Tailored Treatment Based on Helicobacter pylori Genetic Markers of Resistance Is Associated With Higher Eradication Success

INTRODUCTION:

Increasing antimicrobial resistance with Helicobacter pylori infection has focused efforts to tailor eradication therapy based on identifying genetic markers of resistance to predict antimicrobial susceptibility.

METHODS:

In this retrospective study, we report the effect of routine inclusion of antimicrobial susceptibility testing and recommendations for eradication therapy with gastric specimens with H. pylori.

RESULTS:

The use of a recommended treatment regimen based on genetic markers of resistance was associated with an 84% rate of eradication success and 4.4 greater odds of eradication relative to unrecommended treatment.

DISCUSSION:

This is the first study describing the use of H. pylori genetic resistance testing as standard of care.

Helicobacter pylori infection is a leading cause of peptic ulcer disease and gastric cancer worldwide. Owing to widespread use of antibiotics, antimicrobial resistance is increasingly common in H. pylori infections. Molecular methods identifying H. pylori mutations associated with antibiotic resistance provide an efficient means to tailor eradication therapy at the onset of treatment. We previously reported the use of a culture-free next-generation sequencing (NGS) assay to analyze H. pylori extracted from formalin-fixed, paraffin-embedded gastric biopsy specimens for mutations conferring resistance to clarithromycin, levofloxacin, and tetracycline (1). In this study, we described the effect of using this NGS test to identify mutations associated with antimicrobial resistance (MAAR) as part of standard of care. Recommendations for eradication therapy based on MAAR findings were reported as an addendum to the gastric biopsy pathology report in the patient's medical record.

A multidisciplinary team including pathologists with expertise in genomic sequencing (N.S.) and microbiology (D.D.R.), infectious disease experts (L.S.H., D.C.N.), and a gastroenterologist (L.C.C.) convened in early 2020 to develop specific treatment recommendations based on susceptibility testing to guide clinicians in selection of eradication therapy for H. pylori. Treatment recommendations for 14-day eradication regimens were developed based on available guidelines from North America (2,3) and included recommendations to ascertain previous macrolide exposure and to consider allergy testing in patients reporting penicillin allergy. Beginning in June 2020, H. pylori MAAR testing for clarithromycin, levofloxacin, and tetracycline was included as a reflex test for all gastric specimens with H. pylori identified by histopathology within the University Hospitals Health System (including 12 hospitals) in northeast Ohio (see Supplementary Methods, Supplementary Digital Content 1, http://links.lww.com/AJG/C785). MAAR testing with treatment recommendations was reported as an addendum to the pathology report. Treatment recommendations (see Supplementary Table 1, Supplementary Digital Content 2, http://links.lww.com/AJG/C786) avoided the use of antibiotics expected to be resistant.

This study aimed to evaluate the effect of MAAR-informed treatment recommendations on eradication success. Institutional Review Board approval was obtained from University Hospitals Cleveland Medical Center. Information on the prescribed eradication therapy regimen was extracted from the medical record. Results of testing for confirmation of eradication (urea breath test, stool antigen test, or repeat biopsies) for patients receiving eradication therapy were tracked. We evaluated rates of eradication success before and after implementation of reflex MAAR testing in the period from February 1, 2019, to November 1, 2021, in patients without documentation of previous treatment for H. pylori and compared eradication rates using Pearson χ² tests. Patients with treatment data before the intervention were designated cohort 1. Among patients with MAAR results and treatment data after the intervention, we compared eradication success between patients prescribed a regimen consistent with the recommended therapy (designated cohort 2A) and those prescribed a regimen that deviated from the recommendations (designated cohort 2B).

Before the intervention, 866 subjects were considered. Of them, 16% (135/866; cohort 1) had no previous treatment, a documented eradication therapy regimen, and documented eradication testing results. The eradication success rate was 76% (102/135), with a higher eradication success for subjects receiving quadruple therapy (Table 1).

Table 1.

