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.

Background

: We systematically reviewed all available data in the literature to determine the overall eradication rates of currently advised Helicobacter pylori eradication regimens and to resolve conflicting evidence on the impact of antimicrobial resistance on the eradication rates.



Methods

: A comprehensive search of all published trials on H. pylori eradication therapy was carried out via an electronic database search, hand-searching and checking reference lists of pharmaceutical companies and other reviews. Full papers and abstracts in the English language which study currently advised eradication regimes were included.



Results

: 770 study-arms were analysed. Mean eradication rates for bismuth based triple, proton pump inhibitor triple, quadruple and ranitidine bismuth citrate combination therapies vary from 65 to 92%. In case of nitroimidazole resistance, a drop in efficacy of up to 50% was found for bismuth-based triple and proton pump inhibitor-based triple therapies. For quadruple therapy, a significant difference in efficacy was found in the equal-effects analysis; however, this could not be confirmed in the random-effects analysis. In case of clarithromycin resistance, a mean drop in efficacy of 56% was found for one- and two-week clarithromycin containing proton pump inhibitor-triple therapies and of 58% for two-week ranitidine bismuth citrate combined with clarithromycin therapies. For ranitidine bismuth citrate combined with clarithromycin and nitroimidazole, no difference in efficacy was found in case of nitroimidazole or clarithromycin resistance, but data are still scarce.



Conclusions

: The cure rate with most regimens dropped significantly, in case of nitroimidazole-resistant strains, compared to nitroimidazole-susceptible strains. In case of clarithromycin resistance, the efficacy of most regimens is also decreased; however, data are still scarce. These data should allow physicians to make a better choice of an appropriate therapy for their patients.

A systematic review of Helicobacter pylori eradication therapy--the impact of antimicrobial resistance on eradication rates.

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.

Aim

: To assess the influence of metronidazole resistance on the efficacy of ranitidine bismuth citrate-based triple therapy regimens in two consecutive studies.



Methods

: In the first study, patients with a culture-proven Helicobacter pylori infection were treated with ranitidine bismuth citrate 400 mg, metronidazole 500 mg, and clarithromycin 500 mg, all twice daily for 1 week (RMC). In the second study, amoxycillin 1000 mg was substituted for clarithromycin (RMA). Susceptibility testing for metronidazole was performed with the E-test. Follow-up endoscopy was performed after ≥ 4 weeks. Antral biopsy samples were taken for histology and urease test, and culture and corpus samples for histology and culture.



Results

: 112 patients, 53 males, age 55 ± 14 years (39 duodenal ulcer, 7 gastric ulcer and 66 gastritis) were treated with RMC, and 89 patients, 52 males, age 58 ± 15 years (23 duodenal ulcer, 7 gastric ulcer and 59 gastritis) were treated with RMA. For RMC, intention-to-treat eradication results were 98% (59/60, 95% CI: 91–100%) and 95% (20/21, 95% CI: 76–100%) for metronidazole susceptible and resistant strains, respectively (P = 0.45). For RMA these figures were 87% (53/61, 95% CI: 76–94%) for metronidazole susceptible strains and 22% (2/9, 95% CI: 3–60%) for resistant strains (P = 0.0001).



Conclusion

: Both regimens are effective in metronidazole susceptible strains. However, in contrast to the amoxycillin-containing regimen, that containing clarithromycin is also effective in resistant strains.

The influence of metronidazole resistance on the efficacy of ranitidine bismuth citrate triple therapy regimens for 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.

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

One-Week Triple Therapy With Ranitidine Bismuth Citrate, Clarithromycin and Metronidazole Versus Two-Week Dual Therapy With Ranitidine Bismuth Citrate and Clarithromycin for Helicobacter pylori Infection: A Randomized, Clinical Trial

Background:

Furazolidone is an inexpensive antibiotic that has considerable anti-Helicobacter pylori activity in vitro.



Methods:

Twenty-three patients with culture-proven H. pylori infection were treated for one week with a dual therapy containing omeprazole and furazolidone.



Results:

Eradication succeeded in 10 of the first 20 evaluable patients (50%; 95% CI: 27.2–72.8%). This percentage was regarded as too low, and the study was terminated. Side-effects were mild.



Conclusion:

With the possible increase in resistance to metronidazole and clarithromycin world-wide, furazolidone may be a useful alternative in the treatment of H. pylori infection. Dual therapy for one week, however, is not sufficient.

Low cure rate of Helicobacter pylori infection with omeprazole and furazolidone dual therapy for one week

Metronidazole resistance does not influence the efficacy of triple therapy with ranitidine bismuth citrate (RBC), clarithromycin (CLA) and metronidazole (MET) for H-pylori (Hp) infection.

A Kooy

Papers

The influence of metronidazole resistance on the efficacy of ranitidine bismuth citrate triple therapy regimens for Helicobacter pylori infection

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

One-Week Triple Therapy With Ranitidine Bismuth Citrate, Clarithromycin and Metronidazole Versus Two-Week Dual Therapy With Ranitidine Bismuth Citrate and Clarithromycin for Helicobacter pylori Infection: A Randomized, Clinical Trial

Low cure rate of Helicobacter pylori infection with omeprazole and furazolidone dual therapy for one week

Metronidazole resistance does not influence the efficacy of triple therapy with ranitidine bismuth citrate (RBC), clarithromycin (CLA) and metronidazole (MET) for H-pylori (Hp) infection.