Helicobacter pylori: High dose amoxicillin does not improve primary or secondary eradication rates in an Irish cohort

Abstract

BACKGROUND

Helicobacter pylori (H. pylori) eradication rates have fallen globally, likely in large part due to increasing antibiotic resistance to traditional therapy. In areas of high clarithromycin and metronidazole resistance such as ours, Maastricht VI guidelines suggest high dose amoxicillin dual therapy (HDADT) can be considered, subject to evidence for local efficacy. In this study we assess efficacy of HDADT therapy for H. pylori eradication in an Irish cohort.

AIM

To assess the efficacy of HDADT therapy for H. pylori eradication in an Irish cohort as both first line, and subsequent therapy for patients diagnosed with H. pylori.

METHODS

All patients testing positive for H. pylori in a tertiary centre were treated prospectively with HDADT (amoxicillin 1 g tid and esomeprazole 40 mg bid × 14 d) over a period of 8 months. Eradication was confirmed with Urea Breath Test at least 4 wk after cessation of therapy. A delta-over-baseline > 4% was considered positive. Patient demographics and treatment outcomes were recorded, analysed and controlled for basic demographics and prior H. pylori treatment.

RESULTS

One hundred and ninety-eight patients were identified with H. pylori infection, 10 patients were excluded due to penicillin allergy and 38 patients refused follow up testing. In all 139 were included in the analysis, 55% (n = 76) were female, mean age was 46.6 years. Overall, 93 (67%) of patients were treatment-naïve and 46 (33%) had received at least one previous course of treatment. The groups were statistically similar. Self-reported compliance with HDADT was 97%, mild side-effects occurred in 7%. There were no serious adverse drug reactions. Overall the eradication rate for our cohort was 56% (78/139). Eradication rates were worse for those with previous treatment [43% (20/46) vs 62% (58/93), P = 0.0458, odds ratio = 2.15]. Age and Gender had no effect on eradication status.

CONCLUSION

Overall eradication rates with HDADT were disappointing. Despite being a simple and possibly better tolerated regime, these results do not support its routine use in a high dual resistance country. Further investigation of other regimens to achieve the > 90% eradication target is needed.

Key Words: Helicobacter pylori eradication, Helicobacter pylori, High dose amoxicillin, High dose amoxicillin dual therapy, Triple therapy

Core Tip: We present a prospective assessment of high dose amoxicillin dual therapy (HDADT) for Helicobacter pylori in an Irish cohort. Ireland is a 'high dual-resistance country'-(clarithromycin and metronidazole)-mainstays of traditional treatment. Where bismuth-based therapy is unavailable, as in Ireland, European guidelines recommend HDADT can be considered. This is the first data on HDADT to date in Ireland, and despite promising data from Asia, European data remains scant. Our results show disappointing eradication rates; we discuss possible reasons why and provide clinical evidence to authorities for the need to make bismuth-therapy available in our country. We advise against HDADT in European populations.

INTRODUCTION

Helicobacter pylori (H. pylori) is a recognised cause of chronic gastritis, gastric and duodenal ulcers, mucosal associated lymphoid tissue lymphoma, and other gastric cancers[1,2]. In 1994 it was recognised by the World Health Organization as a class 1 carcinogen[3] and in 2015 the Kyoto consensus classified it as an infectious disease, recommending eradication therapy in all diagnosed cases[4].

Although antimicrobial guidelines vary worldwide, since 1997 European guidelines have relied on ‘triple therapy’ consisting of amoxicillin, proton pump inhibitors (PPI) and either clarithromycin or metronidazole for eradication, which has caused an increase in the prevalence of resistance to these agents, and a corresponding decrease in the successful eradication rates in many European countries[5-7]. In areas designated as ‘high resistance countries’ it is imperative we investigate new antimicrobial regimens to achieve the > 90% eradication target which is recommended[8]. Ireland currently is classified as an area of high dual resistance, that is clarithromycin resistance > 15% and metronidazole resistance > 15%[9].

Recently the European Helicobacter pylori Study Group and Consensus Panel have published the Maastricht VI/Florence consensus report on the treatment of H. pylori at a European level and have recommended that in areas of high clarithromycin resistance (> 15%) empiric treatment with bismuth quadruple therapy (BQT) or levofloxacin quadruple therapy may be used. Bismuth is not widely available in Ireland, while combination tablets are also unavailable, and as such the adoption of Bismuth based quadruple therapy among clinicians has been poor. Similarly, concerns regarding the potential adverse events of fluroquinolones and national guidance restricting their used has also limited the uptake of Levofloxacin-based regimens[10,11].

