Helicobacter pylori eradication therapy: indications

Review

Helicobacter pylori eradication therapy: indications, efficacy and safety 1.

Introduction

Avelyn Kwok, Thao Lam, Peter Katelaris & Rupert WL Leong†

2.

Indications for Helicobacter pylori eradication

Concord Hospital, Gastroenterology and Liver Services, Sydney South West Area Health Service, Sydney, Australia

3.

Helicobacter pylori eradication therapy

4.

Penicillin-allergic patients

5.

Eradication failure after first-line treatment

6.

Adverse effects of H. pylori eradication therapy

7.

Conclusion

8.

Expert opinion

ib h Background: Helicobacter pylori infects up to half of the world’s population. o r It remains the major cause of peptic ulcer disease and is recognised p as a y carcinogen for its role in gastric carcinogenesis. Successful leradication of tincluding fewer the bacteria is associated with improved health outcomes c i dyspeptic symptoms, reduced peptic ulcer recurrence tr and rebleeding, s reduced peptic ulcer risk with NSAIDs and as a cure for low-grade gastric n MALT lymphoma. The risk of gastric cancer o is reduced in those without i premalignant mucosal abnormalities at the ttime of eradication. Objective: u and options for therapy of This review outlines the current indications b i H. pylori with particular reference to tr drug-induced adverse events associs ated with treatment. Methods: The for H. pylori eradication are di indications evidence-based and in accordance with recent consensus statements and d treatment is based on numerous clinical recommendations. The eradication n trials and meta-analyses.aResults/conclusion: Eradication therapy, in general, is g Antibiotic therapy may be associated with significant safe and well tolerated. n i t especially gastrointestinal symptoms. drug adverse reactions, n i r , antibiotic, clarithromycin, consensus, eradication, Helicobacter pylori, Keywords: allergy P penicillin, rescue therapy, resistance, salvage therapy, triple therapy Expert Opin. Drug Saf. (2008) 7(3):271-281 . d

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1.

Introduction

The incidence of Helicobacter pylori varies geographically both between and within populations. Acquisition occurs mostly in childhood and intrafamilial spread appears to be the predominant mode of infection. Adult acquisition occurs in both developed and developing countries. A rate of 0.5 – 1.0% has been estimated in the latter from seroepidemiological studies [1,2]. The infection shows an age-dependent pattern, being rare among children but with an increasing rate of infection among older age groups [3]. Socioeconomic conditions in childhood are strongly inversely correlated with the risk of infection [1]. Other higher-risk groups include the institutionalised, health workers, and some indigenous populations [4]. H. pylori infects the stomach, invariably causing active chronic gastritis. Although most infected people are asymptomatic [1], H. pylori infection increases the risk of dyspepsia 2.3-fold [5]. The lifetime risk of peptic ulcer disease is 15 – 20% and 1 – 2% for gastric cancer or gastric mucosal-associated lymphoid tissue (MALT) lymphoma [1,2]. Routine screening and eradication of H. pylori has not been recommended. A test-and-treat approach has been recommended in certain populations such as those with H. pylori-associated symptoms, disease or at increased risk of H. pylori-associated complications [6]. Eradication therapy consists of a combination of antibiotics and an acid-suppressant drug. Generally, eradication therapy is well tolerated. It is, however, associated with significant drug-induced adverse 10.1517/14740330802055002 © 2008 Informa UK Ltd ISSN 1474-0338

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Helicobacter pylori eradication therapy: indications, efficacy and safety

Table 1. Recommendations for Helicobacter pylori eradication [6]. Peptic ulcer disease: gastric or duodenal ulcer; active or past Gastric MALT lymphoma Atrophic gastritis After gastric cancer resection First-degree relatives of patients with gastric cancer Investigated non-ulcer dyspepsia Uninvestigated dyspepsia Naïve users of NSAIDs Chronic users of NSAIDs Unexplained iron deficiency anaemia Patients wishes (after full consultation with their physician) NSAIDs: Nonsteroidal anti-inflammatory drugs.

events compared with acid-suppressing drugs alone. Antibiotic resistance is also an ongoing problem in many countries [7-9]. First-line therapies, therefore, should have the best efficacy in successfully eradicating the bacteria to reduce the chance of H. pylori antibiotic resistance. Therefore, the consideration of eradication therapy takes into account the indication of treatment, choice of drug combination, background antibiotic resistance rates, and alternative drugs available. 2. Indications for Helicobacter pylori eradication

