Management of Helicobacter pylori Infection

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GASTROENTEROLOGY 2007;133:985–1001

EVIEWS IN BASIC AND CLINICALASTROENTEROLOGY

Wafik El-Diery and David Metz, Section EditorsTimothy C. Wang, Guest Section Editor

radication Therapy for Helicobacter pylori

IMISH VAKIL*,‡ and FRANCIS MEGRAUD§,�

‡
Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, and Marquette University College of Health Sciences, Milwaukee,isconsin, §INSERM U853, Bordeaux, and the �University Victor Segalen Bordeaux 2, Laboratoire de Bactériologie, Bordeaux, France
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radication therapy for Helicobacter pylori is recommendedn a number of clinical conditions. In this article, we dis-uss the epidemiology and cellular mechanisms that resultn antimicrobial resistance, the results of current eradica-ion therapies, and new approaches to the management ofelicobacter pylori infection.

elicobacter pylori is an organism that has had anintimate association with mankind for many gen-

rations. Recent studies suggest that H pylori may havepread from east Africa with human migration approxi-

ately 58,000 years ago.1 The discovery of H pylori byarren and Marshall and the development of effective

reatment for this infection has resulted in a remarkablehange in the management of upper gastrointestinal dis-rders with curative antibiotic therapy becoming avail-ble for low-grade gastric mucosa-associated lymphoidissue lymphomas and H pylori-related peptic ulcers.reatment regimens for H pylori that have been used over

he past decade are declining in efficacy, and the treat-ent of H pylori infection is bedeviled by drug-resistant

trains of H pylori. In this article, we discuss the clinicalnd basic issues involved in H pylori eradication, theechanism of antibiotic delivery to the mucus layer of

he stomach, the primary and secondary treatment strat-gies, the causes of treatment failure, and the mecha-isms for the development of antimicrobial resistance.

H pylori is a member of a group of bacteria adapted to lifen the mucus of the digestive tract of vertebrates. Its specificharacteristics include its morphology (spiral shaped, flag-llated) and metabolism (microaerobic, asaccharolytic). Gas-ric Helicobacters have probably evolved from a gut bacte-ial ancestor when the stomach appeared in vertebrates, and

pylori is the Helicobacter specific to humans.

Indications for the Treatment of Hpylori InfectionIndications for H pylori eradication that were de-

eloped by an international consensus of experts (Maas-

richt III Consensus Report) are listed in Table 1.2 Cur-ent US guidelines recommend testing and treatment for

pylori in patients with uninvestigated dyspepsia inreas in which the prevalence of H pylori is greater than0%.3,4 The Maastricht Consensus Group recognized the

inks between gastric cancer and H pylori and recom-ended further work in the area.2 Because of problemsith antimicrobial resistance with current therapies and

he lack of an effective vaccine, mass treatment strategiesave not been implemented. North American practitio-ers should be aware that immigrants from parts ofentral and South America (Costa Rica, Brazil) and thear East (China, Japan, Korea, and Taiwan) are at highisk for gastric cancer, and obtaining a family history isarticularly important in people from this part of theorld.

Delivery of Antibiotics to H pyloriMost antibiotics are formulated for delivery to the

mall bowel to facilitate their absorption and conse-uently their blood-borne effects. The success of antimi-robial therapy for H pylori depends to a large extent onntimicrobial concentrations in the stomach. The prin-iples of antimicrobial delivery to H pylori are importantn understanding the rationale for various antimicrobialombinations that are used in clinical practice. They arellustrated in Figure 1.

Ingestion of AntibioticsIngestion of antibiotics by patients is influenced

y drug adverse effects and regimen complexity. Nauseand vomiting can limit drug ingestion (Figure 1). Regi-ens that require medications to be taken 4 times a day

quadruple therapy) are more likely to have adherence-elated problems than twice-daily therapies.5 There isimited information on the effect of drug formulation on

© 2007 by the AGA Institute0016-5085/07/$32.00

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986 VAKIL AND MEGRAUD GASTROENTEROLOGY Vol. 133, No. 3

reatment efficacy, but studies with amoxicillin suggesthat the liquid preparation has better delivery to all partsf the stomach than capsules.

Luminal FactorsAntibiotics have varying stability at acid pH. Met-

onidazole is very stable in gastric juice at a pH of 2 andpH of 7, with a half-life of over 800 hours. Amoxicillin

s unstable at low pH, but its half-life is still 15 hours atpH of 2. In contrast, clarithromycin is particularly

ensitive to degradation with acid and has a half-life ofess than 1 hour at a pH of 2.6,7 The use of proton pumpnhibitors (PPI) in antimicrobial regimens that containlarithromycin is particularly important in preventingegradation of clarithromycin by acid (Figure 1).

Gastric PhysiologyThe gastric mucus layer acts as a barrier limit-

ng the delivery of antibiotics to H pylori. In animalxperiments, pronase, which digests gastric mucus, in-reases delivery of amoxicillin.8 There is little informa-ion on interventions to change the quality or thick-ess of the mucus layer in the treatment of H pylori

nfection. PPIs may also decrease the viscosity of gas-ric mucus, increasing the delivery of all antibiotics.ccluding the duodenum with a balloon to increase

ontact time of antibiotics with the gastric mucosa haseen attempted in a small study and resulted in a rapidure of H pylori infection.9

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

hey dissolve in the lipids of the cell membrane, and,hen, passive transfer occurs by a concentration gradi-nt.6 Drug ionization also plays a role. Unionized drugsross membranes easily, whereas more polar molecules

able 1. Indications for Helicobacter pylori Eradication

uodenal ulcerastric ulcertrophic gastritisastric MALT lymphomaonulcer dyspepsianinvestigated dyspepsia (in areas with a prevalence �10%)ollowing resection of a gastric cancerirst-degree relatives of patients with gastric cancernexplained iron-deficiency anemia

diopathic thrombocytopenic purpuraefore commencing NSAID therapy in NSAID-naïve patientsatients receiving long-term aspirin therapy who developgastrointestinal bleeding

atient request (after a discussion of risks and benefits)

OTE. Information in Table taken from Malfertheiner et al.2

ALT, mucosa-associated lymphoid tissue; NSAID, nonsteroidal an-iinflammatory drugs.

ross with difficulty. Metronidazole is predominantly F

nionized in plasma and therefore crosses the gastricucosa easily into gastric juice with gastric acid secre-

ion.6 Omeprazole decreases intragastric concentrationsf metronidazole by reducing acid secretion but increasesoncentrations of all agents by decreasing gastric vol-me.10 Some studies have shown that acid inhibitors,uch as omeprazole, increase the concentration of clar-thromycin in gastric tissue, but other studies haveot.11,12

Treatment Strategies for H pyloriOverviewThe treatment of H pylori infection has not

hanged significantly in the last decade, although prom-sing alternatives have recently been suggested. At theresent time, the treatment regimen recommended fororldwide use is triple therapy with PPI, amoxicillin, and

larithromycin.2 Dissatisfaction with this regimen isrowing in most developed countries, and a new initialherapeutic strategy is needed. The alternatives to tripleherapy include quadruple therapy, sequential therapy,nd triple therapy using new antimicrobials such as levo-oxacin, rifabutin, and furazolidone. Each of these isiscussed in more detail below, and a strategy is sug-ested for management.

