Helicobacter Pylori Eradication Failure
Dr Tan Huck Joo
MD (Ire), MRCP (UK), MB BCH BAO (Ire), AM
Introduction
Helicobacter pylori is a unique bacterial infection causing a range
of diseases ranging from inflammation to peptic ulcer disease to cancer. Its
discovery in the early 1980's had changed our understanding of peptic ulcer
disease and also its management. It is a major etiological agent of chronic
active gastritis, peptic ulcer disease and gastric carcinoma. Eradicating
Helicobacter pylori reduces the risk associated with it.
Helicobacter pylori eradication is successful in 80% to 90% of the cases. This means up to 10-20% of the eradication therapy failed. The commonest reasons for failed eradication therapy include bacterial resistance to anti-microbial and patient non-compliance to treatment. Other factors are smoking, alcohol, inadequate dose of acid suppressants and inadequate doses of antibiotics.
Helicobacter pylori eradication rate varies in different parts of the world. This may be related to the genetic difference in the metabolism of the proton pump inhibitor, which can alter the availability of anti-microbial in the stomach. Regional difference in anti-microbial resistance also affects the outcome of therapy. Some studies also suggested that the degree of gastritis and the nature of the underlying disease may affect the outcome of therapy but this is controversial.
Anti-microbial resistance
There is a geographical difference in anti-microbial resistance pattern, even
within the same country (Thyagarajan et al 2003). Primary resistance
is very much related to the antibiotic consumption in the local setting (Perez
Aldana et al 2002, Gomollon et al 2004). In a study from Alaska
(McMahon et al 2003), patients who had taken more than 5 courses of
macrolides had a 28% prevalence of clarithromycin-resistant strains of Helicobacter
pylori compared to 7% in patients who had never received macrolides. Patients
who had received one course of macrolides had a 28% prevalence of resistant
organisms. As Helicobacter pylori eradication rate depends very much
on the primary resistance of anti-microbials, it is important for clinicians
to be aware of the local anti-microbial resistance so that he or she can choose
the appropriate antibiotic wisely. Several risk factors associated with Helicobacter
pylori resistance have been identified (Meyer et al 2002). Clarithromycin
resistance was associated with geographic region, older age, female sex, inactive
ulcer disease and year of study. Metronidazole resistance on the other hand
was significantly associated with female sex, earlier year of enrolment, Asian
ethnicity and study. In general, metronidazole and clarithromycin resistance
is not uncommon and the incidence is rising. In fact dual resistance to metronidazole
and clarithromycin have also been described and this reduces significantly
the eradication rate for Helicobacter pylori (Wang et al 2000).
Alarmingly, primary clarithromycin resistant Helicobacter pylori have
been noted to be increasing in children and adolescent in certain country
(Crone et al 2003). The authors cautioned that the general use of clarithromycin
in children should be restricted to better-defined indications. It is likely
that Helicobacter pylori eradication therapy will need to be modified
in future as the incidence of anti-microbial resistance is rising. Besides,
Helicobacter pylori eradication rate has been shown to be lower in
clinical practice compared to clinical trials. Lee et al studied 308
patients and found that the intention to treat eradication rate for omeprazole,
amoxycillin, clarithromycin (OAC) and omeprazole, amoxycillin, metronidazole
(OAM) as first line regimens were 72% and 73% respectively only. A per protocol
analysis was 78% and 79% respectively. With second line quadruple therapy,
eradication was successful in 67%. Clarithromycin resistance is a more important
determinant of eradication failure than metronidazole resistance. In a systematic
review of the impact of anti-microbial resistance on Helicobacter pylori
eradication therapy, Houben et al (1999) concluded that in cases of
clarithromycin resistance, a mean drop in efficacy of 56% was found in clarithromycin
containing proton pump inhibitor triple therapy and a 58% reduction was noted
in ranitidine bismuth citrate combined with clarithromycin therapies. However,
ranitidine bismuth citrate-based triple therapy seems to produce better eradication
rate compared with the conventional proton pump inhibitor based triple therapy
(Wong et al 2001).