H. pylori eradication is recommended in patients with gastroduodenal diseases such as peptic ulcers, low-grade gastric MALT lymphomas, atrophic gastritis, first-degree relatives of patients with gastric cancer, and in patients with some extra-gastrointestinal diseases. In addition, eradication is recommended in naïve users of NSAIDs. Dyspeptic patients under the age of 45 without any other alarming symptoms may undergo noninvasive investigations – such as H. pylori urea breath test or faecal antigen test – to diagnose H. pylori, followed by eradication treatment. Others with dyspepsia and a concern for possible cancer should be investigated by endoscopy [6]. The current indications for H. pylori eradication are listed in Table 1. 2.1

Peptic ulcer disease

A Cochrane meta-analysis found that H. pylori eradication increased duodenal ulcer healing compared with antisecretory acid-suppressing therapy alone (relative risk [RR] for ulcer persistence was 0.66, 95% confidence interval [CI] 0.58 – 0.76; number needed to treat [NNT] for persistence was 14, 95% CI, 11 – 20) [10]. There was no significant difference in recurrence after ulcer healing between eradication 272

therapy plus antisecretory drugs for 1 month and ongoing maintenance antisecretory drugs alone (RR of ulcer recurring for eradication therapy plus antisecretory drugs, compared with antisecretory drugs alone 0.73, 95% CI, 0.42 – 1.25). H. pylori eradication when compared with no treatment had higher rates of duodenal ulcer healing (RR for persistence 0.37, 95% CI, 0.26 – 0.53; NNT 3, 95% CI, 2 – 4) and lower rates of ulcer recurrence (RR 0.14, 95% CI, 0.09 – 0.20). For gastric ulcer, there was no significant difference in healing between H. pylori eradication therapy plus antisecretory drugs and antisecretory drugs alone (RR for ulcer persistence 1.25, 95% CI, 0.88 – 1.76). H. pylori eradication reduced recurrence of gastric ulcer compared with no treatment (RR 0.29, 95% CI, 0.20 – 0.42; NNT 3, 95% CI, 2 – 5). Therefore, H. pylori eradication therapy is recommended to prevent rebleeding for both duodenal and gastric ulceration. H. pylori eradication is cost-effective in reducing duodenal ulcers over 1 year and gastric ulcers over 2 years [10]. It is less expensive than chronic antisecretory therapy. Antisecretory maintenance therapy for more than 2 weeks following antibiotic therapy is unnecessary after H. pylori eradication [11]. 2.2

NSAID-related peptic ulcers

H. pylori and NSAIDs independently increase the risk of peptic ulcer haemorrhage by two- and fivefold, respectively. When both factors are present, the risk of ulcer haemorrhage increases sixfold [12,13]. A meta-analysis [14] of 939 cases revealed that H. pylori eradication was associated with a reduced incidence of peptic ulcer and upper gastrointestinal bleeding at 6 months in patients using NSAIDs (OR 0.43, 95% CI, 0.20 – 0.93). This risk reduction was evident in NSAID-naïve people (OR 0.26, 95% CI, 0.14 – 0.49), but not for chronic NSAID users (OR 0.95, 95% CI, 0.53 – 1.72). In patients receiving longterm NSAIDs and with peptic ulcer and/or ulcer bleeding, proton pump inhibitor (PPI) maintenance therapy is superior to H. pylori eradication in preventing ulcer recurrence and/or ulcer haemorrhage, with a 6-month recurrent haemorrhage rate of 18.8% for H. pylori therapy compared with 4.4% for PPI therapy (p = 0.005) [13]. 2.3

Gastro-oesophageal reflux disease (GORD)

A systematic review by Raghunath and others [15], which included 27 studies, concluded that there is no association between H. pylori eradication and the development of reflux oesophagitis or worsening of heartburn in either the untreated or in those receiving PPI maintenance treatment. 2.4 Gastric mucosa-associated lymphoid tissue (MALT) lymphoma

Evidence from observational and intervention studies support the role of H. pylori infection in the pathogenesis

Expert Opin. Drug Saf. (2008) 7(3)

Kwok, Lam, Katelaris & Leong

and natural history of MALT lymphoma [15,16]. For localised low-grade gastric MALT lymphoma, H. pylori eradication achieves durable tumour regression in 60 – 90% of patients, so preventing or delaying the need for surgery, chemotherapy or radiotherapy [15,17-19]. H. pylori eradication is the treatment of choice for patients with stage I low-grade gastric MALT lymphoma [6]. 2.5

