Tratamiento Helicobacter Pylori

Practical Aspects inChoosing a Helicobacter
pylori Therapy
Javier Molina-Infante, MDa,*, Akiko Shiotani, MD, PhDb

KEYWORDS

� Helicobacter pylori � Therapy � Eradication � Triple � Quadruple � Concomitant� Bismuth � Resistance

KEY POINTS

� Antibiotic resistance is the critical factor responsible for eradication treatment failure.Because of increasing clarithromycin resistance, first-line triple therapy for Helicobacterpylori (H pylori) infection is currently ineffective in most settings worldwide.

� Treatment results for infectious diseases are best (>90%–95%) when regimens are reli-ably used to treat patients with organisms susceptible to the antimicrobials chosen.Most eradication therapies, however, are prescribed empirically.

� The choice of therapy may depend on patient previous antibiotic treatment, local patternsof antibiotic resistance, and drug availability. Currently, the most effective first-line erad-ication regimens are 14-day bismuth and nonbismuth concomitant quadruple therapies.

� Fluoroquinolone-, furazolidone-, and rifabutin-containing regimens might be effectiverescue treatments, as well as bismuth quadruple therapy if not used previously.

� Optimization of all eradication regimens (increased duration, adequate proton pump inhib-itor, and antibiotic doses and dosing intervals) is key to maximize their efficacy.

� Besides antibiotic resistance, compliance is a major concern with increasing complexeradication therapies. Probiotics show promise as an adjuvant treatment to reduce sideeffects and improve adherence to therapy. Whether probiotics can also increase eradica-tion rates should be further elucidated.

� On large variations inH pylori resistance patterns, the golden rule for choice of treatment isonly to use what works locally (>90%–95% success) and to closely monitor its effective-ness over time.

Disclosure Statement: The authors have no conflict of interest to declare.a Department of Gastroenterology, Hospital San Pedro de Alcantara, C/Pablo Naranjo s/n,Caceres 10003, Spain; b Department of Internal Medicine, Kawasaki Medical School, 577Matsushima, Kurashiki, Okayama Prefecture 701-0114, Japan* Corresponding author.E-mail address: [email protected]

Gastroenterol Clin N Am 44 (2015) 519–535http://dx.doi.org/10.1016/j.gtc.2015.05.004 gastro.theclinics.com0889-8553/15/$ – see front matter � 2015 Elsevier Inc. All rights reserved.

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Molina-Infante & Shiotani520

INTRODUCTION

Thirty years after the transcendental discovery of the originally termed Campylobacterpyloridis as a causative agent for gastritis and peptic ulceration in 1984,1 Helicobacterpylori (H pylori) remains themost common bacterial infection in humans. It is estimatedthat approximately 50% of the world’s population is infected; this infection is currentlythe main cause of gastritis, gastroduodenal ulcer disease, and gastric cancer. Eradi-cation of H pylori infection has dramatically changed the natural history of peptic ulcerdisease.2 Furthermore, the World Health Organization classified H pylori as a definitecarcinogen in 1994 for its established role in the pathogenesis of gastric cancer andgastric mucosa–associated lymphoid tissue lymphoma.3 Emphasis has been latelymade on the importance of primary and secondary gastric cancer prevention, startingwith H pylori eradication.4 In fact, Japan has recently embarked on population-wide Hpylori eradication coupled with surveillance targeted to those with significant remain-ing risk.Standard triple therapy, consisting of a proton pump inhibitor (PPI) plus amoxicillin

and either clarithromycin or metronidazole, has been (and unfortunately still remains inmany settings) the gold standard eradication therapy for H pylori infection over the last2 decades. However, the efficacy of triple therapy at the present time is seriously chal-lenged in many parts of the world, where eradication rates have declined to unaccept-ably low levels, largely related to the development of resistance to clarithromycin.5

Moreover, H pylori resistance to metronidazole is prevalent as well in certaingeographic areas (ie, South America, Turkey, Iran, China) and fluoroquinolone resis-tance is rapidly growing worldwide due to widespread use of levofloxacin for ear,nose and throat, bronchial and urinary tract infections. Failure of H pylori treatment,in addition, selects antibiotic-multiresistant strains, which will be even more difficultto treat. Complicating this scenario, rescue drugs may be unavailable (eg, bismuth,tetracycline, furazolidone) or may lead to severe adverse effects (eg, rifabutin).This article aims to revisit all practical aspects that should be taken into consider-

ation when choosing an H pylori eradication regimen. Increasing antibiotic resistancecoupled with a lack of new therapeutic alternatives can seriously hamper the fightagainst H pylori infection. Now more than ever, a clear understanding of the interplaybetween the bacteria, the individual patient, its geographic area, and the drugsselected becomes pivotal to select and optimize the best therapeutic strategy foreach patient, maximizing the efficacy of eradication regimens and minimizing treat-ment failures, selection of resistant strains, and need for step-up antibiotic therapy.

