Management of Helicobacter pylori Infection

GASTROENTEROLOGY 2007;133:985–1001

REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY Wafik El-Diery and David Metz, Section Editors Timothy C. Wang, Guest Section Editor

Eradication Therapy for Helicobacter pylori NIMISH VAKIL*,‡ and FRANCIS MEGRAUD§,储 *Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, and ‡Marquette University College of Health Sciences, Milwaukee, Wisconsin, §INSERM U853, Bordeaux, and the 储University Victor Segalen Bordeaux 2, Laboratoire de Bactériologie, Bordeaux, France

Eradication therapy for Helicobacter pylori is recommended in a number of clinical conditions. In this article, we discuss the epidemiology and cellular mechanisms that result in antimicrobial resistance, the results of current eradication therapies, and new approaches to the management of Helicobacter pylori infection.

H

elicobacter pylori is an organism that has had an intimate association with mankind for many generations. Recent studies suggest that H pylori may have spread from east Africa with human migration approximately 58,000 years ago.1 The discovery of H pylori by Warren and Marshall and the development of effective treatment for this infection has resulted in a remarkable change in the management of upper gastrointestinal disorders with curative antibiotic therapy becoming available for low-grade gastric mucosa-associated lymphoid tissue lymphomas and H pylori-related peptic ulcers.

Treatment regimens for H pylori that have been used over the past decade are declining in efficacy, and the treatment of H pylori infection is bedeviled by drug-resistant strains of H pylori. In this article, we discuss the clinical and basic issues involved in H pylori eradication, the mechanism of antibiotic delivery to the mucus layer of the stomach, the primary and secondary treatment strategies, the causes of treatment failure, and the mechanisms for the development of antimicrobial resistance.

H pylori is a member of a group of bacteria adapted to life in the mucus of the digestive tract of vertebrates. Its specific characteristics include its morphology (spiral shaped, flagellated) and metabolism (microaerobic, asaccharolytic). Gastric Helicobacters have probably evolved from a gut bacterial ancestor when the stomach appeared in vertebrates, and H pylori is the Helicobacter specific to humans.

Indications for the Treatment of H pylori Infection Indications for H pylori eradication that were developed by an international consensus of experts (Maas-

tricht III Consensus Report) are listed in Table 1.2 Current US guidelines recommend testing and treatment for H pylori in patients with uninvestigated dyspepsia in areas in which the prevalence of H pylori is greater than 10%.3,4 The Maastricht Consensus Group recognized the links between gastric cancer and H pylori and recommended further work in the area.2 Because of problems with antimicrobial resistance with current therapies and the lack of an effective vaccine, mass treatment strategies have not been implemented. North American practitioners should be aware that immigrants from parts of Central and South America (Costa Rica, Brazil) and the Far East (China, Japan, Korea, and Taiwan) are at high risk for gastric cancer, and obtaining a family history is particularly important in people from this part of the world.

Delivery of Antibiotics to H pylori Most antibiotics are formulated for delivery to the small bowel to facilitate their absorption and consequently their blood-borne effects. The success of antimicrobial therapy for H pylori depends to a large extent on antimicrobial concentrations in the stomach. The principles of antimicrobial delivery to H pylori are important in understanding the rationale for various antimicrobial combinations that are used in clinical practice. They are illustrated in Figure 1.

Ingestion of Antibiotics Ingestion of antibiotics by patients is influenced by drug adverse effects and regimen complexity. Nausea and vomiting can limit drug ingestion (Figure 1). Regimens that require medications to be taken 4 times a day (quadruple therapy) are more likely to have adherencerelated problems than twice-daily therapies.5 There is limited information on the effect of drug formulation on © 2007 by the AGA Institute

0016-5085/07/$32.00 doi:10.1053/j.gastro.2007.07.008

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Table 1. Indications for Helicobacter pylori Eradication Duodenal ulcer Gastric ulcer Atrophic gastritis Gastric MALT lymphoma Nonulcer dyspepsia Uninvestigated dyspepsia (in areas with a prevalence ⏎10%) Following resection of a gastric cancer First-degree relatives of patients with gastric cancer Unexplained iron-deficiency anemia Idiopathic thrombocytopenic purpura Before commencing NSAID therapy in NSAID-naïve patients Patients receiving long-term aspirin therapy who develop gastrointestinal bleeding Patient request (after a discussion of risks and benefits) NOTE. Information in Table taken from Malfertheiner et al.2 MALT, mucosa-associated lymphoid tissue; NSAID, nonsteroidal antiinflammatory drugs.

treatment efficacy, but studies with amoxicillin suggest that the liquid preparation has better delivery to all parts of the stomach than capsules.

Luminal Factors Antibiotics have varying stability at acid pH. Metronidazole is very stable in gastric juice at a pH of 2 and a pH of 7, with a half-life of over 800 hours. Amoxicillin is unstable at low pH, but its half-life is still 15 hours at a pH of 2. In contrast, clarithromycin is particularly sensitive to degradation with acid and has a half-life of less than 1 hour at a pH of 2.6,7 The use of proton pump inhibitors (PPI) in antimicrobial regimens that contain clarithromycin is particularly important in preventing degradation of clarithromycin by acid (Figure 1).

Gastric Physiology The gastric mucus layer acts as a barrier limiting the delivery of antibiotics to H pylori. In animal experiments, pronase, which digests gastric mucus, increases delivery of amoxicillin.8 There is little information on interventions to change the quality or thickness of the mucus layer in the treatment of H pylori infection. PPIs may also decrease the viscosity of gastric mucus, increasing the delivery of all antibiotics.

Occluding the duodenum with a balloon to increase contact time of antibiotics with the gastric mucosa has been attempted in a small study and resulted in a rapid cure of H pylori infection.9

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unionized in plasma and therefore crosses the gastric mucosa easily into gastric juice with gastric acid secretion.6 Omeprazole decreases intragastric concentrations of metronidazole by reducing acid secretion but increases concentrations of all agents by decreasing gastric volume.10 Some studies have shown that acid inhibitors, such as omeprazole, increase the concentration of clarithromycin in gastric tissue, but other studies have not.11,12

Treatment Strategies for H pylori Overview The treatment of H pylori infection has not changed significantly in the last decade, although promising alternatives have recently been suggested. At the present time, the treatment regimen recommended for worldwide use is triple therapy with PPI, amoxicillin, and clarithromycin.2 Dissatisfaction with this regimen is growing in most developed countries, and a new initial therapeutic strategy is needed. The alternatives to triple therapy include quadruple therapy, sequential therapy, and triple therapy using new antimicrobials such as levofloxacin, rifabutin, and furazolidone. Each of these is discussed in more detail below, and a strategy is suggested for management.