Prevention of gastric cancer

H. pylori is critical to the development of the majority of noncardia gastric cancer. The magnitude of the relative risk depends on the background prevalence of infection and is estimated at three- to sixfold in lower-prevalence populations [1]. A systematic review of 12 nested prospective case-control studies revealed that there was a strong association between H. pylori infection and the subsequent development of noncardia gastric cancer (OR 5.9, 95% CI, 3.4 – 10.3) [20]. Two randomised controlled trials (RCTs) of H. pyloripositive people found no significant difference in the risk of gastric cancer between H. pylori eradication and placebo after 7 years of follow-up (1.34% for eradication therapy, compared with 1.96% for placebo; HR 0.68, 95% CI, 0.42 – 1.12) [21,22]. The rarity of the end point of gastric cancer and the relatively short time course for slowly progressing dysplasia may have accounted for the negative finding and wide confidence interval. Both studies found that H. pylori eradication increased the regression of highrisk lesions (gastric atrophy or intestinal metaplasia) compared with no eradication. Eradication of H. pylori can result in the arrest or reversal of histological and molecular changes in the gastric epithelium that may be surrogate intermediates in the progression towards gastric cancer [23]. Although intervention studies of eradication of H. pylori for the prevention of gastric cancer have not shown clear benefit overall, the data shows that eradication of H. pylori prior to the development of intestinal metaplasia does reduce gastric cancer rates over 12 years. People from Asia (China, Japan, Korea, and Taiwan) and Central and South America (Costa Rica, Brazil) are at high risk for gastric cancer [24]. Therefore, screening for H. pylori infection is of particular interest in these countries. But more research is required to evaluate the efficacy of H. pylori eradication in preventing gastric cancer in the general population before decisions can be made regarding whether or not screening for H. pylori in countries with a high incidence of gastric cancer would be cost-effective [1]. Firstdegree relatives of gastric cancer patients are likely to be at an increased risk of gastric cancer themselves, and H. pylori eradication therapy is advisable in this cohort [25].

to treat to cure 1 case of dyspepsia is 14 [26]. There is a paucity of any long-term data, but one study did suggest that symptomatic improvement following H. pylori eradication can be as long as 5 years [27]. However, in areas where H. pylori prevalence is < 20%, PPI empirical treatment or a test-and-treat strategy are considered to be equally effective [6,27]. This is similar to the benefit achieved by PPI therapy, but is more cost-effective since the effect persists for at least 2 years [28,29]. Eradication of H. pylori in this cohort is better than any alternative therapy, and also confers the benefit of risk reduction for possible future ulcer or cancer. 2.7

Extragastrointestinal diseases

H. pylori has been shown to be a stressor of iron stores in some populations, but is rarely the major cause of iron deficiency. Nevertheless, H. pylori eradication and a thorough evaluation of of alternative aetiologies is recommended in patients with iron deficiency [6,30]. Platelet count has been shown to improve following successful H. pylori eradication in immune thrombocytopenic purpura [31]. Other diseases implicated or associated with Helicobacter infection include hepatobiliary [32] and ischemic heart diseases [33], but a direct causal role is unproven. 3.

Helicobacter pylori eradication therapy

Despite the large number of studies, the optimal therapeutic regimen is still to be defined and may need to be individualised geographically. H. pylori eradication requires combination of antibiotics plus an antisecretory drug. Incidental eradication is unlikely when antibiotics are used for other infections [34]. The initial course of therapy should offer the best chance of eradicating H. pylori [35]. Later therapies are likely to be less successful, particularly if the same antibiotics are used or if the patient had been previously exposed to any antibiotics contained in the treatment regimen. Thus the choice of treatment regimen must be carefully considered. Factors affecting treatment choice vary in different regions of the world – for example, prevalence of H. pylori, resistance to antibiotics, availability of bismuth and endoscopy, and prevalence of gastric cancer [1]. 3.1

First-line therapy

First-line H. pylori eradication therapy has evolved with time; at present, triple therapies with a PPI, clarithromycin, and either amoxicillin or a nitroimidazole are considered to be the most effective combinations because of their safety, cost-effectiveness and simplicity [6,36]. 3.1.1

2.6

Non-ulcer dyspepsia (NUD)

H. pylori eradication therapy results in a small but significant benefit in treating NUD, with a 10% relative risk reduction in the H. pylori eradication group (95% CI, 10 – 25) compared with placebo. The number needed

PPI triple therapies

Several international consensus groups have produced H. pylori guidelines recommending triple therapy with one PPI and two antibiotics (usually clarithromycin and amoxicillin) as the preferred regimen [1]. The antibiotics used depend on the regional rate of antibiotic