Alternative therapy
It is very important to use the best Helicobacter pylori eradication
therapy as first line treatment, as secondary resistance is very common once
there is any treatment failure (Gomollon et al 2004, Pilotto et
al 2000). Peitz et al (2002) reported resistance rate as high as
90% for metronidazole, 71% for clarithromycin and 68% for dual resistance
after failure of first line therapy. Pilotto et al (2000) reported
secondary antibiotic resistance in 77.8% of treatment failures associated
with proton pump inhibitor, clarithromycin and metronidazole and in 62.5%
of those treated with proton pump inhibitor, amoxycillin and clarithromycin.
Of the treatment failures, 70.6% developed a secondary resistance to metronidazole
and 64.7% to clarithromycin. Maastricht-2 Consensus Report (2002) recommended
quadruple therapy using a proton pump inhibitor, bismuth, metronidazole and
tetracycline as a second-line therapy. Although this is an effective treatment,
the rather complicated regimen of drugs may prove difficult for some patients
and hence non-compliance to treatment. Bismuth is also not readily available
in many countries, including Malaysia, making it difficult to use this treatment
regimen. In clinical trial setting, the eradication rate for quadruple treatment
has ranged from 37% to 91%. This means that a substantial proportion of patients
will have persistent Helicobacter pylori despite undergoing two courses
of eradication therapy. It has been suggested that these patients should undergo
a repeat endoscopy with culture and sensitivity (Maastricht-2 Consensus).
However several trials have demonstrated good success with "rescue therapy"
using rifabutin, levofloxacin, furazolidone and high dose amoxycillin.
Rescue therapy
Rifabutin-based therapy has been proposed as rescue therapy. Perri et al
(2000) treated 41 patients with pantoprazole, amoxycillin and rifabutin and
achieved an eradication rate of 71% on intention to treat analysis and 74%
on per protocol analysis. This was confirmed by Gisbert et al (2003)
with an eradication rate of 79% and they concluded that rifabutin-based rescue
therapy was a good strategy after multiple previous eradication failures with
key antibiotics such as amoxycillin, clarithromycin, metronidazole and tetracycline.
Levofloxacin-based therapy was also proposed as a good rescue therapy regimen. Bilardi et al (2004) randomized 44 patients to pantoprozole, amoxycillin and levofloxacin and 46 patients to omeprazole, metronidazole, tetracycline and bismuth subcitrate. Helicobacter pylori eradication was successful in 70% and 37% in the levofloxacin-based regimen and the quadruple therapy group respectively. Wong et al (2003) compared rabeprazole, bismuth subcitrate, tetracycline and metronidazole with rabeprazole, levofloxacin and rifabutin. They found the intention to treat and per protocol eradication rate were 91%/91% for the triple therapy and 91%/92% for the quadruple therapy group. They concluded both treatment regimens were equally effective as second line treatments for Helicobacter pylori infection.
Wong et al (2002) treated 50 patients with omeprazole, furazolidone and amoxycillin and achieved eradication rate of 53%. Further analysis showed that eradication rate was lower in patients with double resistance to metronidazole and clarithromycin (38%) compared to 88% in patients with sensitive strains. This was confirmed by Qasim et al (2005) recently when they evaluated rifabutin and furazolidone based eradication therapy and obtained eradication rate of 38% and 60% respectively. Isakov et al randomized 70 duodenal ulcer patients to colloidal bismuth subcitrate, tetracycline and furazolidone or standard quadruple therapy. A high eradication rate of 85.7% was found with intention to treat analysis and 90.9% with per protocol analysis in the bismuth, tetracycline and furazolidone treatment group. This result is comparable to the standard quadruple therapy.