Initial Management StrategiesPPI triple therapy. A PPI combined with amoxi-

illin and clarithromycin is the most widely used form ofherapy in the Western world. In areas where clarithro-

ycin resistance rates are high, metronidazole may beubstituted for clarithromycin. Eradication rates withriple therapy have been falling with rising resistanceates to commonly used antimicrobials, and a recentonsensus group considered alternatives to triple therapy

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

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September 2007 ERADICATION THERAPY FOR HELICOBACTER PYLORI 987

ut eventually concluded that PPI-based triple therapyas still the initial treatment of choice.2 Figure 2 shows

he rate of eradication with triple therapy in large, con-rolled trials in the United States.13–18 Note that theonfidence intervals for eradication with 7-day tripleherapy in the most recent trials have been as low as7%–73% (Figure 2, Bochenek et al17) and 67%–79% (Fig-re 2, Vakil et al18) for 10-day triple therapy. When an

ndividual patient is treated in clinical practice, the erad-cation rate may be anywhere within this range. Theuration of the triple therapy regimen has been theubject of debate. Early studies of 7-day therapy in thenited States suggested that the results were poorer than

n Europe, but these studies had low power and wideonfidence intervals making accurate predictions impos-ible.19 A head-to-head comparison of 7-day and 10-dayherapy in the United States found numerical differencesavoring 10-day therapy, but the comparisons betweenhe groups met prespecified US Food and Drug Admin-stration criteria for equivalence.18 A recent Europeantudy found no difference between 1 week and 2 weeks ofPI triple therapy.20 A review of controlled trials sug-ested that 14 days of treatment with triple therapy wasuperior to 7-day therapy (difference, 12%; 95% CI: 7%–7%).21 At this point, it seems prudent to use at least 10ays of treatment in the United States.

Bismuth-based triple/quadruple therapy. Bis-uth triple (bismuth � metronidazole � tetracycline

dministered for 14 days) and quadruple (bismuth �etronidazole � tetracycline � PPI administered for

–10 days) therapies are effective treatment strategies inreas in which metronidazole resistance is low, clarithro-ycin resistance is high, and cost considerations are

aramount. Bismuth triple therapy administered for 14ays has been available for over a decade but has had

imited success with physicians and patients in thenited States or in other Western countries. The princi-

igure 2. Eradication rates in largeS trials of PPI triple therapy. E,someprazole; A, amoxicillin; C,larithromycin; O, omeprazole; B,ismuth; M, metronidazole; T, tetra-ycline; L, lansoprazole; P, panto-razole; R, rabeprazole. Usual doses:PI, twice a day; clarithromycin, 500g twice a day; amoxicillin, 1 g twiceday. Esomeprazole was studied insingle daily dose. *Mean of 2

tudies.

al problem with this regimen is the large number of c

ablets/capsules that need to be taken and the durationf therapy and its complexity. To improve adherence,onvenience packs that contain all the medications on alasticized sheet have been developed. The major advan-age of the bismuth triple therapy regimen is that it isnexpensive and can be used in regions of the world inhich cost is the major consideration. Another advantage

s that this regimen remains effective in areas in whichlarithromycin resistance is high. A large, randomized,ontrolled trial evaluated bismuth triple therapy admin-stered for 14 days and compared it with 7-day PPI tripleherapy (PPI � amoxicillin � clarithromycin) and 7-dayuadruple therapy (bismuth � metronidazole � tetracy-line � PPI).22 Eradication rates were similar with PPIriple therapy (78%) and quadruple therapy (82%), andoth were significantly better than 14-day bismuth tripleherapy (69%). Nonadherence with therapy (15%) wasignificantly greater with bismuth triple therapy admin-stered for 14 days, and moderate-severe adverse eventsere very common (45%). Quadruple therapy adminis-

ered for 7–10 days (the duration should depend onocation and local experience) is therefore preferable toismuth triple therapy administered for 14 days. In an-ther randomized, controlled trial in Spain, 7-day PPIriple therapy was similar to quadruple therapy in theradication of H pylori.23 The dose of bismuth should beased on the preparation used. In the United States, theost frequently used preparation is bismuth subsalicy-

ate (150 mg bismuth per tablet), which is administeredn a dose of 2 tablets 4 times a day along with tetracycline00 mg and metronidazole 250 mg also administered 4imes a day. The patient should be instructed to chew theismuth tablets before swallowing but to swallow theetronidazole and tetracycline without chewing.A relatively new development with quadruple therapy

as been the development of a single capsule preparationf bismuth biskalcitrate with metronidazole and tetracy-
line. Although it reduces the number of pills that need

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o be taken, 3 tablets still need to be taken 4 times a daynd a PPI needs to be taken separately twice a day.esults have been promising, with an eradication rate of3% by intent-to-treat analysis in Europe and 87.7% inhe United States for 10-day therapy.14,24 In the US trial,he results were comparable with 10-day PPI triple ther-py. The treatment remained effective despite the highbserved resistance rate for metronidazole in the Unitedtates (40%), although the absolute number of patientsith resistance was small (n � 51). A meta-analysis eval-ated quadruple therapies and found that there was noignificant difference between PPI triple therapy and qua-ruple therapy when clarithromycin resistance rates were

ess than 15%.25 In patients with clarithromycin resis-ance however, quadruple therapy was significantly betterhan triple therapy. Bismuth-based quadruple therapy for0 days is therefore a suitable salvage therapy of patientsho have failed clarithromycin-based triple therapy.Whether quadruple therapy should replace PPI triple

herapy as the initial treatment of choice is a matter ofebate. A recent meta-analysis found only 4 studies ofufficient quality to allow comparisons and no statisti-ally significant difference between PPI triple therapy anduadruple therapy.26 At the recent Maastricht Interna-ional Consensus Conference of experts on H pylori, aroposal that PPI triple therapy be replaced with quadru-le therapy was made but failed to generate sufficientupport.2 Quadruple therapy is listed as an alternativerst-line therapy to PPI triple therapy and should defi-itely be considered when a clarithromycin-based tripleherapy regimen has failed or in areas in which clarithro-

ycin resistance is particularly high. Another bismuthreparation, ranitidine bismuth citrate, is no longer avail-ble in the United States but has been shown to beffective in H pylori eradication in combination withlarithromycin and amoxicillin in a meta-analysis.27 It is

reasonable alternative in areas in which it remainsvailable.

