Efficacy of Bismuth-Containing Quadruple Therapies for Clarithromycin-, Metronidazole-, and Fluoroquinolone-Resistant Helicobacter pylori Infections in a Prospective Study

doi:10.1016/j.cgh.2013.01.008

Clinical Gastroenterology and Hepatology

Volume 11, Issue 7, July 2013, Pages 802-807.e1

https://doi.org/10.1016/j.cgh.2013.01.008 Get rights and content

Background & Aims

We assessed the efficacy and safety of 4 bismuth-containing quadruple regimens as empiric therapies for Helicobacter pylori infections in patients who did not respond to previous treatment.

Methods

We performed a prospective single-center study of 424 patients with H pylori infection that was not eradicated by previous therapies. Patients were assigned randomly to groups given lansoprazole (30 mg twice daily) and bismuth potassium citrate (220 mg twice daily), along with 500 mg tetracycline and 400 mg metronidazole 4 times daily (LBTM), 500 mg tetracycline and 100 mg furazolidone 3 times daily (LBTF), 1000 mg amoxicillin 3 times and 500 mg tetracycline 4 times daily (LBAT), or 1000 mg amoxicillin and 100 mg furazolidone 3 times daily (LBAF). Eradication was assessed by a ¹³C-urea breath test. Antimicrobial susceptibility was assessed in 188 patients by the agar dilution method.

Results

Per-protocol rates of H pylori eradication were greater than 90% for all regimens: 93.1% for LBTM (95% confidence interval [CI], 88.1%–98.0%), 96.1% for LBTF (95% CI, 92.4%–99.8%), 94.6% for LBAT (95% CI, 90.0%–99.2%), and 99.0% for LBAF (95% CI, 97.0%–100%). The intention-to-treat response rates were 87.9% for LBTM (95% CI, 81.7%–94.0%), 91.7% for LBTF (95% CI, 87.1%–96.3%), 83.8% for LBAT (95% CI, 76.8%–90.9%), and 95.2% for LBAF (95% CI, 91.1%–99.3%). Significantly more patients had infections eradicated by furazolidone-containing regimens than nonfurazolidone regimens (P = .01). Side effects occurred in 33.6% of subjects and occurred significantly more frequently in the LBTM group than the other 3 groups (vs LBTF, P = .006; vs LBAT, P = .003; vs LBAF, P = .02). Metronidazole resistance was 96.8%; no isolates were resistant to amoxicillin, tetracycline, or furazolidone.

Conclusions

Four bismuth-containing quadruple therapies achieved greater than 90% eradication of H pylori in patients who did not respond to previous treatment, including patients with metronidazole resistance. For patients allergic to penicillin, tetracycline and either metronidazole- or furazolidone-containing regimens are recommended. ClincialTrials.gov number, NCT01668927.

Section snippets

Subjects and Study Design

This prospective, open-label trial enrolled H pylori–positive patients with functional dyspepsia and scarred peptic ulcers who previously had failed one or more eradication regimens. All patients had received triple therapies including a PPI, clarithromycin, metronidazole, and/or amoxicillin (if not allergic) for their initial treatment. A total of 197 subjects also had failed an additional levofloxacin-containing therapy.

All subjects were recruited into the study in Renji Hospital, Shanghai,

Results

A total of 424 subjects fulfilling the inclusion criteria were enrolled in this trial including 109 subjects with a pre-existing allergy to penicillin. Relevant demographic and endoscopic data at study entrance are shown in Table 2. At entry, the 4 groups did not differ in terms of age, sex, smoking, and drinking habits. Twenty-seven subjects who received at least one dose of medication (6 subjects in the LBTM group, 5 subjects in the LBTF group, 12 subjects in the LBAT group, and 4 subjects in

Discussion

Successful antimicrobial therapy depends on the use of antibiotics to which H pylori is susceptible (ie, resistance is a main reason for treatment failure).¹¹ For any infectious disease in which resistance is common, treatment based on knowledge of antimicrobial susceptibility is associated with improved outcome. Such knowledge includes using antimicrobials for which resistance is rare and/or pretreatment susceptibility testing for drugs in which resistance is known to be a problem (eg,

Acknowledgements

Xiao Liang and Xiaoqing Xu contributed equally to this work.

References (26)

D.Y. Graham
Efficient identification and evaluation of effective Helicobacter pylori therapies
Clin Gastroenterol Hepatol
(2009)
D.Y. Graham
Therapy of Helicobacter pylori: current status and issues
Gastroenterology
(2000)
M. Romano et al.
Pretreatment antimicrobial susceptibility testing is cost saving in the eradication of Helicobacter pylori
Clin Gastroenterol Hepatol
(2003)
D.Y. Graham et al.
Helicobacter pylori treatment in the era of increasing antibiotic resistance
Gut
(2010)
M. Selgrad et al.
Treatment of Helicobacter pylori
Curr Opin Gastroenterol
(2011)
K.M. Fock et al.
Second Asia-pacific consensus guidelines for Helicobacter pylori infection
J Gastroenterol Hepatol
(2009)
P. Malfertheiner et al.
Management of Helicobacter pylori infection—the Maastricht IV/Florence consensus report
Gut
(2012)
Z.T. Zheng et al.
Double-blind short-term trial of furazolidone in peptic ulcer
Lancet
(1985)
Z.T. Zheng et al.
Treatment of peptic ulcer disease with furazolidone
J Gastroenterol Hepatol
(1992)
X. Calvet et al.
Key points for designing and reporting Helicobacter pylori therapeutic trials: a personal view
Helicobacter
(2011)

D.Y. Graham et al.

