Fourteen-day triple therapy with a proton pump inhibitor (PPI) plus clarithromycin and either amoxicillin or metronidazole is superior to 7-day therapy in eradicating Heliobacter pylori (strength of recommendation [SOR]: A, highquality meta-analysis). Seven-day triple therapy with a PPI or ranitidine bismuth citrate plus clarithromycin and either amoxicillin or metronidazole is also effective (SOR: A, high-quality systematic review). Three-day quadruple therapy with a combination of PPI, clarithromycin, bismuth subcitrate, and metronidazole or a combination of PPI, clarithromycin, amoxicillin, and metronidazole also appears to be effective (SOR: B, unblinded randomized controlled trial)

Malaty, Wail

Stigleman, Sue

University of Missouri: MOspace

OCTOBER 2003 / VOL 52, NO 10 · The Journal of Family Practice 799F R O M T H E F A M I L Y P R A C T I C E I N Q U I R I E S N E T W O R KClinical  InquiriesWhat regimens eradicateHeliobacter pylori?■ EVIDENCE-BASED ANSWERFourteen-day triple therapy with a proton pumpinhibitor (PPI) plus clarithromycin and eitheramoxicillin or metronidazole is superior to 7-daytherapy in eradicating Heliobacter pylori(strength of recommendation [SOR]: A, high-quality meta-analysis). Seven-day triple therapy with a PPI or raniti-dine bismuth citrate plus clarithromycin andeither amoxicillin or metronidazole is also effec-tive (SOR: A, high-quality systematic review). Three-day quadruple therapy with a combina-tion of PPI, clarithromycin, bismuth subcitrate,and metronidazole or a combination of PPI, clarithromycin, amoxicillin, and metronidazolealso appears to be effective (SOR: B, unblindedrandomized controlled trial).■ EVIDENCE SUMMARYThe ideal H pylori eradication regimen shouldreach an intention-to-treat cure rate of 80%(Table).1 Effective regimens are:Fourteen-day triple therapy of PPI + clar-ithromycin + metronidazole or amoxicillin. Ameta-analysis of 13 studies found the eradica-tion rate for 14-day therapy was 81% (95% confidence interval [CI], 77%–85%), comparedwith 72% (95% CI, 68%–76%) for 7-day thera-py. The eradication rate for 10-day therapy(83%; 95% CI, 75%–89%), however, was notsignificantly better than that for 7-day therapy(80%; 95% CI, 71%–86%).2 Side effects weremore frequent in the longer therapies, but didnot lead to discontinuation of therapy. Seven-day triple therapy of PPI + clar-ithromycin + metronidazole or amoxicillin. Ahigh-quality systematic review of 82 studiesusing 7-day triple therapy found clarithromycin500 twice daily yielded a higher eradication ratethan clarithromycin 250 mg twice daily whencombined with a PPI and amoxicillin (87% vs81%; P<.0001). When clarithromycin was combined with a PPI and metronidazole, thehigher dose of clarithromycin did not yield significantly higher eradication rates (88% vs89%, P=.259).3Seven-day triple therapy of ranitidine bis-muth citrate + clarithromycin + metronidazoleor amoxicillin. For these therapies, a high-quality systematic review of 8 studies reportederadication rates of 81% (95% CI, 77%–84%)with amoxicillin and 88% (95% CI, 85%–90%)with metronidazole.4,5 Side effects were notreported in a uniform manner for the 7-day ther-apies, but were noted to be mild and did not leadto significant discontinuation of therapy. Pooleddropout rates were similar among all regimens.4What is a Clinical Inquiry?Clinical Inquiries answer real questions that familyphysicians submit to the Family Practice InquiriesNetwork (FPIN), a national, not-for-profit consortiumof family practice departments, residency programs,academic health sciences libraries, primary carepractice-based research networks, and individualswith particular expertise.Questions chosen for Clinical Inquiries are thoseconsidered most important, according to results ofweb-based voting by family physicians across the U.S.Answers are developed by a specific method:• First, extensive literature searches are con-ducted by medical librarians.• Clinicians then review the evidence and writethe answers, which are then peer reviewed.• Finally, a practicing family physician writes acommentary.C O N T I N U E DC L I N I C A L  I N Q U I R I E S800 OCTOBER 2003 / VOL 52, NO 10 · The Journal of Family PracticeThree-day quadruple therapy of PPI + bismuth + clarithromycin + metronidazole orPPI+ clarithromycin + amoxicillin + metron-idazole. An otherwise high-quality but unblind-ed randomized clinical trial of 234 patientsdemonstrated that 2 days of pretreatment withlansoprazole followed by 3 days of lansoprazolewith clarithromycin, amoxicillin, and metronida-zole yielded eradication rates comparable with5-day treatment (81% vs. 89%; P<.05).6Another randomized clinical trial of 118patients, blinded to investigators but notpatients, showed that quadruple 3-day therapywith lansoprazole + bismuth + clarithromycin+ metronidazole was as effective as 7 