The penicillin allergic patient. Bismuth quadru-le therapy is a reasonable alternative to standard PPIriple therapy when penicillin allergy is present. In re-ions in which ranitidine bismuth citrate is available, aombination of ranitidine bismuth citrate with tetracy-line and metronidazole has been used.28 A combinationf a PPI with metronidazole and clarithromycin has alsoeen used but has a lower eradication rate (77%).17

Sequential therapy for H pylori eradication. Se-uential therapy is a major new innovation in the treat-ent of H pylori. The sequential regimen is a 10-day

reatment consisting of a PPI and amoxycillin 1 g (bothwice daily) administered for the first 5 days followed byriple therapy consisting of a PPI, clarithromycin 500 mg,nd tinidazole 500 mg (all twice daily) for the remainingdays. The idea was born of earlier observations madehen 2-drug therapies (PPI � amoxicillin) were in use. It
as observed that the eradication rate achieved with a s
herapeutic strategy of initially administering 14-dayual therapy (PPI � amoxicillin) followed by 7-day tripleherapy in individuals who failed the original therapy wasignificantly better than the reverse sequence (7-day tripleherapy as an initial strategy with 14-day dual therapy forailures).29 A series of studies performed in Italy havehown excellent results with sequential therapy, and, ifhese results are confirmed in other parts of the world, its likely that we may be looking at eradication therapy in

new light, considering sequences of medications ratherhan complex regimens of individual drugs. Six pub-ished Italian trials that each involve more than 100atients are presented in Table 2.30 –35 The eradicationate was uniformly above 90% (Table 2). A recent Spanishtudy, still in preliminary form, provides evidence fromnother country of the merit of this regimen.36 Therecise mechanism for the success of the sequential ther-py is not known. One possibility is that decreasing theacterial density in the stomach with a drug such asmoxicillin (to which resistance is rare) improves thefficacy of the subsequently administered combination oflarithromycin and tinidazole. It is known that bacteriaan develop efflux channels for clarithromycin, whichapidly transfer the drug out of the bacterial cell, pre-enting binding of the antibiotic to the ribosome.37 Be-ause amoxicillin acts on the bacterial cell wall and weak-ns it, the initial phase of treatment may prevent theevelopment of efflux channels by weakening the cellall of the bacterium.A recent head-to-head comparison of sequential ther-

py with conventional triple therapy found that 10-dayequential therapy had a significantly higher eradicationate (91% by modified intent-to-treat analysis) comparedith 10-day triple therapy (78% by modified intent-to-

reat analysis).35 Of particular note was the success ofequential therapy in patients with clarithromycin-resis-ant strains. The eradication rate in patients with clar-thromycin-resistant strains of H pylori was 89% withequential therapy and 29% with standard triple ther-py.35 Although sequential therapy is currently consid-red a second-line therapy, confirmation of its efficacy inther countries should lead to serious consideration that

t be adopted as initial therapy.

When Eradication Therapy FailsOverviewWhen treatment fails, antimicrobial resistance

nd nonadherence are leading causes. In a recent multi-enter US trial, clarithromycin resistance was noted inne third of cases failing therapy.18 Although this high-

ights the importance of resistance, it also demonstrateshe role of other factors such as adherence (in the re-

aining two thirds) in treatment failure. Antimicrobialusceptibility testing would therefore be a logical first
tep in treatment failures. Unfortunately, antimicrobial

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usceptibility testing is still not widely available in thenited States and other countries, and most communityospitals do not perform culture and antimicrobial sus-eptibility testing of H pylori. If available, antimicrobialusceptibility testing should be performed and a treat-

ent regimen based on the susceptibility of the organ-sm. The availability of new kits that can perform sus-eptibility testing, such as by real-time polymerase chaineaction (PCR) in stool, will likely make matters easier inhe future.

For practitioners, a simple empirical management al-orithm is necessary that allows treatment to be modifiedccording to the treatment regimens the patient haseceived.38 If a patient has received a clarithromycin-ontaining regimen, this drug should generally bevoided in a secondary treatment, with the possible ex-eption of sequential therapy, which has proven quiteffective despite the presence of clarithromycin resis-ance.35 If patients have failed both clarithromycin- and

etronidazole-containing regimens, one of the salvageherapies should be chosen. Amoxicillin continues to besed in most treatment regimens because the emergencef resistance to amoxicillin is uncommon and the prev-lence of resistant strains is very low. Although antimi-robial sensitivity testing may help in the selection of aecond-line treatment for H pylori, controlled trials haveuggested that it may not always be essential for clinical

anagement. In a controlled trial of eradication therapyn patients in whom primary therapy had failed, Lamou-iatte et al reported that, when PPI-based triple therapyailed, approximately equal eradication rates could bebtained with empirical use of omeprazole, amoxicillin,nd metronidazole as with antimicrobial susceptibilityriven choice of therapy.39 This study was performed inrance where bismuth is not available, and, therefore,uadruple bismuth therapy was not an option. In thenited States, a quadruple therapy regimen with a PPI,ismuth, tetracycline, and metronidazole for 10 daysould be preferred.For the patient with failed eradication, 4 possible

hoices are available (Figure 3): (1) Antimicrobial sensi-ivity testing and tailored therapy. (2) Quadruple therapy:his treatment strategy has the advantage of proven

able 2. Sequential Therapy: Trials With More Than 100Patients Given Sequential Therapy

Author(reference) Year

No. ofcenters

Patientsenrolled

Eradicationrate (%) 95% CI

ullo et al30 2003 8 522 92 89.8–93.7assan et al31 2003 1 152 93.4 89.3–96ocareta et al32 2003 1 174 95.4 92–97.4e Francesco33 2004 1 162 93.2 89.2–95.8e Francesco34 2004 2 116 94.8 90.3–97.3aira et al35 2007 2 146 91.1 86.4–94.3

fficacy in larger trials and is described in detail above. (3) t

equential therapy: The impressive results in patientsith clarithromycin resistant strains need confirmation

n other countries. This may be a reasonable alternativen the future. (4) Salvage therapies: Triple therapies com-ining a PPI with amoxicillin and either levofloxacin,ifabutin, or furazolidone are discussed below.

Salvage Regimens Containing Levofloxacin,Rifabutin, and FurazolidoneThree regimens (containing either rifabutin, levo-

oxacin, or furazolidone) have had success in eradications a second- or third-line therapy in European and Asianrials. Two recent meta-analyses compared bismuth-qua-ruple therapy (bismuth � tetracycline � metronidazole

PPI) to triple therapy with levofloxacin (levofloxacin00 mg/day � amoxicillin 1 g twice a day � a PPI twiceday) in patients who failed eradication with standard

riple therapy. Both analyses found that levofloxacin tri-le therapy was better tolerated than quadruple therapynd had better eradication rates (81% vs 70%, respectively;R, 1.80; 95% CI: 0.94 –3.46).40,41 Ten-day levofloxacin

riple therapy was superior to 7-day therapy, and levo-oxacin at 250 mg twice a day was as good as 500 mgwice a day. Of the 3 salvage therapies described in thisection, levofloxacin is the best documented and there-ore the preferred therapy.