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Table 2. Recommendations for treatment of Helicobacter pylori infection formulated in the Maastricht III Consensus Report [6]. Recommendations

Level of evidence

Grade of recommendation

PPI-clarithromycin-amoxicillin or metronidazole treatment remains the recommended first-line choice treatment in populations with < 15 – 20% clarithromycin resistance prevalence. In populations with < 40% metronidazole resistance prevalence, PPI-clarithromycin-metronidazole is preferable

1a

A

Quadruple therapies are alternative first-choice treatments

1a

A

There is a small advantage in using a PPI-clarithromycin-metronidazole combination instead of PPI-clarithromycin-amoxicillin as the first-choice treatment

1a

A

The same first-choice H. pylori treatments are recommended worldwide, although different doses may be appropriate

1b

A

Bismuth-based quadruple therapies remain the best second-choice treatment, if available. If not, a PPI, amoxicillin or tetracycline and metronidazole are recommended

1b

A

Table 3. First-line regimens for Helicobacter pylori eradication (ACG guidelines) [28]. Regimen

Duration

Eradication rates

Comments

Standard dose PPI, clarithromycin 500 mg b.i.d., amoxicillin 1 g b.i.d.

10 – 14 days

70 – 85%

Consider in non–penicillin-allergic, macrolide-naïve patients

Standard dose PPI, clarithromycin 500 mg b.i.d., metronidazole 500 mg b.i.d.

10 – 14 days

70 – 85%

Consider in penicillin-allergic patients who are macrolide-naïve or unable to tolerate bismuth quadruple therapy

Bismuth subsalicylate 525 mg q.i.d., metroidazole 250 mg q.i.d., tetracycline 500 mg q.i.d., ranitidine 150 mg b.i.d. or standard dose PPI b.i.d.

10 – 14 days

75 – 90%

Consider in penicillin-allergic patients

PPI + amoxicillin 1 g b.i.d. followed by: PPI, clarithromycin 500 mg, tinadazole 500 mg b.i.d.

5 days 5 days

> 90%

Requires validation in North America

resistance, local preference and resources. There is still debate about the optimal length of therapy, although 7 – 14 days is preferred. Three systematic reviews comparing dual therapy (one antibiotic + a PPI) to triple therapy (two antibiotics plus either a PPI or bismuth) found that dual regimens resulted in lower rates of H. pylori eradication than triple regimens and, therefore, cannot be recommended [37-39]. A H. pylori eradication regimen should achieve at least 90% eradication rate on a per-protocol analysis and at least 80% on an intent-to-treat (ITT) analysis [28]. A systematic review of 16 studies and 24 abstracts estimated that eradication rates were 46, 70, 80 and 76% for PPI-based dual therapy, PPI-based triple therapy, ranitidine bismuth citrate-based triple therapy, and quadruple therapy, respectively [40]. The PPI + clarithromycin + amoxicillin or metronidazole combination is the recommended first-choice treatment in populations with low clarithromycin resistance of < 20% (Tables 2 and 3) [6,28]. There is some evidence that PPI + 274

clarithromycin + metronidazole has a higher eradication success than the combination of PPI + clarithromycin + amoxicillin (97 versus 88%, respectively) [41]. However, in a meta-analysis of 22 studies, the eradication rates on ITT analysis with PPI + clarithromycin + amoxicillin and PPI + clarithromycin + nitroimidazole were both identical at 81% [42]. H. pylori resistance to metronidazole or clarithromycin are the main factors responsible for treatment failure with regimens that include these compounds. Metronidazole resistance reduced eradication effectiveness by 37.7% (95% CI, 29.6 – 45.7%) and clarithromycin resistance reduced effectiveness by 55% (95% CI, 33 – 78%) [43]. 3.1.2

Bismuth-based therapies

Bismuth triple (bismuth + metronidazole + tetracycline administered for 14 days) and quadruple (bismuth + metronidazole + tetracycline + PPI administered for 7 – 10 days) therapies are effective treatment strategies in



low metronidazole resistance areas, when clarithromycin resistance is high, and when cost considerations are important [24]. The disadvantages are the large number of tablets that need to be taken, the duration of therapy, and its complexity. It is also an alternative to standard PPI triple therapy in the setting of penicillin allergy. Bismuth, however, is currently not readily available in many countries [1,6]. 3.1.3

