Review
Helicobacter pylori and antimicrobial resistance: molecular mechanisms and clinical implications

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Summary

Helicobacter pylori is an important human pathogen that colonises the stomach of about half of the world's population. The bacterium has now been accepted as the causative agent of several gastroduodenal disorders, ranging from chronic active gastritis and peptic ulcer disease to gastric cancer. The recognition of H pylori as a gastric pathogen has had a substantial effect on gastroenterological practice, since many untreatable gastroduodenal disorders with uncertain cause became curable infectious diseases. Treatment of H pylori infection results in ulcer healing and can reduce the risk of gastric cancer development. Although H pylori is susceptible to many antibiotics in vitro, only a few antibiotics can be used in vivo to cure the infection. The frequent indication for anti-H pylori therapy, together with the limited choice of antibiotics, has resulted in the development of antibiotic resistance in H pylori, which substantially impairs the treatment of H pylori-associated disorders. Antimicrobial resistance in H pylori is widespread, and although the prevalence of antimicrobial resistance shows regional variation per antibiotic, it can be as high as 95%. We focus on the treatment of H pylori infection and on the clinical relevance, mechanisms, and diagnosis of antimicrobial resistance.

Introduction

In 1983, Warren and Marshall were the first to report the successful cultivation of the human pathogen Helicobacter pylori from gastric biopsy samples.1, 2 By self-ingestion experiments, they showed that this bacterium indeed caused gastroduodenal disorders, thereby fulfilling Koch's postulates.3, 4 This important discovery, rewarded with the 2005 Nobel prize for physiology or medicine, has changed peptic ulcer disease from a chronic, relapsing disease of uncertain cause into a curable infectious disease. Today, H pylori is accepted as the causative agent of acute and chronic gastritis, and a major predisposing factor for peptic ulcer disease, gastric carcinoma, and gastric lymphoma (figure 1).5, 6

Infection with H pylori occurs worldwide, but there are substantial differences in the prevalence of the infection both within and between countries. In industrialised countries, the overall carriage rate of H pylori infection in middle-aged adults is 20–50%, compared with 80% or more in many developing countries.7, 8 Acquisition of H pylori predominantly occurs during childhood, and once acquired, the infection persists throughout life unless specifically treated. In developing countries the carriage rate of H pylori remains relatively stable, but in the industrialised world these values have substantially decreased over recent decades,9 probably as a result of improved hygiene and sanitation, especially during childhood,9 and active elimination of carriership via antimicrobial treatment.

H pylori-associated disorders usually regress or heal completely after successful treatment of H pylori infection with antimicrobials. However, the available antimicrobial therapies for H pylori infection have many shortcomings—eg, side-effects, the need for combination therapy, and limited efficacy, in particular because of the development of antimicrobial resistance. The continuous increase in the prevalence of antimicrobial resistance in H pylori, together with the lack of forthcoming novel treatment options, already negatively affects eradication of H pylori infection, and is predicted to lead to serious problems for treatment of H pylori-associated disorders in the near future.

Section snippets

Diagnosis of H pylori infection

H pylori infection can be diagnosed by a variety of invasive and non-invasive tests.10 Invasive tests are based on gastric samples, usually mucosal biopsies, which can be screened by rapid urease test, histology, or culture.10 Non-invasive tests require alternative clinical specimens—eg, blood, breath, faeces, urine, or saliva. These samples can be screened by serology, urea breath test, or stool antigen test.10 The choice of a specific test depends on several factors, including gastric

Treatment of H pylori infections

Peptic ulcer disease and other H pylori-associated disorders usually regress or even heal completely after treatment of the H pylori infection.18, 19 In vitro, H pylori is susceptible to most antimicrobials20 but in vivo only a few antimicrobials can be used to cure infected patients.21 The lack of activity in vivo is because of a combination of factors—eg, inability of drugs to achieve appropriate levels in the gastric mucus layer,22, 23 inactivation of drugs at low pH,24, 25 and the slow

Prevalence of antimicrobial resistance

Resistance to nitroimidazoles is the most common form of antimicrobial resistance in H pylori. Metronidazole and tinidazole are the most frequently used nitroimidazoles for treatment of H pylori infection, and there seems to be substantial cross-resistance between these nitroimidazoles.45 In industrialised countries, about 35% of the H pylori strains are resistant to nitroimidazoles (minimum inhibitory concentration [MIC] ≥8 mg/L; susceptibility breakpoint),46, 47 whereas in developing

Clinical effect of antibiotic resistance

Numerous studies have shown that antibiotic resistance substantially impairs the efficacy of anti-H pylori therapy.64, 65, 66, 67, 68, 69 Nevertheless, the clinical relevance of antibiotic resistance in H pylori-associated diseases is still challenged. The extent to which antibiotic resistance reduces the success rates of H pylori treatment depends on a variety of factors—eg, the components used in therapy, the dose of the antimicrobial drugs, the duration of the therapy, and the level of

Antibiotic activity and mechanisms of resistance

In view of the large number of individuals colonised with H pylori, the proportion of individuals who develop disease, and the relative difficulty to treat the infection, it is not surprising that a lot of effort has been spent on understanding the mechanisms of antibiotic resistance. The obtained knowledge (figure 3) could allow for rapid testing of resistance and can provide clues to decrease the spread of antibiotic resistance. In many bacteria, antibiotic resistance mechanisms are located

Detection of antibiotic resistance

Numerous techniques have been developed to detect antibiotic resistance in H pylori. These methods can be divided in culture and nucleic acid-based assays (figure 4). Antibiotic susceptibility in H pylori is usually assessed by culture-based methods (eg, agar dilution, disc diffusion, E-test, breakpoint susceptibility testing, broth microdilution method), but since knowledge of antibiotic resistance mechanisms in H pylori is growing, several (non-)invasive nucleic acid-based tests have been

Alternative treatment options

In the past few years, much time and effort has been spent in developing alternative anti-H pylori treatments, especially via vaccine development. Prophylactic as well as therapeutic vaccination could potentially save millions of lives and reduce the costs related to the treatment of H pylori-associated diseases. Several virulence factors (eg, urease), the vacuolating toxin A (VacA), the cytotoxin-associated antigen (CagA), and the blood-group-antigen binding adhesin (BabA), in combination with

Search strategy and selection criteria

Data for this review were identified by searches of PubMed and references from relevant articles, as well as the personal files of the authors. Search terms included “Helicobacter pylori”, “therapy”, “treatment options”, “antibiotic resistance”, and “clinical implications”. Searches using the names of prominent scientists in the field were also done. The selection of papers was not restricted by language. The final search date was December, 2005.

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