapid transmission by the laboratory of the positive results &#40;and ideally of the negative ones&#41; to initiate appropriate treatment of the episode as soon as possible and effective patient isolation measures&#46; It should be a contact isolation&#44; always trying that the patient be in a single room and&#44; if this is not possible&#44; shared with some other patients with CDI&#46; On the other hand&#44; all health and non-health personnel&#44; who are in contact with the patient should wear gloves and gowns and dispose of them after contact&#44; as well as wash their hands with soap and water &#40;alcoholic solutions are not sporicidal&#41;&#46; It is recommended that any material used with the patient be disposable and&#44; if this is not possible&#44; it should be disinfected prior to use with another patient&#46; The use of rectal thermometers is not recommended&#46; The use of sodium hypochlorite &#40;1000<span class="elsevierStyleHsp" style=""></span>ppm&#41; is recommended for cleaning rooms and hospital equipment&#46; We also recommend the use of specific and exclusive cleaning material for rooms with CDI patients&#46; The rooms for patients with CDI should be cleaned thoroughly through reinforcing hygiene in toilets&#44; devices surrounding the patient and the surfaces frequently used by the staff&#44; always cleaning deeply after patient&#39;s discharge&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a> Certain procedures that allow more terminal decontamination&#44; such as hydrogen peroxide vaporizers or those based on ultraviolet light&#44; appear to be more effective in reducing the risk of acquiring <span class="elsevierStyleItalic">C&#46; difficile</span> in patients who occupy a room previously occupied by a patient with CDI&#46; For preventing <span class="elsevierStyleItalic">C&#46; difficile</span> overgrowth in colonized patients&#44; it is essential to prevent any unnecessary antimicrobial treatment by implementing programs for the rational use of antibiotics&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Several CDI vaccines are currently being developed&#44; including some vaccines inactivated with various substances such as formaldehyde&#44; and other alive substances that express&#44; to a greater or lesser extent&#44; attenuated forms of toxin A and&#47;or toxin B&#46; However&#44; there is still no marketed vaccine that can be used selectively in at-risk groups&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">60</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusions</span><p id="par0140" class="elsevierStylePara elsevierViewall">CDI is the leading cause of nosocomial diarrhea in the first-world countries and an increasingly common cause of community diarrhea&#46; The infection is caused by 2 types of toxins&#44; toxin A and toxin B&#44; while a third toxin&#44; the binary toxin&#44; has a little known role that still has to be elucidated&#46; The arrival in Canada of a new hypervirulent clone belonging to ribotype 027 and its spread to USA and most part of Europe at the beginning of this century greatly increased both the CDI incidence and its associated mortality&#46; The main risk factors for CDI are broad-spectrum antibiotics&#44; hospitalization and advanced age&#44; although there is a significant number of cases without any of these factors leading to a significant underdiagnosis of the disease&#46; Thus&#44; in Spain&#44; one in two episodes of CDI is not diagnosed because there was no clinical suspicion&#44; especially in young and non-hospitalized patients&#44; or because of poor sensitivity of the diagnostic methods&#46; Although it usually occurs in the form of mild diarrhea&#44; CDI can lead to severe forms that can become life-threatening&#46; The emergence of methods of gene amplification of <span class="elsevierStyleItalic">C&#46; difficile</span> toxins has led to a revolution in the diagnosis of this infection&#44; since they allow rapid and effective diagnosis of the disease when used as confirmatory methods in algorithms with screening systems based on GDH detection&#46; The treatment recommended depends on the type of infection and the patient&#39;s characteristics&#44; being metronidazole&#44; vancomycin&#44; fidaxomycin and fecal transplantation the main treatments recommended by international guidelines&#44; which will soon be complemented with the use of monoclonal antitoxin antibodies&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflict of interests</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors report no conflict of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Clostridium difficile</span> infection &#40;CDI&#41; is the main cause of nosocomial diarrhea in industrialized countries and the source of a growing number of cases of diarrhea in the community&#46; The outbreak of the hypervirulent strain belonging to ribotype 027 has increased the incidence and severity of CDI in some countries&#46; Although CDI usually courses as a mild diarrhea it can lead to severe forms such as toxic megacolon or septic shock&#46; One of every 2 episodes of CDI is not diagnosed in Spanish hospitals due to a lack of clinical suspicion or the use of insensitive diagnostic methods&#46; The diagnostic techniques of choice are algorithms based on the detection of glutamate dehydrogenase and molecular detection of the genes of the toxins with or without the direct detection of the toxins&#46; The recommended treatment for CDI depends on the type of infection and the characteristics of the patient&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La infecci&#243;n por <span class="elsevierStyleItalic">Clostridium difficile</span> &#40;ICD&#41; es la principal causa de diarrea nosocomial en pa&#237;ses industrializados y el origen de un n&#250;mero de casos cada vez mayor de diarrea en la comunidad&#46; La irrupci&#243;n de la cepa del ribotipo 027 ha incrementado en algunos pa&#237;ses la