|Year : 2017 | Volume
| Issue : 5 | Page : 265-267
|Failure of optimized dual proton pump inhibitor amoxicillin therapy: What now?
David Y Graham1, Hong Lu2, Akiko Shiotani3
1 Department of Medicine, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA
2 GI Division, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institution of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai, People's Republic of China
3 Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan
Click here for correspondence address and email
|Date of Web Publication||18-Sep-2017|
|How to cite this article:|
Graham DY, Lu H, Shiotani A. Failure of optimized dual proton pump inhibitor amoxicillin therapy: What now?. Saudi J Gastroenterol 2017;23:265-7
For a decade following the initial description of dual amoxicillin–proton pump inhibitor (PPI) therapy by Unge et al., investigators attempted to optimize the doses and duration of this regimen in an attempt to reliably achieve >90% cure rates (reviewed in Dore et al.). When given twice daily PPI and amoxicillin cured approximately 62% patients (range 60–64%), and increasing the omeprazole dosage from 20 to 60 mg b.i.d. did not reliably improve outcome. For example, even amoxicillin 750 mg t.i.d. with omeprazole 40 mg b.i.d. or 40 mg t.i.d. for 14 days cured only approximately 80% of cases. Labenz et al. gave 40–80 mg of omeprazole with amoxicillin 500 mg q.i.d. for 2 weeks with 82.8% success. In the USA, dual therapy with 1 g amoxicillin and 30 mg lansoprazole, each given every 8 h produced a 60–70% cure rate , and even this low cure rate was approved by the Food and Drug Administration (FDA).
By 2000, PPI–amoxicillin dual therapy was largely abandoned as being unable to reliably achieve even 90% cure rates. Failure was in part attributed to antimicrobial dormancy or the persister state. While Helicobacter pylori can survive low pH, it can multiply only between pH 6 and 8. Thus, the majority of time amoxicillin is present in the blood, H. pylori is not replicating and is able to survive. Traditional attempts to overcome persistence include increasing the duration of therapy, increasing the pH, or both. Increasing the duration of therapy to 6 weeks also proved unreliable in improving the outcome. Beta-lactams are pH dependent and most effective and stable at neutral pH., However, even b.i.d. or t.i.d. PPI dosing fails to maintain intragastric pH at 6 for more than 12 h. Most in vivo work on PPI and amoxicillin dosing has been done by Furuta et al. and has been based on the concept that the bactericidal activity of beta-lactam antibiotics is likely to be dependent on time rather than concentration.,, Studies in Japan and Taiwan (areas of high prevalence of CYP2C19 slow metabolizers) have shown that it is possible to maintain a high pH and a Minimal inhibitory concentration (MIC) within the effective range if amoxicillin and PPI were given at approximately 6-h intervals ,, producing high treatment success.
European studies identified the factors predictive of treatment failure with dual therapy which included poor adherence, short duration of therapy, and smoking; in contrast, corpus gastritis was associated with success. Yang et al. also reported that prolonged elevated intragastric pH and improved cure rates were associated with slow CYP2C19 metabolizer genotype and corpus gastritis. Repeating dual therapy after failure of PPI–amoxicillin therapy has proved to usually produce lower cure rates., Dual therapy has also been relatively unsuccessful as rescue therapy. Both observations are consistent with the treatment failures producing a population enriched with poor pH responders (e.g., CYP2C19 rapid metabolizers or natural hyper secretors).
Optimized dual therapy
In 2015, Yang et al. introduced “optimized” dual therapy using a second-generation PPI, rabeprazole, plus 750 mg of amoxicillin four times a day. They also prohibited any acid foods. They achieved relatively high cure rates irrespective of CYP2C19 genotype; for treatment of naïve patients the cure rate was high [intent-to-treat (ITT) = 95.3%; 95% CI = 91–98%; and per protocol (PP) = 96.6%] but was lower among those who had failed previous therapy (ITT = 89.3%; 95% CI = 80–97%, and PP = 89.3%). They suggested this regimen as a possible first line regimen. A similar regimen had been previously examined in Europe, where Miehlke et al. gave 40 mg omeprazole q.i.d. with amoxicillin 750 mg every 6 h for 2 weeks. They achieved lower cure rates: only 75.6% ITT (95% CI = 60–88%) and 83.8% PP (95% CI = 68–94%). In that study, H. pylori was susceptible to amoxicillin, both pre- and posttreatment. CYP2C19 genotypes were not assessed but in Western countries slow metabolizers are infrequent.
