Current regimens for treatment of Helicobacter pylori infection

Current regimens for treatment ofHelicobacter pylori infection

Adam HarrisThe Kent and Sussex Hospital, Royal Tunbridge Wells, Kent, UK

The aim of treatment of Helicobacter pylori is eradication of the bacterium fromthe foregut. Treatment is difficult because of the bacterium's habitat andacquired resistance to commonly used antibiotics. Dual therapy, the 2 weekcombination of omeprazole or ranitidine bismuth citrate and either amoxycillinor clarithromycin, eradicates H. pylori in 50-80% of patients. Classical tripletherapy is commonly associated with side effects, is highly dependent onpatient's compliance, and is significantly less effective in the presence ofmetronidazole-resistant strains of H. pylori, where eradication may be 50%. Oneweek, twice daily, proton pump inhibitor (PPI)-based triple therapy regimenseradicate about 90% of H. pylori and are associated with mild side effects.Second line regimens include 7 days treatment with omeprazole and 3 timesdaily amoxycillin and metronidazole or a PPI-based quadruple therapy regimen.In some cases, the bacterium defeats all attempts at eradication.

Correspondence to: DrAdam Harris, Consultant

Physician and

Gastroenterologist TheKent and Sussex Hospital,

Royal Tunbndge Wells,Kent TN4 BAT, UK

The aim of treatment of H. pylori infection in any clinical situation iseradication of the bacterium from the foregut. Eradication is currentlydefined as negative tests for H. pylori at least 28 days after the end ofantimicrobial therapy.

Treatment of H. pylori infection is difficult for two main reasons.First, the bacterium lives below the gastric mucus adherent to the gastricepithelium and access of antimicrobial drugs to this site is restricted,both from the lumen of the stomach and from the gastric blood supply.

Second, H. pylori may have acquired resistance to the commonly usedantimicrobial agents, such as 5-nitroimidazoles (metronidazole, tinidazole)and macrolides (clarithromycin). Pre-treatment metronidazole-resistantstrains (MRS) of H. pylori are more common among ethnic minoritieswhere these drugs may have been used previously to treat infectiousdiarrhoea. In such cases, the prevalence of MRS of H. pylori may be ashigh as 95%1. Pretreatment clarithromycin-resistant strains (CRS) of H.pylori are less common, but are increasing in prevalence because ofwidespread use of this drug in the community to treat respiratory tractinfections2"3. In the UK, less than 5% of H. pylori have acquired resistance

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Helicobacter infection

to clarithromycin4, but, in Spain and France, the prevalence of CRS ofH. pylori may be as high as 15%2-3. As a result of acquired resistance tothe commonly used agents, treatment regimens have been developedusing two or more antimicrobial drugs, for example triple or quadrupletherapy regimens. Although these are effective, somewhat complex treat-ment schedules and unwanted effects of the drugs, may lessen complianceand thus their efficacy5.

The ideal therapy for H. pylori eradication should be simple, safe, freefrom side effects, with 100% efficacy and low cost. The ideal treatmentregimen has not yet been defined. Research in this area has beencomplicated by the small number of randomised, controlled trials andthe large number of studies mainly published as abstracts (70%, 576 of823 publications to date). Moreover, details of doses and duration oftreatment vary between the various trials, limiting the scope for meta-analysis.

Current eradication regimens are discussed under the heading of dual,classic triple, low-dose triple and quadruple therapy, depending on thenumber and dose of antimicrobial agents used concurrently in thetreatment. Eradication percentage is reported using an intent-to-treat('worst-case') analysis whereby all patients treated are included in theanalysis even if they failed to take the drugs or return for follow-up; inwhich case they are assumed to be treatment failures. Intent-to-treatanalysis provides a more realistic assessment of the H. pylori eradicationtherapy than a per-protocol analysis ('best-case') whereby only thosepatients taking the majority (or all) of the drugs and returning for follow-up are included. A per-protocol analysis provides data about the efficacyof a particular regimen under ideal circumstances, but the results may notbe reproducible outside of clinical trials.