Sequential treatment

A pooled-data analysis of > 1800 patients revealed eradication rates consistently > 90% on an ITT analysis [44]. This analysis showed that sequential treatment was superior to 7- to 10-day triple therapies. Although clarithromycin resistance reduced the efficacy of this regimen, it still outperformed the standard 7- to 10-day triple therapy in this setting. Sequential treatment appears very promising as an alternative first-line eradication regimen. It will need to be validated in other geographical areas, as the current trials have been mainly conducted in Italy. 3.2

Proton pump inhibitor (PPI)

A PPI is included in antibiotic regimens as an acid suppressant. A meta-analysis of 14 studies reported that there was no major difference in eradication rates between the various PPIs (omeprazole, esomeprazole, lansoprazole, or rabeprazole) when used in combination with the same antibiotics in triple therapy [14]. Pretreatment with a PPI prior to H. pylori eradication therapy does not adversely affect treatment outcomes [45]. A H2 receptor antagonist (H2RA) can be substituted if a patient cannot tolerate a PPI [46]. 3.3

Duration of H. pylori eradication therapy

There is no consensus on the optimal duration of treatment (7, 10, or 14 days) [47]. Two earlier meta-analyses [48,49] found that 14 days of therapy provided a moderate eradication rate (9 and 12%, respectively) that is significantly higher than that provided by 7-day therapy. A recent meta-analysis [47] found that extending triple therapy beyond 7 days had a small incremental advantage (approximately 5% increase in eradication rate). The authors reported the relative risks for eradication of 1.05 (95% CI, 1.01 – 1.10) for 7-day compared with 10-day amoxicillin-based triple therapy and 1.07 (CI, 1.02 – 1.12) for 7-day compared with 14-day therapy. Data were incomplete on the frequency, severity, and type of adverse events for the various treatment periods. The relative risk of adverse events was 0.98 (CI, 0.85 – 1.14) and 1.08 (CI, 0.84 – 1.40) for 7-day therapy compared with 10- and 14-day therapy, respectively. The most common side effects (5%) were taste disturbance and diarrhoea. The recommended duration of treatment by the American College of Gastroenterology is 10 – 14 days [28]. 3.4

Predictors of H. pylori treatment outcome

The most important predictors of treatment failure include poor compliance and antibiotic resistance [50]. In a

retrospective analysis of 2751 patients who failed eradication therapy in French clinical trials, factors that were predictive of failed eradication include smoking, triple therapy with a single dose of PPI or H2RA, clarithromycin resistance, the diagnosis of NUD rather than peptic ulcer disease and use of 7-day rather than 10-day therapy [51]. Clarithromycin resistance is the main risk factor for treatment failure [50]. The threshold of clarithromycin resistance at which it should not be used, or a clarithromycin susceptibility test should be performed, is 15 – 20%. Analysis of published studies on H. pylori therapy reported a 56 – 70% decrease in eradication rates if clarithromycin resistance was present and a clarithromycin-containing regimen was used [41,52]. With nitroimidazole resistance, there was a decline in efficacy of up to 50% for bismuthbased triple and metronidazole-based triple therapies [52]; but eradication rates can be improved by using higher doses of metronidazole and/or by adding a PPI to bismuth, tetracycline and metronidazole [50]. There is limited evidence suggesting that smoking and alcohol consumption may reduce the chance of successful eradication [50]. More recently it has been reported that CagA-negative strains of H. pylori [53] and CYP2C19 polymorphisms affecting the metabolism of PPIs [54] could increase the risk of treatment failure. 4.

Penicillin-allergic patients

This group is difficult to manage as therapeutic options are limited by the inability to use amoxicillin, a core component of many validated regimens. While combined treatment with a PPI, clarithromycin and metronidazole appears to be a good option with mean eradication rates of > 80% in non–penicillin-allergic patients [42], a study performed specifically on penicillin-allergic patients found an eradication rate of only 60% [55]. The other concern is that failure of eradication after using a clarithromycin and metronidazole regimen usually means resistance to either one or both antibiotics. This is particularly problematic as the only other validated regimen able to be used is bismuth-based quadruple therapy (or ranitidine bismuth citrate in place of PPI plus bismuth). Until other non-penicillin-containing regimens are validated, first-line therapy in penicillin-allergic patients should be bismuth-based quadruple therapy or PPI + clarithromycin + metronidazole. With limited validated treatment options, the role of culture and susceptibility testing becomes more important in this group of patients. 5.