Rifabutin is a drug used to treat mycobacterial infec-ions. In small trials, it has been shown to be effective inradicating H pylori in patients who have failed tradi-ional therapies. The usual doses in rifabutin triple ther-py are rifabutin 150 mg twice a day, amoxicillin 1 gwice a day, and a PPI administered twice a day. In oneecent study, the eradication rate was 74%.42 In a ran-omized comparison of levofloxacin triple therapy andifabutin triple therapy in patients who had failed 2 otherreatment trials, levofloxacin triple therapy was signifi-antly better than rifabutin triple therapy (85% vs 45%,espectively). Adverse effects occurred frequently withoth regimens: leucopenia with rifabutin in 25% andyalgia with levofloxacin in 30%.43

Furazolidone-based triple therapy has been shown toe effective in small studies. The usual doses are furazo-

idone 100 –200 mg along with amoxicillin 1 g and a PPI,ll administered twice daily for 1 week. In one study, thentent-to-treat eradication rate was 52% in patients whoad failed standard therapy.44 Furazolidone therapiesave been less well studied than rifabutin- and levofloxa-in-based studies. The low cost of furazolidone makeshis regimen particularly attractive in developing coun-ries, but the optimal dose and combination needs fur-her study.

A practical management strategy using these treatmentegimens was evaluated in Ireland45; 3280 patients re-eived standard PPI triple therapy, which was effective in530 (77%) patients. Bismuth-based “quadruple” or a
riple therapy (that did not contain the antibiotic that

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ailed in the original regimen) was successful in 56% of70 failures. Subsequent eradication attempts using ri-abutin-based (n � 34) and furazolidone-based (n � 10)egimens were successful in 38% and 60% patients, re-pectively. The majority of patients could therefore be

anaged by the use of one or more therapies describedbove.

Current and Emerging StrategiesFigure 3 shows various strategies that may be

dopted after initial therapy fails. When initial treat-ent fails, culture and antimicrobial sensitivity testing

re reasonable if available. If culture is not available,uadruple therapy is a reasonable alternative. If thisails as well, levofloxacin-based triple therapy would behe logical choice because it has been studied the most.t this point, an evidence-based ranking of alternatives

s not possible. Decision making should depend on thevailability of culture and antimicrobial sensitivityesting and knowledge of local resistance patterns.

Adverse Effects of MedicationsA Cochrane review reported that the most com-

on adverse effects of therapy for H pylori were diarrhean 8%, altered taste in 7%, nausea and vomiting in 5%,kin rashes in 2%, headache in 4%, abdominal discomfortr pain in 5%, and stomatitis in 2.5% of patients treatedor H pylori.46 Occasional case reports of pseudomembra-ous colitis have appeared, and the adverse effects withewer medications such as rifabutin and levofloxacinave already been described. Discussing the anticipateddverse effects with the regimen may be an importantay to improve compliance.

Alternative TherapiesProbiotics are not effective in H pylori eradication,

igure 3. Treatment strategies for the patient who fails initial therapy.1

ut some studies have shown a decrease in gastritis se- c

erity or in bacterial density with these agents.47 Othertudies have shown a reduction in adverse effects withrobiotics.47 Further research is necessary before thesean be recommended for routine use.

Testing for Confirmation of EradicationIn the past, when eradication rates were high,

outine testing to confirm eradication was recommendednly in high-risk patients (eg, those with peptic ulcerleeding). With the declining rates of eradication withonventional therapy, there is a more pressing need tostablish whether eradication therapy has been success-ul. Both the urea breath test and the stool antigen testave high accuracy in confirming eradication.48 Theonoclonal stool test should be used because it is more

ccurate.49 An evaluation of the cost-effectiveness ofhese tests has been published.50 It concluded that, be-ause the accuracy of the 2 tests is similar, the choice ofne or the other depends on patient convenience and theost of the test. The choice of a test may depend oneography; in the United States, the 13C urea breath tests expensive compared with Europe, but, with the immi-ent expiration of patent protection, price reductions are

ikely. A 14C breath test may be another less expensivelternative. Stool antigen testing and breath testing areow available to the average practitioner in the Unitedtates through large laboratory testing organizations.

Cost-effectiveness ConsiderationsThe cost-effectiveness of H pylori eradication has

een evaluated in a number of settings. Table 3 showsost models related to H pylori eradication and the cor-esponding clinical trial data when they have been per-ormed with economic end points. Cost-effectiveness

odels have demonstrated that eradication of H pylori isost-effective in patients with duodenal and gastric ul-

6,29–36,40–44

er.51 Economic evaluations in a clinical trial show that

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radication is associated with a measurable decrease inlcer-related costs.52 Testing for and treating H pylori

nfection followed by retesting to confirm eradication ofpylori has been shown to be cost-effective in patients

ith bleeding ulcer disease.53 Although this has not beenodeled in other settings, the high failure rates of cur-

ent therapies may make it cost-effective to test all pa-ients, particularly in countries in which breath testingnd/or monoclonal stool tests are inexpensive. Testingnd treating patients with newly diagnosed peptic ulcerisease has been shown to reduce costs related to activeeptic ulcer disease over a 12-month time frame.54 Test-

ng and treating patients with previous peptic ulcer dis-ase has been suggested as a cost-effective strategy. It wasnsuccessful in a US-managed care trial because mostatients receiving acid inhibitors for a diagnosis of pepticlcer disease were dyspeptic patients who tested negative

or H pylori.55 In another trial, the benefit of testing andreatment was limited to patients who had previously

able 3. Cost-effectiveness Models for Helicobacter pylori ErEradication

Clinical setting ReferencesCost-effective

of H pylori

lcer diseaseUncomplicated peptic ulcer 52, 53, 54 Cost-effective

suppressioBleeding peptic ulcer 53 Cost-effective

suppressio

Documented peptic ulcerdisease by endoscopy orradiology

52, 55, 57 Cost-effectivesuppressio

Physician diagnosis ofpeptic ulcer (notconfirmed)

56, 57 Not cost-effesuppressio

yspepsiaPopulation-based testing

and treatment for Hpylori to preventdyspepsia

60–62

Population-based testingand treatment for Hpylori to cure dyspepsiain young patients (�50yr) with no alarmsymptoms

58, 59, 63, 64 Cost-effectivewith early e

Functional dyspepsia 63 Cost-effectivewith early e

opulation-based eradicationfor gastric cancerprevention

68–71 Cost-effectivepopulation

ad a documented peptic ulcer.56 w

In the area of dyspepsia management, early modelsased on high rates of H pylori prevalence and high ratesf underlying peptic ulcer disease suggested a large eco-omic benefit for noninvasive testing for H pylori fol-

owed by treatment.57 As the prevalence of H pylori infec-ion and peptic ulcer disease decreases in a dyspepticopulation, other strategies including acid suppressionave become competing alternatives.58 Managementuidelines for patients presenting with dyspepsia in thenited States recommend the use of empirical testing

nd treatment for H pylori in young patients with unin-estigated dyspepsia, except in areas in which the preva-ence of H pylori infection has dropped below 10%.3,4 Aopulation-based H pylori eradication strategy to preventyspepsia and dyspepsia-related cost has been shown toeduce dyspepsia-related health care costs in the Unitedingdom over a 10-year period.59 The mean cost savingas modest (US $117 over 10 years; 95% CI: $11–$220).he results have been mixed when shorter time periods

tion and Direct Measurements of Cost in a Clinical Trial of

modelsication

Measured cost savingin clinical trials US

$/person Comment

cid $547–$835/yr

cid No clinical trials witheconomic endpoints

Eradication prevents ulcerrecurrence

cid $285–$482/year Recurrent ulcer diseaseis associated with highcosts

vs acid Not cost saving Unconfirmed peptic ulcerdisease is aheterogeneous groupthat includes H pylorinegative dyspepsia

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

Mixed results may berelated to the timeframe of the clinicalstudy. Initial costs oftreatment may beoffset over the long-term.

paredcopy

$337–$389/1 year Testing and treating for Hpylori decreases costsof investigation. Whenthe prevalence is�10%, PPI therapy maybe preferable.