Dual therapy

Dual therapy refers to the combination of omeprazole or ranitidinebismuth citrate (RBC) and either amoxycillin or clarithromycin. Theseregimens were reported to overcome problems that had bedevilledclassic triple therapy, such as side effects, MRS of H. pylori and patient'scompliance with more complex regimens.

Omeprazole and amoxycillin

Most of the work dealing with dual therapy uses omeprazole andamoxycillin (Table 1), is published as abstracts and is based on small,

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H pylori eradication

Table 1 Dual therapy with amoxycillin

Dosing

Duration

H. pylori eradication

Side effects

OmeprazoleAmoxycillin

20-40 mg twice daily750 mg 3 times daily or

50-85%

Ranitidine bismuth citrateAmoxycillin

400-800 mg twice daily1g twice daily 500 mg 4 times daily

2 weeks

65%

Common: diarrhoea

uncontrolled, non-randomised studies6. The results suggest that the dailydose of amoxycillin should be at least 2 g; the frequency ofadministration appears to be less important than the compliance withthe treatment regimen. In combination with amoxycillin, omeprazole ismore effective when given twice daily and at higher than normal doses.Thus, eradication with omeprazole 20 mg or 40 mg once daily withamoxycillin 2 g daily for 2 weeks varies between 0% and 28%, but on20—40 mg twice daily in combination with amoxycillin 1 g twice daily(or 500 mg, 4 times daily) for 2 weeks, eradication was 50-90%6.However, recent data from large, double-blind, randomised controlledtrials of 2 weeks' treatment with omeprazole (20 or 40mg twice daily)and amoxycillin (500 mg or lg 3 times daily) reported H. pylorieradication of only 39-46%7. There are less data on lansoprazole orpantoprazole, in combination with amoxycillin, but preliminary studiessuggest that the results with these newer PPIs are similar6.

Omeprazole with clarithromycin

Inhibition of acid secretion with PPIs increases the intragastric pH to 5.0or more and significantly decreases the minimum inhibitoryconcentration (MICJ0) of amoxycillin and clarithromycin making themmore effective. The combination of various dosages and duration ofomeprazole6, lansoprazole8 or pantoprazole9 with clarithromycin for H.pylori eradication have been studied (Table 2). The frequency of dosingwith clarithromycin is important. Thus, clarithromycin 500 mg giventwice daily in combination with omeprazole 40 mg was apparently lesseffective, with eradication reported as 56%n, compared with 63-81%on clarithromycin 500 mg, 3 times daily6'12. Side effects occur in up tohalf of patients treated with clarithromycin and omeprazole and becomemore common as the dose and frequency of clarithromycin increase, thecommonest being taste disturbance. Clarithromycin is a relativelyexpensive antimicrobial agent, and a 2 week combination of omeprazole

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Table 2 Dual therapy with clarithromycin

Omeprazole Ranitidine bismuth citrateClarithromycin Clarithromycin

Dosing 40 mg once daily 400 mg twice daily

500 mg 3 times dairy 500 mg twice daily

Duration 2 weeks

H. pylon eradication 80%

Side effects Common: taste disturbances, diarrhoea

40 mg daily and clarithromycin 500 mg 3 times daily costs about £100,which is considerably more than most other regimens.

Ranitidine bismuth citrate

Ranitidine bismuth citrate (RBC) is a new chemical compound thatcombines the antisecretory activity of ranitidine with mucoprotectiveand H. pylori suppressive effects of bismuth. Dual therapy with RBC(400 mg twice daily) and amoxycillin (500 mg 4 times daily) orclarithromycin (250 mg 4 times daily or 500 mg twice daily) for 2 weeksis licensed for H. pylori eradication. RBC with amoxycillin willeradicate H. pylori in about 65% of cases13, but with clarithromycin 500mg twice daily, the figures become about 80% (Tables 1 & 2)14"16.Unfortunately, any possible advantages of twice daily dual therapy withRBC and clarithromycin are outweighed by the need for 14 days'treatment and high treatment cost.

