Perspectives in clinical gastroenterology and hepatologyRational Helicobacter pylori Therapy: Evidence-Based Medicine Rather Than Medicine-Based Evidence
Section snippets
Therapy Choice
Similar to other infectious diseases, treatment results are best when reliably excellent regimens are used to treat patients with organisms susceptible to the antimicrobials chosen. Pretreatment susceptibility testing, either by culture of the organism or indirectly by molecular testing of stools of infected patients or fluorescent in-situ hybridization using paraffin-embedded gastric biopsy specimens, allows one to select a regimen tailored by antimicrobial susceptibility (ie, tailored
Using Available Data to Predict Treatment Success
An optimized regimen is defined as one that reliably achieves 95% or greater cures in patients with susceptible organisms. Although the effectiveness of any regimen can be undermined by antimicrobial resistance, the effect of resistance is not random and the effect of any particular level of resistance can be estimated based on studies with that combination elsewhere, for example, use of the optimized regimen (14-day concomitant therapy, consisting of a proton pump inhibitor [PPI],
Resistance Effects
Triple therapies containing a PPI and amoxicillin plus clarithromycin, metronidazole, a fluoroquinolone, or rifabutin all are extremely sensitive to resistance to the third drug. Resistance to clarithromycin, fluoroquinolones, and rifabutin cannot be overcome by increasing the dose or duration. By using the earlier-described formula one can calculate that 7-day clarithromycin-containing triple therapy will decrease to less than 90% success when clarithromycin resistance exceeds 5% (or 15% when
Caveat
It should be recognized that the data pool from which the outcomes of various therapies with susceptible and resistant organisms are available is not large, making the numbers we have used in our calculations imprecise, and our calculations are only approximations (Table 2). Sadly, the lack of data is related to the fact that resistance is not collected in most trials. Nonetheless, the results shown provide reasonable estimates of what can be expected, and the appendix to the recent article by
Clarithromycin-Containing Triple Therapy
Despite the Maastricht IV recommendations, clarithromycin-containing triple therapy (PPI, amoxicillin 1 g, clarithromycin 500 mg, all twice a day for 14 days) is an obsolete therapy whether given for 7, 10, or 14 days.29 The Achilles' heel is clarithromycin resistance, with success depending on clarithromycin resistance and the duration of therapy (Tables 1 and 3). With 14-day therapy the combination remains effective until clarithromycin resistance exceeds approximately 15%, whereas 7-day
Furazolidone Bismuth Quadruple Therapy
There are a number of different formulations but most successful ones are based on bismuth quadruple therapy. One substitutes furazolidone (100 mg 3 times daily) for metronidazole in 14-day bismuth quadruple therapy. Another substitutes amoxicillin (1 g 3 times daily) for tetracycline. Both have proven highly effective in China22 and may prove especially useful in areas where furazolidone is available and tetracycline is difficult to obtain.
Furazolidone is only available in a limited number of
Second or Subsequent Treatments for Treatment Failures
Generally, clinicians should have 2 preferred first-line regimens known to be effective locally, with the choice between them based on the patients history of prior drug use and exposure (Figure 2). The regimen with the highest predicted successful outcome always should be used first.41 Treatment success always should be confirmed, generally using a noninvasive test for active infection such as the stool antigen or urea breath test.42 Confirmation of cure also provides the clinician with an
Compliance and Adherence
Poor compliance with a regimen and antimicrobial resistance are the primary reasons for failure of what is otherwise a reliably excellent regimen. Large multicenter clinical trials have shown that although side effects related to the antibiotics used are common, in the majority of trials the drop-out rates because of side effects are low (eg, in the range of 5%). Although there is considerable literature regarding compliance with medication use, treatment of H pylori has not been a popular area
Recommendations Regarding Developing New Regimens
The trial-and-error approach to the development of H pylori therapies has proven to be inefficient and to provide misleading results. The history of sequential therapy is a good example. Originally, 10-day sequential therapy was devised in response to failure of triple therapy in Italy44, 45 and it proved to be successful and superior to triple therapy.46 Unfortunately, it was presumed to be optimal and no further attempts were made to optimize it or to systematically examine its limitations.
Summary Recommendations
Sufficient data from treatment trials in which the outcomes in relation to susceptibility resistance have been provided to allow an evidence-based approach to choosing anti–H pylori therapies. We now can add to the admonition to use what works locally by being able to reliably identify which regimens have the greatest chance of working. Figure 1 outlines a general schema, with therapy chosen based on pretreatment susceptibility testing, or, if unavailable, based on a combination of local
References (52)
Helicobacter pylori eradication therapy research: ethical issues and description of results
Clin Gastroenterol Hepatol
(2010)- et al.
