Current Pharmaceutical Design - Volume 6, Issue 15, 2000

Since the report of culture of Helicobacter pylori in 1983, there has been increasing agreement that H. pylori infection is etiologically associated with a number of important diseases including chronic active gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, gastric polyps, gastric cancer, as well as suggestions that it may be involved in diseases outside the upper gastrointestinal tract. There have been a number of national and international consensus meetings to propose guidelines to treat H. pylori infection. The recommendations of these conferences are reviewed here and updated to include new indications and concepts regarding H. pylori eradication therapy. Eradication therapy is considered the standard of care for active or inactive peptic ulcer patients including those who use non-steroidal anti-inflammatory drugs (NSAIDs). Other strong indications include MALT lymphoma, hyperplastic polyps, hyperplastic gastropathy, post-endoscopic resection for gastric malignancy, and acute H. pylori gastritis. Other considerations include plan to use chronic NSAID therapy, plan for chronic anti-secretory therapy, and some extra-gastroduodenal diseases such as chronic ureterica. Non-investigated dyspepsia is an indication for diagnostic evaluation and eradication therapy for those with H. pylori infection, whereas non-ulcer dyspepsia (NUD) in which peptic ulcer disease has been excluded is not an indication for evaluation per se. Intervention studies are now in progress to test the hypothesis that prevention of gastric malignancy is an outcome of H. pylori eradication. Because the prevalence of H. pylori infection and the associated diseases such as peptic ulcer or gastric cancer differ among countries as well as different approvals for treatment are required by governments or insurance agencies, the acceptable indications of eradication therapy will, by necessity, vary among countries.

The approach to the patient with suspected H. pylori infection consists of an adequate indication to test for the presence of the infection, choice of an appropriate antimicrobial regimen, and education about its use and side effects, followed by post-therapy testing to confirm cure. We review the drugs and regimens for H. pylori eradication and present a strategy for treating the infection. The major factor in choosing an antibiotic regimen is the pattern of antibiotic resistance in the community. Triple therapy with a proton pump inhibitor (PPI) or ranitidine bismuth citrate (RBC) and two antimicrobials is recommended as the first choice regimen. In regions where metronidazole and clarithromycin resistance are common, initial therapy with quadruple therapy consisting of bismuth, metronidazole, tetracycline, and a PPI is recommended. In general, higher doses and longer durations are associated with better outcomes. For this reason we recommend that the minimum duration of 10 days and we prefer 14 days. The actual choice of the antimicrobial combination will also be influenced by the drugs approved by the local regulatory bodies. Side effects, eradication failure and current as well as future designs of eradication therapies are also discussed.

The majority of Helicobacter pylori (H. pylori) infections appear to be acquired during childhood. Despite this fact, the natural history of H. pylori infection in children, such as the mode of acquisition, the clinical symptoms and signs of infection and the appropriate treatment, is poorly understood. There is no consensus regarding which children with H. pylori infection deserve treatment nor is there agreement on the appropriate treatment regimen. This stems from the lack of controlled studies into H. pylori infection during childhood. For example, there have been no controlled studies to determine effective treatment of H. pylori infection in children. Although published guidelines for the treatment of childhood H. pylori infection do not currently exist, there is reasonable evidence to support treatment in children with gastric or duodenal ulcer, gastric MALT (mucosa-associated lymphoid tissue) lymphoma and atrophic gastritis. There is no strong evidence to recommend treatment of children with H. pylori infection and recurrent abdominal pain, asymptomatic infection, children in chronic care facilities and children who have a family member with H. pylori infection. Current evidence suggests that single and dual therapy regimens for H. pylori infection in children are not effective. ôTriple therapyö, generally the combination of 2 antibiotics and a proton pump inhibitor, given two times daily for 2 weeks appears to offer the best current treatment.

Helicobacter pylori infection causes progressive damage to gastric mucosa and results in serious disease such as peptic ulcer disease, MALT lymphoma, or gastric adenocarcinoma in 20% to 30% of patients. The current approach is to make a firm diagnosis, give combination antibiotic and antisecretory therapy, and confirm that the infection has been cured 4 to 6 weeks later. Antimicrobial resistance is largely responsible for treatment failures. Resistance to metronidazole can frequently be overcome by increasing the dose and duration of treatment with acid suppression. Clarithromycin is the most effective antibiotic against H. pylori but, unfortunately, resistance to it is increasing and can not be overcome by increasing the dose or duration of therapy with clarithromycin. The choice of therapy should be based on local susceptibility patterns. Re-treatment regimens for treatment failure should exclude antibiotics where acquired resistance is expected (i.e., clarithromycin and possibly metronidazole). Where available, treatment failure should prompt endoscopy and culture and susceptibility testing. Overall, higher doses and longer durations of treatment result in the best cure rates. When multiple treatment regimens fail, salvage therapy regimens such as bismuth or furazolidone quadruple therapy (a bismuth and tetracycline HCl 4 times a day along with a proton pump inhibitor twice a day, and either metronidazole 400 or 500 mg three times daily or furazolidone 100 mg three times daily for 14 days) can be used. Newer agents are needed to cope with the increasing prevalence of antibiotic resistance among H. pylori.

