Molecular-based Helicobacter pylori Susceptibility Testing Is Almost Ready for Prime Time

See “Impact of antimicrobial resistance rates on eradication of Helicobacter pylori in a United States population,” by Argueta EA, Alsamman MA, Moss SF, et al, on page 2181. See “Impact of antimicrobial resistance rates on eradication of Helicobacter pylori in a United States population,” by Argueta EA, Alsamman MA, Moss SF, et al, on page 2181. The article by Argueta et al1Argueta E.A. Alsamman M.A. Moss S.F. et al.Impact of antimicrobial resistance rates on eradication of Helicobacter pylori in a US population.Gastroenterology. 2021; 160: 2181-2183Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar in this issue of Gastroenterology retrospectively evaluated molecular-based susceptibility testing performed using paraffin-fixed tissue sections for predicting treatment outcome of Helicobacter pylori infections. Approximately one-third of organisms were resistant to metronidazole, clarithromycin, or levofloxacin. Dual resistance was present in 7%–10%. Outcome comparisons were limited to clarithromycin and metronidazole because resistance to amoxicillin, tetracycline, and rifabutin and levofloxacin use was rare. The cure rates were high with susceptible infections and, as with culture-based susceptibility testing, clarithromycin resistance markedly decreased treatment effectiveness and bismuth quadruple therapy remained relatively effective, despite metronidazole resistance. There are few similar H pylori studies yet available.2Nezami B.G. Jani M. Alouani D. et al.Helicobacter pylori mutations detected by next-generation sequencing in formalin-fixed, paraffin-embedded gastric biopsy specimens are associated with treatment failure.J Clin Microbiol. 2019; 57 (e01834-18)Crossref PubMed Scopus (25) Google Scholar,3Rimbara E. Tamura R. Tanuma M. et al.Evaluation of clarithromycin resistance in Helicobacter pylori obtained from culture isolates, gastric juice, and feces.Helicobacter. 2009; 14: 156-157Crossref PubMed Scopus (9) Google Scholar Molecular testing contrasts with traditional culture-based susceptibility testing that exposes the organisms to increasing concentrations of antibiotics to identify the minimal concentration at which growth is inhibited. The clinical cut-off concentration is established in relation to treatment outcome. Molecular tests are based on identification of mutations that result in loss of function of genes responsible for susceptibility.4Lauener F.N. Imkamp F. Lehours P. et al.Genetic determinants and prediction of antibiotic resistance phenotypes in Helicobacter pylori.J Clin Med. 2019; 8: 53Crossref Scopus (54) Google Scholar Resistance is declared when such mutations are present. Physicians often view susceptibility as a binary outcome with resistance being equated with failure. However, H pylori therapies often contain >1 antibiotic. For example, resistance to 1 antibiotic will change a triple therapy into a dual therapy, typically proton pump inhibitor (PPI)–amoxicillin dual therapy. Amoxicillin was originally added to clarithromycin, and subsequently to metronidazole, and fluoroquinolone-containing triple therapies to prevent resistance from emerging during treatment.5Hopkins R.J. Current FDA-approved treatments for Helicobacter pylori and the FDA approval process.Gastroenterology. 1997; 113: S126-S130Abstract Full Text PDF PubMed Scopus (52) Google Scholar The effectiveness of PPI-amoxicillin dual therapy is dependent on the effectiveness of the antisecretory agent, the dose and frequency of administration of amoxicillin, and the duration of therapy. With clarithromycin and levofloxacin PPI-containing triple therapies, resistance results in a significant reduction in cure rates.2Nezami B.G. Jani M. Alouani D. et al.Helicobacter pylori mutations detected by next-generation sequencing in formalin-fixed, paraffin-embedded gastric biopsy specimens are associated with treatment failure.J Clin Microbiol. 2019; 57 (e01834-18)Crossref PubMed Scopus (25) Google Scholar In the Argueta et al study,1Argueta E.A. Alsamman M.A. Moss S.F. et al.Impact of antimicrobial resistance rates on eradication of Helicobacter pylori in a US population.Gastroenterology. 2021; 160: 2181-2183Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar only 4 patients received PPI–amoxicillin–metronidazole therapy; 1 was resistant and all were cured. The authors suggest that measurement of metronidazole susceptibility may not be clinically relevant. We disagree. Metronidazole is a prodrug that is activated by enzymes present within the micro-organism to produce a toxic product that interacts with cellular DNA that ultimately kills the organism. Two genes, rdxA and frxA, are associated with this transformation and mutations leading to the inactivation of these genes generally forms the basis for prediction of resistance using molecular methods.6Jenks P.J. Edwards D.I. Metronidazole resistance in Helicobacter pylori.Int J Antimicrob Agents. 2002; 19: 1-7Crossref PubMed Scopus (82) Google Scholar However, despite the prediction of resistance using either molecular- or culture-based in vitro methods, it has been shown that resistance can be partially or completely overcome by increasing the metronidazole dose and the duration of therapy.7Graham D.Y. Lee S.Y. How to effectively use bismuth quadruple therapy: the good, the bad, and the ugly.Gastroenterol Clin North Am. 2015; 44: 537-563Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar It is important to note that the Etest often overestimates metronidazole resistance.8Osato M.S. Reddy R. Reddy S.G. et al.Comparison of the Etest and the NCCLS-approved agar dilution method to detect metronidazole and clarithromycin resistant Helicobacter pylori.Int J Antimicrob Agents. 2001; 17: 39-44Crossref PubMed Scopus (105) Google Scholar In the Argueta et al study, the cure rate was high with bismuth quadruple therapy despite metronidazole resistance. Overall, metronidazole susceptibility data is useful as susceptibility correlates with high cure rates with metronidazole triple therapy and with short duration bismuth triple or quadruple therapy. Resistance results in the requirement to increase both the metronidazole dose and the duration of therapy.7Graham D.Y. Lee S.Y. How to effectively use bismuth quadruple therapy: the good, the bad, and the ugly.Gastroenterol Clin North Am. 2015; 44: 537-563Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar,9Bardhan K. Bayerdorffer E. Veldhuyzen van Zanten S.J. et al.The HOMER Study: the effect of increasing the dose of metronidazole when given with omeprazole and amoxicillin to cure Helicobacter pylori infection.Helicobacter. 