days of lansoprazole + clarithromycin + metronidazole(87% vs 86%; P=.94), and had significantlyshorter duration of side effects (2.6 vs 6.2 days; P<.001). Eradication rates were similar in isolates that were resistant or sensitive to either metronidazole or clarithromycin.7The problems of emerging clarithromycinand metronidazole resistance have not beenC O N T I N U E DEffective therapies for Heliobacter pylori eradicationRegimen Dosage Duration (days) Cost ($)b SORPPIa 14 210 AClarithromycin 500 mg twice dailyMetronidazole 500 mg twice daily oramoxicillin 1000 mg twice dailyPPI 7 105 AClarithromycin 500 mg twice dailyAmoxicillin 1000 mg twice dailyPPI 7 105 AClarithromycin 500 mg twice dailyMetronidazole 500 mg twice dailyRanitidine bismuth citrate 400 mg twice daily 7 85 AClarithromycin 500 mg twice dailyAmoxicillin 1000 mg twice dailyRanitidine bismuth citrate 400 mg twice daily 7 82 AClarithromycin 250 mg twice dailyMetronidazole 500 mg twice dailyPPI 3 46 BClarithromycin 500 mg twice dailyMetronidazole 400 mg twice dailyBismuth subcitrate 240 mg twice dailyPPI (5 days) 3 60 BClarithromycin 250 mg twice dailyAmoxicillin 1000 mg twice dailyMetronidazole 400 mg twice dailya. PPI: standard twice-daily dosing—eg, lansoprazole 30 mg or omeprazole 20 mg b. Approximate cost of entire course of therapy from www.drugstore.com, August 2003.PPI, proton pump inhibitor; SOR, strength of recommendation (for an explanation of evidence ratings, see page 779)TA B L EC L I N I C A L  I N Q U I R I E S802 OCTOBER 2003 / VOL 52, NO 10 · The Journal of Family Practiceextensively studied. In 1 review, metronida-zole-containing regimens eradicated metron-idazole-sensitive strains more effectively thanmetronidazole-resistant strains (weighted dif-ference, 15%; 95% CI, 8%–20%).4 When aninfection is resistant to metronidazole, amoxi-cillin should be used instead.4 In areas of highclarithromycin and metronidazole resistance, aquadruple regimen might be more effective.7■ RECOMMENDATIONS FROM OTHERSThe Maastricht Consensus of the EuropeanHeliobacter Study Group1 recommends a 7-daytriple regimen of PPI + clarithromycin + eithermetronidazole or amoxicillin or (if clarithromycinresistance is prevalent) PPI + amoxicillin 500 mg3 times daily + metronidazole 500 mg 3 times daily. The American College of Gastroenterology recommends 14-day therapy of one of the follow-ing options:8• PPI + clarithromycin + (metronidazole or amox-icillin), or ranitidine bismuth citrate + clar-ithromycin + (metronidazole or amoxicillin).Tetracycline 500 mg twice a day can be substitut-ed for amoxicillin or metronidazole• PPI + bismuth subsalicylate 525 mg + metron-idazole 500 mg 3 times daily + tetra-cycline 500mg 4 times daily• Bismuth subsalicylate 525 mg 4 times daily +metronidazole 250 mg 4 times daily + tetra-cycline 500 mg 4 times daily + H2 receptor antag-onist in standard acid-suppression dose (eg, famo-tidine 20 mg twice a day for 4 weeks).The Institute for Clinical Systems Improve-ment recommends as first-choice treatment a 7-day PPI/clarithromycin/amoxicillin combina-tion, and as second choice a 7-day regimen ofPPI, tetracycline 250 mg 4 times daily, metron-idazole 500 mg twice daily, and bismuth subsal-icylate 525 mg 4 times daily.9Wail Malaty, MD, Mountain Area Health EducationCenter Rural Track Family Practice Residency,Hendersonville, NC; Sue Stigleman, MLS, HealthScience Library, Mountain Area Health Education Center,Asheville, NC■ CLINICAL COMMENTARYPatients beginning complex regimensrequire counselingThe most effective regimens (>80% eradica-tion) for H pylori include a 10- to 14-day courseof at least 2 antibiotics and an antisecretoryagent. However, even optimal treatment regi-mens can fail in approximately 10% ofpatients. Poor compliance is among the mostcommon reasons for treatment failure.Medication side effects can affect up to 50% ofpatients taking triple-agent regimens. Treatment regimens with multiple medica-tions administered several times daily can bedifficult to follow. Convenient packaging con-taining all daily medications are available tooptimize adherence.Counseling points for patients shouldinclude how to take the medicine correctly,expected side effects, the importance of completing the entire therapy regimen, andwarnings of specific interactions (eg, alcoholand metronidazole). Lastly, the patient shouldbe made aware of the cost of the entire regimen,which ranges from $50 to $250. Laura B. Hansen, PharmD, BCPS, University ofColorado Health Sciences Center, Denver, ColoradoREFERENCES1. Current European concepts in the management ofHeliobacter pylori infection. The Maastricht ConsensusReport. European Heliobacter Pylori Study Group. Gut1997; 41:8–13.2. Calvet X, Garcia N, Lopez T, Gisbert JP, Gene E, Roque M.A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and either metron-idazole or amoxicillin