Chiara Ricci

Sequential Therapy versus Standard Triple-Drug Therapy for Helicobacter pylori Eradication: A Randomized Trial

Context Eradication rates for Helicobacter pylori infection are decreasing worldwide because of increasing antimicro-bial resistance. Contribution This double-blind trial randomly assigned 300 adults with dyspepsia or peptic ulcers to a 10-day sequential regimen (pantoprazole, amoxicillin, and placebo taken for 5 days followed by pantoprazole, clarithromycin, and tinidazole taken for 5 days) or standard 10-day therapy (pantoprazole, clarithromycin, and amoxicillin). The eradication rate of H. pylori infection was greater with the sequential regimen (89%) than with the standard treatment (77%). Approximately 5% of patients in each group had epigastric pain and 3% to 5% had mild diarrhea. Implication Sequential therapy eradicates H. pylori infection more often than does standard therapy. The Editors Helicobacter pylori infection causes peptic ulcers, gastric mucosaassociated lymphoid tissue lymphoma, and gastric cancer (1). Standard treatments for H. pylori infection that have been endorsed by U.S. and European authorities rely on clarithromycin or metronidazole in conjunction with other antibiotics and acid inhibitors (2, 3). The prevalence of clarithromycin and metronidazole resistance has increased substantially in recent years, and there has been a corresponding decrease in the eradication rate for H. pylori infection (4). Eradication rates in most western countries have declined to unacceptable levels. Eradication therapy fails in approximately 1 in 5 patients (5). A simple, short treatment regimen that would return eradication levels to those seen at the advent of H. pylori treatment is urgently needed (5). Such a regimen should have high efficacy against clarithromycin-resistant and metronidazole-resistant strains of H. pylori because these strains are increasingly encountered in routine clinical practice. Novel 10-day sequential therapy consisting of 5-day dual therapy (proton-pump inhibitor plus amoxicillin) followed by 5-day triple therapy (proton-pump inhibitor, clarithromycin, and tinidazole) has had good eradication success in unblinded trials in elderly and pediatric patients (68). However, no double-blind, controlled trials using conventional therapy have been reported, and the effect of clarithromycin and metronidazole resistance on the outcome of sequential therapy has not been studied prospectively. The aim of this study was to compare a 10-day sequential treatment regimen for H. pylori infection with standard 10-day triple therapy in a randomized, controlled trial. Secondary objectives were to determine the efficacy of the treatment regimen in patients with resistant strains of H. pylori, to assess treatment adherence, and to evaluate side effects. Methods Design Overview This was a prospective, double-blind, controlled study with a parallel-group design. At baseline, patients were evaluated for inclusion and exclusion criteria and provided written informed consent. Patients were then randomly assigned to a treatment group and had follow-up evaluations to assess the eradication rate of H. pylori infection, treatment adherence, and side effects. The study was performed according to good clinical practice and the Declaration of Helsinki. The ethics committees at the 2 participating centers approved the study. The consent form indicated that patients would be randomly assigned to treatment that was the current standard or a new therapy that might have higher eradication rates. Patients were told that eradication failure was possible with any therapy regimen. All patients with eradication failure were offered a rescue therapy on the basis of the results of sensitivity testing. Setting and Participants Between September 2003 and April 2006, consecutive patients with dyspepsia who were at least 18 years of age, who had never received treatment for H. pylori infection, and who had been referred to our hospitals (Bologna, Italy, and Rome, Italy) for a gastroenterology consultation were asked to participate in the study. No special recruitment techniques (such as advertisements or letters sent to primary care physicians) were used. Exclusion criteria were previous treatment for H. pylori infection; use of proton-pump inhibitors, H2-receptor antagonists, bismuth preparations, or antibiotics in the previous 2 weeks; concomitant use of anticoagulants or ketoconazole (because of potential interaction with the nonsteroidal anti-inflammatory drugs) and glucocorticoids (because of association with ulcer disease); the ZollingerEllison syndrome; previous surgery of the esophagus or upper gastrointestinal tract (except appendectomy, polypectomy, or cholecystectomy); severe or unstable cardiovascular, pulmonary, or endocrine disease; clinically significant renal or hepatic disease or dysfunction; hematologic disorders; any other clinically significant medical condition that could increase risk; malignant disease of any kind except for successfully