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No clinical trials witheconomic endpoints

igh-risk No clinical trials witheconomic endpoints

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reatment for H pylori to prevent dyspepsia- and ulcer-elated symptoms and costs showed a small benefit at thend of 1 year, mostly because of a reduction in consul-ation for dyspepsia.60 In another trial, population-basedesting and treatment for H pylori resulted in a reductionn dyspepsia-related consultations, but the cost wasigher in the eradication group at 2 years mostly becausef the high cost of the eradication therapy chosen.61

aken together, these data suggest that the initial invest-ent in therapy for H pylori treatment may not pay off

or several years. There may be additional benefits forradication, eg, the benefits of prevention of gastric can-er that have not been considered in many economicodels. These potential benefits are certainly not cap-

ured by clinical trials that are 1–10 years duration.Cost models have suggested that eradication therapyay be a cost-effective option in functional dyspepsia.62

odels for the management of dyspepsia in patients whoresent to physicians with symptoms (as opposed toopulation-based eradication strategies) have suggestedn economic benefit for H pylori eradication.58,63 In theanadian CADET-HP trial, the cost saving with a test-nd-treat strategy for H pylori in patients presenting torimary care physicians with dyspepsia was significantver a 1-year time frame.64

In choosing H pylori treatment regimens, it is impor-ant to recognize that failed therapy can be an extremelyxpensive undertaking and that the first attempt at ther-py is probably the best. Cost models have shown thempact of nonadherence and the problems associatedith choosing a regimen based on medication costlone.65

Economic analyses have also evaluated the duration ofherapy. An economic analysis comparing 7- and 10-dayherapy found small differences between the costs for the

treatment durations using US prices but found 7-dayherapies were cost-effective in Spain.66 Formal cost-ffectiveness studies have not been performed comparingewer/salvage treatments, but a cost comparison within alinical trial showed that sequential therapy had betterutcomes at lower cost than standard triple therapy withimilar adverse effects.35 An extensive document thatetails the literature on this subject has recently beenublished.67 Except in first-degree relatives of patientsith gastric cancer, eradication therapy is not currently

ecommended to prevent gastric cancer.2 Cost-effective-ess models have suggested that testing followed byreatment in adults may be a cost-effective strategy torevent cancer, particularly in selected high-risk popula-ions, eg, Japanese Americans.68 –70 The assumptions usedn these models have limitations because effectiveness of

pylori eradication in preventing cancer needs furtherefinition and the proportion of patients who may ben-fit and the age at which the testing and treatment
hould take place are uncertain.71 The incidence of distal t
astric cancer is declining, as is the prevalence of H pylorinfection, in many developed countries.

Factors Affecting H pylori EradicationThere are many differences in eradication rates in

ifferent populations.

Genetic Differences in the Metabolism ofDrugsPPIs are an important part of many current treat-

ent strategies for H pylori. Some of the currently avail-ble PPIs are metabolized by the cytochrome P450 systemn the liver, and genetic polymorphism of the cytochromeCYP)2C19 can affect H pylori eradication. Poor metabolicctivity is genetically determined and results in highlasma concentrations of the PPI and a prolonged effect.

recent meta-analysis suggested that eradication ratesight be reduced if the PPI in the eradication regimenas omeprazole, but eradication rates were unchangedhen lansoprazole or rabeprazole was used.72 Poor me-

abolizers are found in 3%–5% of populations of Westernrigin, but prevalence rates of 18%–23% have been re-orted in China, Vietnam, Thailand, and Japan whereifferences in the outcome of therapy may be more rele-ant.

SmokingA meta-analysis of 22 studies including 5538 pa-

ients in the analysis suggested that smoking was asso-iated with a reduced rate of eradication (8.4%; 95% CI:.3%–13.5%), particularly in patients who had nonulceryspepsia. In this analysis, smokers had a higher likeli-ood of failed eradication (OR, 1.95; 95% CI:.55–2.45).73

Underlying Disease StateSome studies have suggested that eradication

ates for H pylori are lower in patients with nonulceryspepsia as opposed to patients with peptic ulcer dis-ase, but the results have been variable, and other studiesave found no difference.18,74 At the present time, adjust-ents to treatment duration are not recommended based

n the indication.2

Adverse Effects and Complexity of theRegimenPatient adherence is a relatively new term for what

as called compliance with therapy in the past. It impliesnd recognizes that patients have choices with regard toaking prescribed medications. Studies with antimicro-ial therapy show that frequent dosing (3 or 4 times aay) is associated with reduced adherence.5 Adverse ef-ects may also play a role, notably diarrhea with amoxi-illin, taste perversion with clarithromycin, and metallicaste with metronidazole. A clear explanation of the an-
icipated adverse effects and the potential adverse conse-

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uences of discontinuing therapy may improve adher-nce.

A retrospective analysis of 2751 patients who failedradication therapy in clinical trials in France suggestedhat many factors played a role in failed eradication.actors that were predictive of failed eradication werelarithromycin resistance, diagnosis of nonulcer dyspep-ia as opposed to peptic ulcer disease, and use of 7-day vs0-day therapy.75 Adherence with the treatment regimen

s difficult to measure, and the traditional methods usedn clinical trials (pill counts) are prone to error.

Resistance to Antimicrobial AgentsAntimicrobial resistance is a major cause of treat-

ent failure and is responsible for the declining rates ofpylori eradication seen in many countries. A systematic

eview of H pylori therapy reported a 56% decrease inradication rates if clarithromycin resistance was presentnd a clarithromycin-containing regimen was used, and,ith nitroimidazole resistance, a drop in efficacy of up to0% was found for bismuth-based triple and metronida-ole-based triple therapies.76 A more recent analysis ofublished studies found a 70% decline in eradicationates if clarithromycin resistance was present and a clar-thromycin-containing regimen was used.77

Recurrence of H pylori Infection AfterSuccessful EradicationStudies of recurrent infection suggest that recur-

ence is rare when effective therapies are used and whenarly recurrences are excluded (these are most often be-ause of failed eradication). In developed countries, theate is approximately 3% per year.78 Most apparent recur-ences are really recrudescences of an infection that hasot been adequately treated, often because of an ineffec-ive treatment regimen.

