Summary


Background Information regarding the effects of drug resistance on therapies for Helicobacter pylori is limited.



Aims  To determine the effect of drug resistance on the efficacy of first-line treatment regimens for H. pylori and identify the most efficacious treatments in the presence of drug resistance.



Methods  We searched for studies using the keywords: ‘Helicobacter pylori’,‘resistance’ and ‘treatment’ or ‘therapy’. Multilevel meta-regression models were used to determine the effect of drug resistance on treatment efficacy.



Results  We analysed data from 93 studies with 10 178 participants. For triple therapies, clarithromycin resistance had a greater effect on treatment efficacy than nitroimidazole resistance. Metronidazole resistance reduced efficacy by 26% in triple therapies containing a nitroimidazole, tetracycline and bismuth, while efficacy was reduced by only 14% when a gastric acid inhibitor was added to the regimen. Quadruple therapies containing both clarithromycin and metronidazole were the most efficacious; >80% of H. pylori infections were consistently eradicated with these regimens.



Conclusions  Drug resistance was a strong predictor of efficacy across triple therapies for the eradication of H. pylori in adults. Resistance to either clarithromycin or metronidazole, but not both simultaneously, may be overcome by using quadruple therapies, especially those containing both clarithromycin and metronidazole.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2036.2007.03386.x

Meta-analysis: the effect of antibiotic resistance status on the efficacy of triple and quadruple first-line therapies for Helicobacter pylori.

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.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(06)70627-2.pdf

Helicobacter pylori and antimicrobial resistance: molecular mechanisms and clinical implications

Our purpose was to define the effect of pretreatment Helicobacter pylori resistance to metronidazole or to clarithromycin on the success of antimicrobial therapy. We used 75 key words to perform a literature search in MEDLINE as well as manual searches to identify clinical treatment trials that provided results in relation to H. pylori susceptibility to metronidazole and clarithromycin or both during the period 1984–1997 (abstracts were not included). Meta-analysis was done with both fixed- and random-effect models; results were shown using Galbraith's radial plots. We identified 49 papers with 65 arms for metronidazole (3594 patients, 2434 harboring H. pylori strains sensitive to metronidazole and 1160 harboring resistant strains). Metronidazole resistance reduced effectiveness by an average of 37.7% (95% CI = 29.6–45.7%). The variability in the risk difference for metronidazole was 122.0 to −90.6 and the chi-square value for heterogeneity was significant (P < 0.001). Susceptibility tests for clarithromycin were performed in 12 studies (501 patients, 468 harboring H. pylori strains sensitive to clarithromycin and 33 harboring resistant strains). Clarithromycin resistance reduced effectiveness by an average of 55% (95% CI = 33–78%). We found no common factors that allowed patients to be divided into subgroups with additional factors significantly associated with resistance. In conclusion, metronidazole or clarithromycin pretreatment resistant H. pylori are the main factors responsible for treatment failure with regimens using these compounds. If H. pylori antibiotic resistance continues to increase, pretherapy antibiotic sensitivity testing might become necessary in many regions.

Effect of pretreatment antibiotic resistance to metronidazole and clarithromycin on outcome of Helicobacter pylori therapy: a meta-analytical approach.

Resistance of Helicobacter pylori to macrolides is a major cause of failure of eradication therapies. Single base substitutions in the H. pylori 23S rRNA genes have been associated with macrolide resistance in the United States. Our goal was to extend this work to European strains, to determine the consequence of this mutation on erythromycin binding to H. pylori ribosomes, and to find a quick method to detect the mutation. Seven pairs of H. pylori strains were used, the parent strain being naturally susceptible to macrolides and the second strain having acquired an in vivo resistance during a treatment regimen that included clarithromycin. The identity of the strains was confirmed by random amplified polymorphic DNA testing with two different primers, indicating that resistance was the result of the selection of variants of the infecting strain. All resistant strains were found to have point mutations at position 2143 (three cases) or 2144 (four cases) but never on the opposite DNA fragment of domain V of the 23S rRNA gene. The mutation was A-->G in all cases except one (A-->C) at position 2143. Using BsaI and BbsI restriction enzymes on the amplified products, we confirmed the mutations of A-->G at positions 2144 and 2143, respectively. Macrolide binding was tested on purified ribosomes isolated from four pairs of strains with [14C]erythromycin. Erythromycin binding increased in a dose-dependent manner for the susceptible strain but not for the resistant one. In conclusion we suggest that the limited disruption of the peptidyltransferase loop conformation, caused by a point mutation, reduces drug binding and consequently confers resistance to macrolides. Finally, the macrolide resistance could be detected without sequencing by performing restriction fragment length polymorphism with appropriate restriction enzymes.

Macrolide resistance in Helicobacter pylori: rapid detection of point mutations and assays of macrolide binding to ribosomes.

The bacterium Helicobacter pylori can infect the stomach during childhood and cause lifelong chronic gastritis, which can lead to peptic ulcer disease. Curing H pylori infection cures ulcer disease.1–5 And since reinfection in adults is extremely rare,6 adequate treatment permanently cures this former chronic recurrent, serious disease. If ulcers do not recur neither do ulcer perforation or bleeding; quality of life increases,7 sick leave decreases, and less money is spent on visiting the doctor and drugs.

Antibiotic resistance needs to be taken into account when designing treatment for H pylori infection.8 Over the past decade many different therapies were promoted and recommendations changed rapidly. Most doctors lost track, and a great variety of treatments is being used.9 In this article we will try to provide a basic framework on which treatment can be based.

#### Summary points

The therapeutic goal is to cure H pylori infection in all ulcer patients

Several equally effective regimens are available, but even the best fail in 5-20% of patients

Antibiotic resistance is usually induced after failure, and initial regimens should not compromise future therapeutic possibilities

Doctors should choose two complementary regimens, which if used consecutively come close to 100% cure

Treatment should start with a regimen based on clarithromycin with a back up regimen based on metronidazole unless resistance is above 15%, in which case the order should be reversed

Triple regimens which combine clarithromycin and metronidazole should not be used as there is no valid empirical back up regimen after failure

This article is based largely on our experience in treating H pylori infection. We base our recommendations on basic bacteriological principles and on a regularly updated in-house computer database that contains the results of all published therapeutic studies.

Treatment to eradicate H pylori in patients with a proved …

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Treatment of Helicobacter pylori infection

Background: Triple therapy involving a proton pump inhibitor and two antibiotics has been suggested as an effective treatment for Helicobacter pylori infection. The impact of imidazole resistance on the efficacy of such regimens is largely unknown.



Methods: One hundred patients with culture proven H. pylori infection were treated with omeprazole 40 mg b.d., amoxycillin 1000 mg b.d., and tinidazole 500 mg b.d. for one week. Pre-treatment imidazole susceptibility was measured by disk diffusion. Resistance was confirmed by E-test. Eradication was assessed by endoscopy 6–8 weeks after the end of treatment. In cases of doubt a 13C-urea breath test was performed. Side-effects were scored using a semiquantitative scale.



Results: H. pylori was eradicated in 95% of the patients with an imidazole-susceptible strain and in 69% of the patients with a resistant strain (P<0.005). Significant side-effects were seen in 12%.



Conclusion: This proton pump inhibitor triple therapy is a simple, reasonably effective regimen with few significant side-effects. The efficacy is dependent on the susceptibility of the infecting H. pylori strain.

W. J. Thijs

Papers

One-week triple therapy with omeprazole, amoxycillin and tinidazole for Helicobacter pylori infection: the significance of imidazole resistance