Eradication failure after first-line treatment

Eradication rates with first-line PPI-based triple therapy have decreased to 70 – 85% worldwide due to the increasing prevalence of resistant H. pylori [7,8,56]. Eradication failure will become an even more relevant issue in the future as


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antibiotics such as clarithromycin are being used more readily for commonplace infections and at the same time, therapy for H. pylori infection is being prescribed more frequently. The best chance of eradication is with the first attempt; therefore choosing the optimal first-line treatment regimen is still the best method of avoiding the need for ‘salvage’ therapy. With the decrease in successful eradication rates after first-line therapy, a paradigm shift has occurred. Instead of focusing on the results of primary therapy alone, eradication strategies are now concentrating on finding a combination of two regimens that, when employed consecutively, come as close as possible to a 100% eradication rate. The recent Maastricht III consensus report recommended a combination of PPI + clarithromycin + amoxicillin or metronidazole as first-line eradication therapy, and bismuth-based quadruple therapy as second-line eradication therapy [6]. This combination leads to overall eradication rates of 95 – 99% [9,57]. In patients with persistent H. pylori infection, the re-treatment regimen should avoid resistance-inducing antibiotics that have been previously used, namely clarithromycin and metronidazole. Repeating the same regimen offers no eradication advantage, even if higher doses are used and/or the re-treatment period is extended [58]. Therefore, if a patient has not been previously treated with a clarithromycin-based regimen, re-treatment with a PPI + clarithromycin + amoxicillin is an appropriate choice. For example, in a patient who has failed therapy with a PPI + amoxicillin + metronidazole, second-line treatment with a PPI + clarithromycin + amoxicillin yields success rates of 75 – 100% [59,60]. Most patients, however, are now treated with clarithromycinbased regimens as first-line therapy, in accordance with international consensus and guidelines [6,28]. After failure with combination PPI + clarithromycin + amoxicillin, a theoretically appropriate re-treatment regimen would be PPI + metronidazole + amoxicillin, as there is no crossresistance between clarithromycin and metronidazole. In practice, though, this yields eradication rates of < 50% [59]. Quadruple therapy (PPI + bismuth + tetracycline + metronidazole) is the most commonly used salvage therapy and has been recommended as salvage therapy in several guidelines [6,28]. It gives mean eradication rates of 77% after failure of combination PPI, clarithromycin and amoxicillin [60]. A 7-day course of quadruple therapy appears to be adequate, as similar eradication rates are achieved with prolonged 10- or 14-day courses [61]. Failure after combination PPI + clarithromycin + metronidazole is often problematic. Although this regimen is very effective, patients who fail this regimen have resistance to clarithromycin, metronidazole or both [62]. At present, quadruple therapy is the most validated in this setting, with eradication rates of up to 80% [59]. A pooled analysis of 16 studies and 24 abstracts demonstrated an average eradication rate of 76% (range 60 – 100%) 276

for quadruple therapy as salvage therapy [40]. Although it contains metronidazole, this combination appears effective in metronidazole-resistant strains [8]. There are, however, many disadvantages including availability, large daily pill count (14 – 18 tablets), dosing frequency (usually four times daily) and the frequency of minor side effects such as gastrointestinal upset. Ranitidine bismuth citrate (RBC) has been evaluated in some studies in place of the PPI and bismuth components [63,64]. One randomised study compared conventional bismuth quadruple therapy to that of RBC-tetracycline-metronidazole after failure with combination PPI + clarithromycin + amoxicillin. ITT eradication was achieved in 57% compared with 83% (p < 0.05) respectively [64]. Thus, RBC appears to be a good option if available, as it has the added advantage of reducing the pill count by four tablets a day. Since compliance is the other important predictor of treatment failure, it is imperative that the clinician reiterates the importance of compliance as part of the ‘salvage’ therapy. Patients should also be informed of potential side effects of treatment. Patients should be warned that smoking potentially reduces the chance of eradication [65]. 5.1

Newer ‘salvage’ agents Levofloxacin

5.1.1

Levofloxacin is a fluoroquinolone with antibacterial activity against a broad spectrum of Gram-positive, Gramnegative and atypical respiratory pathogens. A recent metaanalysis compared levofloxacin triple therapy (levofloxacin + amoxicillin + PPI) to bismuth-based quadruple therapy (bismuth + tetracycline + metronidazole + PPI) [66]. This revealed that 10-day levofloxacin triple therapy was superior to 7-day bismuth-based quadruple therapy (RR 1.41, 95% CI, 1.25 – 1.59). Overall eradication rates were calculated as 87% (95% CI, 79 – 96%) for the levofloxacin triple therapy compared with 60% (95% CI, 45 – 74%) for the bismuthbased therapy. This meta-analysis also found that adverse events were less common with levofloxacin triple therapy (RR 0.51, 95% CI, 0.34 – 0.75). There is, however, emerging evidence that the prevalence of primary resistance is already up to 17.2% in some countries such as Japan, Belgium and France [67-69]. This has been attributed to the high level of consumption of fluoroquinolones in these areas. Whilst the efficacy and safety of levofloxacin makes it a promising strategy for primary eradication failures, it has not been validated in countries such as the USA, UK and Australia. Primary resistance rates for these countries are also not known. 5.1.2