Antimicrobial ResistanceIn this section, we will review the prevalence and

rends of the antimicrobial resistance and its mecha-isms. Only recent data published since a previous pub-

ished review in 2004 will be considered.77

Specific Features of H pylori AntimicrobialResistanceGenetic support of resistance. Given that pro-

aryotes replicate by duplication, mechanisms are necessaryo generate genetic diversity, which is imperative for theirvolution. There are 2 main possibilities: mutation and genecquisition. Gene acquisition via different mechanisms, ie,ransformation, transduction, and conjugation, is very com-

on among bacteria and is responsible for most antimicro-ial resistance. This is not the case for H pylori, whichevelops antimicrobial resistance largely as a consequencef mutations. The same is true for another well-known
acterium: Mycobacterium tuberculosis. F
There is a general agreement that during the process ofNA replication, errors can occur spontaneously, ie, oneucleotide can be replaced by another. If this point mu-ation does not have a consequence on bacterial fitness, itill remain in the bacterial genome and will be transmit-

ed to the descendents. A low proportion of the bacterialopulation will therefore harbor the mutation. If theacterial population is then exposed to an antibiotic forhich the mutation induces resistance (for example, byreventing binding of the antibiotic to its target), bacte-ia that do not possess the mutation will be progressivelyliminated, whereas those that have the mutation will beelected by the antibiotic. Eventually, we will be left withbacterial population totally resistant to the antibiotic

nstead of the mixed population of sensitive and resistantacteria. This mechanism concerns all of the antibioticso which acquired resistance occurs in H pylori (Table 4).t this stage, furazolidone seems to be the only antibiotic

o which the bacterium has not developed a resistance;nly a decrease in susceptibility has been described.79

lthough it is not possible to detect small numbers ofutant organisms in a bacterial population, indirect data

avor their presence. For example, when H pylori strainsere exposed in vitro to subinhibitory concentrations of

larithromcyin, the number of subcultures required tobtain an 8- to 32-fold increase in minimum inhibitoryoncentrations (MIC) was significantly lower if the sus-eptible strain originated from a patient with treatmentailure rather than a patient with treatment success.80 Inivo, the process of selection is most likely favored by theresence of a subinhibitory concentration of the antibi-tic in the mucosa as is the case in vitro. This situationan occur when a patient is not compliant and forgets toake his/her drugs as prescribed. Recently, the role ofntracellular bacteria has been put forward. Pretreatmentsolates of H pylori from the failure group of a clinicalrial had a higher ability to penetrate intracellulary thanhose from the group that were successfully cured, andesistance to clarithromycin and metronidazole was sig-ificantly associated with this property compared withusceptible isolates.81 These 2 potential causes of treat-

ent failure are the result of selection of resistantutants.Acquisition of genes by horizontal transfer is also pos-

ible but does not seem to play an important role in Hylori, perhaps because this bacterium is most likely alonen its special ecologic niche. Transformation can occurecause H pylori is naturally competent for exogenousNA uptake and recombination.82,83 However, inter-

train diversity of restriction modification systems con-titutes a barrier for DNA fragment transfer includinglasmids and bacteriophages.84

Biochemical mechanism of resistance. The ge-etic support of resistance observed in H pylori restrictshe possible biochemical mechanisms of the resistance.
or example, the production of an enzyme that degrades

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he antibiotic, eg, a �-lactamase, is not found in wildtrains. The resistance mechanism is a modification ofhe antibiotic target to which the drug no longer binds.nother potential resistance mechanism is the develop-ent of drug efflux proteins but, in contrast to what is

sually described for gram-negative bacteria, it washown that efflux systems do not play a role in thentrinsic resistance of H pylori to antibiotics or in ac-uired resistance to amoxicillin.85,86 A putative tetracy-line gene HP1165, which displays a 50% identity withhe tetracycline efflux gene tetA from Clostridium perfrin-ens, may be involved in the inducible tetracycline resis-ance of some strains.87 The importance of several non-pecific multidrug resistance proteins described needsurther clarification.88

Antibiotics affected by acquired resistance. Mac-olides. Because the resistance mechanism is the same forhe different compounds in this class of antibiotics,ross-resistance is observed. There are 2 adjacent ad-nines located in special positions on the 23S ribosomalNA peptidyl transferase loop, which are concerned andan be substituted by a guanine (A2142G, A2143G) or aytosine (A2142C) leading to a conformational change inhe ribosome and a lack of binding of the antibiotic,voiding the interruption of protein synthesis. The fewutational events involved allow an effective detection

y molecular methods.Amoxicillin. Amoxicillin acts by interfering with

he peptidoglycan synthesis, especially by blocking trans-orters named penicillin-binding proteins (PBP). The raremoxicillin-resistant H pylori strains harbor mutations onhe pbp-1a gene. A mutation Ser 414 ¡ Arg was found inhe first resistant strain described.89 Following analysis ofurther resistant strains, it appears that various muta-ional changes located in or adjacent to the second andhird PBP motifs of PBP-1A could be involved.90 In aecent study on an in vitro selected amoxicillin-resistanttrain, amino acid substitution in the outer membraneroteins, HopB and HopC, also seemed to contribute toesistance.91

Tolerance to amoxicillin has also been described andas associated to the lack of another PBP: PBP-D.92

iven the diversity of mutations by which resistance canevelop, it is unlikely that a simple molecular method

able 4. Genes Involved by Point Mutation or Other GeneticEvents Leading to Antibiotic Resistance inHelicobacter pylori

Antibiotics Genes concerned

Macrolides rrn 23SMetronidazole rdxA, frxAFluoroquinolones gyrARifampins rpoBAmoxicillin pbp1Tetracycline rrn 16S

an be used to detect resistance. d

Tetracyclines. Tetracyclines interfere with proteinynthesis at the ribosome level by binding to the 30Subunit. If a mutation in a nucleotide triplet developspositions 926, 927, 928), there is lack of binding to the1 loop, the binding site for tetracyclines. When theubstitution involves the 3 nucleotides together (AGA26 to 928 TTC), the corresponding MIC is high; if onlyingle or dual mutations are present, intermediate MICsre observed. As previously mentioned, an efflux mecha-ism seems to be the mechanism involved in the absencef mutations.93

Rifampins. Rifampins inhibit the � subunit of theNA-dependent RNA polymerase encoded by the rpoB

ene. Point mutations occur in the rpoB gene at codons24, 525, and 585 as in other bacteria.94 In a recent study,3 H pylori isolates resistant to both rifampicin andifabutin harbored these mutations. Four other isolates,

oderately resistant to rifampicin but not to rifabutin,id not have the mutations.95 Silent mutations, ie, mu-ations without impact on the resistance, are alsoommon.

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

utations occur in the quinolone resistance determiningegion as for other bacteria. Amino acid positions 87 and1 are mainly concerned, but a mutation in position 86as also been described.96 –99 There is cross-resistanceetween the different fluoroquinolones. For susceptibletrains, levofloxacin and moxifloxacin lead to the bestlinical results.