Classic triple therapy

Classic triple therapy (Table 3) consists of a bismuth compound (colloidalbismuth subcitrate (CBS) or bismuth subsalicylate, BSS), metronidazoleand either amoxycillin or tetracycline. There are wide variations in thedosage and treatment schedules used in these regimens, with eradicationresults varying from 30-95%6. It is difficult to account for thesedifferences, except by invoking the customary factors of dissimilarities inpatient populations, incidence of metronidazole resistance, degree ofcompliance with the treatment and the like. Triple therapy given for lessthan 7 days has not been successful and when given for longer than 14days appears to give no further therapeutic advantage6.

Classic triple therapy is significantly less effective against pretreatmentMRS of H. pylori, with most eradication results falling between 30%and 60% in this group of patients6'17-18.

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Table 3 Triple therapy

Dosing

DurationH. pylori eradication

Side effects

combinations with amoxycillin

OmeprazoleAmoxycillinMetronidazole

40 mg once dally500 mg 3 times daily400 mg 3 times daily

7 days95% in MSS75% in MRS

and metronidazole

RanitidineAmoxycillin

Metronidazole

300 mg once daily750 mg 3 times daily500 mg 3 times daily

12 days90% in MSS50% in MRS

Common: diarrhoea, nausea

Colloidal bismuth subcitrateTetracycline or amoxycillinMetronidazole

120 mg 4 times daily500 mg 4 times daily200-400 mg 4 times daily

2 weeks60-90% in MSS50% in MRS

MSS = metronidazole-sensitive strains of H. pyloriMRS = metronidazole-resistant strains of H. pylori.

Alternative triple therapy regimens

Antisecretory drugs have been tried in place of bismuth as part of atriple therapy with some success (Table 3). Thus, ranitidine 300 mg dailycombined with metronidazole 500 mg 3 times daily and amoxycillin 750mg 3 times daily for 12 days was shown to eradicate around 90% of H.pylori19. However, this regimen is far less effective against MRS of H.pylori, where eradication is around 50%19>20.

The combination of omeprazole 40 mg21, lansoprazole 30 mg22 orpantoprazole 40mg23 with amoxycillin 500 mg 3 times daily andmetronidazole 400 mg 3 times daily for 1 week is an effective tripletherapy, with H. pylori eradication in around 90% of the patients. Inpatients with pretreatment MRS of H. pylori, the omeprazole-basedregimen was shown to be effective in about 75% of cases21.Thus, inareas with a high prevalence of MRS and CRS of H. pylori, 1 week'streatment with omeprazole, amoxycillin and metronidazole may be thefirst choice. Moreover, this regimen is one of the cheapest costingaround £20.

Low-dose triple therapy

In 1993, Bazzoli and colleagues reported 100% H. pylori eradication in36 patients using a 1 week, low-dose triple therapy regimen of omeprazole20 mg daily, clarithromycin 250 mg and tinidazole 500 mg taken twicedaily24. Subsequent studies in large randomised, comparative trials haveconfirmed that the combination of omeprazole25 or lansoprazole26 plus

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Table 4 Low-dose

Dosing

Duration


Side effects

triple therapy regimens

PPIClarithromycinMetronidazole

once daily or twice daily250 mg twice daily400 mg twice daily

7 days

90%(75% in MRS)

Uncommon: nausea.

PPIAmoxycillinClarithromycin

twice daily1 g twice daily250-500 mg twice daily

90%

diarrhoea

PPI = proton pump inhibitorMRS = metronidazole-resistant strains of H. pylori.

clarithromycin and a nitroimidazole or amoxycillin taken twice daily for1 week will eradicate about 90% of H. pylori (Table 4). Similar resultshave been reported using pantoprazole27"28. These low-dose regimensappear to be associated with few side-effects; nausea and diarrhoea beingthe commonest25'26.

