When repeated Helicobacter pylori therapies fail, what should we do?

Abstract

If Barry Marshall conducts his famous experiment to ingest Helicobacter pylori today instead of 25 years ago, he may find that eradicating the bacterium with metronidazole alone is not as easy. Now, a few decades after its discovery, H. pylori is established as an atrocious culprit for gastroduodenitis, peptic ulcers, and malignancies including gastric cancer and mucosaassociated lymphoid tissue (MALT) lymphoma. Eradication of H. pylori cures peptic ulcers and reduces incidence of gastric cancer especially in regions with high prevalence. In spite of these benefits, eradication of H. pylori is becoming more challenging as resistance to antimicrobials, including clarithromycin, metronidazole, and levofloxacin, is on the rise globally. In a systematic review and meta-analysis of antibiotic resistance in the Asia-Pacific region, the mean prevalence of primary H. pylori resistance to metronidazole was 44% (ranged from 10% in Japan to 88% in Nepal), 20% to clarithromycin, and 21% to levofloxacin. The rising resistance has reduced the eradication rates of some standard therapies to below 80%. This has entailed a need for alternative strategies, such as incorporating drug sensitivity testing and other therapeutic regimens in the treatment algorithms. Some of these strategies include the use of resistance-testing guided therapies, or other second-line or thirdline regimens such as bismuth quadruple therapy, levofloxacincontaining or rifabutin-containing therapies, and recently vonoprazan-based therapy. In this issue of the Journal of Gastroenterology and Hepatology, Lee et al. have presented their works on investigating risk factors for failure using rescue bismuth quadruple therapy. The authors have enrolled 54 patients who failed first-line therapy and had H. pylori cultured for antimicrobial susceptibility testing. These patients were given bismuth quadruple therapies and were assessed for their eradication rate, compliance to treatment, and risk factors for therapeutic failure. The authors reported an overall eradication rate of 88.8%. Multivariate analysis showed that high metronidazole resistance (minimum inhibitory concentration [MIC] > 32 μg/mL) was an independent risk factor for eradication failure of bismuth quadruple therapy (odds ratio = 14.3, P = 0.007). Although generally regarded as an effective rescue therapy, efficacy of bismuth quadruple therapy can still be hampered by metronidazole resistance. In a meta-analysis that studied effects of antibiotic resistance on eradicating H. pylori, bismuth quadruple therapy had a mean efficacy of 79% against metronidazole-resistant strains. This figure was 14% lower than that against metronidazole-sensitive strains. The current study by Lee et al. has taken this further to assess the level of metronidazole resistance with pretreatment MIC level. Results of this study suggest that low level (MIC 8–32 μg/mL) of metronidazole resistance can still be successfully treated by bismuth quadruple therapy. Yet high level metronidazole resistance (MIC > 32 μg/mL) may necessitate an alternative eradication regimen. Therefore, before choosing bismuth quadruple rescue therapy, the susceptibility breakpoint and quantitative level of metronidazole resistance should be provided by the laboratory, to achieve a better success. The use of novel potassium-competitive acid blocker (PCAB) is another promising strategy to improve eradication of resistant H. pylori. Vonoprazan, the first-in-class PCAB, was approved in Japan for H. pylori eradication therapy in 2014. It is a potent long-acting acid suppressant and can reliably achieve an intragastric pH > 5, an important factor for successful H. pylori eradication. Previous studies indicated that vonoprazan-based triple therapy was effective as first-line or second-line therapy for H. pylori eradication and may be even more effective than protonpump inhibitor (PPI)-based triple therapies for eradicating clarithromycin-resistant strains. In this current issue of the Journal, Sue et al. have compared the 7-day triple therapy with vonoprazan, amoxicillin, and sitafloxacin, against an equivalent PPI-based as a third-line therapy for eradicating H. pylori. In the 63 enrolled patients, the authors observed a superior perprotocol eradication rate of the vonoprazan-based regimen (83.3%) over PPI-based regimens (57.1%), with no significant difference in the frequency of adverse events. However, the intention-to-treat results have failed to prove superiority. This study provides encouraging data that vonoprazan-based regimen is indeed useful as another rescue therapy for clarithromycin-resistant H. pylori. It would also be interesting to compare the two triple therapies given for a longer period of 10–14 days comparing their efficacy in H. pylori eradication. With H. pylori remains to be a prevalent infection that poses great threat to human, these two studies highlight some directions in its future treatment. The increasing antimicrobial resistance rates have led to advocacy for more susceptibility testing provided by laboratories to guide therapy. Blind-folded empirical therapies may lead to antimicrobial misuse and result in more resistant strains emerging. The paper by Lee et al. has not only highlighted the importance of antibiotic susceptibility testing but also suggesting to define a level of metronidazole resistance that could undermine therapeutic efficacy. This quantitative level of resistance may add a new perspective in choosing eradication therapy and predicting therapeutic success. On the other hand, the study by Sue et al. has illustrated how PCABs may add to our armamentarium against resistant H. pylori, as we await more treatment efficacy and safety data from properly designed clinical trials. As we add more drugs to the list of armamentarium, we have different therapeutic options to treat resistant H. pylori. Choosing the right rescue therapy should require consideration on patient’s allergic history (if any), prior antibiotic choice, and susceptibility test results. Another therapeutic option, although debatable, is to consider “tolerant” to resistant H. pylori strain after failing multiple (> 3) eradication therapies. Withholding treatment after several unsuccessful attempts in patients with no or minimal gastritis and absence of premalignant gastric lesions is an option that we should doi:10.1111/jgh.14668