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Helicobacter pylori is the only major infection for which antimicrobial therapy is not designed using the principles of antimicrobial stewardship. Traditionally, antimicrobial therapy is a susceptibility-based therapy, achieves high cure rates, and includes surveillance programs to regularly provide updated data regarding resistance, outcomes, and treatment guidelines. Current H. pylori therapies identified by trial-and-error, and treatment recommendations and guidelines are based on comparisons among regimens that rarely take into account the prevalence or effect of resistance. The majority of patients currently treated achieve suboptimal results. A paradigm shift is required to abandon current approaches and embrace antimicrobial stewardship, and therefore reliably achieve high cure rates; develop, propagate, and update best practice guidelines; and provide surveillance of local or regional susceptibility/resistance patterns. These also require timely updates to clinicians regarding the current status of resistance, antimicrobial effectiveness, and ways to prevent antimicrobial misuse to extend the useful life of currently available antibiotics. Here, we discuss the differences among current approaches to H. pylori therapy and antimicrobial stewardship and identify what is required to achieve the transition. Conceptually, the differences are significant, and the transition will likely need to be both abrupt and complete. Recommendations for therapy during the transition period are given.

The WHO listed Helicobacter pylori among 16 antibiotic-resistant bacteria that pose the greatest threat to human health. Given the alarmingly high H. pylori antibiotic resistance rates, antibiotic stewardship programmes need to be developed and implemented. Future research should explore provider and systems-level barriers to H. pylori antibiotic susceptibility testing.

The major barrier to research and development of effective interventions for human noroviruses (HuNoVs) has been the lack of a robust and reproducible in vitro cultivation system. HuNoVs are the leading cause of gastroenteritis worldwide. We report the successful cultivation of multiple HuNoV strains in enterocytes in stem cell-derived, nontransformed human intestinal enteroid monolayer cultures. Bile, a critical factor of the intestinal milieu, is required for straindependent HuNoV replication. Lack of appropriate histoblood group antigen expression in intestinal cells restricts virus replication, and infectivity is abrogated by inactivation (e.g., irradiation, heating) and serum neutralization. This culture system recapitulates the human intestinal epithelium, permits human host-pathogen studies of previously noncultivatable pathogens, and allows the assessment of methods to prevent and treat HuNoV infections.

ObjectiveOperative link on gastritis assessment (OLGA) staging for gastritis ranks the risk for gastric cancer (GC) in progressive stages (0–IV). This prospective study aimed at quantifying the cancer risk associated with each gastritis stage.DesignA cohort of 1755 consecutive patients with dyspepsia underwent initial (T-0) oesophagogastroduodenoscopy with mapped gastric biopsies, OLGA staging and assessment of Helicobacter pylori infection. Patients were followed for 55 months (median); patients with stages II III and IV underwent a second endoscopy/restaging (T-1), and those with stages 0 and I were followed clinically and through in-depth clinical and record checking. Endpoints were OLGA stage at T-1 and development of gastric epithelial neoplasia.ResultsAt T-0, 77.6% of patients had stage 0, 14.4% stage I, 5.1% stage II, 2.1% stage III and 0.85% stage IV. H. pylori infection was detected in 603 patients at T-0 and successfully eradicated in 602 of them; 220 had a documented history of H. pylori eradication; and 932 were H. pylori naïve-negative. Incident neoplastic lesions (prevalence=0.4%; low-grade intraepithelial neoplasia (IEN)=4; high-grade IEN=1; GC=2) developed exclusively in patients with stages III–IV. The risk for epithelial neoplasia was null in patients at stages 0, I and II (95% CI 0 to 0.4), 36.5 per 1000 person-years in patients at stage III (95% CI 13.7 to 97.4) and 63.1 per 1000 person-years in patients at stage IV (95% CI 20.3 to 195.6).ConclusionsThis prospective study confirms that OLGA staging reliably predicts the risk for development of gastric epithelial neoplasia. Although no neoplastic lesions arose in H. pylori-naïve patients, the H. pylori eradication in subjects with advanced stages (III–IV) did not abolish the risk for neoplastic progression.