Why Is Helicobacter pylori Difficult to Treat?

The H pylori infection should be treated by means of a combination of acid-suppressive agents and several antibiotics, yet it has proven challenging to cure.Several factors may account for difficulties associated with cure of the infection,including bacteria-, environmental-, host-, and drug-associated variables. All of thesefactor influencing eradication rates and potential solutions to overcome these obsta-cles are summarized in Table 1. By far, the most important factor is the developmentof H pylori resistance to many antimicrobial agents, especially clarithromycin, metro-nidazole, and fluoroquinolones. In H pylori infection, resistance usually developsbecause of the outgrowth of a small existing population of resistant organisms. Clar-ithromycin must bind to ribosomes in order to killH pylori. Acquired resistance is asso-ciated with failure to bind to ribosomes, such that resistance cannot be overcome byincreasing the dose or duration. Likewise, resistance to fluoroquinolones (eg, levoflox-acin, moxifloxacin) is not responsive to changes in dose or duration. Metronidazole

Table 1Theoretic causes explaining why H pylori is difficult to cure and potential solutions tocircumvent these difficulties

Causes Mechanisms Potential Solutions

Microorganism itself Phenotypical antibiotic resistance(persistence of nonreplicatingmicroorganisms)

High bacterial load

Increasing amoxicillin/metronidazole duration anddoses or shortening dosinginterval

Increasing PPI doses and/orshortening interval dosing

Increasing the dose and durationof antibiotic therapy

Combining several antibiotics (oneof which will probably kill theresistant organisms)

Pretreatment with PPI andbismuth, reducing the bacterialload (which would make survivalof the minor populations lesslikely)

Gastric environment Acid gastric pH (H pylori becomesphenotypically resistant with apH range between 3 and 6,usually in the mucus. Increasingthe pH in this layer to 6 or 7allows the bacteria to enter thereplicative state, where theybecome susceptible toamoxicillin and clarithromycin.)

Increasing PPI doses and/orshortening interval dosing

Antibiotics Clarithromycin andfluoroquinolone resistance

Metronidazole resistance

Amoxicillin and clarithromycinrequire microbial replication tokill microorganisms.

Not responsive to increasing dosesor duration

Increasing the dose and durationcan partially overcome bacterialresistance.

Increasing duration of therapyIncreasing PPI doses and/or

shortening interval dosing

Helicobacter pylori Therapy 521

resistance can be partially overcome by increasing the dose and duration. In contrast,bismuth resistance does not occur and acquired resistance to either amoxicillin ortetracycline is rare in most regions.However, treatment may also fail while the organism remains susceptible to the anti-

biotic.5 This treatment failure is most commonly seen with amoxicillin, for whichacquired resistance is rare. This form of reversible resistance is termed phenotypicalantibiotic resistance, and it is often caused by the presence of nonreplicating popula-tion of organisms. Bacteria usually oscillate between a nonreplicating (phenotypicallyresistant) and replicating state (phenotypically susceptible), during which they cannotand can be eradicated, respectively.5 As shown in Table 1, short duration or shortageof antibiotic drugs may limit the presence of antibiotic drugs during susceptibility pe-riods. Furthermore, insufficient acid suppression, keeping acid gastric pH between 3and 6, may predispose microorganisms to a nonreplicative state; this is a phenotyp-ically resistant state. Additionally, amoxicillin and clarithromycin are effective antibi-otics against H pylori provided microbial replication is present.


Another H pylori intrinsic obstacles for eradication regimens might be the high bac-terial load ofH pylori organisms in the stomach, resulting in an inoculum effect, and thewide variety of niches where the microorganism can reside (intracellularly, mucuslayer).5 Therefore, drug regimens, including PPI and antibiotics doses and dosing in-tervals, should be specifically designed to target all of these problems (see Table 1).