The current study  tested the Yang et al. hypothesis that “optimized” PPI–amoxicillin dual anti-H. pylori therapy would achieve high cure rates. The study was done in China, which like Taiwan, has a high prevalence of slow CYP2C19 metabolizers. The authors used rabeprazole (10 or 20 mg) and amoxicillin (750 mg) given q.i.d. (before and after meals and bedtime) for 14 days in two groups of approximately 90 subjects each. The cure rates were low with ITT cure rates of 78.1%; 95% CI = 68–86%, and 81.6%; 95% CI = 73–89%, and PP cure rates of 79.1%; 95% CI = 70–87%, and 83.5%; 95% CI = 71–87% for the 10 and 20 mg rabeprazole doses, respectively. The CYP2C19 genotypes were not assessed although the use of a relatively CYP2C19-independent PPI makes this important. The difference between this study and the Yang et al. study included possibly a slight difference in the timing of dosing and the non-restriction on acidic foods; though none has been shown to be critical.
Where do we go from here?
The success of dual therapy is based on two untested hypotheses:First, it is possible to reliably achieve an intragastric pH of 6 or greater using antisecretory therapy alone; and second, maintaining a high amoxicillin MIC is necessary throughout most or all of the 24-h period. The PPIs are imperfect antisecretory drugs as the full effect requires 3–5 days of therapy and the results in terms of pH control in individual patients are highly variable. It is also unknown whether it is critical to maintain the MIC during the entire 24-h period, as only during this period the pH is between 6 and 8, or can this period differ. There There are many infections effectively treated with pulse rather than continuous penicillin therapy, showing that high continuous MIC level is not always a prerequisite for success.,
It seems likely that the current “optimized” regimen does not reliably maintain the pH at 6 or greater, over the entire 24-h period. In our experience in the USA, dual PPI–amoxicillin therapy using 40 mg of esomeprazole and 500 mg of amoxicillin every 6-h for 14 days results in unacceptable low cure rate when used as rescue therapy, after treatment failures with other regimens. Reliable success in the general population probably requires use of a more potent and reliable long-acting antisecretory agent such as vonoprazan. Possibly, the combination of a PPI and an antacid to help maintain pH might also be effective. Vonoprazan (20 mg) with amoxicillin b.i.d., reliably achieved a cure rate of approximately 80% in Japan. There were several abstracts presented at the US DDW using t.i.d. amoxicillin and b.i.d. vonoprazan with relatively high cure rates, but to the best of the author's knowledge, none has achieved 95% or greater treatment success. The traditional answer for an infectious disease in which antimicrobial therapy fails although the infection remains susceptible after treatment failure (e.g., tuberculosis) is that the duration of therapy was insufficient (i.e., failure is often because of dormancy or persistence). The dosage and duration of vonoprazan remains unknown, but considering the presence of dormancy, longer duration is probably better. Optimal doses and duration of any regimen can only be identified through experimentation; thus it is always prudent to start with longer durations (e.g., 14 days) so that one does not need to repeat the study if the initial results are below expectation. We believe that dual therapy will ultimately prove successful. The current study shows that the future remains in the future.
Dr. Graham is a consultant for RedHill Biopharma and does research on novel Helicobacter pylori therapies, and has received research support for culture of H. pylori and is the PI of an international study on the use of antimycobacterial therapy for Crohn's disease. He is also a consultant for BioGaia in relation to probiotic therapy for H. pylori infection and for Takeda in relation to H. pylori therapies. Dr. Shiotani has received research grants from AstraZeneca Co. Ltd., Astellas Pharmaceutical, Otsuka Pharmaceutical, Daiichi Sankyo Co. Ltd., and Eisai Co. Ltd.
Financial support and sponsorship
Dr. Graham is supported in part by the Office of Research and Development Medical Research Service Department of Veterans Affairs, Public Health Service grant DK56338 which funds the Texas Medical Center Digestive Diseases Center.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Unge P, Gad A, Gnarpe H, Olsson J. Does omeprazole improve antimicrobial therapy directed towards gastric Campylobacter pylori
in patients with antral gastritis? A pilot study. Scand J Gastroenterol Suppl 1989;167:49-54.