This Review addresses the problem of Helicobacter pylori resistance. The authors discuss concepts of resistance that have become part of mainstream thinking for other infectious diseases but not for H. pylori . In addition, data on the pharmacokinetics and pharmacodynamics of the drugs used in H. pylori therapy and the effect of host cytochrome P450 genotypes are put in context with treatment outcome. The prevalence of antimicrobial drug resistance is now so high that all patients infected with Helicobacter pylori should be considered as having resistant infections. Ideally, therapy should be based on pretreatment antibiotic-susceptibility testing but this strategy is not currently practical. At present, clarithromycin-containing triple therapies do not reliably produce a ≥80% cure rate on an intention-to-treat basis and are, therefore, no longer acceptable as empiric therapy. In this Review, we discuss concepts of resistance that have become part of mainstream thinking for other infectious diseases but have not yet become so with regard to H. pylori . We also put data on the pharmacokinetics and pharmacodynamics of the drugs used in H. pylori therapy and the effect of host cytochrome P450 genotypes in context with treatment outcomes. Our primary focus is to address the problem of H. pylori resistance from a novel perspective, which also attempts to anticipate the direction that research will need to take to provide clinicians with reliable approaches to this serious infection. We also discuss current therapies that provide acceptable cure rates when used empirically (i.e. sequential therapy; four-drug, three-antibiotic, non-bismuth-containing 'concomitant' therapy; and bismuth-containing quadruple therapy) and how they might be further improved. Key Points Traditional triple therapy remains effective only when used to treat infections with susceptible organisms The prevalence of antibiotic resistance has increased to such an extent that, to maintain acceptable cure rates, all patients should be considered as having resistant infections Therapies that do not reliably yield ≥90% cure rates on an intention-to-treat basis should not be prescribed empirically; triple therapies that contain combinations of a PPI, amoxicillin, clarithromycin or metronidazole now typically yield cure rates <80% and are no longer acceptable as empiric therapy Initial empiric therapy options currently include the following: sequential therapy; concomitant, four-drug, antibiotic therapy; and bismuth-containing, high-dose metronidazole, quadruple therapy Sequential and concomitant (i.e. four drugs, three of which are antibiotics) therapies have the potential to be improved by simple measures such as increasing the duration of treatment High-dose, frequent-administration PPI therapy can reduce phenotypic resistance and should increase the cure rates achieved with amoxicillin-containing dual therapy into the acceptable range

Background. Noroviruses are the most common cause of gastroenteritis in the United States. An understanding of the infectious dose of these viruses is important for risk assessment studies. Methods. Healthy adults were enrolled in a randomized, double-blind, placebo-controlled evaluation of different dosages of Norwalk virus. Eligible subjects were monitored for clinical gastroenteritis, and infection status was determined. The presence of virus in vomitus was also assessed. Results. Fifty-seven persons were enrolled; 8 received placebo and an additional 8 persons were considered to be nonsusceptible on the basis of being secretor negative. Twenty-one persons were infected (all blood group O or A), and 67% of those infected developed viral gastroenteritis. The 50% human infectious dose was calculated to be 3.3 reverse transcription polymerase chain reaction units (approximately 1320 genomic equivalents [gEq]) for secretorpositive blood group O or A persons and 7.0 (approximately 2800 gEq) for all secretor-positive persons. The time of illness onset was inversely correlated with inoculum dose. The maximal concentration of virus shedding was higher for persons with gastroenteritis. Norwalk virus was identified in 15 of 27 (56%) vomitus samples at a median concentration of 41000 gEq/mL. Conclusions. The 50% human infectious dose measured is higher than previous estimates and similar to that of other RNA viruses. Clinical TriaU Registration. NCT00138476.

