Multitarget Stool DNA Test Performance in an Average-Risk Colorectal Cancer Screening Population.

INTRODUCTION: We set out to evaluate the performance of a multitarget stool DNA (MT-sDNA) in an average-risk colonoscopy-controlled colorectal cancer (CRC) screening population. MT-sDNA stool test results were evaluated against fecal immunochemical test (FIT) results for the detection of different lesions, including molecularly defined high-risk adenomas and several other tumor characteristics. METHODS: Whole stool samples (n = 1,047) were prospectively collected and subjected to an MT-sDNA test, which tests for KRAS mutations, NDRG4 and BMP3 promoter methylation, and hemoglobin. Results for detecting CRC (n = 7), advanced precancerous lesions (advanced adenoma [AA] and advanced serrated polyps; n = 119), and non-AAs (n = 191) were compared with those of FIT alone (thresholds of 50, 75, and 100 hemoglobin/mL). AAs with high risk of progression were defined by the presence of specific DNA copy number events as measured by low-pass whole genome sequencing. RESULTS: The MT-sDNA test was more sensitive than FIT alone in detecting advanced precancerous lesions (46% (55/119) vs 27% (32/119), respectively, P < 0.001). Specificities among individuals with nonadvanced or negative findings (controls) were 89% (791/888) and 93% (828/888) for MT-sDNA and FIT testing, respectively. A positive MT-sDNA test was associated with multiple lesions (P = 0.005), larger lesions (P = 0.03), and lesions with tubulovillous architecture (P = 0.04). The sensitivity of the MT-sDNA test or FIT in detecting individuals with high-risk AAs (n = 19) from individuals with low-risk AAs (n = 52) was not significantly different. DISCUSSION: In an average-risk screening population, the MT-sDNA test has an increased sensitivity for detecting advanced precancerous lesions compared with FIT alone. AAs with a high risk of progression were not detected with significantly higher sensitivity by MT-sDNA or FIT.

Is Clinical Research in Oesophageal Cancer in South Africa in Crisis? A Systematic Review.

Oesophageal cancer (OC) is responsible for the second highest number of cancer-related deaths in South Africa (SA). Squamous cell carcinoma is the most prevalent type with an incidence of 46.7/100,000 and 19.2/100,000 for males and females. This is a systematic review of the clinical diagnosis and management of OC within the South African context. This protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (registration number CRD42016034053) with adherence to PRISMA guidelines. An online search was performed using MEDLINE, EBSCOHost and PubMed. Eligibility criteria for articles included published, original peer-reviewed research addressing clinical management of oesophageal cancer in South Africa. Review articles, case reports, scientific letters and studies published in languages other than English or Afrikaans were excluded. The research terms were 'etiology', 'human', 'esophageal cancer', 'esophageal carcinoma', 'oesophageal cancer', and 'oesophageal carcinoma', 'squamous cell carcinoma', 'Africa' and 'South Africa'. A total of 336 articles were identified. Of these, 146 were immediately excluded and a further 159 were excluded after review. A total of 31 appropriate articles, i.e. 9.2% of searched articles, were included. Thirteen articles addressed chemotherapy and/or radiotherapy, 9 oesophageal luminal therapy, 7 oesophageal surgery and 2 screening. OC research of in SA over the last two decades has mainly been in the form of reviews and opinion papers. Clinical research, auditing and prospectively analysing OC management and outcomes in SA hospitals are sorely needed and should be promoted by both healthcare workers and policy makers alike.

Oesophageal squamous cell cancer in a South African tertiary hospital: a risk factor and presentation analysis.