Initial Management Strategies PPI triple therapy. A PPI combined with amoxicillin and clarithromycin is the most widely used form of therapy in the Western world. In areas where clarithromycin resistance rates are high, metronidazole may be substituted for clarithromycin. Eradication rates with triple therapy have been falling with rising resistance rates to commonly used antimicrobials, and a recent consensus group considered alternatives to triple therapy

Systemic Delivery of Antibiotics to the Stomach Antibiotics move across cells by lipid diffusion.

They dissolve in the lipids of the cell membrane, and, then, passive transfer occurs by a concentration gradient.6 Drug ionization also plays a role. Unionized drugs cross membranes easily, whereas more polar molecules cross with difficulty. Metronidazole is predominantly

Figure 1. Factors affecting antibiotic delivery to the gastric mucus.

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Figure 2. Eradication rates in large US trials of PPI triple therapy. E, esomeprazole; A, amoxicillin; C, clarithromycin; O, omeprazole; B, Bismuth; M, metronidazole; T, tetracycline; L, lansoprazole; P, pantoprazole; R, rabeprazole. Usual doses: PPI, twice a day; clarithromycin, 500 mg twice a day; amoxicillin, 1 g twice a day. Esomeprazole was studied in a single daily dose. *Mean of 2 studies.

but eventually concluded that PPI-based triple therapy was still the initial treatment of choice.2 Figure 2 shows the rate of eradication with triple therapy in large, controlled trials in the United States.13–18 Note that the confidence intervals for eradication with 7-day triple therapy in the most recent trials have been as low as 57%–73% (Figure 2, Bochenek et al17) and 67%–79% (Figure 2, Vakil et al18) for 10-day triple therapy. When an individual patient is treated in clinical practice, the eradication rate may be anywhere within this range. The duration of the triple therapy regimen has been the subject of debate. Early studies of 7-day therapy in the United States suggested that the results were poorer than in Europe, but these studies had low power and wide confidence intervals making accurate predictions impossible.19 A head-to-head comparison of 7-day and 10-day therapy in the United States found numerical differences favoring 10-day therapy, but the comparisons between the groups met prespecified US Food and Drug Administration criteria for equivalence.18 A recent European study found no difference between 1 week and 2 weeks of PPI triple therapy.20 A review of controlled trials suggested that 14 days of treatment with triple therapy was superior to 7-day therapy (difference, 12%; 95% CI: 7%– 17%).21 At this point, it seems prudent to use at least 10 days of treatment in the United States.

Bismuth-based triple/quadruple therapy. 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 areas in which metronidazole resistance is low, clarithromycin resistance is high, and cost considerations are paramount. Bismuth triple therapy administered for 14 days has been available for over a decade but has had limited success with physicians and patients in the United States or in other Western countries. The principal problem with this regimen is the large number of

tablets/capsules that need to be taken and the duration of therapy and its complexity. To improve adherence, convenience packs that contain all the medications on a plasticized sheet have been developed. The major advantage of the bismuth triple therapy regimen is that it is inexpensive and can be used in regions of the world in which cost is the major consideration. Another advantage is that this regimen remains effective in areas in which clarithromycin resistance is high. A large, randomized, controlled trial evaluated bismuth triple therapy administered for 14 days and compared it with 7-day PPI triple therapy (PPI ⫹ amoxicillin ⫹ clarithromycin) and 7-day quadruple therapy (bismuth ⫹ metronidazole ⫹ tetracycline ⫹ PPI).22 Eradication rates were similar with PPI triple therapy (78%) and quadruple therapy (82%), and both were significantly better than 14-day bismuth triple therapy (69%). Nonadherence with therapy (15%) was significantly greater with bismuth triple therapy administered for 14 days, and moderate-severe adverse events were very common (45%). Quadruple therapy administered for 7–10 days (the duration should depend on location and local experience) is therefore preferable to bismuth triple therapy administered for 14 days. In another randomized, controlled trial in Spain, 7-day PPI triple therapy was similar to quadruple therapy in the eradication of H pylori.23 The dose of bismuth should be based on the preparation used. In the United States, the most frequently used preparation is bismuth subsalicylate (150 mg bismuth per tablet), which is administered in a dose of 2 tablets 4 times a day along with tetracycline 500 mg and metronidazole 250 mg also administered 4 times a day. The patient should be instructed to chew the bismuth tablets before swallowing but to swallow the metronidazole and tetracycline without chewing.

A relatively new development with quadruple therapy has been the development of a single capsule preparation of bismuth biskalcitrate with metronidazole and tetracycline. Although it reduces the number of pills that need

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to be taken, 3 tablets still need to be taken 4 times a day and a PPI needs to be taken separately twice a day.

Results have been promising, with an eradication rate of 93% by intent-to-treat analysis in Europe and 87.7% in the United States for 10-day therapy.14,24 In the US trial, the results were comparable with 10-day PPI triple therapy. The treatment remained effective despite the high observed resistance rate for metronidazole in the United States (40%), although the absolute number of patients with resistance was small (n ⫽ 51). A meta-analysis evaluated quadruple therapies and found that there was no significant difference between PPI triple therapy and quadruple therapy when clarithromycin resistance rates were less than 15%.25 In patients with clarithromycin resistance however, quadruple therapy was significantly better than triple therapy. Bismuth-based quadruple therapy for 10 days is therefore a suitable salvage therapy of patients who have failed clarithromycin-based triple therapy.

Whether quadruple therapy should replace PPI triple therapy as the initial treatment of choice is a matter of debate. A recent meta-analysis found only 4 studies of sufficient quality to allow comparisons and no statistically significant difference between PPI triple therapy and quadruple therapy.26 At the recent Maastricht International Consensus Conference of experts on H pylori, a proposal that PPI triple therapy be replaced with quadruple therapy was made but failed to generate sufficient support.2 Quadruple therapy is listed as an alternative first-line therapy to PPI triple therapy and should definitely be considered when a clarithromycin-based triple therapy regimen has failed or in areas in which clarithromycin resistance is particularly high. Another bismuth preparation, ranitidine bismuth citrate, is no longer available in the United States but has been shown to be effective in H pylori eradication in combination with clarithromycin and amoxicillin in a meta-analysis.27 It is a reasonable alternative in areas in which it remains available.

