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, 44 (3), 537-63

How to Effectively Use Bismuth Quadruple Therapy: The Good, the Bad, and the Ugly


How to Effectively Use Bismuth Quadruple Therapy: The Good, the Bad, and the Ugly

David Y Graham et al. Gastroenterol Clin North Am.


Bismuth triple therapy was the first effective Helicobacter pylori eradication therapy. The addition of a proton pump inhibitor helped overcome metronidazole resistance. Its primary indication is penicillin allergy or when clarithromycin and metronidazole resistance are both common. Resistance to the primary first-line therapy have centered on complexity and difficulties with compliance. Understanding regional differences in effectiveness remains unexplained because of the lack of studies including susceptibility testing and adherence data. We discuss regimen variations including substitutions of doxycycline, amoxicillin, and twice a day therapy and provide suggestions regarding what is needed to rationally and effectively use bismuth quadruple therapy.

Keywords: Adherence; Bismuth; Helicobacter pylori; Metronidazole; Proton pump inhibitors; Side effects; Tetracycline; Therapy.

Conflict of interest statement

Potential conflicts: Dr. Graham is a unpaid consultant for Novartis in relation to vaccine development for treatment or prevention of H. pylori infection. Dr. Graham is a also a paid consultant for RedHill Biopharma regarding novel H. pylori therapies, for Otsuka Pharmaceuticals regarding diagnostic testing, and for BioGaia regarding use of probiotics for H. pylori infections. Dr. Graham has received royalties from Baylor College of Medicine patents covering materials related to 13C-urea breath test. Dr. Lee has nothing to declare.


Figure 1
Figure 1. Effect of removing the metronidazole and or the PPI from bismuth quadruple therapy
Peptic ulcer patients received either TCN (tetracycline HCl 500 mg, q.i.d, and BSS (bismuth subsalicylate (Pepto Bismol) 2 tablets q.i.d. with or without Omp (omeprazole 40 mg in the a.m.) for 14 days. Data from Al-Assi MT, Genta RM, Graham DY. Short report: omeprazole-tetracycline combinations are inadequate as therapy for Helicobacter pylori infection. Aliment Pharmacol Ther 1994;8:259-262.
Figure 2
Figure 2. Effect of 14-day bismuth quadruple therapy in patients with pretreatment proven metronidazole resistant infections
Therapy consisted of tetracycline HCL 500 mg and bismuth subsalicylate (Pepto Bismol) 2 tablets both q.i.d. with meals, plus metronidazole 500 mg t.i.d. and omeprazole 20 mg in the a.m.. Data from Graham DY, Osato MS, Hoffman J, et al. Metronidazole containing quadruple therapy for infection with metronidazole resistant Helicobacter pylori: a prospective study. Aliment Pharmacol Ther 2000;14:745-750.
Figure 3
Figure 3. Empirically derived estimation of effectiveness of 14-day bismuth quadruple therapy in regions where success is known to be dependent on doses, duration, metronidazole resistance, and adherence
The formula is [(success rate with susceptible strains times proportion with susceptible strains) + (success rate with resistant strains time proportion with resistant strains) = outcome per protocol].
Figure 4
Figure 4. Intention-to-treat results of recent studies of 7 or 10 day bismuth quadruple therapy with various doses and drugs used for the comparison against clarithromycin-containing triple therapy generally in areas of high clarithromycin and variable metronidazole resistance
Data from Malfertheiner P, Bazzoli F, Delchier JC, et al. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial. Lancet 2011;377:905-913; and original study publications.
Figure 5
Figure 5. Effect of treatment duration on treatment success of bismuth quadruple therapy
Therapy consisted of bismuth quadruple therapy (Pylera) plus omeprazole 20 mg b.i.d. for 14 days. Thirty-nine percent of strains cultured were metronidazole resistance. All (100%) of those receiving therapy for 14 days with resistant strains were cured. The duration of therapy was patient-determined based on withdrawal for side effects or other reasons. The number and success for each duration is shown. Data from Salazar CO, Cardenas VM, Reddy RK, Dominguez DC, Snyder LK, Graham DY. Greater than 95% success with 14-day bismuth quadruple anti-Helicobacter pylori therapy: A pilot study in US Hispanics. Helicobacter 2012;17:382-389.
Figure 6
Figure 6. Results of changing the doses and timing of administration and adherence on outcome of bismuth triple therapy plus ranitidine
Therapy consisted of two 14 day regimes of 4 vs. 5 drug administrations per day (between 7 a.m. and 11 p.m.). The doses used were 108 mg of bismuth subcitrate in both arms, 500 mg of tetracycline q.i.d. vs. 250 mg 5 times daily, and 250 mg of metronidazole q.i.d. vs. 200 mg 5 times per day (i.e., the total amount of tetracycline was reduced from 2 g to 1.25 g, the dose of metronidazole was 1 gram but was less per dose plus ranitidine 300 mg at night. Data from Borody TJ, Brandl S, Andrews P, et al. Use of high efficacy, lower dose triple therapy to reduce side effects of eradicating Helicobacter pylori. Am J Gastroenterol 1994;89:33-38.
Figure 7
Figure 7. Results of randomized 14-day trial in Turkey showing poor results irrespective of the addition of bismuth
Therapy consisted of 10-day regimens consisting of lansoprazole 30 mg b.i.d. metronidazole 500 mg b.i.d., tetracycline 500 mg q.i.d. (LMT) with more traditional bismuth quadruple therapy (LMTB) and that regimen with the addition of ranitidine bismuth subcitrate 400 mg b.i.d. (LMTB-RBC). Data from Songur Y, Senol A, Balkarli A, et al. Triple or quadruple tetracycline-based therapies versus standard triple treatment for Helicobacter pylori treatment. Am J Med Sci 2009;338:50-53.

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