BACKGROUND: Squamous carcinoma of the oesophagus (SCO) is the most common form of oesophageal cancer in South Africa (SA). Risk factors include male gender, smoking, alcohol consumption and low socio-economic status (SES). This study assessed the risk factors for SCO in KwaZulu-Natal. METHOD: Information on patients managed at Inkosi Albert Luthuli Central Hospital (IALCH), Durban, South Africa, between 1 October 2013 and 31 December 2014 was retrieved from a prospective database of Oesophageal Cancer (OC). Data collected included demographics, risk factors, symptoms and clinical findings. RESULTS: One hundred and fifty-nine patients (159) with SCO were identified. The site of tumour location was in the middle 96 (60.4%), distal 42(26.4%) and proximal 17(10.6%) oesophagus. The male to female ratio was 1:1 with an age range of 22-93 years (mean 60.6; SD±12.1). Females were significantly older than males (p = 0.018). Eighty-eight per cent were Black African. Dysphagia was reported in 158 (99.4%) of patients and loss of weight in 149(95.5%). Thirty-six patients were HIV positive (age 52.8; SD±9.7) and significantly younger than those without HIV infection (age 61.2; SD±11.5). Most patients had low SES and poor dental health. Male patients were significantly more likely to use tobacco (p < 0.001; Odds Ratio (OR) 7.8) and consume alcohol (p < 0.001; OR 7.7) than females who were 2.5 times more likely to report a family history of cancer (p = 0.017; OR 2.6). CONCLUSION: An equal gender distribution was observed. Male patients with SCO reported the expected risk factors; however these were not observed amongst women. SES may contribute to the development of SCO. Poor dental health may be a surrogate marker for low SES and a possible risk factor for SCO. HIV positive individuals present a decade younger when compared with HIV negative patients.

HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1.

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Optimal strategies to identify aberrant intra-epithelial lymphocytes in refractory coeliac disease.

INTRODUCTION: Different strategies have been developed to identify those refractory celiac disease (RCD) patients who are at risk to develop an enteropathy associated T-cell lymphoma (EATL). Flow cytometric analysis of intra-epithelial lymphocytes (IEL) with an aberrant phenotype is considered the golden standard but is not widely available. Immunohistochemistry (IHC) and T-cell receptor (TCR) rearrangement studies are commonly available but may lack sensitivity and specificity. Here, we compared the three different methods in the workup of patients suspected for RCD. METHODS: Duodenal biopsies from control patient (n = 5), RCD patients with moderately increased aberrant IEL populations (20-50 %: n = 14), and RCD patients with high numbers of aberrant IEL (>50 %: n = 5) as determined by flow cytometry were analysed by IHC and TCR-γ chain rearrangement analysis. Three pathologists scored the slides independently. RESULTS: Sensitivity of IHC and TCR-γ rearrangement analysis in RCD patients with high numbers of aberrant IELs was 100 and 71 %, respectively. RCD patients with aberrant cells between 25 and 50 % however, were missed by IHC and TCR in 50 and 57 % of cases, respectively. In addition, inter-rater reliability analysis of the IHC scoring revealed coder-pair Kappa coefficients between 0.28 and 0.85. CONCLUSION: Immunohistochemistry and to a lesser extent TCR-γ clonality analysis are sensitive in identifying patients with high numbers of aberrant IEL populations, yet miss half of RCD patients with moderately increased numbers. In addition, IHC has a high inter-observer variability. Therefore, patients suspected for RCD should undergo flow cytometric analysis of the duodenum.

Bomb calorimetry, the gold standard for assessment of intestinal absorption capacity: normative values in healthy ambulant adults.

BACKGROUND: Intestinal absorption capacity is considered to be the best method for assessing overall digestive intestinal function. Earlier reference values for intestinal function in healthy Dutch adults were based on a study that was conducted in an inpatient metabolic unit setting in a relatively small series. The present study aimed to readdress and describe the intestinal absorption capacity of healthy adults, who were consuming their usual (Western European) food and beverage diet, in a standard ambulatory setting. METHODS: Twenty-three healthy subjects (aged 22-60 years) were included in the analyses. Nutritional intake (energy and macronutrients) was determined with a 4-day nutritional diary. Subsequently, mean faecal losses of energy (by bomb calorimetry), fat, protein and carbohydrate were determined following a 3-day faecal collection. Finally, intestinal absorption capacity was calculated from the differences between intake and losses. RESULTS: Mean (SD) daily faeces production was 141 (49) g (29% dry weight), containing 891 (276) kJ [10.7 (1.3) kJ g(-1) wet faeces; 22.6 (2.5) kJ g(-1) dry faeces], 5.2 (2.2) g fat, 10.0 (3.8) g protein and 29.7 (11.7) g carbohydrates. Mean (SD) intestinal absorption capacity of healthy subjects was 89.4% (3.8%) for energy, 92.5% (3.7%) for fat, 86.9% (6.4%) for protein and 87.3% (6.6%) for carbohydrates. CONCLUSIONS: The present study provides normative values for both stool nutrient composition and intestinal energy and macronutrient absorption in healthy adults on a regular Dutch diet in an ambulatory setting. Intestinal energy absorption was found to be approximately 90%.