The penicillin allergic patient. Bismuth quadruple therapy is a reasonable alternative to standard PPI triple therapy when penicillin allergy is present. In regions in which ranitidine bismuth citrate is available, a combination of ranitidine bismuth citrate with tetracycline and metronidazole has been used.28 A combination of a PPI with metronidazole and clarithromycin has also been used but has a lower eradication rate (77%).17 Sequential therapy for H pylori eradication. Sequential therapy is a major new innovation in the treatment of H pylori. The sequential regimen is a 10-day treatment consisting of a PPI and amoxycillin 1 g (both twice daily) administered for the first 5 days followed by triple therapy consisting of a PPI, clarithromycin 500 mg, and tinidazole 500 mg (all twice daily) for the remaining 5 days. The idea was born of earlier observations made when 2-drug therapies (PPI ⫹ amoxicillin) were in use. It was observed that the eradication rate achieved with a

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therapeutic strategy of initially administering 14-day dual therapy (PPI ⫹ amoxicillin) followed by 7-day triple therapy in individuals who failed the original therapy was significantly better than the reverse sequence (7-day triple therapy as an initial strategy with 14-day dual therapy for failures).29 A series of studies performed in Italy have shown excellent results with sequential therapy, and, if these results are confirmed in other parts of the world, it is likely that we may be looking at eradication therapy in a new light, considering sequences of medications rather than complex regimens of individual drugs. Six published Italian trials that each involve more than 100 patients are presented in Table 2.30 –35 The eradication rate was uniformly above 90% (Table 2). A recent Spanish study, still in preliminary form, provides evidence from another country of the merit of this regimen.36 The precise mechanism for the success of the sequential therapy is not known. One possibility is that decreasing the bacterial density in the stomach with a drug such as amoxicillin (to which resistance is rare) improves the efficacy of the subsequently administered combination of clarithromycin and tinidazole. It is known that bacteria can develop efflux channels for clarithromycin, which rapidly transfer the drug out of the bacterial cell, preventing binding of the antibiotic to the ribosome.37 Because amoxicillin acts on the bacterial cell wall and weakens it, the initial phase of treatment may prevent the development of efflux channels by weakening the cell wall of the bacterium.

A recent head-to-head comparison of sequential therapy with conventional triple therapy found that 10-day sequential therapy had a significantly higher eradication rate (91% by modified intent-to-treat analysis) compared with 10-day triple therapy (78% by modified intent-totreat analysis).35 Of particular note was the success of sequential therapy in patients with clarithromycin-resistant strains. The eradication rate in patients with clarithromycin-resistant strains of H pylori was 89% with sequential therapy and 29% with standard triple therapy.35 Although sequential therapy is currently considered a second-line therapy, confirmation of its efficacy in other countries should lead to serious consideration that it be adopted as initial therapy.

When Eradication Therapy Fails Overview When treatment fails, antimicrobial resistance and nonadherence are leading causes. In a recent multicenter US trial, clarithromycin resistance was noted in one third of cases failing therapy.18 Although this highlights the importance of resistance, it also demonstrates the role of other factors such as adherence (in the remaining two thirds) in treatment failure. Antimicrobial susceptibility testing would therefore be a logical first step in treatment failures. Unfortunately, antimicrobial

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Table 2. Sequential Therapy: Trials With More Than 100 Patients Given Sequential Therapy Author (reference) al30

Zullo et Hassan et al31 Focareta et al32 De Francesco33 De Francesco34 Vaira et al35

Year

No. of centers

2003 2003 2003 2004 2004 2007

8 1 1 1 2 2

Patients Eradication enrolled rate (%) 522 152 174 162 116 146

92 93.4 95.4 93.2 94.8 91.1

95% CI 89.8–93.7 89.3–96 92–97.4 89.2–95.8 90.3–97.3 86.4–94.3

susceptibility testing is still not widely available in the United States and other countries, and most community hospitals do not perform culture and antimicrobial susceptibility testing of H pylori. If available, antimicrobial susceptibility testing should be performed and a treatment regimen based on the susceptibility of the organism. The availability of new kits that can perform susceptibility testing, such as by real-time polymerase chain reaction (PCR) in stool, will likely make matters easier in the future.

For practitioners, a simple empirical management algorithm is necessary that allows treatment to be modified according to the treatment regimens the patient has received.38 If a patient has received a clarithromycincontaining regimen, this drug should generally be avoided in a secondary treatment, with the possible exception of sequential therapy, which has proven quite effective despite the presence of clarithromycin resistance.35 If patients have failed both clarithromycin- and metronidazole-containing regimens, one of the salvage therapies should be chosen. Amoxicillin continues to be used in most treatment regimens because the emergence of resistance to amoxicillin is uncommon and the prevalence of resistant strains is very low. Although antimicrobial sensitivity testing may help in the selection of a second-line treatment for H pylori, controlled trials have suggested that it may not always be essential for clinical management. In a controlled trial of eradication therapy in patients in whom primary therapy had failed, Lamouliatte et al reported that, when PPI-based triple therapy failed, approximately equal eradication rates could be obtained with empirical use of omeprazole, amoxicillin, and metronidazole as with antimicrobial susceptibility driven choice of therapy.39 This study was performed in France where bismuth is not available, and, therefore, quadruple bismuth therapy was not an option. In the United States, a quadruple therapy regimen with a PPI, bismuth, tetracycline, and metronidazole for 10 days would be preferred.

For the patient with failed eradication, 4 possible choices are available (Figure 3): (1) Antimicrobial sensitivity testing and tailored therapy. (2) Quadruple therapy: This treatment strategy has the advantage of proven efficacy in larger trials and is described in detail above. (3)

Sequential therapy: The impressive results in patients with clarithromycin resistant strains need confirmation in other countries. This may be a reasonable alternative in the future. (4) Salvage therapies: Triple therapies combining a PPI with amoxicillin and either levofloxacin, rifabutin, or furazolidone are discussed below.

Salvage Regimens Containing Levofloxacin, Rifabutin, and Furazolidone Three regimens (containing either rifabutin, levofloxacin, or furazolidone) have had success in eradication as a second- or third-line therapy in European and Asian trials. Two recent meta-analyses compared bismuth-quadruple therapy (bismuth ⫹ tetracycline ⫹ metronidazole ⫹ PPI) to triple therapy with levofloxacin (levofloxacin 500 mg/day ⫹ amoxicillin 1 g twice a day ⫹ a PPI twice a day) in patients who failed eradication with standard triple therapy. Both analyses found that levofloxacin triple therapy was better tolerated than quadruple therapy and had better eradication rates (81% vs 70%, respectively; OR, 1.80; 95% CI: 0.94 –3.46).40,41 Ten-day levofloxacin triple therapy was superior to 7-day therapy, and levofloxacin at 250 mg twice a day was as good as 500 mg twice a day. Of the 3 salvage therapies described in this section, levofloxacin is the best documented and therefore the preferred therapy.