Background. Norovirus infection is the leading cause of acute nonbacterial gastroenteritis. Histoblood group antigens (HBGAs) are host susceptibility determinants for Norwalk virus (NV) infection. We hypothesized that antibodies that block NV-HBGA binding are associated with protection from clinical illness following NV exposure. Methods. We developed an HBGA blocking assay to examine the ability of human serum to block the interaction of NV viruslike particles with H type 1 and H type 3 glycans. Serum samples from persons who were experimentally challenged with NV were evaluated. Results. There was a high correlation between the H type 1 and H type 3 synthetic glycan assays (r=0.977; P<.001); the H type 1 assay had higher quantitative sensitivity (P<.001). Among 18 infected secretor-positive individuals, blocking titers peaked by day 28 after challenge and were higher for individuals who did not develop gastroenteritis than for those who developed gastroenteritis on days 0, 14, 28, and 180 (P<.05 for each). In addition, 6 of 6 subjects without gastroenteritis had measurable prechallenge blocking titers (>25), compared with 2 of 12 subjects with gastroenteritis (P=.002). Conclusions. Blocking antibodies correlate with protection against clinical NV gastroenteritis. This knowledge will help guide the evaluation of new vaccine strategies and the elucidation of the nature of immunity to the virus. Trial registration. ClinicalTrials.gov identifier: NCT00138476.

Human noroviruses (HuNoVs) cause sporadic and epidemic outbreaks of gastroenteritis in all age groups worldwide. We previously reported that stem cell-derived human intestinal enteroid (HIE) cultures support replication of multiple HuNoV strains and that some strains (e.g., GII.3) replicate only in the presence of bile. Heatand trypsin-treatment of bile did not reduce GII.3 replication, indicating a nonproteinaceous component in bile functions as an active factor. Here we show that bile acids (BAs) are critical for GII.3 replication and replication correlates with BA hydrophobicity. Using the highly effective BA, glycochenodeoxycholic acid (GCDCA), we show BAs act during the early stage of infection, BA-dependent replication in HIEs is not mediated by detergent effects or classic farnesoid X receptor or Takeda G protein-coupled receptor 5 signaling but involves another G protein-coupled receptor, sphingosine-1-phosphate receptor 2, and BA treatment of HIEs increases particle uptake. We also demonstrate that GCDCA induces multiple cellular responses that promote GII.3 replication in HIEs, including enhancement of 1) endosomal uptake, 2) endosomal acidification and subsequent activity of endosomal/lysosomal enzyme acid sphingomyelinase (ASM), and 3) ceramide levels on the apical membrane. Inhibitors of endosomal acidification or ASM reduce GII.3 infection and exogenous addition of ceramide alone permits infection. Furthermore, inhibition of lysosomal exocytosis of ASM, which is required for ceramide production at the apical surface, decreases GII.3 infection. Together, our results support a model where GII.3 exploits rapid BA-mediated cellular endolysosomal dynamic changes and cellular ceramide to enter and replicate in jejunal HIEs.

The discovery of Helicobacter pylori as the cause of gastritis and peptic ulcers ushered in the modern era of research into gastritis and into acid-peptic diseases and rekindled interest in the role of ascorbic acid in the pathophysiology and treatment of gastritis and peptic ulcer disease. Here, we review historic and modern studies on ascorbic acid and gastric diseases with an emphasis on H. pylori gastritis and its sequelae. The relationship of ascorbic acid and gastritis and peptic ulcer and its complications was extensively studied during the 1930s through the 1950s. Much of this extensive literature has been effectively “lost.” Ascorbic acid deficiency was associated with all forms of gastritis (e.g., autoimmune, chemical, and infectious) due in varying degrees to insufficient intake, increased metabolic requirements, and destruction within the GI tract. Importantly, gastritis-associated abnormalities in gastric ascorbic acid metabolism are reversed by H. pylori -eradication and potentially worsened by proton pump inhibitor therapy. Diets rich in naturally occurring ascorbic acid are associated with protection of the gastric corpus from atrophy and a reduction in the incidence of gastric cancer possibly through the ability of ascorbic acid to reduce oxidative damage to the gastric mucosa by scavenging carcinogenic N -nitroso compounds and free radicals and attenuating the H. pylori -induced inflammatory cascade. Ascorbic acid supplementation was possibly associated with a decreased incidence of bleeding from peptic ulcer disease. Pharmacologic doses of ascorbic acid also may improve the effectiveness of H. pylori -eradication therapy. Occasionally, looking back can help plot the way forward.