Rifabutin

Rifabutin is a rifamycin antimicrobial that has activity against Mycobacterium tuberculosum. H. pylori has high in vitro susceptibility to rifabutin [70]. Little has been reported on rifabutin resistance in clinical practice.



Table 4. Common side effects of Helicobacter pylori eradication therapy. PPI

Headache and diarrhoea

Amoxicillin

Gastrointestinal (GI) upset, headache and diarrhoea

Clarithromycin

GI upset, diarrhoea, altered taste and (rarely) QT prolongation

Metronidazole

Metallic taste, dyspepsia, disulfiram-like reaction with alcohol consumption, peripheral neuropathy and seizures

Tetracycline

GI upset, photosensitivity, tooth discoloration if aged < 8 years

Bismuth

Darkening of the tongue and stool, nausea and GI upset

Eradication rates with a rifabutin-based regimen (rifabutin + amoxicillin + PPI) have been reported in the range of 62 – 86% when used as salvage therapy after one or more previous eradication attempts [71-73]. A recent study using rifabutin triple therapy (rifabutin 150 mg b.i.d. + amoxicillin 1 g b.i.d. + standard dose PPI b.i.d.) for 10 days revealed a 95% eradication rate when used as second-line therapy [74]. Rifabutin as rescue therapy has also been compared with the recommended bismuth quadruple therapy regimen. A randomised study was performed in which three groups of patients were treated for 10 days with pantoprazole + amoxicillin + rifabutin (at either 150 mg or 300 mg once daily) or quadruple therapy [75]. On an ITT analysis, eradication rates were found to be 67% for the rifabutin 150 mg and quadruple therapy groups (95% CI, 53 – 80%) and 87% in the rifabutin 300 mg group (95% CI, 76 – 96%). Side effects were significantly less with both the rifabutin groups. 5.1.3

Furazolidone

Furazolidone is an inexpensive antibiotic commonly used in treating infectious diarrhoea and enteritis caused by bacteria or protozoa. There have been a number of small studies evaluating the efficacy of furazolidone-containing therapies in eradicating H. pylori. These studies are difficult to interpret, as some have used furazolidone in a modified quadruple therapy whereas others have used it as triple therapy. The furazolidone used in these studies has also been in doses of 50 – 200 mg b.i.d. Eradication rates for these studies are in the range of 52 – 92% [35,76,77]. Though cost-effective, this therapy is not recommended until the appropriate regimen and dose can be validated. 5.2

culture requires endoscopy, is expensive, time-consuming, tests susceptibility to only a few antibiotics and is not always routinely available. The sensitivity of culture of endoscopyobtained specimens is only around 80% in trials enrolling patients who had failed one or more eradication attempts [78]. This number is likely to be even lower in clinical practice. Even when the bacterium is isolated and in vitro susceptibility is known, eradication is often not complete [79]. The novel minimally invasive ‘string test’ (Entero-test Hp) may successfully obtain the Helicobacter organism to culture and to test antibiotic sensitivity without performing a gastroscopy [80]. If culture and susceptibilities are not available or not performed, the same principle applies to third-line therapy as with second-line therapy: avoid resistance-inducing antibiotics that have been used previously. It is reasonable to assume that if clarithromycin or metronidazole has been used previously, resistance has developed. Bismuth-based quadruple therapy would be a reasonable empirical treatment option if not already used as second-line; otherwise levofloxacin-, rifabutin-, or furazolidone-based therapies can be considered. There is some evidence that PPI + levofloxacin + amoxicillin may be more efficacious than PPI + rifabutin + amoxicillin in this scenario [81]. A recent prospective study reported H. pylori eradication rates of 70, 74 and 76% with tailored second-, third- and fourth-line rescue regimens, respectively [82]. The cumulative H. pylori eradication rate with four successive treatments was 99.5%. The authors concluded that it was possible to achieve good eradication rates with a well-tailored consecutive eradication regimen without requiring knowledge of bacterial susceptibilities. 6. Adverse effects of H. pylori eradication therapy