Rifabutin is a drug used to treat mycobacterial infections. In small trials, it has been shown to be effective in eradicating H pylori in patients who have failed traditional therapies. The usual doses in rifabutin triple therapy are rifabutin 150 mg twice a day, amoxicillin 1 g twice a day, and a PPI administered twice a day. In one recent study, the eradication rate was 74%.42 In a randomized comparison of levofloxacin triple therapy and rifabutin triple therapy in patients who had failed 2 other treatment trials, levofloxacin triple therapy was significantly better than rifabutin triple therapy (85% vs 45%, respectively). Adverse effects occurred frequently with both regimens: leucopenia with rifabutin in 25% and myalgia with levofloxacin in 30%.43 Furazolidone-based triple therapy has been shown to be effective in small studies. The usual doses are furazolidone 100 –200 mg along with amoxicillin 1 g and a PPI, all administered twice daily for 1 week. In one study, the intent-to-treat eradication rate was 52% in patients who had failed standard therapy.44 Furazolidone therapies have been less well studied than rifabutin- and levofloxacin-based studies. The low cost of furazolidone makes this regimen particularly attractive in developing countries, but the optimal dose and combination needs further study.

A practical management strategy using these treatment regimens was evaluated in Ireland45; 3280 patients received standard PPI triple therapy, which was effective in 2530 (77%) patients. Bismuth-based “quadruple” or a triple therapy (that did not contain the antibiotic that

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Figure 3. Treatment strategies for the patient who fails initial therapy.14,22–26,29 –36,40 – 44

failed in the original regimen) was successful in 56% of 270 failures. Subsequent eradication attempts using rifabutin-based (n ⫽ 34) and furazolidone-based (n ⫽ 10) regimens were successful in 38% and 60% patients, respectively. The majority of patients could therefore be managed by the use of one or more therapies described above.

Current and Emerging Strategies Figure 3 shows various strategies that may be adopted after initial therapy fails. When initial treatment fails, culture and antimicrobial sensitivity testing are reasonable if available. If culture is not available, quadruple therapy is a reasonable alternative. If this fails as well, levofloxacin-based triple therapy would be the logical choice because it has been studied the most.

At this point, an evidence-based ranking of alternatives is not possible. Decision making should depend on the availability of culture and antimicrobial sensitivity testing and knowledge of local resistance patterns.

Adverse Effects of Medications A Cochrane review reported that the most common adverse effects of therapy for H pylori were diarrhea in 8%, altered taste in 7%, nausea and vomiting in 5%, skin rashes in 2%, headache in 4%, abdominal discomfort or pain in 5%, and stomatitis in 2.5% of patients treated for H pylori.46 Occasional case reports of pseudomembranous colitis have appeared, and the adverse effects with newer medications such as rifabutin and levofloxacin have already been described. Discussing the anticipated adverse effects with the regimen may be an important way to improve compliance.

Alternative Therapies Probiotics are not effective in H pylori eradication, but some studies have shown a decrease in gastritis se-

verity or in bacterial density with these agents.47 Other studies have shown a reduction in adverse effects with probiotics.47 Further research is necessary before these can be recommended for routine use.

Testing for Confirmation of Eradication In the past, when eradication rates were high, routine testing to confirm eradication was recommended only in high-risk patients (eg, those with peptic ulcer bleeding). With the declining rates of eradication with conventional therapy, there is a more pressing need to establish whether eradication therapy has been successful. Both the urea breath test and the stool antigen test have high accuracy in confirming eradication.48 The monoclonal stool test should be used because it is more accurate.49 An evaluation of the cost-effectiveness of these tests has been published.50 It concluded that, because the accuracy of the 2 tests is similar, the choice of one or the other depends on patient convenience and the cost of the test. The choice of a test may depend on geography; in the United States, the 13C urea breath test is expensive compared with Europe, but, with the imminent expiration of patent protection, price reductions are likely. A 14C breath test may be another less expensive alternative. Stool antigen testing and breath testing are now available to the average practitioner in the United States through large laboratory testing organizations.

Cost-effectiveness Considerations The cost-effectiveness of H pylori eradication has been evaluated in a number of settings. Table 3 shows cost models related to H pylori eradication and the corresponding clinical trial data when they have been performed with economic end points. Cost-effectiveness models have demonstrated that eradication of H pylori is cost-effective in patients with duodenal and gastric ulcer.51 Economic evaluations in a clinical trial show that

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Table 3. Cost-effectiveness Models for Helicobacter pylori Eradication and Direct Measurements of Cost in a Clinical Trial of Eradication

Clinical setting Ulcer disease Uncomplicated peptic ulcer

References 52, 53, 54

Cost-effectiveness models of H pylori eradication Cost-effective vs acid suppression Cost-effective vs acid suppression

Bleeding peptic ulcer

53

Documented peptic ulcer disease by endoscopy or radiology Physician diagnosis of peptic ulcer (not confirmed)

52, 55, 57

Cost-effective vs acid suppression

56, 57

Not cost-effective vs acid suppression

Dyspepsia Population-based testing and treatment for H pylori to prevent dyspepsia

Population-based testing and treatment for H pylori to cure dyspepsia in young patients (⬍50 yr) with no alarm symptoms Functional dyspepsia

Population-based eradication for gastric cancer prevention

60–62

Measured cost saving in clinical trials US $/person $547–$835/yr No clinical trials with economic end points $285–$482/year

Not cost saving

Mixed results (saving ⫽ $117/10 yr; increased cost ⫽ $148/2 yr)

58, 59, 63, 64

Cost-effective compared with early endoscopy

$337–$389/1 year

63

Cost-effective compared with early endoscopy

68–71

Cost-effective in high-risk populations

No clinical trials with economic end points No clinical trials with economic end points

eradication is associated with a measurable decrease in ulcer-related costs.52 Testing for and treating H pylori infection followed by retesting to confirm eradication of H pylori has been shown to be cost-effective in patients with bleeding ulcer disease.53 Although this has not been modeled in other settings, the high failure rates of current therapies may make it cost-effective to test all patients, particularly in countries in which breath testing and/or monoclonal stool tests are inexpensive. Testing and treating patients with newly diagnosed peptic ulcer disease has been shown to reduce costs related to active peptic ulcer disease over a 12-month time frame.54 Testing and treating patients with previous peptic ulcer disease has been suggested as a cost-effective strategy. It was unsuccessful in a US-managed care trial because most patients receiving acid inhibitors for a diagnosis of peptic ulcer disease were dyspeptic patients who tested negative for H pylori.55 In another trial, the benefit of testing and treatment was limited to patients who had previously had a documented peptic ulcer.56

Comment

Eradication prevents ulcer recurrence Recurrent ulcer disease is associated with high costs Unconfirmed peptic ulcer disease is a heterogeneous group that includes H pylori negative dyspepsia Mixed results may be related to the time frame of the clinical study. Initial costs of treatment may be offset over the longterm.

Testing and treating for H pylori decreases costs of investigation. When the prevalence is ⬍10%, PPI therapy may be preferable.