Dore MP, Lu H, Graham DY. Role of bismuth in improving Helicobacter pylori
eradication with triple therapy. Gut 2016;65:870-8.
van der Hulst RW, Keller JJ, Rauws EA, Tytgat GN. Treatment of Helicobacter pylori
infection: A review of the world literature. Helicobacter 1996;1:6-19.
Bayerdorffer E, Miehlke S, Mannes GA, Sommer A, Hochter W, Weingart J, et al
. Double-blind trial of omeprazole and amoxicillin to cure Helicobacter pylori
infection in patients with duodenal ulcers. Gastroenterology 1995;108:1412-7.
Fleischmann R, Demharter R, Barnert J, Fuger K, Wienbeck M, Busch R. Eradication of Helicobacter pylori
in peptic ulcer disease with amoxicillin, 2.0 g, and omeprazole, 80 or 120 mg: A prospective randomized trial. Eur J Gastroenterol Hepatol 1997;9:593-8.
Labenz J, Leverkus F, Borsch G. Omeprazole plus amoxicillin for cure of Helicobacter pylori
infection. Factors influencing the treatment success. Scand J Gastroenterol 1994;29:1070-5.
Schwartz H, Krause R, Sahba B, Haber M, Weissfeld A, Rose P, et al
. Triple versus dual therapy for eradicating Helicobacter pylori
and preventing ulcer recurrence: A randomized, double-blind, multicenter study of lansoprazole, clarithromycin, and/or amoxicillin in different dosing regimens. Am J Gastroenterol 1998;93:584-90.
Harford W, Lanza F, Arora A, Graham D, Haber M, Weissfeld A, et al
. Double-blind, multicenter evaluation of lansoprazole and amoxicillin dual therapy for the cure of Helicobacter pylori
infection. Helicobacter 1996;1:243-50.
Graham DY, Shiotani A. New concepts of resistance in the treatment of Helicobacter pylori
infections. Nat Clin Pract Gastroenterol Hepatol 2008;5:321-31.
Attumi TA, Graham DY. Increasing the duration of dual amoxicillin plus omeprazole Helicobacter pylori
eradication to 6 weeks: A pilot study. J Gastroenterol Hepatol 2012;27:59-61.
McNulty CA. Bacteriological and pharmacological basis for the treatment of Campylobacter pylori
infection. In: Rathbone BJ and Heatley RV, editors. Campylobacter and gastro-duodenal disease. Oxford: Blackwell Scientific Publications; 1989. p. 209-16.
Marcus EA, Inatomi N, Nagami GT, Sachs G, Scott DR. The effects of varying acidity on Helicobacter pylori
growth and the bactericidal efficacy of ampicillin. Aliment Pharmacol Ther 2012;36:972-9.
Midolo PD, Turnidge JD, Munckhof WJ. Is bactericidal activity of amoxicillin against Helicobacter pylori
concentration dependent? Antimicrob Agents Chemother 1996;40:1327-8.
Furuta T, Shirai N, Kodaira M, Sugimoto M, Nogaki A, Kuriyama S, et al
. Pharmacogenomics-based tailored versus standard therapeutic regimen for eradication of H. pylori
. Clin Pharmacol Ther 2007;81:521-8.
Sugimoto M, Shirai N, Nishino M, Kodaira C, Uotani T, Sahara S, et al
. Comparison of acid inhibition with standard dosages of proton pump inhibitors in relation to CYP2C19 genotype in Japanese. Eur J Clin Pharmacol 2014;70:1073-8.
Yang JC, Wang HL, Chern HD, Shun CT, Lin BR, Lin CJ, et al
. Role of omeprazole dosage and cytochrome P450 2C19 genotype in patients receiving omeprazole-amoxicillin dual therapy for Helicobacter pylori
eradication. Pharmacotherapy 2011;31:227-38.
Furuta T, Graham DY. Pharmacologic aspects of eradication therapy for Helicobacter pylori
infection. Gastroenterol Clin North Am 2010;39:465-80.
Malaty H, El-Zimaity HM, Genta RM, Cole RA, Graham DY. High-dose proton pump inhibitor plus amoxicillin for the treatment or retreatment of Helicobacter pylori
infection. Aliment Pharmacol Ther 1996;10:1001-4.