Nitroimidazoles. 5-Nitroimidazoles are prodrugshat have to be reduced in the cell to be detrimental toacterial DNA. The main gene involved in this process isdxA, an oxygen-insensitive nitroreductase. Frameshift

utations in rdxA have been associated with metronida-ole resistance.100 The possibility that frameshift muta-ions occur in other genes, such as frxA, coding for aavin oxidoreductase, has been proposed but is moreontroversial.101–103 By using saturation transposon mu-agenesis, inactivation of rdxA was solely able to confer

etronidazole resistance.104 Among the related com-ounds, furazolidone is active against metronidazole re-istant isolates, indicating that the mechanism of actions different.

Detection methods. As for any bacterium, anti-icrobial susceptibility testing of H pylori can be per-

ormed by phenotypic methods, eg, disk diffusion (stan-ard antibiogram), Etest (a quantitative variant of diskiffusion), agar or broth dilution method, or break-pointesting.105 These methods have the advantage of evaluat-ng all of the drugs at the same time, and, for most ofhem, an exact MIC can be determined for each isolate.he agar dilution method has been proposed by thelinical Laboratory Standard Institute (CLSI), formerly

he National Committee for Clinical Laboratory Stan-
ards (NCCLS), as the method to be used for H pylori

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larithromycin susceptibility testing. For the other anti-iotics, no official recommendation exists, but the meth-ds cited can also be used. For metronidazole alone, the

ack of reproducibility of antimicrobial testing and theoor correlation with clinical results makes testing lessseful in the clinical setting. The Maastricht III Consen-us Report does not recommend routine metronidazoleusceptibility testing.2

Phenotyipc methods require a delay of several days tobtain a result, and they are time-consuming to carry outnd expensive. For these reasons, and because resistances due to a limited number of mutations, molecular

ethods have been proposed.Because clarithromycin is the most clinically relevant

ntibiotic and few mutations are concerned, numerousenotypic methods have been developed to detect thisesistance as indicated in Table 5. The most promisingechnique is probably the real-time PCR based on 23Sibosomal DNA specific sequence detection using a bi-robe and the fluorescence-resonance energy transferrinciple. It allows, first, the specific detection of H pylori

n a specimen and, second, after melting curve analysis ofhe amplicons, the detection of possible mutations. Aucleotide mismatch between the isolate sequence andhe hybridization probe leads to a difference in the melt-ng peak.

This method represents an important step forward inhe diagnosis of H pylori because the result can be ob-ained within 2 hours and there is a limited risk ofontamination with the amplicons given that the reac-ion is performed in a closed tube. In addition to gastriciopsy specimens, this method can also be applied totools, which is a real breakthrough in diagnosis becauset leads to a susceptibility result without performing anndoscopy.106

Another interesting method that does not require am-lification and can be performed on histologic slides isuorescence in situ hybridization using a set of fluores-ent labeled oligonucleotide probes.107 Although not asommon, molecular methods for detecting resistance tontibiotics other than clarithromycin have been pro-osed: PCR-restriction fragment length polymorphismor tetracycline resistance and real-time fluorescence res-nance energy transfer (FRET)-PCR with melting curvenalysis for fluoroquinolones and tetracyclines.108 –110

Research is still going on to find a suitable molecularethod for detecting metronidazole resistance; possibil-

ties include either the use of microarrays or optimizationf the detection of the RdxA protein by immunoblottings previously described.111,112

Prevalence of H pylori AntimicrobialResistanceA large number of studies have been published

egarding the prevalence of H pylori antimicrobial re-
istance. Because resistance is an evolving process, only E
he most recent studies (for the most part since theear 2000) will be presented. The majority of thesetudies were cross-sectional and may have inclusioniases. The most relevant study design is a population-ased study, such as the one performed in Sweden:000 subjects were randomly selected to fill out auestionnaire, one third of the responders (74%) were

nvited for an endoscopy, and, finally, isolates of 333ubjects were obtained and tested for antimicrobialusceptibility by agar dilution.113 Another possible de-ign is to request selected endoscopists to send biopsypecimens from their patients on one or several ran-omly chosen days during the year. Using this method,45 isolates were obtained in France a few years ago.114

sing data obtained at inclusion in clinical trialsimed at eradicating H pylori was also an accurate wayf obtaining data in the 1990s.115 However, most of thetudies reported the results of successive patients con-ulting in specialized centers. A summary of recentlyublished articles is presented in Table 6.

Clarithromycin and metronidazole. Primary resis-ance. Adults: An H pylori antimicrobial resistance moni-oring program was established in the United States for

pylori. The data from 1999 to 2002 have been analyzed.he resulting prevalence is in the range of data obtained

n the past, ie, 10%–12% for clarithromycin and 25.1% foretronidazole.116 The situation is quite different in the

tate of Alaska where clarithromycin resistance ac-ounted for 31% and metronidazole resistance for 44% ofsolates from natives undergoing upper endoscopy, dur-ng the period 1999-2003.117

Data gathered in Europe are in line with those re-orted from the large prospective multicenter study car-ied out in 1998 in 17 countries.118 Countries fromorthern Europe (Denmark, Finland, Sweden, The Neth-

rlands) have a low prevalence of resistance to clarithro-ycin (1%–3%),113,119 –121 Bulgaria in Central Europe hasmoderate prevalence (12.6%),122 and Italy in Southern

able 5. Genotypic Methods Used to Detect MacrolideResistance in Helicobacter pylori

Using 23S rDNA amplificationSequencing, pyrosequencingRestriction fragment length polymorphismOligonucleotide ligation assayDNA enzyme immunoassayLine probe assayPreferential homoduplex formation assay3= Mismatched PCR3= Mismatched reverse PCRReal-time PCRMicroelectronic chip arrayElectrocatalytic detectionPCR-based denaturating HPLC assay

Without using 23S rDNA amplificationFluorescence in situ hybridization

PLC, high-performance liquid chromatography.

urope has a rate that exceeds 20%.123

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In the Middle East, data are available from Iran: therevalence of clarithromycin resistance was 16.7% andetronidazole resistance 57.5%.124 The same high rate ofetronidazole resistance was found in Kuwait, but, sur-

risingly, no clarithromycin resistance could be de-ected.125 For the first time, prevalence data from Africare available. In a study carried out in Nairobi, Kenya, in003-2004, the prevalence of clarithromycin resistance

able 6. Resistance of Helicobacter pylori to Clarithromycin,the World

Country YearType ofstudy Method of te

rimary resistanceAdults

North AmericaUnited States

(global)1999–2002 Multi-C Agar dilutio

United States(Alaska)

1999–2003 Multi C Agar dilutio

EuropeBulgaria 1996–2004 Mono C Agar dilutioDenmark 2001–2003 Mono C Disk dffusioFinland 2000–2002 Multi C EtestItaly 2004–2005 Multi C Real-time PThe Netherlands 1997–2002 Mono C Disk diffusiSweden 1998–2001 Multi C Agar dilutioUnited Kingdom(Wales)

