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

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Key points

  • Bismuth quadruple therapy, consisting of a proton pump inhibitor, bismuth, metronidazole, and tetracycline, is a good alternative first-line therapy and is especially useful when penicillin cannot be used or when clarithromycin and metronidazole resistance is common.

  • The literature is confusing because bismuth quadruple therapy is used to denote regimens that differ greatly in terms of duration, doses, and administration in relation to meals.

  • Proton pump inhibitors can help negate the deleterious

Background

Eberle, in 1834, noted that bismuth, primarily as the white oxide, was introduced into medicine in 1697 by Jacobi and that its use was later popularized by Drs Odier of Geneva and De la Roche, of Paris.1 Throughout the nineteenth century, bismuth salts were widely and successfully used in gastroenterology.2 Bismuth continued to be used as a primary or adjuvant therapy for dyspepsia and peptic ulcer until being replaced successively by antacids, histamine-2 receptor antagonists, and proton pump

Bismuth in the era of new concepts regarding pathogenesis and treatment of peptic ulcer

In the mid-twentieth century, peptic ulcer and its complications were a major medical problem in western countries. The importance of peptic ulcer was illustrated by the awarding of a Nobel prize to James Black in 1988 for the discovery of the histamine-2 receptor antagonists (in 1972) and for β-blockers (in 1964). The late 1970s and early 1980s saw the introduction of many new antiulcer agents (eg, sucralfate, histamine-2 receptor antagonists, synthetic prostaglandins, a tablet formulation of

Bismuth quadruple therapy for H pylori eradication

Starting in the mid to late 1980s, there were numerous clinical trials attempting to cure H pylori infections.12 When a single antibiotic proved ineffective, dual- and triple-drug therapies were tried, and eventually an effective regimen consisting of bismuth subcitrate, tetracycline, and metronidazole was identified by Tom Borody and colleagues24 in Australia.12, 25 That original study used bismuth subcitrate 120 mg and tetracycline 500 mg, both 4 times a day, for 28 days and metronidazole

The effect of metronidazole resistance as examined by meta-analysis

Several meta-analyses involving bismuth quadruple therapy have focused on understanding the results in terms of antimicrobial resistance (eg,31, 32, 33, 37). The beneficial effect of adding a PPI in relation to metronidazole resistance was confirmed in an analysis of 93 studies (10,178 participants) that showed that metronidazole resistance reduced efficacy of bismuth, metronidazole, and tetracycline therapy (of different durations and dosing) on average by 26%. The reduction was only 14%

Calculation of the effectiveness of bismuth quadruple therapy

In most western countries and in Korea and China, the an unsatisfactory outcome with bismuth quadruple therapy (eg, <90% or <85% treatment success per protocol) can be identified if one examines the duration of therapy, the doses used, patient adherence to the regimen, and whether metronidazole resistance was present. With clarithromycin-containing triple and quadruple therapies, the outcome can be reliably predicted provided one has data concerning the effectiveness of that therapy in relation

Adherence to the Protocol

Many anti-H pylori regimens are somewhat complicated and require taking drugs 2 to 4 times daily. In order to achieve the high degrees of success reported in clinical studies, it is important that both the clinician and the patient adhere to the details of successful protocols. Arbitrary changes in the protocol (eg, dose, duration, formulation) are similar to making arbitrary changes in a published recipe for French bread and then being surprised when the product is less than anticipated. Fig. 4

How to make bismuth quadruple therapy more acceptable

As noted previously, Borody and colleagues44 attempted to reduce the side effects by changing the frequency of dose administration and the doses with some success. The current standard regimen consists of a PPI 2 times a day, tetracycline 500 mg 4 times a day, at least 1500 of metronidazole, and bismuth 4 times a day. Shorter durations have been recommended, but this is generally a marketing ploy because bismuth quadruple therapy is generally reserved for patients in whom metronidazole

Doxycycline

The original experience with doxycycline was that it could not substitute successfully for tetracycline in bismuth triple therapy.60 Since that time, it has been recommended not to substitute doxycycline for tetracycline. However, randomized trials comparing tetracycline and doxycycline in full-dose 14-day traditional bismuth quadruple therapy are lacking. In the United States, tetracycline has often become largely unavailable, and many pharmacies attempted to substitute doxycycline for