CHOICE OF THERAPY

The strongest predictor of H pylori treatment failure using a regimen proven to beeffective elsewhere is antimicrobial resistance. From a microbiological standpoint,treatment results are best when regimens are used to treat patients with organismssusceptible to the antimicrobials chosen. Pretreatment susceptibility testing, eitherby direct culture of the organism from gastric biopsies or indirectly by moleculartesting in gastric biopsies/stools, can be used for this purpose. Nonetheless, this strat-egy is hampered by the wide unavailability of these techniques, besides the need foran invasive procedure (endoscopy), cost, or time consumption. Another choice wouldbe using bismuth quadruple therapy because resistance to tetracycline is negligibleand metronidazole resistance can be partially overcome by increasing doses andduration. Nonetheless, this approach is limited to regions where bismuth salts andtetracycline are both available.6 The launch of Pylera (the 3-in-1 capsule containingbismuth, tetracycline, and metronidazole, therefore, decreasing pill burden and theo-retically improving compliance) might be a good therapeutic option where available.7

Therefore, one often must choose antibiotic therapy empirically; the best approachis using regimens that have proven to be reliably excellent locally. Considering H pyloriis an infectious disease and 100% success might be obtainable, the efficacy of anantimicrobial therapy should be scored as excellent (>95% success), good (>90%success), borderline acceptable (85%–89% success), poor (80%–84% success), orunacceptably low (<80%).8 The choice should take advantage of knowledge of localresistance patterns, clinical experience, and patient history. The history of patients’prior antibiotic use and any prior therapies will help identify which antibiotics are likelyto be successful and those where resistance is probable.6 In fact, treatment outcomein a population or a patient can be calculated based on the effectiveness of a regimenfor infections with susceptible and with resistant strains coupled with knowledge of theprevalence of resistance (ie, based on formal measurement, clinical experience, orboth). The formula and calculations for predicting the outcome of any antimicrobialtherapy have been recently reported.6 The therapeutic expectations for an individualpatient with clarithromycin-based therapies (triple, sequential, concomitant) and bis-muth quadruple therapy, depending on the rate of clarithromycin and metronidazoleresistance, are shown in Table 2.In this current era of increasing antibiotic resistance, all therapies should be opti-

mized. High-dose PPI therapy (eg, 40 mg of omeprazole or equivalent twice a day)is recommended in order to guarantee effective and prolonged gastric acid suppres-sion. All PPI molecules are metabolized by cytochrome P450 (CYP) 2C19. Fourdifferent genotypes have been described: ultrarapid, rapid/extensive, intermediate,and poor metabolizers. The prevalence of CYP2C19 rapid metabolizer genotypehas been shown to be highest in Europe and in North America (56%–81%), whereasthe proportion is lower (27%–38%) in the Asian population. Plasma PPI levels andintragastric pH levels during PPI treatment are inversely related to the CYP2C19 geno-type. Accordingly, several meta-analyses have shown eradication rates are inverselyrelated to the ability to metabolize the PPIs (eg, the ultrarapid and rapid metabolizergroups have lower eradication rate compared with other groups).9,10 Therefore, it is

Table 2Example of efficacy of clarithromycin-containing regimens for an individual patient, based on predicted resistance to clarithromycin and metronidazole

Antimicrobial Prediction7-d TripleTherapy

14-d TripleTherapy

10-d SequentialTherapy

14-d SequentialTherapy

10-d ConcomitantTherapy

14-d ConcomitantTherapy

14-d BismuthQuadruple Therapy

Clarithromycin andmetronidazole susceptible (%)

94 97 95 98 94 97 99

Clarithromycin resistant-metronidazole susceptible (%)

<20 50 80 88 94 97 99

Clarithromycin susceptible-metronidazole resistant (%)

94 97 75 75 94 97 95

Clarithromycin andmetronidazole resistant (%)

<20 50 <20 <20 <25 <50 95

Data from Graham DY, Lee YC, Wu MS. Rational Helicobacter pylori therapy: evidence based medicine rather than medicine based evidence. Clin GastroenterolHepatol 2014;12:177–86.