In these circumstances, high dose amoxicillin dual therapy (HDADT) or rifabutin triple therapy may be trialed, subject to local evidence of efficacy[12]. HDADT has been advocated as possible second line or rescue treatment in other jurisdictions with reasonable eradication success reported[13].

While evidence is lacking currently for HDADT as a first line treatment in Europe, several studies in Asian populations have demonstrated promise[14-17]. In theory, HDADT as a primary treatment would make sense as reported resistance rates to amoxicillin in Naïve patients are low, its use would represent good antibiotic stewardship, and it would also represent a simpler regimen which may impact patient compliance.

We aimed to prospectively assess the efficacy of HDADT therapy for H. pylori eradication in an Irish cohort.

MATERIALS AND METHODS

Study population

This was a prospective open label study performed in a tertiary referral centre in Ireland. After approval by our institution as a quality improvement initiative, all adult patients > 18 years of age diagnosed with H. pylori via urea breath test (UBT) or upper endoscopy were sequentially enrolled. Exclusion criteria included: Known or suspected Penicillin allergy, refusal to consent or refusal to attend for Post-Eradication UBT.

Treatment regimen

All patients were prescribed a 14-d course of HDADT consisting of amoxicillin (1 g tid) and esomeprazole (40 mg bid). At the end of the study compliance to therapy and side effects were assessed by phone interview. At least 4 wk after the cessation of antimicrobial therapy a post-eradication a ¹³C UBT was performed using our standard protocol with × 50 mg Urea (Diabact, Laboratoires Mayoly Spindler, France) to evaluate H. pylori status. All patients were advised to avoid PPI for 7 d, antibiotics for 28 d, and to fast for 6 h prior to attending for their breath test. A delta-over-baseline > 4% was considered positive.

Analysis

Patient demographics and prior medical histories were recorded from their electronic patient record. H. pylori testing data and eradication rates were accessed from the GI lab database. The effects of demographic data on eradication rates were analysed via Fisher Exact test, logistical regression or χ² where appropriate.

RESULTS

One hundred and eighty-seven patients were identified with H. pylori infection over the 8 months timeframe of the study. Of these, 10 patients were excluded due to penicillin allergy and 38 patients refused follow up testing. Of the 139 patients included in the analysis, 55% (n = 76) were female, the mean age was 46.6 years (SD: ± 15.9, range: 19-83 years). In all 93 (67%) patients received HDADT as their first-line therapy, while 46 (33%) received HDADT after at least one course of alternative treatment. All patients were receiving empirical therapy, none had undergone antibiotic resistance testing prior to treatment. Demographics were similar among naïve and prior treatment groups. Overall only 78 (56%) were UBT negative post HDADT treatment (Figure 1).

Figure 1 Study population and treatment outcomes.

Eradication rates were statistically worse for those with previous treatment [43% (20/46) vs 62% (58/93), P = 0.02], odds ratio = 2.2 (95%CI: 1.1090-4.7074) (Table 1).

Table 1 First line vs prior therapy eradication rates.

Post treatment UBT result	First line therapy group	Prior therapy group	Total
Negative	58	20	78
Positive	35	26	61a
Total	93	46	139

^aP = 0.02, odds ratio = 2.2 (95%CI: 1.1090-4.7074).

UBT: Urea breath test.

Of note, all patients in the ‘previous treatment’ group had been exposed to treatment regimens including amoxicillin.

There was no statistically significant difference in eradication rates by gender (P = 0.8648) (Table 2), or age (by logistical regression, AUC = 0.5483, P = 0.3320) (Figure 2).

Figure 2 Logicstical regression of Helicobacter pylori eradication by age.

Table 2 Helicobacter pylori eradication rates by gender.

Post treatment UBT	Negative	Positive	Total
Female	42	34	76
Male	36	27	63a
Total	78	61	139

^aP = 0.8648.

UBT: Urea breath test.

In the previous treatment cohort, n = 46, 32 (70%) had previously had a single therapy with clarithromycin based triple therapy for 14 d, 10 patient (22%) had had two therapies, and 4 (9%) were receiving rescue therapies.

Eradication rates in the previous treatment cohort ranged from 44 to 100%, but the sample size for each regiment was too small to support further meaningful statistical analysis (Table 3).

Table 3 Breakdown of non treatment-naive cohort by prior therapy and eradication status.