In combination with clarithromycin and a nitroimidazole, there appearsto be no therapeutic advantage in increasing the dose of omeprazole above20 mg daily29, lansoprazole above 30 mg daily30 or pantoprazole above 40mg daily27. There is a paucity of data comparing the different PPIs usingthe same antimicrobials, but recently a randomised trial showed nosignificant difference in H. pylori eradication between lansoprazole 30 mgtwice daily or omeprazole 20 mg twice daily in combination withamoxycillin 1 g twice daily and clarithromycin 500 mg twice daily31.

The data are conflicting regarding the best dose of clarithromycin (250or 500 mg twice daily) in combination with a PPI and either amoxycillinor metronidazole32"34. In the MACH 1 study, omeprazole, amoxycillinand clarithromycin produced higher H. pylori eradication withclarithromycin 500 mg twice daily, but with omeprazole, metronidazoleand clarithromycin, the lower dose of clarithromycin 250 mg twice dailywas more effective25. Interestingly, a study from Japan reported H.pylori eradication in 100 of 101 (99%) patients after 1 week's treatmentwith omeprazole 40 mg twice daily, amoxycillin 2 g twice daily andclarithromycin 1.6 g twice daily35.

Preliminary data using twice daily RBC in combination with twoantimicrobials look promising36"38. A recently reported randomisedstudy of RBC 400 mg twice daily, clarithromycin 500 mg twice dailyand amoxycillin 1 g twice daily for 2 weeks reported H. pylorieradication in 21 of 22 (95%) patients (intent-to-treat)36. Similar results

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were reported from a randomised study of 7 days' treatment with RBC400 mg twice daily, clarithromycin 250 mg twice daily andmetronidazole 500 mg twice daily with H. pylori eradication in 31 of 36(86%) patients38. Unfortunately, the prevalence of MRS of H. pylori wasnot determined. An open study of 1 week's treatment with RBC 400 mgtwice daily, clarithromycin 500 mg twice daily and tetracycline 500 mgtwice daily reported H. pylori eradication in 43 of 48 (90%) patients(intent-to-treat analysis)37. Side effects, such as diarrhoea, nausea andtaste disturbances, were commonly reported.

Effect of metronidazole-resistance

In the UK and Eire multicentre study of 1 week, low-dose, PPI-basedtriple therapy regimens, pretreatment H. pylori antimicrobialsensitivities were determined on culture of gastric biopsies26. The threemetronidazole-containing regimens were similarly effective in patientswith pretreatment MSS strains of H. pylori, but were significantly (P <0.05) less effective against MRS of H. pylori. More recently, the efficacyof omeprazole, clarithromycin and metronidazole was reported to besignificantly decreased against MRS of H. pylori, where H. pylorieradication decreased from 95% for strains susceptible to metronidazoleto 76% for resistant strains39. MRS of H. pylori may reach 90%prevalence in inner city areas1, where the metronidazole-containingregimens may be less effective. In such areas, an eradication regimencomprising a PPI, amoxycillin and clarithromycin may be preferable.

Duration of treatment

Tompkins et at40 recently reported the results of a randomised studyusing 5 days' treatment with lansoprazole 30 mg and clarithromycin250 mg with either amoxycillin 1 g or metronidazole 400 mg; all drugstaken twice daily. Lansoprazole, amoxycillin and clarithromycineradicated H. pylori in 29 of 47 (62%) patients, which is considerablyless than that reported from a larger randomised trial using the sametreatment for 7 days, where H. pylori was eradicated in 104 of 121(86%) patients26. Five days' treatment with lansoprazole, clarithromycinand metronidazole eradicated H. pylori in 38 of 45 (84%) patients.Interestingly, in those patients with MSS of H. pylori this 5 daytreatment eradicated the bacterium in 13 of 14 patients (93%), but wassignificantly less effective in those with MRS of H. pylori (13 of 19,68%). These findings suggest that, in the presence of MSS of H. pylori,5 days' treatment with lansoprazole, clarithromycin and metronidazole