Helico

bacte

rpylo

riTherapy

523


conceivable that all patients, especially in Europe and North America, should receivehigh-dose PPI therapy with a proper dosing interval (twice or more than a day) in orderto circumvent the selection of nonreplicative H pylori strains, increase the effective-ness of amoxicillin and clarithromycin, and achieve similar efficacy rates in either rapidand poor CYP2C19metabolizers5,6 (see Table 1). Moreover, a 14-day duration is rec-ommended, given the fact it has proven a therapeutic benefit for triple, bismuthquadruple, and nonbismuth quadruple sequential and concomitant therapy.6,11–13

FIRST-LINE REGIMENS

Available first-line regimens, with preferred drug doses and dosing intervals, alongwith caveats for each treatment, are summarized in Table 3. The preferred empiricalchoices are currently 14-day bismuth quadruple therapy or 14-day nonbismuthquadruple concomitant or hybrid (sequential-concomitant) therapy, depending onlocal resistance pattern, clinical experience, and patient history of antibiotic use.

Table 3Current first-line therapeutic recommendations in the era of increasing clarithromycin andmetronidazole resistance

Eradication RegimensPreferred Dosages andDosing Intervals Caveat

14-d Bismuth-containingclassic quadruple therapy

Bismuth salts qidPPI (double doses) bidTetracycline 500 mg qidNitroimidazole 500 mg tid

AvailabilityComplexitySide effectsCompliance

14-d Bismuth-containingquadruple therapy usingPylera

PPI (double doses) bidPylera 3 pills qid

AvailabilityCostRelatively low tetracycline doses

14-d Nonbismuth quadrupleconcomitant therapy

PPI (double doses) bidAmoxicillin 1 g bidClarithromycin 500 mg bidNitroimidazole 500 mg bid

Cure rates �90% if dualresistance rate �15%

14-d Nonbismuth quadruplehybrid therapy

7 dPPI (double doses) bidAmoxicillin 1 g bid

7 dPPI (double doses) bidAmoxicillin 1 g bidClarithromycin 500 mg bidNitroimidazole 500 mg bid

Cure rates <90% if dualresistance rate >9%

14-d Nonbismuth quadruplesequential therapy

7 dPPI (double doses) bidAmoxicillin 1 g bid

7 dPPI (double doses) bidClarithromycin 500 mg bidNitroimidazole 500 mg bid

Cure rates <90% if dualresistance rate >5%

Not recommended as anempirical therapy

14-d Triple therapy PPI (double doses) bidAmoxicillin 1 g bidClarithromycin 500 mg bid

Cure rates <90% ifclarithromycinresistance >15%

Not recommended as anempirical therapy

Dual resistant H pylori: microorganism resistant to both clarithromycin and metronidazole.


The Achilles heel of standard triple therapy is clarithromycin resistance. Because ofthe increasing worldwide clarithromycin resistance, triple therapy should no longer beprescribed on an empirical basis and its use should be strictly restricted to a minorityof settings where clarithromycin resistance is known to be low (ie, Northern Europe14

or Thailand15) or where cure rates greater than 90% to 95% have been documented inclinical practice.16 When used, it should be given for 14 days with double-dose PPItwice a day, because this strategy can increase eradication rates by 10%.11

The Achilles heel of clarithromycin-containing nonbismuth quadruple therapies(sequential, hybrid, and concomitant) is dual H pylori resistance to clarithromycinand metronidazole. Sequential, hybrid, and concomitant therapies have been shownto fail when the rate of dual resistant strains is greater than 5%, greater than 9%, orgreater than 15%, respectively.6 Therefore, any empirical nonbismuth quadruple ther-apy would likely be a poor choice in settings with documented high clarithromycin andmetronidazole resistance (eg, Turkey,17,18 Korea19,20; see later discussion) or in somespecific high-risk patients for acquired antibiotic resistance (eg, patients who previ-ously used clarithromycin- and/or metronidazole-containing eradication regimens,women who used metronidazole for trichomonas infections, immigrants from devel-oping countries).6 A decision-making algorithm taking all these considerations into ac-count for first-line eradication regimens is displayed in Fig. 1.

Nonbismuth Quadruple Therapies

Sequential therapySequential therapy was developed in Italy in 2000 as a replacement for triple therapy inorder to overcome the problem of clarithromycin resistance. It initially consisted of

Fig. 1. Recommended approach for Helicobacter pylori therapy.