Baseline characteristics and eradication success by initial treatment regimen before and after implementation of reflex reporting of Helicobacter pylori mutations associated with antimicrobial resistance with treatment recommendations

After the intervention, 603 subjects were considered. Of them, 21% (127/603; cohort 2) had no previous treatment, a documented eradication therapy regimen, and documented eradication testing results. MAAR for clarithromycin, levofloxacin, and combined levofloxacin/clarithromycin resistance were detected in 34% (43/127), 36% (46/127), and 16% (20/127) of subjects, respectively, after the intervention (Table 2). Eighty percent (101/127) of cohort 2 was prescribed a recommended regimen (cohort 2A), and 20% (26/127) of subjects were prescribed an unrecommended regimen (cohort 2B). Based on chart review, 58% (15/26) of subjects in cohort 2B were prescribed treatment before the release of the MAAR report. In an additional 31% (8/26) of subjects in cohort 2B for whom treatment was prescribed on or after the release of the MAAR report, provider notes regarding treatment did not acknowledge MAAR testing results.

Table 2.

Predicted antimicrobial resistance after implementation of reflex reporting of Helicobacter pylori mutations associated with antimicrobial resistance

After the intervention, the eradication success rate was 84% (85/101) for cohort 2A and 54% (14/26) for cohort 2B (P = 0.001). Among 70 subjects in cohort 2 with any antimicrobial resistance, the eradication success rate was 84% (41/49) for cohort 2A and 48% (10/21) for cohort 2B (P = 0.002). In a multivariable logistic regression including all subjects in cohort 2, being prescribed a recommended regimen (cohort 2A) was independently associated with 4.4 times greater odds of treatment success after adjusting for any antimicrobial resistance, age, sex, race, and any antibiotic allergy (95% confidence interval 1.61–12.51; Table 3).

Table 3.

Factors associated with eradication success after implementation of reflex reporting of Helicobacter pylori mutations associated with antimicrobial resistance

The cure rate with empiric therapy in our population (represented by cohort 1) was <90%, the threshold suggested in a recently proposed algorithm for the use of susceptibility testing before therapy (4). Notably, mutations associated with antibiotic resistance were identified in 55% of samples tested. Of most importance, we found that treatment with regimens containing an antimicrobial drug for which the H. pylori is expected to be resistant based on testing (cohort 2B) was more likely to fail than when using a recommended regimen (cohort 2A).

Recent communications have reported the use of NGS methods to evaluate H. pylori antimicrobial resistance (5–7). One study reported a 53% rate of clarithromycin resistance (6). Our study revealed a 34% rate of clarithromycin resistance, which well exceeds the 10%–18% rate reported in a systematic review for Americas region (8) and the 15% threshold above which guidelines recommend against empiric clarithromycin triple therapy (2). To our knowledge, this is the first study describing the use of H. pylori genetic resistance testing as standard of care. The study demonstrates that routine evaluation of MAAR for H. pylori can direct initial therapy, improve patient outcomes, and promote antimicrobial stewardship by avoiding the use of ineffective antibiotics. Moreover, this analysis reports local eradication success rates for specific regimens, in keeping with recommendations in recent literature on H. pylori therapy (9–11). Our study is limited by lack of eradication data on the majority of patients, inability to assess adherence to eradication therapy, and the inability to confirm that clinician treatment decisions were made in response to treatment guidance. Future studies should identify methods to improve adoption of recommended therapies and evaluate the utility of personalized treatment recommendations paired with active antimicrobial stewardship interventions targeting H. pylori eradication.

CONFLICTS OF INTEREST

Guarantor of the article: Navid Sadri, MD, PhD.

Specific author contributions: L.C.C.: conceptualization: equal, formal analysis: equal, writing-original draft: lead. L.S.H.: conceptualization: equal, formal analysis: equal, statistical analysis: lead, IRB: lead, writing-original draft: equal. D.C.N.: data curation: supporting, writing—review and editing: supporting. L.M.S.: writing—review and editing: equal. D.D.R.: conceptualization: equal, writing—review and editing: equal. N.S.: conceptualization: lead, methodology: lead, data curation: lead, formal analysis: equal, writing—review and editing: equal. All authors have approved the final draft.

Financial support: Funding for open access publication charges provided by University Hospitals Health System.

Potential competing interests: None to report.

Supplementary Material

acg-118-360-s001.docx ^{(13.6KB, docx)}

acg-118-360-s002.docx ^{(13KB, docx)}