treated skin cancer (basal- or squamous-cell carcinoma) during the previous 5 years; Barrett esophagus or high-grade dysplasia; drug, alcohol, or medication abuse within the past year; severe psychiatric or neurologic disorders; and pregnancy or lactation, as well as sexually active women of child-bearing years who were not willing to practice medically acceptable contraception (oral or injectable contraceptives, implantable or mechanical intrauterine or vaginal devices, or vasectomy for the partner) for the study duration. Randomization and Interventions Patient allocation was determined with a random-number chart that was concealed from investigators and patients by using numbered blister packs of the study medication that corresponded to the random-number chart. A computer-generated randomization chart was used to determine allocation, which was stratified according to center by using a block design and a block size of 4. Allocation was concealed with an opaque envelope, which contained a number that corresponded to the numbered blister packs. The envelope was opened when the patient met the inclusion criteria and provided informed consent. Patients and investigators were blinded to treatment group. Patients were randomly allocated to receive a 10-day sequential regimen (40 mg of pantoprazole, 1 g of amoxicillin, and placebo, each administered twice daily for the first 5 days, followed by 40 mg of pantoprazole, 500 mg of clarithromycin, and 500 mg of tinidazole, each administered twice daily for the remaining 5 days); or standard therapy (40 mg of pantoprazole, 500 mg of clarithromycin, and 1 g of amoxicillin, each administered twice daily for 10 days). Medications were contained in individual blisters in the package. A placebo that was identical in color and shape to the clarithromycin capsule was administered during the first 5 days of sequential therapy to maintain blinding. This ensured that all patients took 3 medications twice a day for 10 days. Measurements and Outcomes The primary outcome of the study was eradication of H. pylori infection. Secondary outcomes were to determine the efficacy of sequential treatment against clarithromycin-resistant strains of H. pylori, to assess adherence to therapy, and to determine the frequency of self-reported side effects. 13C-Urea Breath Test Urea breath tests were done after an overnight fast. A baseline breath sample was obtained, and 75 mg of 13C-urea with citric acid (1.5 g) was administered as an aqueous solution. Another breath sample was collected 30 minutes after the test solution was administered. The results of the test were considered positive if the difference between the baseline sample and the 30-minute sample exceeded 4.5 parts per 1000 of 13CO2. All breath samples were analyzed in Bologna by using a single gas isotope ratio mass spectrometer (Finnigan, Bremen, Germany). The accuracy of the urea breath test was previously validated in our laboratory. We reported sensitivity and specificity values of 94.7% and 95.7%, respectively (9). Endoscopy All patients with positive results on the urea breath test had upper endoscopy, and 5 biopsy specimens were obtained during the procedure. Two specimens were taken from the antrum and 2 were taken from the corpus for histologic evaluation. The specimens were stained with hematoxylin and eosin and Giemsa stains, and gastritis was scored by using the updated Sydney System (10). The pathologist who performed the histologic examination was blinded to the results of all other tests. One biopsy specimen was obtained from the antrum for the rapid urease test (Campylobacter pylori test, Yamanouchi Pharma S.p.A, Corrugate, Milan, Italy). Two additional biopsy samples from the antrum were collected for bacterial culture and susceptibility testing. We performed cultures without knowing the other test results. For this purpose, biopsy specimens were sent to a single microbiological laboratory in Bologna within 24 hours and were stored at 70C. Isolated strains were tested for primary clarithromycin and metronidazole resistance by using an agar dilution method, which was defined as a minimal inhibitory concentration greater than 1 mg/L and greater than 8 mg/L for clarithromycin and metronidazole, respectively (11). Strains were classified as having isolated resistance to clarithromycin or metronidazole if the organisms were only resistant to 1 antibiotic. Dual resistance was defined as resistance to clarithromycin and metronidazole. At baseline, patients were classified as having H. pylori infection if the results on the urea breath test were positive and if the results on at least 2 of the following 3 tests were positive: rapid urease test, histologic examination, and culture. An expert panel recommended these criteria for use in clinical trials of H. pylori infection (12). Follow-up Procedures Treatment Adherence and Side Effects Patients were asked to return at the completion of therapy for a physical evaluation and to assess adherence to therapy and side effects. We first aske