Helicobacter pylori therapy demystified

Helicobacter

(2011)

I. Kobayashi et al.

Helicobacter pylori isolated from patients who later failed H. pylori eradication triple therapy readily develop resistance to clarithromycin

J Med Microbiol

(2006)

Q.J. Sun et al.

Resistance of Helicobacter pylori to antibiotics from 2000 to 2009 in Shanghai

World J Gastroenterol

(2010)

Cited by (139)

Empirical Second-Line Therapy in 5000 Patients of the European Registry on Helicobacter pylori Management (Hp-EuReg)
2022, Clinical Gastroenterology and Hepatology
Citation Excerpt :
This compound, therefore, has a synergistic effect with antibiotics, with no resistance described.25 Adding bismuth to either triple or quadruple therapy may further enhance effectiveness and overcome bacterial antibiotic resistance.19,26,27 Such a strategy of adding bismuth to different antibiotic combinations may explain the increase in the eradication rates of rescue treatments used in our cohort, despite first-line treatment failure with clarithromycin.
After a first Helicobacter pylori eradication attempt, approximately 20% of patients will remain infected. The aim of the current study was to assess the effectiveness and safety of second-line empiric treatment in Europe.
This international, multicenter, prospective, non-interventional registry aimed to evaluate the decisions and outcomes of H pylori management by European gastroenterologists. All infected adult cases with a previous eradication treatment attempt were registered with the Spanish Association of Gastroenterology–Research Electronic Data Capture until February 2021. Patients allergic to penicillin and those who received susceptibility-guided therapy were excluded. Data monitoring was performed to ensure data quality.
Overall, 5055 patients received empiric second-line treatment. Triple therapy with amoxicillin and levofloxacin was prescribed most commonly (33%). The overall effectiveness was 82% by modified intention-to-treat analysis and 83% in the per-protocol population. After failure of first-line clarithromycin-containing treatment, optimal eradication (>90%) was obtained with moxifloxacin-containing triple therapy or levofloxacin-containing quadruple therapy (with bismuth). In patients receiving triple therapy containing levofloxacin or moxifloxacin, and levofloxacin–bismuth quadruple treatment, cure rates were optimized with 14-day regimens using high doses of proton pump inhibitors. However, 3-in-1 single capsule or levofloxacin–bismuth quadruple therapy produced reliable eradication rates regardless of proton pump inhibitor dose, duration of therapy, or previous first-line treatment. The overall incidence of adverse events was 28%, and most (85%) were mild. Three patients developed serious adverse events (0.3%) requiring hospitalization.
Empiric second-line regimens including 14-day quinolone triple therapies, 14-day levofloxacin–bismuth quadruple therapy, 14-day tetracycline–bismuth classic quadruple therapy, and 10-day bismuth quadruple therapy (as a single capsule) provided optimal effectiveness. However, many other second-line treatments evaluated reported low eradication rates. ClincialTrials.gov number: NCT02328131.
Materials for restoring lost Activity: Old drugs for new bugs
2022, Advanced Drug Delivery Reviews
The escalation of bacterial resistance to conventional medical antibiotics is a serious concern worldwide. Improvements to current therapies are urgently needed to address this problem. The synergistic combination of antibiotics with other agents is a strategic solution to combat multi-drug-resistant bacteria. Although these combinations decrease the required high dosages and therefore, reduce the toxicity of both agents without compromising the bactericidal effect, they cannot stop the development of further resistance. Recent studies have shown certain elements restore the ability of antibiotics to destroy bacteria that have acquired resistance to them. Due to these synergistic activities, organic and inorganic molecules have been investigated with the goal of restoring antibiotics in new approaches that mitigate the risk of expanding resistance. Herein, we summarize recent studies that restore antibiotics once thought to be ineffective, but have returned to our armamentarium through innovative, combinatorial efforts. A special focus is placed on the mechanisms that allow the synergistic combinations to combat bacteria. The promising data that demonstrated restoration of antimicrobials, supports the notion to find more combinations that can combat antibiotic-resistant bacteria.
V Spanish Consensus Conference on Helicobacter pylori infection treatment
2022, Gastroenterologia y Hepatologia
La infección por Helicobacter pylori es muy frecuente entre la población española y representa la causa fundamental de gastritis crónica, úlcera péptica y cáncer gástrico. Previamente se han llevado a cabo cuatro reuniones de Consenso sobre el manejo de la infección por H. pylori en España, la última de ellas en 2016. Los cambios en los esquemas de tratamiento y la creciente evidencia disponible al respecto han justificado la organización de esta V Conferencia Española de Consenso en mayo de 2021, centrada en el tratamiento de esta infección. Participaron 14 expertos sobre el tema, que realizaron una búsqueda sistemática de la evidencia científica y elaboraron una serie de recomendaciones que fueron sometidas a un proceso de interacción de votaciones anónimas seriadas mediante metodología Delphi. Para clasificar la evidencia científica y la fuerza de las recomendaciones, se utilizó el sistema GRADE. Este consenso establece, como punto de partida, un aumento de la exigencia en la eficacia de los tratamientos recomendados, que deben alcanzar, o preferiblemente superar, el 90% de curación al ser administrados empíricamente. De este modo, tanto en primera como en segunda línea se recomiendan tratamientos cuádruples con o sin bismuto, generalmente prescritos durante 14 días. Como tratamiento de primera línea se recomienda una pauta cuádruple concomitante sin bismuto (inhibidor de la bomba de protones, claritromicina, amoxicilina y metronidazol) o una combinación cuádruple con bismuto (inhibidor de la bomba de protones, bismuto, tetraciclina y metronidazol). En el presente consenso se revisan también con detalle otras alternativas de tratamiento de rescate.
Helicobacter pylori infection is very common in the Spanish population and represents the main cause of chronic gastritis, peptic ulcer, and gastric cancer. The last iteration of Spanish consensus guidelines on H. pylori infection was conducted in 2016. Recent changes in therapeutic schemes along with increasing supporting evidence were key for developing the V Spanish Consensus Conference (May 2021). Fourteen experts performed a systematic review of the scientific evidence and developed a series of recommendations that were subjected to an anonymous Delphi process of iterative voting. Scientific evidence and the strength of the recommendation were classified using GRADE guidelines. An eradication therapy, when prescribed empirically, is considered acceptable when it reliably achieves, or preferably surpass, 90% cure rates. Currently, only quadruple therapies (with or without bismuth) and generally lasting 14 days, accomplish this goal in first- and second-line therapies. A non-bismuth quadruple concomitant regimen (proton pump inhibitor, clarithromycin, amoxicillin, and metronidazole) or a quadruple bismuth-based combination (proton pump inhibitor, bismuth, tetracycline, and metronidazole), are recommended as first-line regimens. Rescue therapies after eradication failure and management of H. pylori infection in peptic ulcer disease were also reviewed.
A Counterion-Free Strategy for Chronic Metabolic Acidosis Based on an Orally Administered Gut-Restricted Inorganic Adsorbent
2023, Advanced Materials
The Efficacy and Safety of Regimens for Helicobacter pylori Eradication Treatment in China A Systemic Review and Network Meta-Analysis
2023, Journal of Clinical Gastroenterology
Rifabutin-Containing Triple Therapy Versus Bismuth Quadruple Therapy for Helicobacter pylori Rescue Treatment: A Multicenter, Randomized Controlled Trial
2023, Journal of Infectious Diseases

