Giulia Fiorini

Sequential therapy for Helicobacter pylori eradication: the time is now!

Helicobacter pylori treatment still remains a challenge for physicians, and no current first-line therapies are able to cure the infection in all treated patients. Two very large meta-analysis studies showed that standard 7—14 days triple therapies fail to eradicate H. pylori infection in up to 20—25% of patients [Fuccio et al. 2007; Zullo et al. 2007]. In addition, the efficacy of these regimens is even decreasing worldwide. Indeed, during the last few years, different studies have found that the success rate following such regimens is disappointingly low, with values less than 45—60% in some countries [Gumurdulu et al. 2004; Vakil et al. 2004]. This phenomenon most likely depends on an increased bacterial resistance to antibiotics, particularly against clari-thromycin — the key antibiotic in H. pylori treatment [Megraud 2004]. In detail, clarithromycin resistance reduces success rate of standard triple therapies to mean values as low as 18—44%. Consequently, several patients deserve two or more therapeutic attempts to cure H. pylori infection in clinical practice. Therefore, as well as first-line regimens, both second-line and ‘rescue’ therapies have been advised in the updated international guidelines for H. pylori management [Caselli et al. 2007; Malfertheiner et al. 2007]. However, to cure the infection following a failed initial triple therapy is particularly difficult and costly, due to the need for further therapies and diagnostic tests. In a recent study, the cumulative eradication rate was 89.6% by using three consecutive standard therapies in patients treated in clinical practice, being only 70.3%, 69.1% and 70% following first-, second-, and third-line regimens, respectively [Rokkas et al. 2009]. All these observations clearly suggest that more efficacious therapy regimens are required as an initial therapy for clinical practice, the best first-line treatment being still regarded as the best ‘rescue’ therapy [Huang and Hunt 1999]. In 2000, we conceived a novel therapeutic approach to cure H. pylori infection, namely a 10-day sequential therapy, which achieved a very high eradication rate [Zullo et al. 2000]. The sequential therapy is a simple dual therapy including a proton pump inhibitor (PPI) plus amoxicillin 1 g (both twice daily) given for the first 5 days followed by a triple therapy including a PPI, clarithromycin 500 mg, and tinidazole (all twice daily) for the remaining 5 days [Zullo et al. 2007]. To date, the efficacy of such a therapy regimen has been investigated in several trials overall enrolling more than 2000 patients. Based on these results, sequential therapy is now recognized as first-line therapy in the current Italian guidelines [Caselli et al. 2007].

Culture-based Selection Therapy for Patients Who Did Not Respond to Previous Treatment for Helicobacter pylori Infection

BACKGROUND & AIMS Eradication of Helicobacter pylori using empiric therapy has become difficult as a result of increasing resistance to antibiotics. We evaluated the efficacy of specific treatments, selected based on response of bacterial samples to culture with clarithromycin, levofloxacin, and metronidazole, for patients infected with resistant strains of H pylori. METHODS We performed a prospective study at a single center of 236 consecutive patients with persistent H pylori infection, despite 1 or more treatment attempts, and documented resistance to at least 1 antimicrobial agent (based on bacterial culture tests). Biopsy samples were collected by endoscopy and cultured in selective media. Patients received either 10 days of levofloxacin (250 mg twice daily for 131 patients with susceptible infections) or 12 days of rifabutin (150 mg once daily for 105 patients resistant to levofloxacin) in combination with amoxicillin (1 g twice daily) and esomeprazole (40 mg twice daily). Efficacy of eradication was determined by the (13)C-urea breath test, 6 to 8 weeks after therapy. Compliance and side effects were determined via personal interviews at the end of therapy. Rifabutin toxicity was monitored by analysis of blood samples. RESULTS H pylori infection was cured in 118 of the patients who received levofloxacin triple therapy (90%; 95% confidence interval, 85%-95%) and 93 of the patients who received rifabutin triple therapy (88.6%; 95% confidence interval, 82%-95%). In each group, the cure rate did not differ significantly between patients infected with H pylori strains resistant to single or multiple antibiotics. Mild side effects occurred in 15.5% and 14.9% of patients resistant to single or multiple antibiotics, respectively, and self-limiting neutropenia was observed in 1 (0.7%) case. CONCLUSIONS Selection of triple therapy with either levofloxacin or rifabutin, based on results from bacterial culture tests, cures H pylori infection in about 90% who did not previously respond to antibiotics.

