Current issues of ACP Journal Club are published in Annals of Internal Medicine


Review: Quadruple therapies appear to be more effective than triple therapies for eradicating single-drug–resistant Helicobacter pylori


ACP J Club. 2008 Jan-Feb;148:9. doi:10.7326/ACPJC-2008-148-1-009

Clinical Impact Ratings

GIM/FP/GP: 5 stars

Gastroenterology: 5 stars

Infectious Disease: 5 stars

Source Citation

Fischbach L, Evans EL. Meta-analysis: the effect of antibiotic resistance status on the efficacy of triple and quadruple first-line therapies for Helicobacter pylori. Aliment Pharmacol Ther. 2007;26:343-57. [PubMed ID: 17635369]



What is the effect of drug resistance on therapies for Helicobacter pylori infection? Which therapies are most effective for eradicating nitroimidazole (NTM)- or clarithromycin (CTM)-resistant H. pylori?


Data sources: MEDLINE (to February 2007) and bibliographies of relevant reviews.

Study selection and assessment: English- or Spanish-language studies evaluating triple or quadruple therapies for eradicating H. pylori in patients who were either all sensitive or all resistant to CTM or NTM. Studies had to include ≥ 4 patients per treatment group with H. pylori infection at baseline. Studies of monotherapy or dual therapies were excluded. 93 randomized controlled trials (RCTs) (n = 10 178) met the selection criteria; 68% of treatment groups came from RCTs, 67% of patients had peptic ulcer disease, and 30% had nonulcer dyspepsia. {Individual study quality indicators were included in the metaregression model as suggested by Greenland.}*

Outcomes: Eradication of H. pylori infection.

Main results

Meta-analysis showed that both NTM and CTM resistance reduced efficacy of triple therapies for eradicating H. pylori infection, but CTM resistance reduced efficacy more than did NTM resistance (Table). Quadruple therapies appeared to be more effective than triple therapies for eradicating single-drug–resistant H. pylori infection (Table).


Clarithromycin resistance is associated with lower efficacy of triple therapies than is nitroimidazole resistance for eradicating Helicobacter pylori infection. Quadruple therapies appear to be more effective than triple therapies for eradicating single-drug–resistant H. pylori infection.

*Reference provided by author: Greenland S. Meta-analysis. In: Rothman KJ, Greenland S, eds. Modern epidemiology. 2nd ed. Philadelphia: Lippincott-Raven; 1998:643-73.

Source of funding: No external funding.

For correspondence: Dr. L. Fischbach, University of North Texas Health Science Center, Fort Worth, TX, USA. E-mail

Table. Effect of drug resistance on triple or quadruple therapies for eradicating Helicobacter pylori infection†

Therapy Number of studies (n) Reduction in treatment efficacy (95% CI)
NTM resistance CTM resistance Dual resistance
AMX-NTM-BIS 6 (319) 38% (15 to 62)
NTM-TET-BIS 14 (711) 26% (14 to 38)
AMX-NTM-GAI 24 (1945) 30% (22 to 38)
CTM-NTM-GAI 34 (3128) 18% (13 to 23) 35% (25 to 45) 13% (−22 to 49)‡
AMX-CTM-GAI 24 (2556) 66% (58 to 74)
MTN-TET-BIS-GAI 16 (889) 14% (5 to 23)
CTM-MTN-BIS-RNT 5 (265) 1.5% (−1.7 to 4.7)‡ 13% (−27 to 1.6)‡ 44% (38 to 52)
AMX-CTM-MTN-GAI 2 (365) Negligible Negligible Negligible

†AMX = amoxicillin; BIS = bismuth; CTM = clarithromycin; GAI = gastric acid inhibitor; MTN = metronidazole; NTM = nitroimidazole; RNT = ranitidine; TET = tetracycline. CI defined in Glossary.
‡Not significant.


First-line therapy for H. pylori eradication has been triple therapy with a proton-pump inhibitor (PPI), CTM, and amoxicillin (AMX) or metronidazole (MTN). The comprehensive meta-analysis by Fischbach and colleagues affirms the deleterious effect of CTM resistance on CTM-containing triple therapies and helps explain their declining efficacy.

MTN resistance seems to be less important than CTM resistance because it can be overcome to some extent. With the AMX-NTM-bismuth (BIS) triple therapy, a larger daily dose of NTM (1500 mg) can eradicate resistant strains. With NTM-tetracycline (TET)-BIS therapy, efficacy was better with MTN plus tinidazole, suggesting that the type of NTM used may be important. Adding a gastric acid inhibitor (GAI) improved efficacy of MTN-TET-BIS triple therapy. With CTM-NTM-GAI triple therapy, CTM resistance reduced efficacy by 35%, whereas MTN resistance reduced efficacy by only 18%; dosing both CTM and MTN twice daily improved efficacy. With AMX-CTM-GAI triple therapy, CTM resistance reduced efficacy by as much as 66%. Unfortunately, little can be done to overcome CTM resistance during eradication of H. pylori.

Quadruple therapy increased efficacy compared with triple therapies. The mean efficacy of PPI-MTN-TET-BIS on MTN-resistant strains was high (79%). Better success was seen with ≥ 7 days of treatment and when certain PPIs were used. A quadruple therapy containing both MTN and CTM (AMX-CTM-MTN-GAI) was particularly effective, but too few patients were treated to be certain of its efficacy. Ranitidine bismuth citrate with CTM and MTN was particularly effective, but this drug is no longer available in most parts of the world. This is unfortunate, and perhaps it could be brought back.

It is costly and difficult to culture H. pylori and test antibiotic resistance, and assays are not routinely available. Furthermore, results do not necessarily predict clinical outcomes. In clinical practice, clinicians should avoid CTM-containing regimens in patients with prior exposure to macrolides. In patients with prior NTM use and patient populations with high baseline NTM resistance, this meta-analysis suggests that a first-line MTN-TET-BIS-GAI quadruple therapy for 7 to 14 days may be best. However, the large number of pills and complex dosing regimen may impair compliance.

Naoki Chiba, MD
McMaster University
Hamilton, Ontario, Canada