Examination of outcome in regions where bismuth quadruple therapy frequently fails (eg, Turkey and Iran)

In the west, in China, and in Korea, the results with bismuth triple therapy generally follow expectations, and poor results can be understood when one takes into account the doses used, the duration of therapy, and patient adherence. However, even when these factors are taken into account, the results with bismuth quadruple therapy have often been unsatisfactory in Turkey and Iran65, 66, 67, 68, 69, 70, 71, 72, 73, 74 (Table 4). Data from Turkey are especially interesting because there have

Bismuth, tetracycline, amoxicillin, proton pump inhibitors quadruple therapy

Amoxicillin was found not be inferior to metronidazole in bismuth triple therapy.32, 87 Its role in quadruple therapy has not been extensively studied88, 89, 90 (Table 5). As noted previously, in China the combination of bismuth subcitrate 2 times a day, tetracycline 500 mg 4 times a day, and high-dose amoxicillin (1000 mg 3 times a day) for 14 days cured 94.6% of 93 subjects per protocol.36 Additional studies of 14-day therapy are needed before a reliable estimation of its value can be

Bismuth sequential therapies

Sequentially administered drugs were attempted in some early regimens (eg, Logan and colleagues91 in 1994); however, the first true sequential therapy was a bismuth-containing regimen used to treat a patient who had failed therapy with then standard bismuth, metronidazole, tetracycline triple therapy (n = 31) or dual PPI plus amoxicillin therapy (n = 88).92 The study was done in Greece, which has a high background rate of metronidazole resistance and was typically an outlier in terms of cure

Information needed to obtain generalizable results

As a general rule, data needed to explain poor results should be collected and published. When unexpected poor results occur, one should provide results in relation to antimicrobial susceptibility/resistance. In this era of generic drugs, one should also provide details about the manufacture of the drugs used because fake and inferior drugs are now widely available, especially in developing countries. In the past, when faced with unexpectedly poor results, the authors have confirmed the potency

Relation of Drug Administration and Meals

The relation between treatment outcome and drug administration in relation to meals remains largely unstudied. This issue encompasses the proportion of the benefit derived from the topical action of the drugs versus the systemic antimicrobial activity. It has been proposed that administration with meals will enhance retention within the stomach and distribution of the drugs over the surface of the stomach. These potential benefits come with dilution of the drug concentration by the food and

Proton pump inhibitors dosage

With PPI, amoxicillin, clarithromycin triple therapy, higher-dose PPI therapy (eg, double dose) typically improves outcome. The effectiveness of both amoxicillin and clarithromycin is greater at higher pH. If the pH is consistently greater than 6, the clarithromycin is often no longer needed. However, tetracycline and metronidazole are relatively pH-insensitive antimicrobials. The interaction of bismuth salts with acid leads to the formation of bismuth oxychloride, which some think is the

Efficient study design

Efficient study design implies that the variables are controlled as much as possible and that stopping rules are in place to limit exposure when it becomes clear that a regimen cannot succeed.108 The use of stopping rules allows most efficient use of resources and has been used successfully with bismuth quadruple therapy.63

Recommendations

All therapy should be guided by the regional, local, and patient-specific antimicrobial resistance patterns and knowledge about the effectiveness of anti-H pylori regimens available locally. Patient-specific information is obtained from knowledge of about resistance patterns and the patient's history of antimicrobial use or by testing directly (eg, by culture) or indirectly (by molecular testing of stool or biopsy samples) for resistance. Bismuth quadruple therapy is an excellent alternate

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    Author Contributions: Each of the authors has been involved equally and has read and approved the final article. Each meets the criteria for authorship established by the International Committee of Medical Journal Editors and verifies the validity of the results reported.

    Supportive Foundations: Dr D.Y. Graham is supported in part by the Office of Research and Development Medical Research Service Department of Veterans Affairs, Public Health Service grants DK067366 and DK56338, which funds the Texas Medical Center Digestive Diseases Center. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the Veterans Affairs or National Institutes of Health.

    Potential Conflicts: Dr D.Y. Graham is an unpaid consultant for Novartis in relation to vaccine development for treatment or prevention of H pylori infection. Dr D.Y. Graham is 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 D.Y. Graham has received royalties from Baylor College of Medicine patents covering materials related to 13C-urea breath test. Dr S.-Y. Lee has nothing to declare.

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