In the area of dyspepsia management, early models based on high rates of H pylori prevalence and high rates of underlying peptic ulcer disease suggested a large economic benefit for noninvasive testing for H pylori followed by treatment.57 As the prevalence of H pylori infection and peptic ulcer disease decreases in a dyspeptic population, other strategies including acid suppression have become competing alternatives.58 Management guidelines for patients presenting with dyspepsia in the United States recommend the use of empirical testing and treatment for H pylori in young patients with uninvestigated dyspepsia, except in areas in which the prevalence of H pylori infection has dropped below 10%.3,4 A population-based H pylori eradication strategy to prevent dyspepsia and dyspepsia-related cost has been shown to reduce dyspepsia-related health care costs in the United Kingdom over a 10-year period.59 The mean cost saving was modest (US $117 over 10 years; 95% CI: $11–$220).

The results have been mixed when shorter time periods were studied. A population-based study of testing and

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treatment for H pylori to prevent dyspepsia- and ulcerrelated symptoms and costs showed a small benefit at the end of 1 year, mostly because of a reduction in consultation for dyspepsia.60 In another trial, population-based testing and treatment for H pylori resulted in a reduction in dyspepsia-related consultations, but the cost was higher in the eradication group at 2 years mostly because of the high cost of the eradication therapy chosen.61 Taken together, these data suggest that the initial investment in therapy for H pylori treatment may not pay off for several years. There may be additional benefits for eradication, eg, the benefits of prevention of gastric cancer that have not been considered in many economic models. These potential benefits are certainly not captured by clinical trials that are 1–10 years duration.

Cost models have suggested that eradication therapy may be a cost-effective option in functional dyspepsia.62 Models for the management of dyspepsia in patients who present to physicians with symptoms (as opposed to population-based eradication strategies) have suggested an economic benefit for H pylori eradication.58,63 In the Canadian CADET-HP trial, the cost saving with a testand-treat strategy for H pylori in patients presenting to primary care physicians with dyspepsia was significant over a 1-year time frame.64 In choosing H pylori treatment regimens, it is important to recognize that failed therapy can be an extremely expensive undertaking and that the first attempt at therapy is probably the best. Cost models have shown the impact of nonadherence and the problems associated with choosing a regimen based on medication cost alone.65 Economic analyses have also evaluated the duration of therapy. An economic analysis comparing 7- and 10-day therapy found small differences between the costs for the 2 treatment durations using US prices but found 7-day therapies were cost-effective in Spain.66 Formal costeffectiveness studies have not been performed comparing newer/salvage treatments, but a cost comparison within a clinical trial showed that sequential therapy had better outcomes at lower cost than standard triple therapy with similar adverse effects.35 An extensive document that details the literature on this subject has recently been published.67 Except in first-degree relatives of patients with gastric cancer, eradication therapy is not currently recommended to prevent gastric cancer.2 Cost-effectiveness models have suggested that testing followed by treatment in adults may be a cost-effective strategy to prevent cancer, particularly in selected high-risk populations, eg, Japanese Americans.68 –70 The assumptions used in these models have limitations because effectiveness of H pylori eradication in preventing cancer needs further definition and the proportion of patients who may benefit and the age at which the testing and treatment should take place are uncertain.71 The incidence of distal

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gastric cancer is declining, as is the prevalence of H pylori infection, in many developed countries.

Factors Affecting H pylori Eradication There are many differences in eradication rates in different populations.

Genetic Differences in the Metabolism of Drugs PPIs are an important part of many current treatment strategies for H pylori. Some of the currently available PPIs are metabolized by the cytochrome P450 system in the liver, and genetic polymorphism of the cytochrome (CYP)2C19 can affect H pylori eradication. Poor metabolic activity is genetically determined and results in high plasma concentrations of the PPI and a prolonged effect.

A recent meta-analysis suggested that eradication rates might be reduced if the PPI in the eradication regimen was omeprazole, but eradication rates were unchanged when lansoprazole or rabeprazole was used.72 Poor metabolizers are found in 3%–5% of populations of Western origin, but prevalence rates of 18%–23% have been reported in China, Vietnam, Thailand, and Japan where differences in the outcome of therapy may be more relevant.

Smoking A meta-analysis of 22 studies including 5538 patients in the analysis suggested that smoking was associated with a reduced rate of eradication (8.4%; 95% CI: 3.3%–13.5%), particularly in patients who had nonulcer dyspepsia. In this analysis, smokers had a higher likelihood of failed eradication (OR, 1.95; 95% CI: 1.55–2.45).73

Underlying Disease State Some studies have suggested that eradication rates for H pylori are lower in patients with nonulcer dyspepsia as opposed to patients with peptic ulcer disease, but the results have been variable, and other studies have found no difference.18,74 At the present time, adjustments to treatment duration are not recommended based on the indication.2

Adverse Effects and Complexity of the Regimen Patient adherence is a relatively new term for what was called compliance with therapy in the past. It implies and recognizes that patients have choices with regard to taking prescribed medications. Studies with antimicrobial therapy show that frequent dosing (3 or 4 times a day) is associated with reduced adherence.5 Adverse effects may also play a role, notably diarrhea with amoxicillin, taste perversion with clarithromycin, and metallic taste with metronidazole. A clear explanation of the anticipated adverse effects and the potential adverse conse-

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quences of discontinuing therapy may improve adherence.

A retrospective analysis of 2751 patients who failed eradication therapy in clinical trials in France suggested that many factors played a role in failed eradication.

Factors that were predictive of failed eradication were clarithromycin resistance, diagnosis of nonulcer dyspepsia as opposed to peptic ulcer disease, and use of 7-day vs 10-day therapy.75 Adherence with the treatment regimen is difficult to measure, and the traditional methods used in clinical trials (pill counts) are prone to error.

Resistance to Antimicrobial Agents Antimicrobial resistance is a major cause of treatment failure and is responsible for the declining rates of H pylori eradication seen in many countries. A systematic review of H pylori therapy reported a 56% decrease in eradication rates if clarithromycin resistance was present and a clarithromycin-containing regimen was used, and, with nitroimidazole resistance, a drop in efficacy of up to 50% was found for bismuth-based triple and metronidazole-based triple therapies.76 A more recent analysis of published studies found a 70% decline in eradication rates if clarithromycin resistance was present and a clarithromycin-containing regimen was used.77

Recurrence of H pylori Infection After Successful Eradication Studies of recurrent infection suggest that recurrence is rare when effective therapies are used and when early recurrences are excluded (these are most often because of failed eradication). In developed countries, the rate is approximately 3% per year.78 Most apparent recurrences are really recrudescences of an infection that has not been adequately treated, often because of an ineffective treatment regimen.

Antimicrobial Resistance In this section, we will review the prevalence and trends of the antimicrobial resistance and its mechanisms. Only recent data published since a previous published review in 2004 will be considered.77

Specific Features of H pylori Antimicrobial Resistance Genetic support of resistance. Given that prokaryotes replicate by duplication, mechanisms are necessary to generate genetic diversity, which is imperative for their evolution. There are 2 main possibilities: mutation and gene acquisition. Gene acquisition via different mechanisms, ie, transformation, transduction, and conjugation, is very common among bacteria and is responsible for most antimicrobial resistance. This is not the case for H pylori, which develops antimicrobial resistance largely as a consequence of mutations. The same is true for another well-known bacterium: Mycobacterium tuberculosis.