High eradication rates of Helicobacter pylori with a new sequential treatment

Background : Eradication rates of Helicobacter pylori with standard triple therapy are disappointing, and studies from several countries confirm this poor performance.

Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet

Background  Expected benefits of gluten‐free diet (GFD) in coeliac patients include healing of small intestinal mucosa, but it remains unclear to what extent this benefit is achieved in adults.

A 10-day levofloxacin-based triple therapy in patients who have failed two eradication courses

Background : A standard third‐line treatment is lacking, and European guidelines recommend performing culture in these patients. However, the use of this procedure as ‘routine practice’ is definitively not feasible.

The Stool Antigen Test for Detection of Helicobacter pylori after Eradication Therapy

Context Standard treatment regimens do not eradicate infection in approximately 10% to 20% of people with ulcers or gastritis caused by Helicobacter pylori. Symptoms do not reliably identify patients who have persistent infection despite treatment. Although positive results on a urea breath test done 4 weeks after treatment reliably identify persistent infection, a noninvasive test that detects successful eradication earlier would be useful. Contribution This multicenter study shows that a positive finding on a stool antigen test done as early as 1 week after treatment identifies about 95% (range, 70% to 100%) of cases of persistent infection. Generalization Cautions Findings are from patients with dyspepsia who were referred for endoscopy; 20% of patients were still infected at 1 month despite eradication therapy. The Editors Noninvasive tests for Helicobacter pylori are important in primary care, both for initial diagnosis of H. pylori infection and for confirmation of eradication. Current guidelines recommend noninvasive testing and treatment of young dyspeptic patients without alarm symptoms (such as dysphagia or weight loss that suggest underlying malignant disease) in a primary care setting by using low-cost noninvasive tests (1, 2). Randomized, controlled trials have shown that a test and eradicate strategy toward H. pylori is effective in patients with dyspepsia seen in primary care settings who have not undergone investigations such as endoscopy or radiographic studies (3). Post-therapy testing is also growing in importance. Resistant strains of H. pylori are now widely prevalent in the United States and Europe, and eradication therapy with current regimens fails in 10% to 20% of patients (4, 5). Furthermore, some patients with ulcer disease remain symptomatic despite successful eradication of H. pylori and healing of the ulcer (6). In patients with persistent symptoms, testing for persistent H. pylori infection is important to direct further therapy. Routine testing to confirm eradication in patients with complicated ulcer disease, such as bleeding peptic ulcer, is necessary because the risk for rebleeding is greatly increased in patients with persistent infection (7). The choice of tests in the post-therapy setting is limited. Serologic tests are unreliable in determining eradication (8). Endoscopic tests (rapid urease test, histologic examination, or culture) are reliable, but endoscopy is expensive and inconvenient. Until recently, the only noninvasive test that reliably demonstrated whether eradication was successful was the urea breath test (9). This test has high sensitivity and specificity in the post-therapy setting but cannot be used until 4 weeks after treatment. Moreover, the breath test is still not widely available in the United States. The fecal antigen test is a relatively new noninvasive test for detection of H. pylori (10). This test detects the presence of infection by measuring the fecal excretion of H. pylori antigens. It has been approved by the U.S. Food and Drug Administration for detection of H. pylori before and after therapy. We sought to determine whether a stool antigen test administered at various times after treatment correctly identifies persons in whom H. pylori infection persists despite eradication therapy. Methods We prospectively studied 84 patients infected with H. pylori at six clinical centers (31 in Bologna, Italy; 29 in Amsterdam, the Netherlands; 9 in Rome, Italy; 8 in Lisbon, Portugal; 4 in Madrid, Spain; and 3 in Milwaukee, Wisconsin). The sample consisted of consecutive patients with dyspepsia (defined as pain or discomfort centered in the upper abdomen) who were referred by primary care physicians for upper endoscopy (11). Consenting patients were enrolled if they tested positive for H. pylori on endoscopic tests. Patients enrolled in this study have not been enrolled in other studies. Patients were excluded if they had taken proton-pump inhibitors, H2-receptor antagonists, nonsteroidal anti-inflammatory agents, or antibiotics in the 4 weeks before the study. Failure to return for follow-up endoscopy was an a priori exclusion criterion. All patients gave written informed consent, and the study was approved by the human subjects review committee or equivalent at each participating institution. At baseline, patients underwent endoscopy with biopsy sampling for histologic examination (two samples from the antrum and two from the corpus), culture (two samples from the antrum and two from the corpus), and a rapid