incidencia y la gravedad de la ICD&#46; Aunque suele cursar como una diarrea leve&#47;moderada&#44; puede dar lugar a formas graves&#44; como megacolon t&#243;xico y <span class="elsevierStyleItalic">shock</span> s&#233;ptico&#46; Uno de cada 2 episodios de ICD no es diagnosticado en los hospitales espa&#241;oles por falta de sospecha cl&#237;nica o por el uso de m&#233;todos diagn&#243;sticos poco sensibles&#46; Se recomiendan algoritmos diagn&#243;sticos basados en la detecci&#243;n de glutamato deshidrogenasa y en la detecci&#243;n molecular de los genes de las toxinas con o sin la detecci&#243;n directa de las toxinas&#46; El tratamiento recomendado de la ICD depende del tipo de infecci&#243;n y las caracter&#237;sticas del paciente&#46;</p></span>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Diagnostic algorithms for <span class="elsevierStyleItalic">Clostridium difficile</span> infection&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">EIA&#58; enzyme immunoassay&#59; GDH&#58; glutamate dehydrogenase&#59; ToxAB&#58; toxins A and B&#46;</p>"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">CDI&#58; <span class="elsevierStyleItalic">Clostridium difficile</span> infection&#59; HIV&#58; human immunodeficiency virus&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of episode&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="8" align="left" valign="top">First episode</td><td class="td" title="table-entry  " align="left" valign="top">Antibiotics &#40;clindamycin&#44; beta-lactams&#44; fluoroquinolones and others&#41; for 6&#8211;8 previous weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Prolonged hospital stay&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Advanced age&#44; consequence of higher number of underlying diseases and low level of protective antibodies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oncological diseases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">immunosuppression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Malnutrition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Solid organ transplantation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HIV infection&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="7" align="left" valign="top">Recurrence</td><td class="td" title="table-entry  " align="left" valign="top">Advanced age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antimicrobial maintenance after CDI episode&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Low albumin levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Prolonged hospital stay&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Admission to an intensive care unit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Severe underlying disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">High toxin burden in feces&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab1436577.png"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Major risk factors for health center-associated <span class="elsevierStyleItalic">Clostridium difficile</span> infection&#46;</p>"
        ]
      ]
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        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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        "mostrarDisplay" => false
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        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Modified from Cohen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">37</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of <span class="elsevierStyleItalic">Clostridium difficile</span> infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical or laboratory characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mild&#47;moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Leukocytosis<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>15&#44;000<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;l or serum creatinine &#60;1&#46;5 times baseline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Serious&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Leukocytosis<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>15&#44;000<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;l or serum creatinine<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>1&#46;5 times baseline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Serious-complicated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypotension or shock&#44; ileus&#44; megacolon&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Classification of <span class="elsevierStyleItalic">Clostridium difficile</span> infection depending on its severity&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Degree of strength of recommendation&#58; A&#44; strongly recommends its use&#59; B&#44; moderately recommends its use&#59; C&#44; recommends its use marginally&#59; D&#44; recommends non-use&#46; Quality of Evidence&#58; I&#44; evidence of at least one randomized&#44; correctly designed&#44; controlled clinical trial&#59; II&#44; evidence of at least one well-designed non-randomized clinical trial&#44; from analytical cohort or case-control studies &#40;preferably more than one-center&#41;&#44; multiple time series&#44; or irrefutable results from uncontrolled experimental studies&#59; III&#44; evidence of expert opinions based on their clinical experience&#44; descriptive case studies&#44; or expert committee reports&#46;</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Modified from Debast et al&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="7" align="left" valign="top">Non-serious disease</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Oral antibiotic therapy</td><td class="td" title="table-entry  " align="left" valign="top">Oral metronidazole 500<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;A-I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Vancomycin 125<span