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There is a general agreement that during the process of DNA replication, errors can occur spontaneously, ie, one nucleotide can be replaced by another. If this point mutation does not have a consequence on bacterial fitness, it will remain in the bacterial genome and will be transmitted to the descendents. A low proportion of the bacterial population will therefore harbor the mutation. If the bacterial population is then exposed to an antibiotic for which the mutation induces resistance (for example, by preventing binding of the antibiotic to its target), bacteria that do not possess the mutation will be progressively eliminated, whereas those that have the mutation will be selected by the antibiotic. Eventually, we will be left with a bacterial population totally resistant to the antibiotic instead of the mixed population of sensitive and resistant bacteria. This mechanism concerns all of the antibiotics to which acquired resistance occurs in H pylori (Table 4).

At this stage, furazolidone seems to be the only antibiotic to which the bacterium has not developed a resistance; only a decrease in susceptibility has been described.79 Although it is not possible to detect small numbers of mutant organisms in a bacterial population, indirect data favor their presence. For example, when H pylori strains were exposed in vitro to subinhibitory concentrations of clarithromcyin, the number of subcultures required to obtain an 8- to 32-fold increase in minimum inhibitory concentrations (MIC) was significantly lower if the susceptible strain originated from a patient with treatment failure rather than a patient with treatment success.80 In vivo, the process of selection is most likely favored by the presence of a subinhibitory concentration of the antibiotic in the mucosa as is the case in vitro. This situation can occur when a patient is not compliant and forgets to take his/her drugs as prescribed. Recently, the role of intracellular bacteria has been put forward. Pretreatment isolates of H pylori from the failure group of a clinical trial had a higher ability to penetrate intracellulary than those from the group that were successfully cured, and resistance to clarithromycin and metronidazole was significantly associated with this property compared with susceptible isolates.81 These 2 potential causes of treatment failure are the result of selection of resistant mutants.

Acquisition of genes by horizontal transfer is also possible but does not seem to play an important role in H pylori, perhaps because this bacterium is most likely alone in its special ecologic niche. Transformation can occur because H pylori is naturally competent for exogenous DNA uptake and recombination.82,83 However, interstrain diversity of restriction modification systems constitutes a barrier for DNA fragment transfer including plasmids and bacteriophages.84 Biochemical mechanism of resistance. The genetic support of resistance observed in H pylori restricts the possible biochemical mechanisms of the resistance.

For example, the production of an enzyme that degrades

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Table 4. Genes Involved by Point Mutation or Other Genetic Events Leading to Antibiotic Resistance in Helicobacter pylori Antibiotics

Genes concerned

Macrolides Metronidazole Fluoroquinolones Rifampins Amoxicillin Tetracycline

rrn 23S rdxA, frxA gyrA rpoB pbp1 rrn 16S

the antibiotic, eg, a ␤-lactamase, is not found in wild strains. The resistance mechanism is a modification of the antibiotic target to which the drug no longer binds.

Another potential resistance mechanism is the development of drug efflux proteins but, in contrast to what is usually described for gram-negative bacteria, it was shown that efflux systems do not play a role in the intrinsic resistance of H pylori to antibiotics or in acquired resistance to amoxicillin.85,86 A putative tetracycline gene HP1165, which displays a 50% identity with the tetracycline efflux gene tetA from Clostridium perfringens, may be involved in the inducible tetracycline resistance of some strains.87 The importance of several nonspecific multidrug resistance proteins described needs further clarification.88 Antibiotics affected by acquired resistance. Macrolides. Because the resistance mechanism is the same for

the different compounds in this class of antibiotics, cross-resistance is observed. There are 2 adjacent adenines located in special positions on the 23S ribosomal RNA peptidyl transferase loop, which are concerned and can be substituted by a guanine (A2142G, A2143G) or a cytosine (A2142C) leading to a conformational change in the ribosome and a lack of binding of the antibiotic, avoiding the interruption of protein synthesis. The few mutational events involved allow an effective detection by molecular methods.

Amoxicillin. Amoxicillin acts by interfering with the peptidoglycan synthesis, especially by blocking transporters named penicillin-binding proteins (PBP). The rare amoxicillin-resistant H pylori strains harbor mutations on the pbp-1a gene. A mutation Ser 414 ¡ Arg was found in the first resistant strain described.89 Following analysis of further resistant strains, it appears that various mutational changes located in or adjacent to the second and third PBP motifs of PBP-1A could be involved.90 In a recent study on an in vitro selected amoxicillin-resistant strain, amino acid substitution in the outer membrane proteins, HopB and HopC, also seemed to contribute to resistance.91 Tolerance to amoxicillin has also been described and was associated to the lack of another PBP: PBP-D.92 Given the diversity of mutations by which resistance can develop, it is unlikely that a simple molecular method can be used to detect resistance.

Tetracyclines. Tetracyclines interfere with protein synthesis at the ribosome level by binding to the 30S subunit. If a mutation in a nucleotide triplet develops (positions 926, 927, 928), there is lack of binding to the h1 loop, the binding site for tetracyclines. When the substitution involves the 3 nucleotides together (AGA 926 to 928 TTC), the corresponding MIC is high; if only single or dual mutations are present, intermediate MICs are observed. As previously mentioned, an efflux mechanism seems to be the mechanism involved in the absence of mutations.93 Rifampins. Rifampins inhibit the ␤ subunit of the DNA-dependent RNA polymerase encoded by the rpoB gene. Point mutations occur in the rpoB gene at codons 524, 525, and 585 as in other bacteria.94 In a recent study, 13 H pylori isolates resistant to both rifampicin and rifabutin harbored these mutations. Four other isolates, moderately resistant to rifampicin but not to rifabutin, did not have the mutations.95 Silent mutations, ie, mutations without impact on the resistance, are also common.

Fluoroquinolones. Fluoroquinolones inhibit the A subunit of the DNA gyrase, encoded by the gyrA gene.

Mutations occur in the quinolone resistance determining region as for other bacteria. Amino acid positions 87 and 91 are mainly concerned, but a mutation in position 86 has also been described.96 –99 There is cross-resistance between the different fluoroquinolones. For susceptible strains, levofloxacin and moxifloxacin lead to the best clinical results.