5 days of PPI plus amoxicillin, followed by a further 5 days of PPI with 2 other antibi-otics, usually clarithromycin and a nitroimidazole.21,22 Several meta-analyses andpooled data analyses, mostly from Italy, confirmed between 2007 and 2009 the advan-tage of 10-day sequential over 7- or 10-day triple therapy, with mean cure ratesgreater than 90%.23–26 In 2012 and 2013, 2 updatedmeta-analyses27,28 and 2 system-atic reviews,29,30 including studies from Asia, Europe, and Latin America, exhibitedmean eradication rates notably lower (79%–84%) than those reported in early Italiantrials. These poor results were confirmed in a global meta-analyses in 2013 with overallcure rates of 84% (95% confidence interval 82.1%–86.4%), besides confirming thelack of advantage over 14-day triple therapy.31 Further analyses have shown thatmetronidazole resistance and dual clarithromycin-metronidazole resistance under-mined the efficacy of sequential therapy.6,32

Concomitant therapyThe concept of a nonbismuth quadruple regimen or concomitant regimen consists ofconverting standard triple therapy to a quadruple therapy by the addition of 500 mg ofmetronidazole or tinidazole twice daily. This therapeutic regimen resurfaced in 2010 asan alternative therapy to triple and sequential therapy. Recent meta-analyses haveconsistently shown its advantage over triple therapy.33,34 In addition, several recentstudies over the last 4 years18,19,35–50 evaluating the efficacy of concomitant therapyhave been conducted in Latin America,35 Asia (Thailand,36 Japan,37 Taiwan,38,39

China,40 and Korea19,41,42), and Europe (Spain,43–45 Greece,46,47 Italy,48,49 andTurkey18,50). Regardless of the duration of therapy, all studies showed intention-to-treat cure rates ranging between 85% and 94%, with the exceptions of regions wheredual resistance is high (Turkey18 and Korea19) or where the duration of therapy testedwas possibly too short (5 days in Latin America35 and Korea37).The efficacy of 14-day concomitant therapy is not impaired by clarithromycin or

metronidazole isolated resistance, but it is expected to decrease less than 90% inregions where the prevalence of dual clarithromycin-metronidazole resistant strainsis greater than 15%.6 Currently, 14-day concomitant therapy should be the preferrednonbismuth quadruple therapy because it is less complicated than sequential therapybecause the drugs are not changed halfway through the treatment course, besides it isthe most effective to overcome dual resistance. Bringing together all studies in whichH pylori dual resistant strains were treated with these therapies, cure rates forconcomitant therapy have been shown to be notably higher (18 of 23 [78%]) whencompared with those of sequential therapy (9 of 27 [33%]).51 Therefore, concomitanttherapy would always be equal or superior to sequential therapy.6 However, it isimportant to stress that neither therapy should be recommended in settings withhigh rates of metronidazole resistance (>50%–60%) along with high clarithromycinresistance (eg, Latin America, Turkey, Korea) or in populations at high risk of dualresistance (eg, following clarithromycin or metronidazole treatment failures).6 Theserecommendations are in agreement as well with good to excellent results in someAsian countries36–40 and Southern Europe,43–49 where clarithromycin ranges fromlow (9%) to high (40%); but metronidazole resistance remains relatively low (<30%–40%). As a matter of fact, if metronidazole resistance remains stable in these settings,clarithromycin resistance would need to exceed 50% to undermine the efficacy of14-day concomitant therapy.

Hybrid (sequential-concomitant) therapyThe hybrid sequential-concomitant regimen is a therapeutic innovation that includes aPPI plus amoxicillin for 14 days, adding clarithromycin and a nitroimidazole for the final


7 days.52 In other words, it is a 7-day first dual-phase (PPI1 amoxicillin) followed by a7-day quadruple phase (PPI 1 amoxicillin 1 clarithromycin 1 nitroimidazole). Severalrecent studies conducted between 2011 and 2014 have consistently shown cure ratesof 86% or greater in Taiwan,52,53 Iran,54 and Spain/Italy44; but poor results have beenreported in other studies conducted in Italy48,49 and Korea.20 It could be considered inthe same populations where concomitant therapy is recommended; however, 14-dayhybrid therapy is expected to decrease less than 90% when clarithromycin-metronidazole resistance exceeds 9%.6 Hybrid therapy provides the advantage ofimproved safety, convenience, and better compliance. A recent first meta-analyseson hybrid therapy has not shown relevant differences in terms of efficacy with thesequential and concomitant therapy.55 Further studies, however, are required to vali-date this therapy in settings with different patterns of resistance.