Small bowel adenocarcinoma copy number profiles are more closely related to colorectal than to gastric cancers.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare cancer and consequently, the options for clinical trials are limited. As they are treated according to either a colorectal or a gastric cancer regimen and the molecular biology of a tumor is a pivotal determinant for therapy response, chromosomal copy number aberrations were compared with the colorectal and gastric adenocarcinomas. MATERIALS AND METHODS: A total of 85 microsatellite stable (MSS) adenocarcinomas from the stomach, colorectum and small bowel were selected from existing array comparative genomic hybridization (aCGH) datasets. We compared the aCGH profiles of the three tumor sites by supervised analysis and hierarchical clustering. RESULTS: Hierarchical clustering revealed substantial overlap of 27 SBA copy number profiles with matched colorectal adenocarcinomas but less overlap with profiles of gastric adenocarcinomas. DNA copy number aberrations located at chromosomes 1p36.3-p34.3, 4p15.3-q35.2, 9p24.3-p11.1, 13q13.2-q31.3 and 17p13.3-p13.2 were the strongest features discriminating SBAs and colorectal adenocarcinomas from gastric adenocarcinomas. CONCLUSIONS: We show that MSS SBAs are more similar to colorectal than to gastric cancer, based on the 27 genome-wide DNA copy number profiles that are currently available. These molecular similarities provide added support for treatment of MSS small bowel cancers according to colorectal cancer regimens.

Critical reappraisal of anorectal function tests in patients with faecal incontinence who have failed conservative treatment.

OBJECTIVE: Anorectal function tests are often performed in patients with faecal incontinence who have failed conservative treatment. This study was aimed to establish the additive value of performing anorectal function tests in these patients in selecting them for surgery. PATIENTS AND METHODS: Between 2003 and 2009, all referred patients with faecal incontinence were assessed by a questionnaire, anorectal manometry and anal endosonography. Patients with diarrhea, inflammatory bowel disease, pouches or rectal carcinoma were excluded. RESULTS: In total, 218 patients were evaluated. Of these, 107 (49%) patients had no sphincter defects, 71 (33%) had small defects and 40 (18%) had large defects. Anorectal manometry could not differentiate between patients with and without sphincter defects. Patients with sphincter defects were only found to have a significantly shorter sphincter length and reduced rectal capacity compared to patients without sphincter defects. Forty-three patients (20%) had a normal anal pressures ≥ 40 mmHg. Seventeen patients (8%) had also a dyssynergic pelvic floor both on clinical examination and anorectal manometry. Fifteen patients (7%) had a reduced rectal capacity between 65 and 100 ml. There was no difference in anal pressures or the presence of sphincter defects in these patients compared to patients with a rectal capacity >150 ml. There was no correlation between anorectal manometry, endosonography and faecal incontinence severity scores. CONCLUSION: In patients with faecal incontinence who have failed conservative treatment, only anal endosonography can reveal sphincter defects. Anorectal manometry should be reserved for patients eligible for surgery to exclude those with suspected dyssynergic floor or reduced rectal capacity.

Description of a novel grading system to assess the quality of bowel preparation in video capsule endoscopy.

BACKGROUND AND STUDY AIMS: Inadequate bowel preparation negatively influences the reliability of examinations by video capsule endoscopy (VCE). Currently, only subjective scales are available to describe mucosal visibility. We aimed to design a score that was derived directly from the VCE images. PATIENTS AND METHODS: A computed assessment of cleansing score was developed based on color intensities of the tissue color bar. The feasibility of this score was retrospectively tested in 24 VCE studies. A prospective study was conducted using 40 VCE segments from 10 consecutive VCE studies. The computed scores were compared with three existing methods of assessing small-intestinal cleansing. Correlations between the existing scoring systems and the computed score were evaluated using the intraclass correlation coefficient and Spearman's rho correlation. RESULTS: All computed measurements were obtained twice and resulted in exactly the same results. Both overall and segmental mucosal visibility could be assessed. The computed score and the 10-point quantitative index were significantly associated for both readers (Spearman's rho: 0.68 and 0.75, respectively; P < 0.001). The intraclass correlation coefficient for the 4-point qualitative evaluation and the computed score was 0.67 for reader 1 and 0.64 for reader 2. For reader 1, the mean computed score for segments assessed as either inadequately or adequately cleansed was 5.0 and 6.4 ( P = 0.001). For reader 2 these values were 4.0 and 6.3, respectively ( P = 0.005). CONCLUSIONS: A computed assessment of small-bowel mucosal visibility based on the ratio of color intensities of the red and green channel of the tissue color bar is feasible and more reproducible than existing subjective scales. Such a computed scale could be integrated into VCE reading software. For this novel scoring system we propose the term Computed Assessment of Cleansing (CAC) score.

Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.

OBJECTIVE: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. DESIGN: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p<1 x 10(-04) and were then genotyped in an independent Italian coeliac cohort (538 cases and 593 controls). RESULTS: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p = 1.3 x 10(-08), and rs842647 p = 5.2 x 10(-07)). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression. CONCLUSIONS: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappaB) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain approximately 40% of the heritability of coeliac disease.

Unrealized potential of drug repositioning in europe during COVID-19 and beyond: a physcian's perspective.

Drug repositioning is the scientific strategy of investigating existing drugs for additional clinical indications. The advantages of drug repositioning are that it benefits patients and that it adds new indications to existing drugs for lower costs compared to de novo drug development. Clinical research groups recognizing efficacy of these "old" drugs for a new indications often face an uphill struggle due to a lack of funding and support because of poor structural and regulatory support for clinical drug development. The current framework for drug repositioning allows "venture capital" companies to abuse loopholes in the legislation to gain long-term market authorization among with excessive high pricing. A new regulatory framework is needed to prevent abuse of the legislation and promote clinical investigator-driven drug repositioning. The COVID-19 pandemic has boosted funding and regulatory support for drug repositioning. The lessons learned from the COVID-19 pandemic should be implemented in a new clear blueprint for drug repositioning. This blueprint should guide clinicians through legislation for drug repositioning in the EU. This review summarizes the routes for registration and discusses the current state of drug repositioning in Europe.

Recurrent acute biliary pancreatitis: the protective role of cholecystectomy and endoscopic sphincterotomy.

BACKGROUND: Recurrent attacks of acute biliary pancreatitis (RABP) are prevented by (laparoscopic) cholecystectomy. Since the introduction of endoscopic retrograde cholangiopancreaticography (ERCP), several series have described a similar reduction of RABP after endoscopic sphincterotomy (ES). This report discusses the different treatment options for preventing RABP including conservative treatment, cholecystectomy, ES, and combinations of these options as well as their respective timing. METHODS: A search in PubMed for observational studies and clinical (comparative) trials published in the English language was performed on the subject of recurrent acute biliary pancreatitis and other gallstone complications after an initial attack of acute pancreatitis. RESULT: Cholecystectomy and ES both are superior to conservative treatment in reducing the incidence of RABP. Cholecystectomy provides additional protection for gallstone-related complications and mortality. Observational studies indicate that cholecystectomy combined with ES is the most effective treatment for reducing the incidence of RABP attacks. CONCLUSION: From the literature data it can be concluded that ES is as effective in reducing RABP as cholecystectomy but inferior in reducing mortality and overall morbidity. The combination of ES and cholecystectomy seems superior to either of the treatment methods alone. A prospective randomized clinical trial comparing ES plus cholecystectomy with cholecystectomy alone is needed.

The effect of NOD2 activation on TLR2-mediated cytokine responses is dependent on activation dose and NOD2 genotype.

The mechanism by which mutations in NOD2 predispose to Crohn's disease (CD) is incompletely understood. In mice, NOD2 has been found to function as a negative regulator of Toll-like receptor 2 (TLR2) signaling. In contrast, studies in humans so far showed no negative regulatory interaction between NOD2 and TLR2, and in fact suggest a synergistic effect between the two. Here, we show that this interaction is dose dependent. Adding low doses of muramyl dipeptide (MDP) to TLR2 primed monocytes results in a significant increase in cytokine production, whereas adding higher doses of MDP led to a striking downregulation of the responses. This downregulation by high-dose MDP does not occur in monocytes from NOD2-deficient patients. The inhibitory role of NOD2 at high concentrations of MDP implicates a safety mechanism to prevent exaggerated antibacterial immune responses in the gut to high or perpetuating bacterial load. This regulatory mechanism is lost in NOD2-deficient CD patients.

Anti-calreticulin immunoglobulin A (IgA) antibodies in refractory coeliac disease.

Refractory coeliac disease (RCD) is a very rare and dangerous form of CD, in which gluten-free diet loses its therapeutic effect and the damage of intestinal mucosa persists. Because of the adherence to the diet, serological markers of CD [immunoglobulin A (IgA) antibodies against gliadin, tissue transglutaminase (tTG) and endomysium] are often missing in RCD patients. We found substantially elevated levels of IgA anti-calreticulin (CRT) antibodies in the sera of almost all RCD patients tested. These sera were negative for IgA antibodies to gliadin and tTG and only some of them showed IgA antibodies to enterocytes. Analysis of patients' IgA reactivity to CRT fragments (quarters and halves) by Western blotting revealed differences in the specificity of IgA antibodies between RCD and CD patients. We therefore used the Pepscan technique with synthetic overlapping decapeptides of CRT to characterize antigenic epitopes recognized by serum IgA antibodies of RCD patients. Employing this method we demonstrated several dominant antigenic epitopes recognized by IgA antibodies of RCD patients on the CRT molecule. Epitope GVTKAAEKQMKD was recognized predominantly by serum IgA of RCD patients. Our results suggest that testing for serum IgA antibodies against CRT and its selected peptide could be a very useful tool in RCD differential diagnosis.

Absence of nodular regenerative hyperplasia after low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients.

BACKGROUND: The use of 6-thioguanine has been proposed as a rescue drug for inflammatory bowel disease patients. Initial data on short-term efficacy and toxicity of 6-thioguanine were promising; however, these have been challenged by reports concerning its potential hepatotoxic effect (nodular regenerative hyperplasia). We proposed that these histological liver abnormalities may well be dose- or level-dependent. AIMS: We performed a prospective multi-centre study on the hepatotoxic potential of long-term and (as compared with prior studies) low-dose 6-thioguanine use. PATIENTS: Inflammatory bowel disease patients using 6-thioguanine for at least 30 consecutive months and consenting to undergo a liver biopsy were enrolled. METHODS: Liver biopsy specimens were scored by two pathologists, unaware of clinical data. Laboratory parameters, determined prior to initiation of 6-thioguanine therapy and prior to biopsy, were reviewed. RESULTS: Twenty-eight biopsies were analysed. The majority of patients (89%) were azathioprine and/or 6-mercaptopurine intolerant inflammatory bowel disease patients. In 26 patients (93%) no signs of nodular regenerative hyperplasia were detected; in two additional patients nodular regenerative hyperplasia could not be excluded due to inconclusive pathological findings. The mean 6-thioguanine dosage, 6-thioguaninenucleotides level, duration of use and cumulative dosage were 19.5mg, 564 pmol/8 x 10(8) RBC, 38 months and 22491 mg, respectively. CONCLUSIONS: We have demonstrated that low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients is not likely to be associated with induction of nodular regenerative hyperplasia. The induction of nodular regenerative hyperplasia appears to be 6-thioguanine dose or 6-thioguaninenucleotides level dependent.