Graham KS, Malaty H, El-Zimaity HM, Genta RM, Cole RA, Al-Assi MT, et al
. Variability with omeprazole-amoxicillin combinations for treatment of Helicobacter pylori
infection. Am J Gastroenterol 1995;90:1415-8.
Gao CP, Zhou Z, Wang JZ, Han SX, Li LP, Lu H. Efficacy and safety of high-dose dual therapy for Helicobacter pylori
rescue therapy: A systematic review and meta-analysis. J Dig Dis 2016;17:811-9.
Yang JC, Lin CJ, Wang HL, Chen JD, Kao JY, Shun CT, et al
. High-dose dual therapy is superior to standard first-line or rescue therapy for Helicobacter pylori
infection. Clin Gastroenterol Hepatol 2015;13:895-905.
Miehlke S, Kirsch C, Schneider-Brachert W, Haferland C, Neumeyer M, Bastlein E, et al
. A prospective, randomized study of quadruple therapy and high-dose dual therapy for treatment of Helicobacter pylori
resistant to both metronidazole and clarithromycin. Helicobacter 2003;8:310-9.
Hu JL, Yang J, Zhou YB, Li P, Han R, Fang DC. Optimized High-Dose Amoxicillin–Proton-Pump Inhibitor Dual Therapies Fail to Achieve High Cure Rates in China. Saudi J Gastroenterol 2017;23:275-80. [Full text]
Sachs G. Proton pump inhibitors and acid-related diseases. Pharmacotherapy 1997;17:22-37.
Bigger JW. Treatment of staphylococcal infections with penicillin by intermittent sterilisation. Lancet 1944;244:497-500.
Keren I, Kaldalu N, Spoering A, Wang Y, Lewis K. Persister cells and tolerance to antimicrobials. FEMS Microbiol Lett 2004;230:13-8.
Matsumoto H, Shiotani A, Katsumata R, Fujita M, Nakato R, Murao T, et al
. Helicobacter pylori
eradication with proton pump inhibitors or potassium-competitive acid blockers: The effect of clarithromycin resistance. Dig Dis Sci 2016;61:3215-20.
Graham DY. Efficient identification and evaluation of effective Helicobacter pylori
therapies. Clin Gastroenterol Hepatol 2009;7:145-8.
David Y Graham
Michael E. DeBakey Veterans Affairs Medical Center RM 3A-318B (111D), 2002 Holcombe Boulevard, Houston, TX
Source of Support: None, Conflict of Interest: None
|This article has been cited by|
triple therapies contribution to global antimicrobial resistance
| ||David Y Graham, Hong Lu, Akiko Shiotani |
| ||Journal of Gastroenterology and Hepatology. 2021; 36(5): 1159 |
|[Pubmed] | [DOI]|
||Helicobacter pylori diagnosis and therapy in the era of antimicrobial stewardship
| ||Akiko Shiotani, Priya Roy, Hong Lu, David Y. Graham |
| ||Therapeutic Advances in Gastroenterology. 2021; 14: 1756284821 |
|[Pubmed] | [DOI]|
||Probiotics as the live microscopic fighters against Helicobacter pylori gastric infections
| ||Masoud Keikha, Mohsen Karbalaei |
| ||BMC Gastroenterology. 2021; 21(1) |
|[Pubmed] | [DOI]|
||A comparative study of 14-day dual therapy (esomeprazole and amoxicillin four times daily) and triple plus bismuth therapy for first-lineHelicobacter pyloriinfection eradication: A randomized trial
| ||Zhiqiang Song, Liya Zhou, Yan Xue, Baojun Suo, Xueli Tian, Zhanyue Niu |
| ||Helicobacter. 2020; 25(6) |
|[Pubmed] | [DOI]|
||Update on the Use of Vonoprazan: A Competitive Acid Blocker
| ||David Y. Graham, Maria Pina Dore |
| ||Gastroenterology. 2018; 154(3): 462 |
|[Pubmed] | [DOI]|
| Article Access Statistics|
| Viewed||5215 |
| Printed||55 |
| Emailed||0 |
| PDF Downloaded||395 |
| Comments ||[Add] |
| Cited by others ||5 |