	Total	% of total	Eradication	Eradication (%)
CTT	32	70	14	44
CTT, LTT	5	11	4	80
CTT, MTT	4	9	2	50
CTT, MTT, LTT	3	6	1	33
CTT, BQT	1	2	0	0
CTT, LTT, BQT	1	2	1	100

CTT: Clarithromycin triple therapy; LTT: Levofloxacin triple therapy; MTT: Metronidazole triple therapy; BQT: Bismuth triple therapy.

Overall, side effects occurred in 10 (7%) patients. Nausea was recorded in all 10 cases, with diarrhoea additionally reported in 3 (2%). There were no serious adverse drug reactions. Self-reported compliance with the regimen was (134/139) 97%, however it should be noted that all patients who did not complete the full regimen had successful H. pylori eradication.

DISCUSSION

Overall eradication rates were disappointingly low in our prospective single centre open label study of HDADT in an area of high dual clarithromycin and metronidazole resistance. Although patients undergoing first-line therapy were statistically more likely to have successful eradication (62% vs 43%, P = 0.0457), this rate remains far below the target of > 90% successful eradication.

From a cost, antibiotic stewardship and medication compliance perspectives, HDADT could be considered as a viable first line therapy for H. pylori when BQT or other alternatives are unavailable, but our study suggests its efficacy is too low to recommend. Rather, our study further enhances the move towards rapid antibiotic sensitivity testing by either polymerase chain reaction for genes known to be associated with antimicrobial resistance or E-Tests, with clarithromycin triple therapy the preferred option in proven sensitive patients, and bismuth or levofloxacin quadruple preferred in those not sensitive to clarithromycin.

Our study has several limitations. There is potential bias as an open label trial, however it was designed as such as a pilot assessment of a novel treatment, had there been evidence of efficacy a formal randomised controlled trial may have been of value. In addition, the relatively small population size may be an issue, although in our cohort, this represents the growing reality whereby H. pylori infection is infrequently diagnosed even in symptomatic patients presenting to our gastroenterology service. As such any future audit to assess treatment success based on international guidance is going to be performed in a similar cohort. The findings from this study therefore truly reflect our patient population and are therefore relevant to our, and other practices, who care for a similar demographic. Despite the small sample size, as expected we did find a treatment advantage for first line over subsequent treatment courses (odds ratio = -2.5). Of note also is the large number of participants who did not attend for post-eradication testing. 38 patients-representing 19% of those diagnosed in the time frame did not attend, likely representing a re-testing bias towards those with ongoing symptoms and persistent infection. It may the case in the future that the possibility of community-based or at-home testing will improve attendance for post-eradication testing, but currently this is an unfortunate reality of healthcare in Ireland.

Our study is similar to recent data from the European Registry on Helicobacter pylori management which failed to demonstrate that HDADT is effective in a European population of 62 patients[18]. This is in contrast with many larger studies and metanalyses from Asia[14-17]. One explanation for this may be due to the background of amoxicillin usage in our populations. Amoxicillin or amoxicillin-clavulanic acid (co-amoxiclav) represents first line antibiotic therapy for many common infections in Ireland, and so prior exposure to sub-therapeutic doses of this this antibiotic over time may have cultivated resistance in sections of our population.

Also, some of the differences in experience with HDADT eradication rates globally may be due in part to different medication regimens: Some studies suggest that administering 750 mg of amoxicillin four times a day is superior to administering 1 g three times a day[16,17]. This likely related to maintaining a therapeutic drug level throughout the day. Local variations in the rates of drug metabolization, and factors which affect this such as concurrent dietary, alcohol or medication intake may have an effect, as well as the average height and weight of participants in different studies around the world, as these drugs are not dose-adjusted. Other studies have postulated that the difference in common P450 CYP2C19 polymorphisms between European and Asian populations may also influence the differences in HDADT eradication rates, as higher variations in gastric pH levels have been shown to adversely impact on amoxicillin’s bactericidal effects[19-21]. In the future, as personalised medicine and access to genotyping becomes more cost-effective and widespread, screening for patients carrying variant alleles may allow for personalised dosing of PPIs. The more recent development of a new class of drugs; potassium-competitive acid blockers (e.g., vonoprazan) have also shown promise in maintaining lower gastric pH levels and have shown even more promise, again mostly in Asian populations, as part of H. pylori eradication therapy when compared with standard PPI therapy, however these medications have yet to be approved by the European Medicines Agency[22,23].

While the exact causes are not clear, whatever the rational, HDADT eradication rates reported in Asia are different from the European experience, and it cannot be considered a viable first- or second-line treatment in this part of the world.

CONCLUSION

HDADT has insufficient eradication rates to recommend it as first line or second-line therapy in high dual resistance European populations. Further studies into novel regimens are required.