Bismuth Quadruple Therapy

This therapy is the oldest effective therapy, mostly underappreciated, and a resurfacingone on account of increasing failure of clarithromycin-containing therapies. Doses andduration are critical to the outcome, especially in the presence of metronidazole resis-tance. Using this regimen at full doses and for 14 days, one can expect 95% or greatertreatment success, irrespective of the level of metronidazole resistance.6,56 The maindisadvantages are its complexity and frequent side effects, both of which may hampercompliance with therapy. In addition, bismuth salts or tetracycline are not widely avail-able now. Doxycycline cannot successfully substitute for tetracycline and should not beused.6 This regimen is the regimen most in need of clinical trials to simplify and toimprove compliance. Recent studies conducted in Italy and China have shown similarsuccess rates using twice-a-day bismuth and full 4-times-a-day antibiotic doses.57,58

In this context, bismuth-based quadruple therapy in its most recent galenic formulation,bismuth subcitrate potassium, metronidazole, and tetracycline (bismuth, metronidazoleand tetracycline [BMT], sold under license as Pylera), may be an attractive therapeuticoption.7 However, its use is currently limited by its high cost, the fact that only a 10-dayregimen is available in a prepackaged form, and the dose of tetracycline is only1500 mg. Moreover, it remains unknown if these more convenient formulations produceimproved compliance, especially when considering that side effects are often thereason for poor compliance with bismuth therapy. Head-to-head comparisons withstandard bismuth triple therapy and with twice-a-day dosing for bismuth are needed,especially in populations with high rates of metronidazole resistance.

RESCUE THERAPY

Even with the current most effective treatment regimens, a variable proportion ofpatients will fail to eradicate H pylori infection at the first attempt.6,12 Despite the num-ber of studies, the optimal retreatment regimen has not yet been defined. Our thera-peutic target, similar to first-line regimens, should be at least 90% cure rates. Theempirical choice of a rescue treatment primarily depends on which treatment wasused initially (eg, bismuth or nonbismuth quadruple therapy), the local rate of fluoro-quinolone resistance, and availability of either bismuth salts/tetracycline. After failureof a clarithromycin- or metronidazole-containing treatment, clinicians should assumethat H pylori are likely resistant to the antibiotic used, so it is not appropriate to repeatthe same antibiotics. An exception to this rule is amoxicillin, which rarely induces resis-tance. Most will be cured by using bismuth quadruple therapy after failure ofclarithromycin-containing regimens.58,59 In the absence of pretreatment antibioticresistance testing, the most commonly used strategies for a second-line therapy in


regions where bismuth quadruple therapy is unavailable is a fluoroquinolone-containing therapy. This therapy should only be considered if no fluoroquinolone,including ciprofloxacin, was used before.6 Rescue therapy is defined as therapy after2 treatment failures with 2 different regimens.6,60 At this stage, recent European guide-lines recommend that treatment should be guided by antimicrobial susceptibilitytesting, whenever possible.11 The available regimens for rescue therapy, withpreferred duration, doses, and interval dosing, besides potential caveats, are summa-rized in Table 4. Furazolidone quadruple therapy (where available) and rifabutin tripletherapy are typically reserved as salvage therapies of last resort. A recommendedtherapeutic algorithm for H pylori rescue therapy is displayed in Fig. 1.