Smoking increases the treatment failure for Helicobacter pylori eradication
Am J Med
(2006) - et al.
Sequential versus triple therapy for the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial
Lancet
(2013) - et al.
Pharmacologic aspects of eradication therapy for Helicobacter pylori infection
Gastroenterol Clin North Am
(2010) - et al.
14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial
Lancet
(2011) - et al.
Twice daily (mid-day and evening) quadruple therapy for H. pylori infection in the United States
Dig Liver Dis
(2004) - et al.
Comparison of the Etest and the NCCLS-approved agar dilution method to detect metronidazole and clarithromycin resistant Helicobacter pylori
Int J Antimicrob Agents
(2001) - et al.
Which therapy for Helicobacter pylori infection?
Gastroenterology
(2012) - et al.
Follow-up testing after treatment of Helicobacter pylori infections: cautions, caveats, and recommendations
Clin Gastroenterol Hepatol
(2011) Gastric tubes as vectors of Helicobacter pylori transmission
Med Hypotheses
(2010)
Empiric therapies for Helicobacter pylori infections
CMAJ
Optimal therapy for Helicobacter pylori infections
Nat Rev Gastroenterol Hepatol
Intention-to-treat analysis and the goals of clinical trials
Clin Pharmacol Ther
cagA Status and eradication treatment outcome of anti-Helicobacter pylori triple therapies in patients with nonulcer dyspepsia
J Clin Microbiol
Helicobacter pylori eradication with either 7-day or 10-day triple therapies, and with a 10-day sequential regimen
Can J Gastroenterol
Analysis of drug resistance and virulence-factor genotype of Irish Helicobacter pylori strains: is there any relationship between resistance to metronidazole and cagA status?
Aliment Pharmacol Ther
Primary antibiotic resistance in Helicobacter pylori strains isolated in northern and central Italy
Aliment Pharmacol Ther
Optimized non-bismuth quadruple therapies cure most patients with Helicobacter pylori infection in populations with high rates of antibiotic resistance
Gastroenterology
Importance of determining the pattern of H. pylori resistance in countries with a high prevalence of gastric cancer such as Nicaragua
Helicobacter
Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption
Gut
Meta-analysis: four-drug, three-antibiotic, non-bismuth-containing “concomitant therapy” versus triple therapy for Helicobacter pylori eradication
Helicobacter
Review article: non-bismuth quadruple (concomitant) therapy for eradication of Helicobacter pylori
Aliment Pharmacol Ther
Pilot studies to identify the optimum duration of concomitant Helicobacter pylori eradication therapy in Thailand
Helicobacter
Comparison of hybrid and sequential therapies for Helicobacter pylori eradication in Iran: a prospective randomized trial
Helicobacter
Modified sequential Helicobacter pylori therapy: proton pump inhibitor and amoxicillin for 14 days with clarithromycin and metronidazole added as a quadruple (Hybrid) therapy for the final 7 days
Helicobacter
Greater than 95% success with 14-day bismuth quadruple anti-Helicobacter pylori therapy: a pilot study in US Hispanics
Helicobacter
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This article has an accompanying continuing medical education activity on page e13. Learning Objective—At the end of this activity, the successful learner will be able to reliably interpret the available data regarding therapies for H pylori infection, to be able to identify the regimen(s) suitable for empiric use in a region, as well as how modify those choices to identify the regimen for a specific patient that has the greatest chance of achieving a cure.
Conflicts of interest This author discloses the following: David Graham is an unpaid consultant for Novartis in relation to vaccine development for the treatment or prevention of Helicobacter pylori infection, a paid consultant for RedHill Biopharma regarding novel H pylori therapies and for Otsuka Pharmaceuticals regarding diagnostic testing; and has received royalties from Baylor College of Medicine patents covering materials related to the 13C-urea breath test. The remaining authors disclose no conflicts.
Funding Supported in part by the Office of Research and Development of the Medical Research Service Department of Veterans Affairs, a Public Health Service grant (DK56338) that funds the Texas Medical Center Digestive Diseases Center (DK067366 and CA116845 to D.Y.G.). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Veterans Affairs or the National Institutes of Health. Also supported by research grants from the National Science Council of Taiwan for research into the prevention of gastric cancer and the pathogenesis of Helicobacter pylori (Y.-C.L. and M.-S.W.), and by grants from the National Center of Excellence for Clinical Trial and Research in the National Taiwan University Hospital for the foundation of the Taiwan Helicobacter Consortium (M.-S.W.).