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Table 5 Quadruple therapy

Dosing

Duration


Side effects

PPIColloidal bismuth subcitrateTetracyclineMetronidazole

once daily - twice daily120 mg 4 times daily500 mg 4 times dally400-500 mg 4 times daily/3 times daily

7 days

85-95%

Common: diarrhoea, nausea

PPI = proton pump inhibitor.

may be enough, but if the antimicrobial resistance patterns of H. pyloriare unknown, then at least 7 days' treatment is required.

Is there any evidence to recommend using PPI-based triple therapyregimens for 10 days? The studies of 10 days' treatment withomeprazole, amoxycillin and clarithromycin provide conflictingresults41-42. A small randomised trial, compared 7, 10 or 14 days'treatment with omeprazole 20 mg, amoxycillin 1 g and clarithxomycin500 mg twice daily and reported that H. pylori eradication wassignificantly (P < 0.05) higher (83%) with the 10 day, than with the 7day (77%) regimen41. However, another study comparing 7 with 10days' treatment the same regimen reported 95% H. pylori eradication inboth treatment arms43.

Lerang et al33, in a multicentre, randomised, double-blind study,reported H. pylori eradication in 72 of 76 (95%, intent-to-treat) patientstreated for 10 days with twice daily omeprazole 20 mg, clarithromycin250 mg and metronidazole 400 mg. The efficacy of this 10 day regimenwas unaffected by the pretreatment metronidazole sensitivity of H.pylori, with eradication in 17 of 18 (94%) patients with MRS of H.pylori. These conflicting data on the importance of MRS of H. pyloriwhen using PPI, clarithomycin and metronidazole cannot be resolved atpresent, but suggest that a 10 day treatment course of PPI,clarithromycin and metronidazole may overcome MRS of H. pylori.

Quadruple therapy

Quadruple therapy (Table 5) for H. pylori eradication must entail morecompliance problems and side effects than the simpler regimens44'45.

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Despite this, 98% H. pylori eradication has been reported using a 1week combination of omeprazole (20 mg twice daily given for 10 days),CBS (120 mg 4 times daily), tetracycline (500 mg 4 times daily) andmetronidazole (500 mg 3 times daily)45. Compliance was remarkablyhigh in this well performed study, and all patients were followed-up.Only 7.7% of the pretreatment H. pylori isolates were metronidazoleresistant, and this may account for the very high eradication reported.Similar results have been reported using lansoprazole-based quadrupletherapy regimens46.

Twice daily quadruple therapy (bismuth subsalicylate, tetracycline 500mg, metronidazole 500 mg and lansoprazole 15 mg) for 10 days wasreported to be effective against MSS of H. pylori (95% eradication), butwas significantly less effective against MRS of H. pylori (40%eradication) and is, therefore, of no benefit over simpler and shortertwice daily regimens47.

Conclusions

At the time of writing this review article, the ideal treatment for H.pylori eradication does not exist. About 90% H. pylori eradication ispossible after 1 week's treatment with a PPI in combination withclarithromycin 250-500 mg and either amoxycillin 1 g or metronidazole400 mg; all drugs taken twice daily. A second line regimen of 1 week'streatment with omeprazole 40 mg daily, amoxycillin 500 mg 3 timesdaily and metronidazole 400 mg 3 times daily has been shown toeradicate H. pylori in over 75% of the first-line failures. Quadrupletherapy is an alternate second line therapy in motivated patients, butotherwise is best reserved for third line. In some cases the bacteriumdefeats all attempts at eradication and definitive treatment may have toabandoned; fortunately such instances are infrequent.

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Current regimens for treatment of Helicobacter pylori infection

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