2000–2003 Mono C Etest

Middle EastIran 2001–2002 Mono C Disk diffusiKuwait 2003–2005 Mono C Etest

AsiaBangladesh 1999–2001 Mono C Agar dilutioHong Kong 2003–2004 Mono C Etest

AfricaKenya 2003–2004 Mono C Agar dilutio

ChildrenEurope 1999–2002 Multi C EtestBulgaria 1996–2004 Mono C Agar dilutioPortugal 1999–2003 Mono C Etest

econdary resistanceEurope 1999–2002 Multi C EtestBulgaria 1996–2004 Mono C Agar dilutio

Israel 2002–2005 Mono C EtestKorea 2004–2005 Mono C Agar dilutio

OTE. Studies including more than 90 patients for primary.Elviss NC, Owen RJ, Xerry J, Walker AM, Davies K. Helicobacter pylorom a regional population in North Wales. J Antimicrob Chemother 2Gu Q, Xia HH, Wang JD, Wong WM, Chan AO, Lai KC, Chan CK, Yueesistance in Helicobacter pylori in Hong Kong and its effect on claritYahav J, Shumely H, Niv Y, Bechor J, Samra Z. In vitro activity of levoailure. Diagn Microbiol Infect Dis 2006;55:81–83.Kim JM, Kim JS, Kim N, Kim SG, Jung HC, Song IS. Comparison of pelicobacter pylori isolated from Korean patients. Int J Antimicrob Ag

as 6.4%, and all strains were resistant to metronida- r

ole.126 Children: A large study was performed in childrenn 17 pediatric centers from 14 European countries. Aotal of 1037 patients had their H pylori strains tested;0% originated from outside Europe. Clarithromycin re-istance was detected in 20% and metronidazole resis-ance in 23%. Resistance to both antibiotics occurred in.9%.127 The prevalence in children in Bulgaria was loweror both antibiotics, whereas a very high clarithromycin

onidazole, Tetracycline, and Amoxicillin in Different Parts of

Prevalence

No. ofstrainstested Clari Metro Tet Amox Reference

347 12.9 25.1 ND 0.9 119

352 31 44 0 2 120

786 12.6 25.6 5.2 0.8 125�400 3 27 ND ND 122

292 2 38 ND ND 123178 21.3 ND ND ND 126

1127 1 14.4 ND ND 124333 1.5 16.2 0.3 0 116363 7 24 0.3 0 a

120 16.7 57.5 0 1.6 12796 0 67 0 0 128

120 10 77.5 15 6.6 140102 7.8 39.2 ND 0 b

268 6.4 100 1.9 4.6 129

1037 20 23 ND 0.6 130282 12.5 15 3.4 1.5 12594 35 13.8 0 0 131

196 Children 42 35 ND ND 130109 Adults28 Children

36 81.6 ND 1.6 125

70 Adults 65.7 57.1 0 0 c

324 Adults 85.1 70.1 ND 31.3 d

ibiotic resistance patterns and genotypes in adult dyspeptic patients54:435–440., Fung FM, Wong KW, Lam SK, Wong BC. Update on clarithromycinycin-based triple therapy. Digestion 2006;73:101–106.cin against Helicobacter pylori isolates from patients after treatment

y and secondary antimicrobial minimum inhibitory concentrations for2006;28:6–13.

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Secondary resistance. When antimicrobial resistances tested after treatment failure, the rate of resistance is

uch higher (Table 6).Risk factors. There is a trend toward a steady

ncrease in clarithromycin resistance over the years. Intaly, for example, the rate doubled between 1989-199010.2%) and 2004-2005 (21.3%).123 In Japan, it in-reased from nil in 1989-1990 to 20% in 1999-2000129

nd, in Korea, from 2.8% in 1994 to 13.8% in 2003.130

his is due to an increased selection pressure becausef the use of clarithromycin, and possibly other mac-olides such as erythromycin, for infections other than

pylori. A positive correlation was found betweenong-term therapy for chronic respiratory infectionnd the prevalence of H pylori resistance to clarithro-ycin.131 Only countries with a strict policy on the

rescription of antibiotics such as The Netherlandsave experienced a trend toward a decreased prevalencef clarithromycin resistance.121

In the United States, a multivariate analysis revealed thatlack race was the only significant risk factor for clarithro-ycin resistance.116 In several studies carried out in Europe,

n association between clarithromycin resistance and non-lcer dyspepsia has been reported75; however, there does notppear to be an association with the pathogenic factorsagA and VacA.132 In children, clarithromycin resistanceas higher in children younger than 6 years of age com-ared with those older than 12 years of age.127

Concerning 5 nitroimidazoles, the selection pressure isigher in tropical countries, because of treatment di-ected at parasites, than in countries in temperate areasn which these drugs are only used for gynecologic andental infections. The gynecologic treatments explainhy resistance prevalence is higher in females.

Fluoroquinolones. Among fluoroquinolones, levo-oxacin has recently become a good second or third choicereatment in case of eradication failure in adults. However,his antibiotic is increasingly used for other infections, and,onsequently, the prevalence of primary resistance is alreadyigh: 8.8% in Alaska,133 15% in Japan,134 16.8% in Belgium,98

nd 17.2% in France.99 A positive association between fluo-oquinolone consumption and H pylori resistance has beenemonstrated in Alaska.133 Because fluoroquinolones areeldom used in children and adolescents, the prevalence ofesistance is lower: 5.3% in Portugal128 and 5.5% in Japan.135

fter failure of a treatment with fluoroquinolones, highesistance rates have been observed.136

Amoxicillin and tetracycline. The prevalence ofhe resistance to these 2 antibiotics has fortunately re-

ained low. In most studies, it is less than 2%, with thexception of Kenya (4.6%)126 and Bangladesh (6.6%) formoxicillin137 and of Bulgaria (5.2%) for tetracycline.122

Rifampins. Very few surveys have included detec-ion of rifampin resistance. When it was tested, resistance
as rarely found (1.4% in Germany).95
ConclusionIn this review, we have summarized the state of

he art in the treatment of H pylori and highlighted theroblem of resistance that is a major cause of treat-ent failure. Poorly designed trials with small sample

izes and wide confidence intervals continue to beublished, and misconceptions regarding treatmentontinue to plague the literature. A recent review in arominent family practice journal illustrates this prob-

em. It recommends several ineffective and unprovenherapies including 1-day and 5-day treatments thatave not been proven to be effective in large well-ontrolled trials.138 Rational treatment should beased on scientific evidence from well-designed trialsf high quality.

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Received May 17, 2007. Accepted July 9, 2007.Address requests for reprints to: Nimish Vakil, MD, Aurora-Sinaiedical Center, 945 North 12th Street, Room 4040, Milwaukee, Wis-

onsin 53233. e-mail: [email protected]; fax: (414) 219-7108.Supported by Astra-Zeneca, Novartis, Altana, and TAP.Potential conflict of interest for N. Vakil: consultant for Astra-Zen-

ca, Orexo, Novartis, TAP, Proctor and Gamble, Altana, and Malesci
nd on the speaker’s bureau for Astra-Zeneca.

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Management of Helicobacter pylori Infection