urease test (one sample from the antrum). All patients were infected with H. pylori at baseline, as demonstrated by positive results on both rapid urease testing and histologic examination or a positive culture for H. pylori. Within 24 hours of the endoscopy, all patients underwent a 13C or 14C urea breath test. The breath test was chosen according to local availability and experience, but in all cases a validated breath test analysis system was used. Cut-off values were determined according to the recommendations of the various manufacturers of these tests. Patients collected stool using a kit consisting of a plastic spoon that is used to scoop a small amount of stool from the toilet paper or toilet bowl into an airtight container. At all sites, the stool assay was performed by using the Premier Platinum HpSA test (Meridian Diagnostics, Inc., Cincinnati, Ohio). The assay is a microwell-based enzyme immunoassay that uses polyclonal antiH. pylori capture antibody adsorbed to microwells. Diluted patient samples and a peroxidase-conjugated polyclonal antibody were added to the wells and incubated at room temperature for 1 hour. A wash was performed to remove unbound material. Substrate was added and incubated for 10 minutes at room temperature. Color develops in the presence of bound enzyme. Stop solution was added, and the results were inspected spectrophotometrically at 450 nm within 15 minutes of adding the stop solution. Visual determination can also be used; this has been shown to have similar results (12). A positive control and a negative control are built into the test. The cut-off values were classified as negative (<0.140), indeterminate (0.140 to 0.159), or positive (>0.160). After completion of the baseline procedures, treatment was begun with ranitidine bismuth citrate (400 mg twice daily) or omeprazole (20 mg twice daily) in combination with amoxicillin (1 g twice daily) and clarithromycin (500 mg twice daily) for 7 to 10 days. Seven-day eradication therapy was used in Europe, where it is approved by the European Union and has been shown to be effective (5). Ten-day triple therapy with proton-pump inhibitors was used in the United States, where it is approved by the U.S. Food and Drug Administration. Patients collected stool for the stool antigen test on days 3, 7, 15, 21, 28, and 35 after completion of H. pylori eradication therapy. On day 35 after completion of eradication therapy, endoscopy was repeated and biopsy samples were again obtained for histologic examination, culture, and the rapid urease test, as performed at the baseline visit. The 13C or 14C urea breath test was repeated on day 35 by using the same method and cut-off values as at baseline. Patients were classified as being infected with H. pylori at baseline and having persistent infection on day 35 if culture of gastric biopsy specimens was positive for H. pylori or results of the rapid urease test and histologic examination were positive. All other patients were classified as negative. These criteria have been recommended by an expert panel for use in clinical trials of H. pylori eradication (13). At baseline, the sensitivity of the stool test and urea breath test were calculated by using the presence of infection (defined above) as the gold standard. At each time point after completion of therapy (days 3, 7, 15, 21, 28), predictive values were calculated by using continued infection on day 35 as the gold standard (positive result on culture or on rapid urease test and histologic examination). Trained investigators who were blinded to the results of the other diagnostic studies performed the stool assays. The first endoscopy procedure was performed before the stool and breath tests. Therapy was given on the basis of results on endoscopic testing. Endoscopists were blinded to the results of post-treatment stool studies and the breath test until all evaluations were completed. Long-Term Follow-up Patients in whom eradication of H. pylori was successful were eligible for entry into a long-term study evaluating the stool antigen test. For 6 months, stool antigen tests were done monthly and a urea breath test was obtained every 3 months. Statistical Analysis Statistical analysis was performed by using StatView for Windows, version 5.01 (SAS Institute, Inc., Cary, North Carolina). Results are presented as the mean (SD). Sensitivity, specificity, probabilities, and predictive values are presented with 95% exact binomial CIs. Equivocal stool tests are considered by inclusion in the denominator of sensitivity and specificity. Stool antigen concentrations at individual time points were compared by using theMannWhitney test with downward adjustment of the P values for repeated observations (14). Role of the Funding Source The manufacturer (Meridian Diagnostics, Inc.) provided the stool kits. The study had no other funding source. Collection, analysis, and interpretation of the data, including the decision to publish, were solely the decision of the authors; the manufacturer of the test had no role in this process. Results The mean age of the 84 study patients was 52 years (range, 18 to 81 years). Fifty-three patients were women, and 31 were men. Endoscopic findings were as follows: normal (7 patients), esophagitis (2 patients), erythema in the antrum (45 patients), erosions in the antrum (11 patients), erosive duodenitis (9 patients), duodenal ulcers (8 patients), gastric ulcer (2 p