High dose proton pump inhibitor and amoxycillin therapy has also been suggested as an effective second line treatment. Furuta et al (2003) treated 17 patients with high dose proton pump inhibitor and amoxycillin after failure of initial therapy of a proton pump inhibitor, clarithromycin and amoxycillin. They were able to eradicate Helicobacter pylori in all the patients regardless of CYP2C19 genotype status. CYP2C19 polymorphism is believed to be important in the treatment of Helicobacter pylori. The "poor metabolizer" genotype, present in 12-70% of Asian populations, is associated with more profound gastric acid suppression and improved Helicobacter pylori eradication rates compared to the "extensive metabolizer" genotype, which occurs in up to 95% of Caucasians. In the latter, Kita et al (2002) have suggested that 80mg of omeprazole has a similar acid suppressing action as 20mg in poor metabolizers and a daily dose of 160mg may be required for optimal anti-Helicobacter pylori activity. Viiala et al studied 15 patients who have failed eradication therapy with some patients failing up to four courses of eradication therapy. All of their patients had metronidazole resistance and 66% were clarithromycin resistance. With high dose proton pump inhibitor and amoxycillin, they were able to eradicate Helicobacter pylori in 67% of the patients. This was also confirmed by Miehlke et al (2003) who demonstrated that high dose dual therapy (omeprazole 40mg qid and amoxycillin 750mg qid) was as effective as the standard quadruple therapy for the treatment of Helicobacter pylori resistant to both metronidazole and clarithromycin. They were able to eradicate Helicobacter pylori in 83.8%/75.6% (per protocol/intention to treat) with dual therapy compared to 92.1%/81.4% (PP/ITT) in quadruple therapy. This regimen therefore may represent a simple treatment option in patients who have failed standard proton pump inhibitor-based triple therapy.
Coelho et al (2005) recently showed that the combination of rabeprazole, levofloxacin and furazolidone in a single daily dose for ten days was highly effective and cost effective as a salvage therapy in patients who have failed at least two previous Helicobacter pylori treatment. This may constitute an effective and simple to use regimen but more studies are required.
Non-ulcer dyspepsia versus peptic ulcer disease
Some studies have suggested that Helicobacter pylori eradication therapy
is more effective in patients with peptic ulcer disease than in those with
non-ulcer dyspepsia. Wong et al ((2005) demonstrated that a significantly
higher eradication rate was found in patients with duodenal ulcer than those
with non-ulcer dyspepsia. However, clarithromycin resistance rate was higher
in patients with non-ulcer dyspepsia than those with duodenal ulcer in this
study. This was in contrast to a systematic review by Huang et al (2005)
evaluating 22 studies and found that although Helicobacter pylori eradication
rate was slightly higher in peptic ulcer disease compared to non-ulcer dyspepsia,
this difference did not reach statistical significance. The authors therefore
concluded that there was no convincing evidence to suggest that non-ulcer
dyspepsia patients respond to Helicobacter pylori eradication therapy
differently from those with peptic ulcer disease.
Summary
We have come a long way to treat Helicobacter pylori and the diseases
associated with it since its discovery. Apart from knowing well the first
line eradication regimen, clinicians should also be prepared to face Helicobacter
pylori treatment failures. After failure of a combination of proton pump
inhibitor, amoxycillin and clarithromycin, the use of empirical quadruple
therapy (PPI-bismuth-tetracycline-metronidazole) has been generally accepted
as an optimal second line therapy. This treatment of course is limited by
the rather complex treatment regimen and hence patient non-compliance, and
also the availability of bismuth in some countries, including Malaysia. Even
after two consecutive failures, several studies have demonstrated that Helicobacter
pylori eradication can be achieved if rescue therapies are given. It seems
that performing culture even after a second eradication failure may not be
necessary. The newer combination of drugs such as rifabutin and furazolidone
with proton pump inhibitor seem promising but again cost and availability
may be a limiting factor. Levofloxacin and high dose amoxycillin in combination
with a proton pump inhibitor may be an effective alternative especially in
Malaysia. With the rising anti-microbial resistance worldwide, it is likely
that Helicobacter pylori eradication regimen may need to be modified
in future.
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