class="elsevierStyleHsp" style=""></span>mg&#47;6<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;B-I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Fidaxomycin 200<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;B-I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Without antibiotic therapy</td><td class="td" title="table-entry  " align="left" valign="top">Withdrawal of inducing antibiotics<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>clinical observation 48<span class="elsevierStyleHsp" style=""></span>h &#40;C-II&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Immunotherapy with human monoclonal antibodies &#40;C-I&#41; or immune serum &#40;C-II&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Probiotics &#40;D-I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Toxin binding &#40;D-I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">First recurrence or risk of recurrence</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Oral antibiotic therapy</td><td class="td" title="table-entry  " align="left" valign="top">Oral Vancomycin 125<span class="elsevierStyleHsp" style=""></span>mg&#47;6<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;B-I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Fidaxomycin 200<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;B-I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral metronidazole 500<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;C-I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="7" align="left" valign="top">Multiple recurrences</td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Oral antibiotic therapy</td><td class="td" title="table-entry  " align="left" valign="top">Oral vancomycin in a gradual reduction and&#47;or in discontinued doses &#40;B-II&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Fidaxomycin 200<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;B-II&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Vancomycin 500<span class="elsevierStyleHsp" style=""></span>mg&#47;6<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;C-II&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Vancomycin 500<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;D-II&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Without antibiotic therapy</td><td class="td" title="table-entry  " align="left" valign="top">Fecal transplantation &#40;combined with oral antibiotic therapy&#41; &#40;A-I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Probiotics &#40;D-I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Passive Immune therapy with immune serum &#40;D-I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Severe disease or complicated course</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Oral antibiotic therapy</td><td class="td" title="table-entry  " align="left" valign="top">Oral vancomycin 125<span class="elsevierStyleHsp" style=""></span>mg&#47;6<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;A-I&#41; or oral vancomycin 500<span class="elsevierStyleHsp" style=""></span>mg&#47;6<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;B-III&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Fidaxomycin 200<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;B-I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oral Metronidazole 500<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;D-II&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">No possibility of oral therapy</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral Metronidazole 500<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;A-II&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Metronidazole iv 500<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;A-II&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>enteral vancomycin 500<span class="elsevierStyleHsp" style=""></span>mg&#47;6<span class="elsevierStyleHsp" style=""></span>h&#47;10 days &#40;severe disease&#41; &#40;B-III&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tigecycline iv 50<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#47;14 days &#40;severe disease&#41; &#40;C-III&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Treatment of <span class="elsevierStyleItalic">Clostridium difficile</span> infection&#46;</p>"
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    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:60 [
            0 => array:3 [
              "identificador" => "bib0305"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intestinal flora in newborn infants with a description of a new pathogenic anaerobe&#44; <span class="elsevierStyleItalic">Bacillus difficilis</span>"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "I&#46;C&#46; Hall"
                            1 => "E&#46; O&#8217;Toole"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Am J Dis Child"
                        "fecha" => "1935"
                        "volumen" => "49"
                        "paginaInicial" => "390"
                        "paginaFinal" => "402"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0310"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of <span class="elsevierStyleItalic">Clostridium difficile</span> in antibiotic-associated pseudomembranous colitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "J&#46;G&#46; Bartlett"
                            1 => "N&#46; Moon"
                            2 => "T&#46;W&#46; Chang"
                            3 => "N&#46; Taylor"
                            4 => "A&#46;B&#46; Onderdonk"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Gastroenterol"
                        "fecha" => "1978"
                        "volumen" => "75"
                        "paginaInicial" => "778"
                        "paginaFinal" => "782"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0315"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
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