Fluoroquinolone-Containing Therapy

Levofloxacin is a fluoroquinolone with a broad spectrum of activity against H pylori.Fluoroquinolone-based therapy has been proposed in several international guidelinesas a rescue therapy. However, prevalence of fluoroquinolone resistance has increasedrapidly in recent years, mostly because of widespread use of levofloxacin for respira-tory tract, urinary, and ear, nose, and throat infections. Recent studies have reportedhigh levofloxacin resistance rates, ranging from 63% in China to 14% in Europe.6,14 Arecent review revealed a weighted efficacy of 76% for levofloxacin-containing rescueregimens.60 Indeed, 7-day triple therapy, including PPI, amoxicillin, and levofloxacin,provides cure rates of typically less than 80%; extending the duration to 10 daysimproves outcomes, but the treatment success has remained typically less than90%.60–63 Treatment success would decrease to less than 90% with 14-day

Table 4Current rescue therapeutic recommendations, in the era of increasing fluoroquinoloneresistance, in patients with high risk of acquired clarithromycin and/or metronidazoleresistance after failure of first eradication regimen

Eradication Regimens Preferred Dosages Caveat

14-d Fluoroquinolone tripletherapy

PPI (double doses) bidAmoxicillin 1000 mg bidLevofloxacin 500 mg

Cure rates �90% if levofloxacinresistance �12%

14-d Bismuth-containingfluoroquinolonequadruple therapy

Bismuth salts 240 mg bidPPI (double doses) bidAmoxicillin 1000 mg bidLevofloxacin 250 mg bid

Cure rates �90% if levofloxacinresistance �25%

14-d Bismuth quadrupleconcomitant therapy

PPI (double doses) bidBismuth salts 240 mg bidPlus a combination of 2antibiotics among thefollowing:Amoxicillin 1 g tid/bidNitroimidazole 500 mg tidTetracycline 500 mg qidFurazolidone 100 mg tid

AvailabilitySide effectsComplexityCompliancePotential genotoxic and

carcinogenetic effects offurazolidone

14-d Rifabutin-containingtherapy

PPI (double doses) bid, tidAmoxicillin 1000 mg tidRifabutin 150 mg bid

CostPotential severe side effects

(myelotoxicity andhepatotoxicity)

Risk of development of resistancein M tuberculosis


fluoroquinolone triple therapy when fluoroquinolone resistance rates exceed approx-imately 12%,64 whereas 14-day bismuth-containing fluoroquinolone quadruple ther-apy will not reach 90% cure rates in areas with a fluoroquinolone resistance of upto approximately 25%.65 Therefore, awareness of local resistance rates or close moni-toring of cure rates are mandatory in order to promptly detect inefficacy of these ther-apies. The role of newer fluoroquinolones, such as sitafloxacin and gemifloxacin, toovercome fluoroquinolone resistance needs to be validated in further studies.

Bismuth Quadruple Therapy, Including Furazolidone-Containing Regimens

Classic bismuth quadruple regimen has also been proposed in international guidelinesas a rescue therapy.11 In a recent review, its weighted efficacy was 77% (includingdifferent durations, drug doses, and interval dosing).60 Concerns with this therapyare complexity, patient compliance, and availability. Meta-analyses comparingfluoroquinolone-based triple therapy and bismuth quadruple therapies for rescue ther-apy did not find significant differences between both therapies regarding efficacy,albeit fluoroquinolone therapy was significantly better tolerated and induced signifi-cantly fewer side effects.60–62 Importantly, the results with both regimens were likelyunacceptably low because of the poor choices of doses, duration, and the presenceof resistance.Bismuth quadruple therapy, however, is the regimen with the most unanswered

questions regarding what the optimal doses are and the frequencies of drug adminis-tration. A recent study from China has evaluated the efficacy of 14-day bismuthquadruple therapies (PPI, bismuth salts, and 2 antibiotics) with different antibioticcombinations in patients with previous eradication treatment failure.58 They used forall 4 evaluated regimens twice-a-day bismuth (220 mg twice a day) and full dosesand adequate dosing intervals for the antibiotics (amoxicillin 1 g 3 times a day, tetra-cycline 500 mg 4 times a day, metronidazole 400 mg 3 times a day, furazolidone100 mg 3 times a day). Cure rates were excellent (>90%), regardless of the presenceof clarithromycin, levofloxacin, or metronidazole resistance, with the best results forfurazolidone-containing regimens. Of note, these bismuth quadruple regimens wereequally effective for patients allergic to penicillin, combining tetracycline with eithermetronidazole or furazolidone. However, furazolidone is seldom available in devel-oped countries; concerns about possible genotoxic and carcinogenetic effects mayprevent its implementation. This study, however, importantly highlights that both effi-cacy and compliance with bismuth quadruple therapy can be improved through opti-mization of therapy.