There are multiple test methodologies to determine the antibiogram of an organism. Standardized susceptibility test methods are based upon rapidly growing, aerobic microorganisms in which overnight incubation results in definitive endpoints. In vitro susceptibility testing for fastidious organisms that require complex media for growth, require incubation in atmospheres other than ambient air, or are slow-growing (anaerobes, mycobacteria, filamentous fungi) are problematic and in general are not standardized. H. pylori falls into this category of troublesome organisms. For the microaerobic organism H. pylori, testing is challenging because the organism grows slowly even under optimal culture conditions. Recently the National Committee for Clinical Laboratory Standards (NCCLS) approved the agar dilution method as the test of choice for testing H. pylori. While not entirely reliable in predicting the outcome of treatment for metronidazole resistant organisms, the resistance determined for clarithromycin by this method generally predicts treatment failure. Quality control breakpoints for H. pylori ATCC 43504 were established and breakpoints for clarithromycin were approved by the NCCLS in 1999. Breakpoints are minimum inhibitory concentrations (MIC) of a drug at which an organism is deemed either susceptible or resistant to the antibiotic using standard dosing regimens containing that drug. Significant progress has been made with respect to development of tests to detect antimicrobial resistance, but there still remains no consensus as to the breakpoints for agents used in the treatment of H. pylori infection other than clarithromycin. This article will address the controversies associated with the reporting of antibiotic resistance data and the interpretation of these data.

Approximately 50% of humanity is infected with Helicobacter pylori. Normally, this is a life-long infection indicating that the host response to natural infection fails to yield protective immunity. Moreover, the chronic inflammatory response associated with this infection can contribute to tissue damage and the pathogenesis of gastroduodenal disease including atrophic gastritis, peptic ulcer and gastric cancer. These damaging immune responses are attributed to a subset of helper T cells, so-called Th1 cells, that enhance cell-mediated immunity and induce damage to the gastric epithelium. Thus, it is desirable to have effective vaccines that could prevent and cure infection or at least, modify the host response in a manner that prevents immune-mediated disease. Using animal models as a tool to understand the immunobiology of Helicobacter infections, several investigators have shown that effective vaccines can be developed. Thus, prophylactic and even therapeutic vaccines have been described in various animal models. The basis for the effectiveness of these vaccines seems to be found in their ability to alter the gastric immune response, perhaps away from a homogeneous Th1 response towards a mixed Th1 and Th2 response. Using these encouraging approaches, vaccines are being developed for use in humans for the treatment and prevention of H. pylori infection and the gastroduodenal diseases associated with this infection.

Triple therapy with a proton pump inhibitor plus two antibiotics is recently standard regimen for treatment of H. pylori infection. However, the agents that are used for H. pylori eardication are not always limited to drugs whose primary use is as an antimicrobial agent. Anti-H. pylori activity has been reported for non-traditional antimicrobials such as proton pump inhibitors, bismuth compounds, mucosal defensive agents, and some other agents. Proton pump inhibitors and their acid-activated derivatives have significant activities against H. Pylori, potent inhibitors of urease, proton motive force, and ATPase of H. pylori. Some bismuth compounds and compound of a mixture of ranitidine hydrochloride and bismuth citrate were shown to inhibit the growth of H. pylori in vitro, to eradicate H. pylori in vivo, and to decrease the development of H. pylori secondary resistance to antibiotics. The mechanism of bactericidal action of bismuth compounds has not been clear. Mucosal defensive agents that enhance defense factors of gastro-duodenal mucosa are locally acting anti-ulcer drugs. Each mucosal defensive agent was found to have direct or indirect different activities against H. pylori in vitro. Though studies attempting to improve the eradication rate by the addition of mucosal defensive agents to conventional therapy have been tried, additive effects of these agents were equivocal. Therapeutic approaches with other agents such as Lactobacillus, lactoferrin, and dietary constituents to cure H. pylori infection are under investigation. Non-traditional antimicrobials by them selves are unable to cure H. pylori infection in spite of anti-H. pylori activities. Studies are needed to establish the clinical utility of non-traditional antimicrobial agents in prevention and eradication of H. pylori infection since eradication of antibiotic resistance H. pylori would become a difficult problem.