A Cochrane review reported that eradication therapy significantly increased adverse events compared with antisecretory drugs or no treatment (RR 2.24, 95% CI, 1.72 – 2.93). The most common adverse effects of H. pylori therapy were diarrhoea (8%), altered taste (7%), nausea and vomiting (5%), skin rashes (2%), headache (4%), abdominal pain (5%) and stomatitis (2.5%) [10]. Another systematic review found that minor adverse effects were common with bismuth (40% of people), metronidazole (39%), clarithromycin (22%) and tinidazole (7%). Discontinuation of treatment due to severe adverse effects was rare (bismuth 4%, metronidazole 2%, clarithromycin 1% and tinidazole < 1%) [37]. The common side effects of specific agents are shown in Table 4.

Culture and sensitivity testing

The Maastricht consensus recommends that culture and sensitivity testing should be performed after two failed treatments [6]. However, this is not evidence based nor is it commonly carried out in clinical practice. Bacterial

6.1

Safety of newer ‘salvage’ agents Levofloxacin

6.1.1

Adverse effects related to levofloxacin are generally mild and related to the gastrointestinal system, including nausea and


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diarrhoea [83]. Compared with other fluoroquinolones, levofloxacin has low photosensitising potential, and clinically significant adverse cardiac and hepatic events are rare. Gatifloxacin, a similar fluoroquinolone studied in H. pylori eradication, was withdrawn from the market in 2006 due to serious adverse reactions including prolonged QT interval prolongation. Although the risk with levofloxacin appears to be lower, it should not be used in patients who demonstrate prolonged QT on ECG or who have a family history of QT prolongation. 6.1.2

Rifabutin

Rifabutin appears to be a promising rescue therapy, but there are some concerns regarding its use. Firstly, rifabutin is expensive and availability in some countries is limited. Associated adverse events are mostly mild, such as rash, nausea and diarrhoea [84]. However, there have been reported cases of severe – albeit reversible – leukopenia and thrombocytopenia [35,85]. One study reported a mild leukopenia in 25% (5 of 20 subjects) of the patients given rifabutin triple therapy [81]. Another concern has been the fear of selecting resistance in Mycobacterium tuberculosum. 6.1.3

Furazolidone

Reported side effects for furazolidone are mild in up to onethird of patients and include nausea, vomiting, headache and malaise. Rare side effects include hypersensitivity, a disulfiram-like reaction to alcohol and mild, reversible haemolytic anaemia [76,86,87]. 7.

the greatest chance of successful eradication, as subsequent choices in treatment are less likely to achieve a cure. In general, the success rate of eliminating the organism remains high, but antibiotic resistance may require second-line therapies and individualizing treatment. There also needs to be further research on the use of alternative antibacterial products and novel salvage agents and combinations. Overall, antibiotic combination therapy tends to be safe. Minor adverse drug effects are not uncommon, and emphasis on completion of the full course of treatment needs to be stressed to maximize the H. pylori eradication rate. Proof of cure with a urea breath test is recommended, especially if the indication for treatment is of a serious nature, such as to prevent recurrence of peptic ulcer haemorrhage. 8.

Expert opinion

Clarithromycin resistance has resulted in a decline in the successful eradication rate of H. pylori and may be related to the use (and overuse) of this antibiotic for non-H. pylori infections. The diminished availability of bismuth in some parts of the world has also resulted in a reduction of rescue treatment options. Alternative antibiotic combinations, and research into novel non-antibiotic agents such as lactoferrin and probiotics, may produce new treatment strategies for managing antibiotic resistance. Apart from the culture of the organism followed by susceptibility testing, molecular analysis of H. pylori for antibiotic resistance mutations after failed eradication may improve the individualisation of treatment and choice of second- and third-line antibiotics.

Conclusion Declaration of interest

Published studies support the eradication of H. pylori to treat and prevent recurrence of peptic ulcers and reduce the risk of gastric malignancies. First-line therapies should offer Bibliography

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Affiliation Avelyn Kwok MBBS, Thao Lam MBBS, Peter Katelaris MBBS MD FRACP FRCP & Rupert WL Leong† MBBS MD FRACP †Author for correspondence Concord Hospital, Department of Gastroenterology and Hepatology, Ambulatory Care Endoscopy Unit, Level 1 West, Hospital Road, Concord NSW 2139, Sydney, Australia Tel: +61 2 9767 6111; Fax: +61 2 9767 6767; E-mail: [email protected]

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