Rifabutin-Containing Therapy

Rifabutin is a rifamycin-S derivative, which shares many of the properties of rifampin(rifampicin). Rifabutin is commonly used to treatMycobacterium avium andMycobac-terium intracellulare; it has shown utility againstH pylori seeing as the in vitro sensitivityis high and prevalence rate of rifabutin resistance is very low, only about 1%. A recentsystematic review disclosed the mean H pylori eradication rate with rifabutin-containing rescue regimens was 73%.66 Respective cure rates for second-, third-and fourth/fifth-line rifabutin therapies were 79%, 66%, and 70%. The mostprescribed regimen has been a triple therapy combining PPI, amoxicillin, and rifabutin.The most effective dose is 300 mg/d; the ideal length remains unclear, although 10- to14 day-regimens are generally recommended. The most successful cure rates (�90%)have been reported using high-dose PPI (60 mg twice a day, 80 mg 3 times a day),high-dose amoxicillin (1.0 or 1.5 g 3 times a day), and rifabutin (150 mg twice a day)for 7 to 12 days.67,68 The main disadvantages of this drug are its high cost, uncommon


but relevant adverse effects (mainly myelotoxicity and hepatotoxicity), and the poten-tial development of resistance toM tuberculosis in populations with a high prevalenceof tuberculosis. Owing to all these reasons, it should be kept as the last therapeuticresort.

PROBIOTICS

Probiotics are live microorganisms or produced substances that are orally adminis-trated, usually in addition to conventional antibiotic therapy for H pylori infection.They may modulate the human microbiota, stimulate the immune response, anddirectly compete with pathogenic bacteria, besides preventing antibiotic side ef-fects.69 Indeed, probiotics have exhibited inhibitory activity against H pylori in vitroand in vivo.70,71 Now 10 meta-analyses have been published addressing the specificbenefit of Lactobacillus and Bifidobacterium,72,73 bovine lactoferrin,74,75 fermentedmilk-based,76 Lactobacillus,77,78 and Saccharomyces boulardii79 probiotic formula-tions as well as probiotics as a whole therapeutic group.80–82 Available evidencecollectively points toward a benefit of using probiotic for decreasing antibiotic-related side effects and, to a much lesser extent, increasing cure rates.However, several considerations should be taking into consideration when it comes

to probiotic supplementation. To begin with, they add complexity as they mean afourth or fifth drug, depending on dealing with triple and quadruple therapies, and itmay increase the risk of poor compliance with therapy. Furthermore, probiotics areover-the-counter medications; the cost of eradication therapy may notably increase.Unlike meta-analyses, several studies have failed to find any advantage by addingprobiotics to H pylori therapy.83–85 Most likely, the discordant results are probablyrelated to the different products used and their different concentrations, probioticstrain, dose, and the length of duration. Further studies, refining the most effectiveprobiotic and the patient profile that will most benefit from probiotic supplementationare needed before a general recommendation in clinical practice can be made.

SUMMARY

H pylori infection has proven challenging to eradicate because of several bacteria-,environmental-, host-, and drug-associated factors. An effective therapy is definedas one achieving at least a 90% eradication rate with the first attempt. Cure rates ofH pylori with triple therapy have declined to unacceptable levels worldwide, mostlybecause of increasing clarithromycin resistance rates. Therefore, novel first-line treat-ments are required and should be chosen on local prevalence of H pylori antimicrobialresistance or, if unavailable, empirically based on a combination using only regimensthat have proven to be reliably excellent locally and knowledge of prior use of antibi-otics by patients. The preferred empirical choices are currently 14-day concomitanttherapy and 14-day bismuth quadruple therapy. Optimization of eradication schemesshould always be ensured to maximize their efficacy. Rescue therapy after failureeradication regimens should be tailored based on antimicrobial susceptibility testingand, if not available, chosen on which treatments used initially (eg, bismuth or nonbis-muth quadruple therapy) and the prevalence of fluoroquinolone resistance locally.Where available, furazolidone- and rifabutin-containing therapies are likely to be suc-cessful as a rescue therapy. Probiotics may reduce side effects and improve adher-ence to increasingly complex regimens. Whether probiotics can also increaseeradication rates should be further elucidated. On large variations in H pylori resis-tance patterns, the golden rule for choice of treatment is only to use what works locally(>90%–95% success) and to closely monitor its effectiveness over time.


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