Abstract
Purpose
H. pylori with triple-drug resistance (TR) to clarithromycin, metronidazole, and levofloxacin limits the success of rescue therapy. We aimed to identify the optimal breakpoints of antibiotic minimal inhibitory concentration (MIC) to predict the success of rescue therapy for TR H. pylori infection.
Methods
We consecutively enrolled 430 patients with at least one course of failed H. pylori eradications to receive an H. pylori culture for antibiotic MIC test. Seventy-three (17%) had TR H. pylori infection (MIC of clarithromycin > 0.5, levofloxacin > 1, and metronidazole > 8 mg/L, respectively). Sixty-nine cases with TR H. pylori infection received rescue therapy with either ATBP (amoxicillin, tetracycline, bismuth, and PPI) or MTBP (metronidazole, tetracycline, bismuth and PPI) for 7–14 days. Fourteen patients with positive 13C-urea breath test after the first rescue therapy were retreated with a crossover second rescue therapy.
Results
The MTBP regimen had higher eradication success than the ATBP regimen as the first rescue therapy for TR H. pylori (intent-to-treat (ITT) analysis, 70.3 vs. 46.9%, p = 0.048; per protocol (PP) analysis, 78.8% vs. 51.7%, p = 0.025). For MTBP regimen, tetracycline MIC ≤ 0.094 mg/L (p < 0.001) with a 14-day treatment duration (p = 0.037) could predict eradication success with 100% accuracy. For the ATBP regimen, amoxicillin MIC selected as ≤ 0.032 mg/L could optimally determine eradication success (72.2 vs. 33.3%, p = 0.025).
Conclusion
Optimizing the MIC breakpoints of amoxicillin and tetracycline resistance better predicts the outcome of bismuth quadruple therapy. Further prospective studies using the revised MIC breakpoints to select antibiotics are warranted.
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References
Calvet X, Ramirez Lazaro MJ, Lehours P, Megraud F (2013) Diagnosis and epidemiology of Helicobacter pylori infection. Helicobacter 18(Suppl 1):5–11. https://doi.org/10.1111/hel.12071
Liou JM, Lee YC, El-Omar EM, Wu MS (2019) Efficacy and long-term safety of H. pylori eradication for gastric cancer prevention. Cancers 11(5). https://doi.org/10.3390/cancers11050593
Sheu BS, Wu MS, Chiu CT, Lo JC, Wu DC, Liou JM, Wu CY, Cheng HC, Lee YC, Hsu PI, Chang CC, Chang WL, Lin JT (2017) Consensus on the clinical management, screening-to-treat, and surveillance of Helicobacter pylori infection to improve gastric cancer control on a nationwide scale. Helicobacter 22(3):e12368. https://doi.org/10.1111/hel.12368
El-Serag HB, Kao JY, Kanwal F, Gilger M, LoVecchio F, Moss SF, Crowe S, Elfant A, Haas T, Hapke RJ, Graham DY (2018) Houston consensus conference on testing for Helicobacter pylori infection in the United States. Clin Gastroenterol Hepatol 16(7):992–1002 e1006. https://doi.org/10.1016/j.cgh.2018.03.013
Sugano K, Tack J, Kuipers EJ, Graham DY, El-Omar EM, Miura S, Haruma K, Asaka M, Uemura N, Malfertheiner P, faculty members of Kyoto Global Consensus C (2015) Kyoto global consensus report on Helicobacter pylori gastritis. Gut 64(9):1353–1367. https://doi.org/10.1136/gutjnl-2015-309252
Thung I, Aramin H, Vavinskaya V, Gupta S, Park JY, Crowe SE, Valasek MA (2016) Review article: the global emergence of Helicobacter pylori antibiotic resistance. Aliment Pharmacol Ther 43(4):514–533. https://doi.org/10.1111/apt.13497
Malfertheiner P, Megraud F, O'Morain CA, Gisbert JP, Kuipers EJ, Axon AT, Bazzoli F, Gasbarrini A, Atherton J, Graham DY, Hunt R, Moayyedi P, Rokkas T, Rugge M, Selgrad M, Suerbaum S, Sugano K, El-Omar EM, European H, Microbiota Study G, Consensus p (2017) Management of Helicobacter pylori infection-the Maastricht V/Florence consensus report. Gut 66(1):6–30. https://doi.org/10.1136/gutjnl-2016-312288
Gao W, Cheng H, Hu F, Li J, Wang L, Yang G, Xu L, Zheng X (2010) The evolution of Helicobacter pylori antibiotics resistance over 10 years in Beijing, China. Helicobacter 15(5):460–466. https://doi.org/10.1111/j.1523-5378.2010.00788.x
Liou JM, Chen PY, Luo JC, Lee JY, Chen CC, Fang YJ, Yang TH, Chang CY, Bair MJ, Chen MJ, Hsu YC, Hsu WF, Chang CC, Lin JT, Shun CT, El-Omar EM, Wu MS, Taiwan Gastrointestinal D, Helicobacter C (2018) Efficacies of genotypic resistance-guided vs empirical therapy for refractory Helicobacter pylori infection. Gastroenterology 155(4):1109–1119. https://doi.org/10.1053/j.gastro.2018.06.047
Malfertheiner P, Bazzoli F, Delchier JC, Celinski K, Giguere M, Riviere M, Megraud F, Pylera Study G (2011) 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 377(9769):905–913. https://doi.org/10.1016/S0140-6736(11)60020-2
Salazar CO, Cardenas VM, Reddy RK, Dominguez DC, Snyder LK, Graham DY (2012) Greater than 95% success with 14-day bismuth quadruple anti- Helicobacter pylori therapy: a pilot study in US Hispanics. