Intravenous versus subcutaneous delivery of biotherapeutics in IBD: an expert's and patient's perspective.

Several biologic treatments are available in addition to intravenous also in subcutaneous form for treatment of chronic diseases. Benefits of the subcutaneous application of drugs include self-administration by the patient, shorter time of application process with less infusion related adverse events and consequently lower healthcare costs. With appropriate education and support patients are able to administer their treatments at home. This leads to improvement of quality of life, reduction of time needed to travel to the healthcare institution and consequently also reduces costs also for the patient.Over one million residents in the USA and 2.5 million in Europe are estimated to have inflammatory bowel disease (IBD), with substantial costs for health care. These estimates do not factor in the 'real' price of IBD, which can impede career aspirations, instil social stigma and impair quality of life in patients.The Virtual Community Meeting, which offered an exchange of experience and opinions from healthcare professionals who are active in treating IBD, and patients with this chronic disease, revealed in-depth arguments and answers to some essential questions: which patients prefer subcutaneous over intravenous dosing; which patients continue to favour intravenous infusions; what are the limitations regarding both applications; what is the patient's role in therapeutical decision-making and how does IBD affect the patient's work, finances and quality of life? The aim of this article is to discuss the differences between subcutaneous and intravenous dosing from the health-economic, scientific, and personal perspectives.The meeting offered strong confirmation that most of the patients and healthcare professionals prefer subcutaneous over intravenous drug administration but emphasise the management of risks associated with treatment compliance. Patient education provided by the IBD team in this regard is mandatory. Quality of life of patients is poorer during active disease, but the findings that it can improve over time, including as a result of home- or self-administration of biologics, may be encouraging for individuals with this chronic disease.

Interleukin-6 compared to the other Th17/Treg related cytokines in inflammatory bowel disease and colorectal cancer.

BACKGROUND: The connection between inflammatory bowel disease (IBD) and colorectal cancer (CRC) is well-established, as persistent intestinal inflammation plays a substantial role in both disorders. Cytokines may further influence the inflammation and the carcinogenesis process. AIM: To compare cytokine patterns of active IBD patients with early and advanced CRC. METHODS: Choosing a panel of cytokines crucial for Th17/Treg differentiation and behavior, in colon specimens, as mRNA biomarkers, and their serum protein levels. RESULTS: We found a significant difference between higher gene expression of FoxP3, TGFb1, IL-10, and IL-23, and approximately equal level of IL-6 in CRC patients in comparison with IBD patients. After stratification of CRC patients, we found a significant difference in FoxP3, IL-10, IL-23, and IL-17A mRNA in early cases compared to IBD, and IL-23 alone in advanced CRC. The protein levels of the cytokines were significantly higher in CRC patients compared to IBD patients. CONCLUSION: Our findings showed that IL-6 upregulation is essential for both IBD and CRC development until the upregulation of other Th17/Treg related genes (TGFb1, IL-10, IL-23, and transcription factor FoxP3) is a crucial primarily for CRC development. The significantly upregulated IL-6 could be a potential drug target for IBD and prevention of CRC development as well.

Primary Helicobacter pylori resistance in elderly patients over 20 years: A Bulgarian study.

We evaluated the antibiotic susceptibility of 233 Helicobacter pylori strains isolated in the period 2011-2016, involving 62 strains from elderly patients aged 66-93years and 171 strains from younger adults. To assess resistance evolution, primary resistance rates in 92 strains from as many patients aged ≥60years in 1996-2003 were compared with those in 85 strains from infected patients in the same age group in 2011-2016. In the patients aged >65years evaluated during the last 6 years, amoxicillin resistance according to EUCAST and prior breakpoints was 1.6 and 0%, respectively. Resistance rates were the same by both breakpoint systems to metronidazole (35.5%), clarithromycin (22.6%), tetracycline (1.6%) and levofloxacin (32.3%). In 2011-2016, there were no significant differences between resistance rates in the subjects aged >65years and the younger adults. Notably, during the last 6 years, double/triple resistance was found in 21.0% of the subjects aged >65years. Moreover, the prevalence of quinolone primary resistance (30.0%) was significantly (3.4-fold) higher than that (8.9%) observed in 1996-2003. Briefly, the presence of both combined resistance and a strikingly high primary levofloxacin resistance in the elderly implies a cautious antibiotic choice for H. pylori eradication. In vitro susceptibility testing of the strains is highly important in this age group. The results can be linked to more frequent comorbidities and co-infection treatment in older compared with younger patients and, additionally, to the national antibiotic consumption. The high prevalence of quinolone resistance in the elderly patients is an alarming finding.

Alterations in cytokine gene expression profile in colon mucosa of Inflammatory Bowel Disease patients on different therapeutic regimens.

Inflammatory bowel disease (IBD) is assumed to be caused by genetic and environmental factors that interact together in promoting intestinal immune dysregulation where cytokines have validated role. However, the underlying intimate mechanisms in the human IBD involving cytokines still needs to be supplemented especially in the clinical context. The aim of this study was to investigate the expression of some inflammatory and regulatory cytokines (IL-17A, IL-23, IL-6, TGFß1, and IL-10) as well as of the transcription factor FoxP3 in mucosal samples of IBD and non-IBD patients. We assessed the mRNA relative quantities (RQ) of the above-mentioned cytokines and the transcription factor FoxP3 in paired colonic samples (inflamed and adjacent normal mucosa) from 37 patients with IBD and in normal mucosal tissue in 12 persons without IBD by performing a qRT-PCR assay and tested the protein levels of target cytokines in serum samples. The patients were divided into three groups: without any therapy (n=10), on 5-ASA (n=11) and on immunosuppressants (Azathioprine±5-ASA/corticosteroids) (n=16) in order to compare the RQ values for each therapeutic group. All investigated genes were found upregulated in the inflamed mucosa of IBD patients in the following order: IL-6>FoxP3>TGFß1>IL-23>IL-17A>IL-10. We also observed that the gene expression of FoxP3 and IL-6 were substantially higher in the inflamed mucosal tissue of the IBD patients than the adjacent normal mucosa (p=0.035, p=0.03 respectively). Differences between higher mRNA expression of FoxP3 and IL-6 in inflamed tissue were considered significant in patients with ulcerative colitis (UC) (p=0.011, p=0.000 respectively) and with Crohn's disease (CD) (p=0.008, p=0.000 respectively) in comparison to the normal mucosa of non-IBD persons and we found increased TGFß1 in CD patients alone (p=0.041). Furthermore, IL-6 and TGFß1 were overexpressed (RQ>10) in non-inflamed mucosa from IBD patients compared to the normal mucosa from the controls. When we compared the gene expression for paired mucosa in the immunosuppressive treated group with the 5-ASA treated group we observed opposite changes in IL-6 and TGFß1 expression. Additionally, we found higher serum levels of IL-23 (p=0.008), TGFß1 and IL-6 in IBD patients compared to non-IBD patients. The obtained specific expression profile consisting of IL-6, TGFß1, IL-10 and FoxP3 may represent a transcriptional hallmark for IBD. Furthermore, we found that treatment with immunosuppressive therapy was more beneficial for driving cytokine expression to restore immune regulation in patients with IBD, unlike the 5-ASA therapy.

Helicobacter pylori resistance to six antibiotics by two breakpoint systems and resistance evolution in Bulgaria.

BACKGROUND: Helicobacter pylori resistance to antibiotics is the main cause for eradication failures. METHODS: Antibiotic resistance in 299 H. pylori strains from 233 untreated adults, 26 treated adults, and 40 untreated children was assessed by E tests and, for metronidazole, by breakpoint susceptibility testing and two breakpoint systems. RESULTS: Using EUCAST breakpoints (EBPs) and previous breakpoints (PBPs), overall resistance rates were: amoxicillin 4.0 and 0.6%, metronidazole 33.8 and 33.8%, clarithromycin 28.1 and 27.4%, levofloxacin 19.4 and 19.4%, tetracycline 3.7 and 1.5%, respectively, and rifampin 8.3% (EBP). Multidrug resistance was detected in treated and untreated adults and an untreated child and included 17 (EBPs) and 15 strains (PBPs). Differences between susceptibility categories were found for amoxicillin (3.5% of strains), clarithromycin (0.7%), and tetracycline (2.2%). Using PBPs, from 2005-2007 to 2010-2015, overall primary clarithromycin resistance continued to increase (17.9-25.6%) as noted in our previous study. However, in 2010-2015, overall primary metronidazole (24.0-31.5%) and fluoroquinolone (7.6-18.3%) resistance rates also increased. Primary resistance rates in children and adults were comparable. CONCLUSIONS: Briefly, differences in resistance rates by the two breakpoint systems affected the results for three antibiotics. National antibiotic consumption was linked to macrolide resistance in adults. Current primary H. pylori resistance to three antibiotics increased in all untreated patients and in the untreated adults, with the sharpest rise for the fluoroquinolones. The presence of fivefold H. pylori resistance to metronidazole, clarithromycin, tetracycline, levofloxacin, and amoxicillin according to EBPs is alarming.

Numerous risk factors for Helicobacter pylori antibiotic resistance revealed by extended anamnesis: a Bulgarian study.

The aim of this study was to assess risk factors for primary Helicobacter pylori antibiotic resistance by an extended anamnesis. In total, 519 H. pylori strains from untreated symptomatic adults who answered a questionnaire were evaluated. Strain susceptibility was assessed by a breakpoint susceptibility test. Primary resistance rates were 29.5 % for metronidazole, 17.9 % for clarithromycin, 7.3 % for metronidazole+clarithromycin, 4.0 % for tetracycline and 10.8 % for ciprofloxacin. On multivariate analysis, younger (≤65 years) age was an independent predictor for metronidazole resistance. To our knowledge, for the first time, being a member of the health-care profession was revealed as a risk factor for H. pylori resistance to metronidazole and both metronidazole and clarithromycin. Respiratory and urinary tract infections were independent predictors of clarithromycin and ciprofloxacin resistance, respectively. The presence of co-infections was an independent risk factor for clarithromycin, metronidazole and ciprofloxacin resistance. Surprisingly, female sex was the only predictor for tetracycline resistance. The antibiotic resistance rates were not associated with disease type, place of residence, birthplace, educational level, non-steroidal anti-inflammatory drug or proton pump inhibitor use, smoking or dietary factors, such as consumption of coffee, yogurt, green tea, raw garlic, raw onion, honey or meat. There was a trend for higher metronidazole resistance in strains from diabetic patients. In conclusion, the extended anamnesis of H. pylori-positive patients should include data on patient age, sex, whether they are in the health-care profession, co-infections and possibly diabetes to improve the choice of empiric therapy. Tailored treatment based on the extended anamnesis is suggested, and susceptibility testing of the strains is recommended for patients at risk for antibiotic resistance, especially to clarithromycin, fluoroquinolones or both metronidazole and clarithromycin.

Two-decade trends in primary Helicobacter pylori resistance to antibiotics in Bulgaria.

Evaluating long-term trends in antibiotic resistance can predict earlier the short-term changes in resistance patterns. The aim of the present study was to compare primary resistance rates in 501 Helicobacter pylori strains in 2007 to 2009 to those in 1990 to 1995 (179 strains) and the antibiotic MICs to detect the 20-year resistance evolution. In 2007 to 2009, strains from children exhibited lower resistance rates to metronidazole (16.4%) and ciprofloxacin (2.7%) than those from adults (27.3% and 10.3%, respectively). In 2008 to 2009, more children (29.3%) harbored clarithromycin-resistant strains compared to the adults (17.4%). Overall clarithromycin resistance rate (19.4%) in 2007 to 2009 was much higher than that in 1990 to 1995 (6.2%). MIC(90) of erythromycin in 1990 to 1995 was 142.2-fold lower than that of clarithromycin in 2007 to 2009. Clarithromycin MIC(90) increased >42-fold since 2001 to 2004. Quinolone resistance rate increased 7.7-fold, being 9.2% in 2007 to 2009 versus 1.2% in 1990 to 1995, with a 5-fold increase in MIC(90). Conversely, the amoxicillin resistance decreased from 3.2% in 1996 to 1999 to 0.4% in 2007 to 2009. The MIC(90)'s of tetracycline remained stable but MIC(50)'s of both metronidazole and tetracycline before 1996 decreased about 4-fold to 2007 to 2009. In conclusion, associations between the resistance evolution and patients' age groups as well as the national outpatient antibiotic use have been found. H. pylori resistance to antibiotics showed many long-term changes, with a more rapid evolution for clarithromycin than for the other antibiotics. Metronidazole and tetracycline did not show a resistance evolution but exhibited a decrease in MIC(50) since 1990. The significant increase in ciprofloxacin resistance was found only by extending the study period to 20 years.

Evaluation of clinical and socio-demographic risk factors for antibacterial resistance of Helicobacter pylori in Bulgaria.

The aim of this study was to assess the clinical and socio-demographic risk factors for primary Helicobacter pylori antibacterial resistance. In total, 266 consecutive H. pylori strains, from untreated symptomatic adult patients who answered a questionnaire, were evaluated. Strain susceptibility to amoxicillin, metronidazole, clarithromycin and tetracycline was tested by a breakpoint susceptibility test. Metronidazole resistance was found in fewer (17.0 %) peptic ulcer patients than in non-ulcer subjects (28.3 %, P=0.037), as well as in fewer patients born in villages (12.7 %) than in those born in towns (27.6 %, P=0.016). Clarithromycin resistance varied from 8.8 to 23.4 % (P=0.009) within the hospital centres. The highest clarithromycin resistance rate was found in hospital centre A (23.4 %) compared to other centres (12.9 %, P=0.041). The factors sex, age, symptom duration, non-steroidal anti-inflammatory drug use, diabetes, type of profession and educational level were not associated with H. pylori resistance. Logistic regression revealed that the risk factors for metronidazole resistance were non-ulcer disease [odds ratio (OR) 1.95, 95 % confidence interval (95 % CI) 1.04-3.65] and a birthplace of a town (OR 2.64, 95 % CI 1.18-5.93). The hospital centre may be a risk factor (OR 2.07, 95 % CI 1.02-4.21) for clarithromycin resistance but further studies are required to verify this suggestion. In conclusion, the knowledge of the risk factors for H. pylori resistance to antibacterials could facilitate the treatment choice for H. pylori eradication.

Antibacterial resistance in Helicobacter pylori strains isolated from Bulgarian children and adult patients over 9 years.

The aim of this study was to evaluate the primary, combined and post-treatment antibacterial resistance rates in 1205 Helicobacter pylori strains from non-treated (786 adults, 282 children) and treated (109 adults, 28 children) patients in Bulgaria. Susceptibility was tested by the limited agar dilution method. Overall primary resistance rates to metronidazole, clarithromycin, amoxicillin, tetracycline and both metronidazole and clarithromycin were respectively 15.0, 12.5, 1.5, 3.4 and 4.7% in children and 25.6, 12.6, 0.8, 5.2 and 4.9% in adults. Primary metronidazole resistance in adults was more common than in children, but the differences for other agents tested were not significant. Primary resistance rates were in the range of those reported worldwide. There was no significant increase in primary resistance rates from 1996/1999 to 2003/2004; however, clarithromycin resistance rates exhibited a slight tendency to increase. Post-treatment resistance to amoxicillin was detected in 1.6% of 63 strains. Post-treatment resistance to metronidazole was common (81.6%) and that to clarithromycin was considerable (36%). Alarming emergence of strains with triple resistance to amoxicillin, metronidazole and clarithromycin was found in two non-treated and three treated patients. The results motivate a larger and continuing surveillance of H. pylori resistance in Bulgaria and worldwide.

Campylobacter infection in 682 bulgarian patients with acute enterocolitis, inflammatory bowel disease, and other chronic intestinal diseases.

The aim of the study was to assess Campylobacter infections in 309 patients with acute enterocolitis, 272 patients with relapses of chronic enterocolitis, 70 patients with inflammatory bowel disease (involving Crohn's disease and ulcerative colitis) and 31 patients with other chronic intestinal illnesses. Isolation and identification were performed conventionally. Limited agar dilution method was used for susceptibility testing of the strains. Campylobacter species were isolated in patients with acute enterocolitis (7.8%), chronic enterocolitis (6.2%), Crohn's disease (6.2%), ulcerative colitis (3.7%), and irritable bowel syndrome (8.3%). Hippurate-positive Campylobacter jejuni isolates accounted for 62.2% of Campylobacter strains. One tetracycline resistant Campylobacter upsaliensis isolate was detected from a girl with acute enterocolitis. Resistance rates to erythromycin (31.1%) and clarithromycin (22.2%) were high, whereas those to amoxicillin/clavulanate (4.4%), ampicillin/sulbactam (13.3%), tetracycline (24.4%) and ciprofloxacin (22.2%) were relatively low. Resistance to erythromycin and either tetracycline or ciprofloxacin was detected in 8.9% and 6.7%. The involvement of Campylobacter infection in relapses of chronic intestinal disorders and the susceptibility patterns of the strains strongly emphasize the role of Campylobacter as a cause of infection in this group of patients.

Primary and combined resistance to four antimicrobial agents in Helicobacter pylori in Sofia, Bulgaria.

The aim of this study was to evaluate the primary and combined resistance of Helicobacter pylori against four antimicrobial agents by a screening agar method (SAM) and a modified disk diffusion method (MDDM) alone and in combination. Pre-treatment H. pylori isolates from 192 consecutive H. pylori-positive patients at three hospitals in Sofia were investigated. MDDM was performed with disks containing metronidazole (5 microg), clarithromycin (15 microg) or erythromycin (15 microg), ciprofloxacin (5 microg) and tetracycline (30 microg). Resistance was determined by an inhibitory zone of <16 mm for metronidazole and < or =30 mm for other agents tested. The cut-off concentrations used to define resistance by SAM were: metronidazole >8 mg/L, clarithromycin >2 mg/L, tetracycline >4 mg/L and ciprofloxacin >1 mg/L. Primary resistance rates in H. pylori were: metronidazole 28.6%, clarithromycin 9.7%, metronidazole + clarithromycin 2.8%, ciprofloxacin 3.9%, metronidazole + ciprofloxacin 2.3%, tetracycline 1.9% and metronidazole + tetracycline 1.2%. Among metronidazole-resistant isolates, combined resistance to clarithromycin, ciprofloxacin and tetracycline was present in 11.4% (5 of 44 strains), 8.3% (3 of 36) and 4.9% (2 of 41), respectively. Two strains exhibited triple resistance to macrolides, metronidazole and either ciprofloxacin or tetracycline. Three tetracycline-resistant strains were detected in 1999; however, resistance rates to other agents were relatively stable during the 6 years. Primary H. pylori resistance to metronidazole is moderate and resistance to clarithromycin and to ciprofloxacin is considerable in comparison with results in most other countries. The alarming appearance of strains harbouring combined resistance or multiresistance provides the motivation for continued surveillance of H. pylori at global, national and regional levels.