2000; 5: 196-201Crossref PubMed Scopus (65) Google Scholar Molecular-based testing is now available commercially, although it may not be covered by insurance. Susceptibility testing, whether assessed by culture- or molecular-based methods, greatly increases the probability of treatment success provided that the details of the regimen (dose, drugs, formulation, frequency of administration, and duration) are optimal and the patient is adherent to treatment. In most countries the prevalence of resistance to clarithromycin, levofloxacin, and metronidazole has increased to the point that none should be used empirically as triple therapies.10Savoldi A. Carrara E. Graham D.Y. et al.Prevalence of antibiotic resistance in helicobacter pylori: a systematic review and meta-analysis in World Health Organization Regions.Gastroenterology. 2018; 155: 1372-1382Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar However, clarithromycin and metronidazole remain excellent choices for susceptibility-based therapy optimized triple therapies (eg, 14 days with ≥40 mg omeprazole equivalent PPI).11Yu L. Luo L. Long X. et al.Susceptibility-guided therapy for Helicobacter pylori infection treatment failures.Therap Adv Gastroenterol. 2019; 12 (1756284819874922)Crossref Scopus (20) Google Scholar Levofloxacin is also effective,11Yu L. Luo L. Long X. et al.Susceptibility-guided therapy for Helicobacter pylori infection treatment failures.Therap Adv Gastroenterol. 2019; 12 (1756284819874922)Crossref Scopus (20) Google Scholar but has received black box warning from the US Food and Drug Administration and its use should probably be restricted to situations where it is the only option.12Keller A. Fluoroquinolones. 2020; (Available:)ConsumerNotice.orgGoogle Scholar It is apparent that the current guidelines for H pylori therapy and the approach to therapy using trial and error has failed and we must therefore transition to practices based on the general principles of antimicrobial therapy and of antimicrobial stewardship.13Graham D.Y. El-Serag H.B. European Registry on Helicobacter pylori management shows that gastroenterology has largely failed in its efforts to guide practitioners.Gut. 2021; 70: 1-2Crossref PubMed Scopus (12) Google Scholar, 14Dyar O.J. Huttner B. Schouten J. et al.What is antimicrobial stewardship?.Clin Microbiol Infect. 2017; 23: 793-798Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar, 15Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9Google Scholar By definition, all highly effective antimicrobial therapy is susceptibility based, irrespective of whether the determination is made prospectively or by clinical experience.13Graham D.Y. El-Serag H.B. European Registry on Helicobacter pylori management shows that gastroenterology has largely failed in its efforts to guide practitioners.Gut. 2021; 70: 1-2Crossref PubMed Scopus (12) Google Scholar,15Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9Google Scholar With H pylori, most therapy is empiric and poorly infective.13Graham D.Y. El-Serag H.B. European Registry on Helicobacter pylori management shows that gastroenterology has largely failed in its efforts to guide practitioners.Gut. 2021; 70: 1-2Crossref PubMed Scopus (12) Google Scholar,16Nyssen O.P. Bordin D. Tepes B. et al.European Registry on Helicobacter pylori management (Hp-EuReg): patterns and trends in first-line empirical eradication prescription and outcomes of 5 years and 21 533 patients.Gut. 2021; 70: 40-54Crossref PubMed Scopus (53) Google Scholar With infectious diseases, an empiric therapy is one proven to be reliably highly effectively locally.15Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9Google Scholar It is generally most efficient and effective to develop and use antibiotics based on susceptibility data. There are advantages of molecular-based testing because it can use clinical isolates, fresh or formalin-fixed gastric biopsies, or stool samples and can rapidly provide data on multiple antibiotics whereas culture-based susceptibility requires intragastric contents and often several weeks.17Brennan D.E. Omorogbe J. Hussey M. et al.Molecular detection of Helicobacter pylori antibiotic resistance in stool vs biopsy samples.World J Gastroenterol. 2016; 22: 9214-9221Crossref PubMed Scopus (25) Google Scholar To use these data effectively, we need studies to identify the strengths and limitations of molecular methods using different types of samples as well as more comparisons between molecular- and culture-based methods in relation to treatment outcome. Treatment success also depends on utilization of optimized therapies defined as therapies that reliably achieve cure rates of ≥95% in susceptible infections and adherent patients; for an empiric therapy, one that reliably achieves >90% locally.15Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9Google Scholar With other infectious diseases, treatment outcomes and susceptibility patterns are monitored routinely so the recommendations can be adjusted when conditions change. This practice is also possible with H pylori; therapy should also be followed by a test of cure that provides an indirect assessment of susceptibility or resistance.15Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9Google Scholar Sharing those data with colleagues and the agencies responsible for gathering local susceptibility data and for making antimicrobial recommendations would promote therapeutic decisions based on local experience as required for antimicrobial stewardship.15Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9Google Scholar Culture-based susceptibility testing and molecular-based testing are now commercially available. Gastroenterologists no longer have an excuse to use poorly effective H pylori therapies. Guidelines and practices must now change.