Accuracy of a new ultrafast rapid urease test to diagnose Helicobacter pylori infection in 1000 consecutive dyspeptic patients

Background  Rapid diagnostic tools for Helicobacter pylori are important in endoscopy.

Change of point mutations in Helicobacter pylori rRNA associated with clarithromycin resistance in Italy.

Primary clarithromycin resistance is the main factor affecting the efficacy of Helicobacter pylori therapy. This study aimed: (i) to assess the concordance between phenotypic (culture) and genotypic (real-time PCR) tests in resistant strains; (ii) to search, in the case of disagreement between the methods, for point mutations other than those reported as the most frequent in Europe; and (iii) to compare the MICs associated with the single point mutations. In order to perform real-time PCR, we retrieved biopsies from patients in whom H. pylori infection was successful diagnosed by bacterial culture and clarithromycin resistance was assessed using the Etest. Only patients who had never been previously treated, and with H. pylori strains that were either resistant exclusively to clarithromycin or without any resistance, were included. Biopsies from 82 infected patients were analysed, including 42 strains that were clarithromycin resistant and 40 that were clarithromycin susceptible on culture. On genotypic analysis, at least one of the three most frequently reported point mutations (A2142C, A2142G and A2143G) was detected in only 23 cases (54.8%), with a concordance between the two methods of 0.67. Novel point mutations (A2115G, G2141A and A2144T) were detected in a further 14 out of 19 discordant cases, increasing the resistance detection rate of PCR to 88% (P<0.001; odds ratio 6.1, 95% confidence interval 2-18.6) and the concordance to 0.81. No significant differences in MIC values among different point mutations were observed. This study suggests that: (i) the prevalence of the usually reported point mutations may be decreasing, with a concomitant emergence of new mutations; (ii) PCR-based methods should search for at least six point mutations to achieve good accuracy in detecting clarithromycin resistance; and (iii) none of the tested point mutations is associated with significantly higher MIC values than the others.

Newer agents for Helicobacter pylori eradication

Helicobacter pylori infection remains widespread internationally, with a definite morbidity and mortality. The efficacy of standard 7–14 day triple therapies is decreasing, mainly due to increasing primary bacterial resistance to antibiotics. Currently, the most effective treatments are either the sequential regimen or the concomitant therapy. Different patents have been registered showing high bactericidal effects in vitro, some of which are active against clarithromycin- and metronidazole-resistant strains, even at low pH values. Among these novel molecules, benzimidazole-derivatives, polycyclic compounds, pyloricidin, and arylthiazole analogues seem to be the more promising. The identification of essential genes for either bacterial colonization or growth represents a route for potential target therapies in the near future.

Impact of primary antibiotic resistance on the effectiveness of sequential therapy for Helicobacter pylori infection: lessons from a 5‐year study on a large number of strains

The increasing prevalence of strains resistant to antimicrobial agents is a critical issue in the management of Helicobacter pylori (H. pylori) infection.

Tablet and oral liquid L-thyroxine formulation in the treatment of naïve hypothyroid patients with Helicobacter pylori infection

To compare the clinical efficacy of tablet and oral liquid L-thyroxine (LT4) formulation in naïve hypothyroid subjects with Helicobacter pylori infection. Forty-seven adult naïve hypothyroid subjects with dyspeptic symptoms were investigated with upper endoscopy and divided into: 28 patients with Helicobacter pylori infection (Group A); 15 patients without gastric alterations (group B); 4 patients with autoimmune gastritis were excluded from the study. Subjects were randomly treated with a same dose of LT4 tablet (TAB) or oral liquid formulation (SOL), for 9 months on group A and 6 months on group B. Helicobacter pylori infection was eradicated after 3 months of LT4 treatment. On group A, after 3 months (before Helicobacter pylori eradication), subjects treated with SOL showed a greater thyroid-stimulating hormone reduction (ΔTSH3–0: TAB = −4.1 ± 4.6 mU/L; SOL = −7.7 ± 2.5 mU/L; p = 0.029) and a greater homogeneity in the thyroid-stimulating hormone values (TSH3mo: TAB = 5.7 ± 4.9 mU/L; SOL = 4.1 ± 2.0 mU/L; p = 0.025), compared to LT4 tablet. At 9 months (after 6 months of Helicobacter pylori eradication) mean thyroid-stimulating hormone values were lower in subjects treated with LT4 tablet (TSH9mo: TAB = 1.8 ± 1.2 mU/L; SOL = 3.2 ± 1.7 mU/L; p = 0.006). On group B no difference were observed, at each time point, in the mean thyroid-stimulating hormone values and thyroid-stimulating hormone variations between two LT4 formulations. LT4 liquid formulation may produce a better clinical response compared to the tablet formulation in hypothyroid subjects with Helicobacter pylori infection.