for treating Heliobacter pylori infection. Aliment Pharmacol Ther 2000; 14:603–609.3. Huang J, Hunt RH. The importance of clarithromycin dosein the management of Heliobacter pylori infection: a meta-analysis of triple therapies with a proton pump inhibitor,clarithromycin, and amoxicillin or metronidazole. AlimentPharmacol Ther 1999; 13:719–729.4. Janssen MJ, Van Oijen AH, Verbeek AL, Jansen JB, DeBoer WA. A systematic comparison of triple therapies fortreatment of Heliobacter pylori infection with proton pumpinhibitor/ranitidine bismuth citrate plus clarithromycinand either amoxicillin or a nitroimidazole. AlimentPharmacol Ther 2001; 15:613–624.5. Delaney B, Moayyedi, P, Forman, D. Heliobacter pylori.Clin Evid [online], Issue 8. London: BMJ PublishingGroup, Last updated 2003 March. Available atwww.ovid.com. Accessed on March 4, 2003.C L I N I C A L  I N Q U I R I E SOCTOBER 2003 / VOL 52, NO 10 · The Journal of Family Practice 8036. Treiber G, Wittig J, Ammon S, Walker S, van Doorn LJ,Klotz U. Clinical outcome and influencing factors for anew short-term quadruple therapy for Heliobacter pylorieradication: a randomized controlled trial (MACLORstudy). Arch Intern Med 2002; 162:153–160.7. Wong BC, Wang WH, Wong WM, et al. Three-day lanso-prazole quadruple therapy for Heliobacter pylori-positiveduodenal ulcers: a randomized controlled study. AlimentPharmacol Ther 2001; 15:843–849.8. Howden CW, Hunt RH, Guidelines for the management ofHeliobacter pylori infection. Ad Hoc Committee on thePractice Parameters of the American College ofGastroenterology. Am J Gastroenterol 1998; 93:2330–2338.9. Institute for Clinical Systems Improvement (ICSI).Dyspepsia. Bloomington, Minn: ICSI; last updated January 2003. Available at: http://www.icsi.org/knowledge/detail.asp?catID=29&itemID=171. Accessedon September 8, 2003.Does a knee brace decreaserecurrent ACL injuries?■ EVIDENCE-BASED ANSWERAfter surgical anterior cruciate ligament(ACL) reconstruction, knee bracing does notsignificantly protect against injury duringrecovery or afterwards (strength of recom-mendation [SOR]: C, based on expert opinion).In addition, the use of a knee brace followingACL reconstruction does not improve stabilityor hasten rehabilitation, either immediately orfor up to 2 years (SOR: A, based on random-ized controlled trials with heterogenousresults). Patients wearing a knee brace after ACLreconstruction may report subjective enhancedperformance, but measured performance is better without the brace (SOR: B, based on anindividual case-control study). We found no information specifically aboutfunctional bracing following ACL injuries thathave been managed conservatively. ■ EVIDENCE SUMMARYFunctional braces are designed to provide stabili-ty for the unstable knee, but few trials report re-injury rates as an outcome. Cadaver studiesshow that braces limit tibial rotation and antero-posterior translation. However, the mechanicaleffects of knee bracing in vivo are controversial. A study involving 5 patients with chronicunstable ACL injuries showed some limitation ofmovement with functional bracing, but it wasaccompanied by slowed muscle performance andused only low-stress forces.1 Objective findingsduring physiologic stress loads are inconclusive.2Three recent randomized controlled trials compared functional bracing with no bracing inrehabilitation after ACL reconstruction. In aprospective study of 62 patients, researchersfound no benefit from using a postoperative kneebrace at any stage (2 and 6 weeks; 3, 6, and 24months) after surgery. Moreover, the brace did notcontribute to a more stable knee during rehabili-tation or 2-year follow-up.3A similar study of 50 patients demonstrated nosignificant difference in function or laxity at 2 years.4 A 2-year study comparing 30 braced with30 nonbraced patients showed improved functionalstability (P<.05) but increased thigh muscle atro-phy (P<.0001) at 3-month follow-up in the bracedgroup. However, no significant differences wereseen at other follow-up intervals up to 2 years.5One study evaluated running, jumping, andturning performance with and without a function-al brace in 31 patients who had had an ACL reconstruction 5 to 26 months previously. Theymeasured significantly better performance with-out bracing; however, more than half the groupperceived enhanced performance with the brace.6■ RECOMMENDATIONS FROM OTHERSThe American Association of OrthopaedicSurgeons believes that rehabilitative and func-tional knee braces can be effective in manytreatment programs. Rehabilitative braces aremore effective in protecting against excessiveflexion and extension than against anterior andC O N T I N U E DPatients wearing a knee brace feelthey perform better, but measuredperformance improves without one

What regimens eradicate Heliobacter pylori?

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