[Continued development of drugs: the path of thioguanine]. / Van doorontwikkeling van een geneesmiddel tot registratie-uitbreiding.

Continued development of existing drugs ('drug rediscovery') may offer new therapeutic options and be cost-effective. Rediscovered drugs are commonly prescribed off-label, although licensing can be important to allow safe and controlled prescription of the drugs to patients. Licensing of a new indication for a generic drug, however, is a complicated process since there is no blueprint for this and there is little interest from the pharmaceutical industry due to an unattractive cost-recovery model. In this article, we illustrate the successful license-extension for thioguanine - initially developed in 1950 for leukaemia - as a new treatment for patients with inflammatory bowel disease.

Host factors are more important in predicting recurrent Clostridium difficile infection than ribotype and use of antibiotics.

OBJECTIVE: A frequent complication of Clostridium difficile infection (CDI) is recurrent disease. The aim of this study was to determine whether early recurrence risk was higher after infection with ribotype 027 (outbreak strain) compared with infection with endemic strain types of C. difficile. METHODS: Consecutive patients diagnosed with CDI between May 2013 and March 2014 were included (outbreak strain, and non-outbreak strains). Patients who developed recurrent CDI within 30 days after completion of CDI treatment, were compared with patients without a recurrence. Medical charts were reviewed for demographic and clinical characteristics. General practitioners were contacted to complete data about the occurrence of recurrent CDI, and the use of medication after hospital discharge. RESULTS: In total, 135 patients were at risk for the development of recurrent CDI; 74 patients were infected by ribotype 027, and 61 patients by other ribotypes. Thirty-nine patients (29%) developed recurrent CDI within 30 days after completion of CDI treatment. In multivariable analysis, age ≥70 years (HR 3.05, 95% CI 1.54-6.03), and a duration of CDI treatment ≥11 days (HR 1.92, 95% CI 1.00-3.69) were clearly associated with recurrence; infection with ribotype 027 showed a HR of 1.72 (95% CI 0.88-3.33). CONCLUSION: During this outbreak of C. difficile in a tertiary care centre, age and a prolonged duration of CDI therapy (which is most likely a marker of underlying disease severity) were the main risk factors for recurrent CDI. This points to host factors as more important predictors for recurrent CDI than strain type or antibiotic use.

Update of treatment algorithms for Clostridium difficile infection.

BACKGROUND: Clostridium difficile is the leading cause of antibiotic-associated diarrhoea, both in healthcare facilities and in the community. The recurrence rate of C. difficile infection (CDI) remains high, up to 20%. Since the publication of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidance document on CDI treatment in 2014, new therapeutic approaches have been developed and tested to achieve higher sustained clinical cure in CDI. AIM: To review novel treatments and approaches for CDI, except probiotics and vaccines. We focused on new antibiotics, antibiotic inactivators, monoclonal antibodies and gut microbiota modulating therapies. SOURCES: A literature review was performed for clinical trials published in PubMed, Embase or Cochrane Library between January 2013 and November 2017. CONTENT: We analysed 28 clinical trials and identified 14 novel agents. Completed phase 2 studies were found for cadazolid, LFF571, ridinilazole and nontoxigenic C. difficile strains. Four phase 3 active comparator studies comparing vancomycin with bezlotoxumab, surotomycin (n = 2) and rifaximin have been published. Seven clinical trials for treatment of multiple recurrent CDI with faecal microbiota transplantation were analysed, describing faecal microbiota transplantation by upper or lower gastrointestinal route (n = 5) or by capsules (n = 2). IMPLICATIONS: Metronidazole is mentioned in the ESCMID guideline as first-line therapy, but we propose that oral vancomycin will become the first choice when antibiotic treatment for CDI is necessary. Fidaxomicin is a good alternative, especially in patients at risk of relapse. Vancomycin combined with faecal microbiota transplantation remains the primary therapy for multiple recurrent CDI. We anticipate that new medication that protects the gut microbiota will be further developed and tested to prevent CDI during antibiotic therapy.