Primary antibiotic resistance in Helicobacter pylori strains isolated in northern and central Italy

Background  Helicobacter pylori resistance to antibiotics is increasing worldwide, and it reduces the efficacy of therapy.

Incidence of Post-Infectious Irritable Bowel Syndrome and Functional Intestinal Disorders Following a Water-Borne Viral Gastroenteritis Outbreak

OBJECTIVES:Post-infectious irritable bowel syndrome (PI-IBS) may develop in 4–31% of affected patients following bacterial gastroenteritis (GE), but limited information is available on long-term outcome of viral GE. During summer 2009, a massive outbreak of viral GE associated with contamination of municipal drinking water (Norovirus) occurred in San Felice del Benaco (Lake Garda, Italy). To investigate the natural history of a community outbreak of viral GE, and to assess the incidence of PI-IBS and functional gastrointestinal disorders, we carried out a prospective population-based cohort study with a control group.METHODS:Baseline questionnaires were administered to the resident community within 1 month of the outbreak. Follow-up questionnaires of the Italian version of Gastrointestinal Symptom Rating Scale (GSRS, a 15-item survey scored according to a 7-point Likert scale) were mailed to all patients responding to baseline questionnaire at 3 and 6 months, and to a cohort of unaffected controls, living in the same geographical area, at 6 months after the outbreak. The GSRS item were grouped in five dimensions: abdominal pain, reflux, indigestion, diarrhea, and constipation. At month 12, all patients and controls were interviewed by a health assistant to verify Rome III criteria of IBS. Students t-test and χ2- or Fishers exact test were used as appropriate.RESULTS:Baseline questionnaires were returned by 348 patients: mean age±s.d. 45±22 years, 53% female. At outbreak, nausea (scored ≥4), vomiting, and diarrhea lasting 2–3 days or more were reported by 66, 60, and 77% of patients, respectively. A total of 50% reported fever and 19% reported weight loss (mean 3 kg). Follow-up surveys were returned at month 6 by 186 patients and 198 controls: mean GSRS score was significantly higher in patients than in controls for abdominal pain, diarrhea, and constipation. At month 12, we identified 40 patients with a new diagnosis of IBS (Rome III criteria), in comparison with 3 subjects in the control cohort (P<0.0001; odds ratio 11.40; 95% confidence intervals 3.44–37.82). The 40 cases of PI-IBS were subtyped according to the predominant stool pattern as follows: 4 IBS with constipation, 7 IBS with diarrhea, 16 with mixed IBS, and 13 with unsubtyped IBS.CONCLUSIONS:Our study provides evidence that Norovirus GE leads to the development of PI-IBS in a substantial proportion of patients (13%), similar to that reported after bacterial GE.

Effect of proton pump inhibitors and antacid therapy on 13C urea breath tests and stool test for Helicobacter pylori infection.

OBJECTIVE:There is uncertainty about the best method of testing patients for Helicobacter pylori (H. pylori) infection while they are taking proton pump inhibitors. The aim of this study was to determine: (i) if the decreased sensitivity of the urea breath test during proton pump inhibitor is corrected by different techniques for breath testing and (ii) if the sensitivity of stool test is decreased with the administration of proton pump inhibitors.METHODS:Prospective randomized single-blind study was performed in a tertiary care university hospital. Out of 72 H. pylori infected patients endoscoped for upper abdominal symptoms 48 were randomized to proton pump inhibitors (omeprazole 20 mg each day or esomeprazole 40 mg each day) and 24 to antacid (aluminum hydroxide 800 mg each day) for 14 days. Several breath tests (standard 75 mg 13C-UBT with citric acid, with orange juice, a tablet breath test with 100 and 50 mg of 13C), and a stool test were carried out. Baseline samples were collected before and after treatment.RESULTS:The baseline sensitivity for all breath tests was 100% in both groups; for stool test it was 97.8% (95% CI: 88.7–96.6) and 90% (95% CI: 69.9–97.2) in the proton pump inhibitor and antacid group, respectively. After treatment, the sensitivity of tests was significantly low (UBTs range: 77.1%–85.4%; stool test: 83%; 95% CI: 63.9–91.1), while it was unchanged in the antacid group.CONCLUSIONS:False negative breath and stool tests are equally common in patients taking proton pump inhibitors. Antacids do not impair the sensitivity of the breath tests or the stool test.

High rate of Helicobacter pylori eradication with sequential therapy in elderly patients with peptic ulcer: a prospective controlled study

Background : Helicobacter pylori eradication rates with triple therapies are decreasing, and few data in elderly patients are available. A 10‐day sequential regimen succeeded in curing such H. pylori infection in unselected patients.

Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas)

Objectives Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. Design Retrospective multinational study including SCN diagnosed between 1990 and 2014. Results 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16–99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2–200)), 9% had resection beyond 1 year of follow-up (3 years (1–20), size at diagnosis: 25 mm (4–140)) and 39% had no surgery (3.6 years (1–23), 25.5 mm (1–200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCNs related mortality was 0.1% (n=1). Conclusions After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. Trial registration number IRB 00006477.