Nitroimidazoles. 5-Nitroimidazoles are prodrugs that have to be reduced in the cell to be detrimental to bacterial DNA. The main gene involved in this process is rdxA, an oxygen-insensitive nitroreductase. Frameshift mutations in rdxA have been associated with metronidazole resistance.100 The possibility that frameshift mutations occur in other genes, such as frxA, coding for a flavin oxidoreductase, has been proposed but is more controversial.101–103 By using saturation transposon mutagenesis, inactivation of rdxA was solely able to confer metronidazole resistance.104 Among the related compounds, furazolidone is active against metronidazole resistant isolates, indicating that the mechanism of action is different.

Detection methods. As for any bacterium, antimicrobial susceptibility testing of H pylori can be performed by phenotypic methods, eg, disk diffusion (standard antibiogram), Etest (a quantitative variant of disk diffusion), agar or broth dilution method, or break-point testing.105 These methods have the advantage of evaluating all of the drugs at the same time, and, for most of them, an exact MIC can be determined for each isolate.

The agar dilution method has been proposed by the Clinical Laboratory Standard Institute (CLSI), formerly the National Committee for Clinical Laboratory Standards (NCCLS), as the method to be used for H pylori

September 2007

clarithromycin susceptibility testing. For the other antibiotics, no official recommendation exists, but the methods cited can also be used. For metronidazole alone, the lack of reproducibility of antimicrobial testing and the poor correlation with clinical results makes testing less useful in the clinical setting. The Maastricht III Consensus Report does not recommend routine metronidazole susceptibility testing.2 Phenotyipc methods require a delay of several days to obtain a result, and they are time-consuming to carry out and expensive. For these reasons, and because resistance is due to a limited number of mutations, molecular methods have been proposed.

Because clarithromycin is the most clinically relevant antibiotic and few mutations are concerned, numerous genotypic methods have been developed to detect this resistance as indicated in Table 5. The most promising technique is probably the real-time PCR based on 23S ribosomal DNA specific sequence detection using a biprobe and the fluorescence-resonance energy transfer principle. It allows, first, the specific detection of H pylori in a specimen and, second, after melting curve analysis of the amplicons, the detection of possible mutations. A nucleotide mismatch between the isolate sequence and the hybridization probe leads to a difference in the melting peak.

This method represents an important step forward in the diagnosis of H pylori because the result can be obtained within 2 hours and there is a limited risk of contamination with the amplicons given that the reaction is performed in a closed tube. In addition to gastric biopsy specimens, this method can also be applied to stools, which is a real breakthrough in diagnosis because it leads to a susceptibility result without performing an endoscopy.106 Another interesting method that does not require amplification and can be performed on histologic slides is fluorescence in situ hybridization using a set of fluorescent labeled oligonucleotide probes.107 Although not as common, molecular methods for detecting resistance to antibiotics other than clarithromycin have been proposed: PCR-restriction fragment length polymorphism for tetracycline resistance and real-time fluorescence resonance energy transfer (FRET)-PCR with melting curve analysis for fluoroquinolones and tetracyclines.108 –110 Research is still going on to find a suitable molecular method for detecting metronidazole resistance; possibilities include either the use of microarrays or optimization of the detection of the RdxA protein by immunoblotting as previously described.111,112

Prevalence of H pylori Antimicrobial Resistance A large number of studies have been published regarding the prevalence of H pylori antimicrobial resistance. Because resistance is an evolving process, only

ERADICATION THERAPY FOR HELICOBACTER PYLORI 995

Table 5. Genotypic Methods Used to Detect Macrolide Resistance in Helicobacter pylori Using 23S rDNA amplification Sequencing, pyrosequencing Restriction fragment length polymorphism Oligonucleotide ligation assay DNA enzyme immunoassay Line probe assay Preferential homoduplex formation assay 3= Mismatched PCR 3= Mismatched reverse PCR Real-time PCR Microelectronic chip array Electrocatalytic detection PCR-based denaturating HPLC assay Without using 23S rDNA amplification Fluorescence in situ hybridization HPLC, high-performance liquid chromatography.

the most recent studies (for the most part since the year 2000) will be presented. The majority of these studies were cross-sectional and may have inclusion biases. The most relevant study design is a populationbased study, such as the one performed in Sweden: 3000 subjects were randomly selected to fill out a questionnaire, one third of the responders (74%) were invited for an endoscopy, and, finally, isolates of 333 subjects were obtained and tested for antimicrobial susceptibility by agar dilution.113 Another possible design is to request selected endoscopists to send biopsy specimens from their patients on one or several randomly chosen days during the year. Using this method, 545 isolates were obtained in France a few years ago.114 Using data obtained at inclusion in clinical trials aimed at eradicating H pylori was also an accurate way of obtaining data in the 1990s.115 However, most of the studies reported the results of successive patients consulting in specialized centers. A summary of recently published articles is presented in Table 6.

Clarithromycin and metronidazole. Primary resistance. Adults: An H pylori antimicrobial resistance moni-

toring program was established in the United States for H pylori. The data from 1999 to 2002 have been analyzed.

The resulting prevalence is in the range of data obtained in the past, ie, 10%–12% for clarithromycin and 25.1% for metronidazole.116 The situation is quite different in the state of Alaska where clarithromycin resistance accounted for 31% and metronidazole resistance for 44% of isolates from natives undergoing upper endoscopy, during the period 1999-2003.117 Data gathered in Europe are in line with those reported from the large prospective multicenter study carried out in 1998 in 17 countries.118 Countries from Northern Europe (Denmark, Finland, Sweden, The Netherlands) have a low prevalence of resistance to clarithromycin (1%–3%),113,119 –121 Bulgaria in Central Europe has a moderate prevalence (12.6%),122 and Italy in Southern Europe has a rate that exceeds 20%.123

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Table 6. Resistance of Helicobacter pylori to Clarithromycin, Metronidazole, Tetracycline, and Amoxicillin in Different Parts of the World Prevalence

Country Primary resistance Adults North America United States (global) United States (Alaska) Europe Bulgaria Denmark Finland Italy The Netherlands Sweden United Kingdom (Wales) Middle East Iran Kuwait Asia Bangladesh Hong Kong Africa Kenya Children Europe Bulgaria Portugal Secondary resistance Europe Bulgaria Israel Korea

No. of strains tested

Clari

Metro

Tet

Amox

Year

Type of study

1999–2002

Multi-C

Agar dilution

347

12.9

25.1

ND

0.9

119

1999–2003

Multi C

Agar dilution

352

31

44

0

2

120

1996–2004 2001–2003 2000–2002 2004–2005 1997–2002 1998–2001 2000–2003

Mono C Mono C Multi C Multi C Mono C Multi C Mono C

Agar dilution Disk dffusion Etest Real-time PCR Disk diffusion Agar dilution Etest