View all citing articles on Scopus

: Conflicts of interest The authors disclose no conflicts.

: Funding Supported by the grant from the National Natural Science Foundation of China (30770112 and 81170355).

View full text

Original articleAlimentary tractEfficacy of Bismuth-Containing Quadruple Therapies for Clarithromycin-, Metronidazole-, and Fluoroquinolone-Resistant Helicobacter pylori Infections in a Prospective Study

Background & Aims

Methods

Results

Conclusions

Section snippets

Subjects and Study Design

Results

Discussion

Acknowledgements

Clin Gastroenterol Hepatol

Gastroenterology

Clin Gastroenterol Hepatol

Helicobacter pylori treatment in the era of increasing antibiotic resistance

Gut

Treatment of Helicobacter pylori

Curr Opin Gastroenterol

Second Asia-pacific consensus guidelines for Helicobacter pylori infection

J Gastroenterol Hepatol

Management of Helicobacter pylori infection—the Maastricht IV/Florence consensus report

Gut

Double-blind short-term trial of furazolidone in peptic ulcer

Lancet

Treatment of peptic ulcer disease with furazolidone

J Gastroenterol Hepatol

Key points for designing and reporting Helicobacter pylori therapeutic trials: a personal view

Helicobacter

Helicobacter pylori therapy demystified

Helicobacter

Helicobacter pylori isolated from patients who later failed H. pylori eradication triple therapy readily develop resistance to clarithromycin

J Med Microbiol

Resistance of Helicobacter pylori to antibiotics from 2000 to 2009 in Shanghai

World J Gastroenterol

Original article
Alimentary tract
Efficacy of Bismuth-Containing Quadruple Therapies for Clarithromycin-, Metronidazole-, and Fluoroquinolone-Resistant Helicobacter pylori Infections in a Prospective Study