Rescue therapy with bismuth quadruple regimen in patients with Helicobacter pylori -resistant strains

Bismuth quadruple therapy (BQT) is the recommended rescue therapy for Helicobacter pylori (H. pylori) infection. This study aimed to assess the efficacy and safety of a 10‐day BQT regimen in patients who failed previous therapies and were infected with multiresistant H. pylori strains

Gastroesophageal reflux disease and Barrett’s esophagus

Gastroesophageal reflux disease is the most common gastrointestinal diagnosis recorded during visits to outpatient clinics. The spectrum of injury includes esophagitis, stricture, the development of columnar metaplasia in place of the normal squamous epithelium (Barrett’s esophagus), and adenocarcinoma. Barrett’s esophagus is a premalignant lesion detected in the majority of patients with esophageal and gastroesophageal adenocarcinoma. The incidence of these cancers has been increasing in the United States and they are associated with a low rate of survival (5-year survival rate, 15–20%). When symptoms of gastroesophageal reflux disease are typical and the patient responds to therapy, no diagnostic tests are necessary to verify the diagnosis. Endoscopy is the primary test in patients whose condition is resistant to empirical therapy but its yield in this setting is low because of the poor correlation between symptoms attributed to the condition and endoscopic features of the disease. Clinical experience suggests that lifestyle modifications may be beneficial for gastroesophageal reflux disease although trials of the clinical efficacy of dietary or behavioral changes are lacking. Abundant data from randomized trials show benefits of inhibiting gastric acid secretion and suggest that proton-pump inhibitors are superior to H2-blockers and that both are superior to placebo. In patients with Barrett’s esophagus, antireflux interventions are intended to control symptoms of reflux and promote healing of the esophageal mucosa. If a patient has symptoms refractory to proton-pump inhibitors or cannot tolerate such therapy, antireflux surgery, most commonly Nissen fundoplication, may be an alternative management approach. In patients with high-grade dysplasia, endoscopic therapies or surgical resection must be considered.

A Novel Stool PCR Test for Helicobacter pylori May Predict Clarithromycin Resistance and Eradication of Infection at a High Rate

ABSTRACT Clarithromycin-based regimens are commonly used as a first-line therapy for Helicobacter pylori-positive patients; however, resistance to clarithromycin has led to treatment failures. The aim of this study was to evaluate the feasibility of using stool samples to detect the presence of H. pylori DNA while concurrently detecting mutations associated with resistance to clarithromycin. For this purpose, total DNA was extracted from 294 raw stool specimens from H. pylori-positive and -negative patients. TaqMan real-time PCR amplification was used to detect the presence of H. pylori as well as to predict the phenotype of the organism and the related outcome for patients treated with clarithromycin. Clarithromycin resistance was determined upon analysis of the PCR result. Patients were also tested by a urea breath test and were subjected to esophagogastroduodenoscopy, followed by histology, culture, and a rapid urease test, in order to obtain a consensus patient infection status. Of 294 total stool samples, 227 were deemed true positive. The sensitivity of H. pylori detection by PCR was 93.8%. Of 213 true-positive samples that were sequenced, 36.2% showed point mutations associated with clarithromycin resistance (A2142C, A2142G, A2143G). The final correlation of the mutant genotypes as determined by sequencing with the eradication of infection was 86%. We found that Helicobacter pylori DNA can be detected in human stool specimens with high sensitivity and can therefore be used to determine the presence of the bacterium without obtaining a biopsy sample. Moreover, genotypic resistance to clarithromycin can be predicted without obtaining a biopsy sample, facilitating the choice of the right therapeutic approach.