786 ⬎400 292 178 1127 333 363

12.6 3 2 21.3 1 1.5 7

25.6 27 38 ND 14.4 16.2 24

5.2 ND ND ND ND 0.3 0.3

0.8 ND ND ND ND 0 0

125 122 123 126 124 116

2001–2002 2003–2005

Mono C Mono C

Disk diffusion Etest

120 96

16.7 0

57.5 67

0 0

1.6 0

127 128

1999–2001 2003–2004

Mono C Mono C

Agar dilution Etest

120 102

10 7.8

77.5 39.2

15 ND

6.6 0

140

2003–2004

Mono C

Agar dilution

268

6.4

1.9

4.6

129

1999–2002 1996–2004 1999–2003

Multi C Mono C Mono C

Etest Agar dilution Etest

1037 282 94

20 12.5 35

23 15 13.8

ND 3.4 0

0.6 1.5 0

130 125 131

1999–2002 1996–2004

Multi C Mono C

Etest Agar dilution

42 36

35 81.6

ND ND

ND 1.6

130 125

2002–2005 2004–2005

Mono C Mono C

Etest Agar dilution

Children Adults Children Adults Adults

65.7 85.1

57.1 70.1

0 ND

0 31.3

Method of testing

196 109 28 70 324

100

Reference

a

b

c d

NOTE. Studies including more than 90 patients for primary. aElviss NC, Owen RJ, Xerry J, Walker AM, Davies K. Helicobacter pylori antibiotic resistance patterns and genotypes in adult dyspeptic patients from a regional population in North Wales. J Antimicrob Chemother 2004;54:435– 440. bGu Q, Xia HH, Wang JD, Wong WM, Chan AO, Lai KC, Chan CK, Yuen MF, Fung FM, Wong KW, Lam SK, Wong BC. Update on clarithromycin resistance in Helicobacter pylori in Hong Kong and its effect on clarithromycin-based triple therapy. Digestion 2006;73:101–106. cYahav J, Shumely H, Niv Y, Bechor J, Samra Z. In vitro activity of levofloxacin against Helicobacter pylori isolates from patients after treatment failure. Diagn Microbiol Infect Dis 2006;55:81– 83. dKim JM, Kim JS, Kim N, Kim SG, Jung HC, Song IS. Comparison of primary and secondary antimicrobial minimum inhibitory concentrations for Helicobacter pylori isolated from Korean patients. Int J Antimicrob Agents 2006;28:6 –13.

In the Middle East, data are available from Iran: the prevalence of clarithromycin resistance was 16.7% and metronidazole resistance 57.5%.124 The same high rate of metronidazole resistance was found in Kuwait, but, surprisingly, no clarithromycin resistance could be detected.125 For the first time, prevalence data from Africa are available. In a study carried out in Nairobi, Kenya, in 2003-2004, the prevalence of clarithromycin resistance was 6.4%, and all strains were resistant to metronida-

zole.126 Children: A large study was performed in children in 17 pediatric centers from 14 European countries. A total of 1037 patients had their H pylori strains tested; 40% originated from outside Europe. Clarithromycin resistance was detected in 20% and metronidazole resistance in 23%. Resistance to both antibiotics occurred in 6.9%.127 The prevalence in children in Bulgaria was lower for both antibiotics, whereas a very high clarithromycin resistance was observed in Portugal.128

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Secondary resistance. When antimicrobial resistance is tested after treatment failure, the rate of resistance is much higher (Table 6).

Risk factors. There is a trend toward a steady increase in clarithromycin resistance over the years. In Italy, for example, the rate doubled between 1989-1990 (10.2%) and 2004-2005 (21.3%).123 In Japan, it increased from nil in 1989-1990 to 20% in 1999-2000129 and, in Korea, from 2.8% in 1994 to 13.8% in 2003.130 This is due to an increased selection pressure because of the use of clarithromycin, and possibly other macrolides such as erythromycin, for infections other than H pylori. A positive correlation was found between long-term therapy for chronic respiratory infection and the prevalence of H pylori resistance to clarithromycin.131 Only countries with a strict policy on the prescription of antibiotics such as The Netherlands have experienced a trend toward a decreased prevalence of clarithromycin resistance.121 In the United States, a multivariate analysis revealed that black race was the only significant risk factor for clarithromycin resistance.116 In several studies carried out in Europe, an association between clarithromycin resistance and nonulcer dyspepsia has been reported75; however, there does not appear to be an association with the pathogenic factors CagA and VacA.132 In children, clarithromycin resistance was higher in children younger than 6 years of age compared with those older than 12 years of age.127 Concerning 5 nitroimidazoles, the selection pressure is higher in tropical countries, because of treatment directed at parasites, than in countries in temperate areas in which these drugs are only used for gynecologic and dental infections. The gynecologic treatments explain why resistance prevalence is higher in females.

Fluoroquinolones. Among fluoroquinolones, levofloxacin has recently become a good second or third choice treatment in case of eradication failure in adults. However, this antibiotic is increasingly used for other infections, and, consequently, the prevalence of primary resistance is already high: 8.8% in Alaska,133 15% in Japan,134 16.8% in Belgium,98 and 17.2% in France.99 A positive association between fluoroquinolone consumption and H pylori resistance has been demonstrated in Alaska.133 Because fluoroquinolones are seldom used in children and adolescents, the prevalence of resistance is lower: 5.3% in Portugal128 and 5.5% in Japan.135 After failure of a treatment with fluoroquinolones, high resistance rates have been observed.136 Amoxicillin and tetracycline. The prevalence of the resistance to these 2 antibiotics has fortunately remained low. In most studies, it is less than 2%, with the exception of Kenya (4.6%)126 and Bangladesh (6.6%) for amoxicillin137 and of Bulgaria (5.2%) for tetracycline.122 Rifampins. Very few surveys have included detection of rifampin resistance. When it was tested, resistance was rarely found (1.4% in Germany).95

ERADICATION THERAPY FOR HELICOBACTER PYLORI 997

Conclusion In this review, we have summarized the state of the art in the treatment of H pylori and highlighted the problem of resistance that is a major cause of treatment failure. Poorly designed trials with small sample sizes and wide confidence intervals continue to be published, and misconceptions regarding treatment continue to plague the literature. A recent review in a prominent family practice journal illustrates this problem. It recommends several ineffective and unproven therapies including 1-day and 5-day treatments that have not been proven to be effective in large wellcontrolled trials.138 Rational treatment should be based on scientific evidence from well-designed trials of high quality.

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Received May 17, 2007. Accepted July 9, 2007.

Address requests for reprints to: Nimish Vakil, MD, Aurora-Sinai Medical Center, 945 North 12th Street, Room 4040, Milwaukee, Wisconsin 53233. e-mail: nvakil@wisc.edu; fax: (414) 219-7108.

Supported by Astra-Zeneca, Novartis, Altana, and TAP. Potential conflict of interest for N. Vakil: consultant for Astra-Zeneca, Orexo, Novartis, TAP, Proctor and Gamble, Altana, and Malesci and on the speaker’s bureau for Astra-Zeneca.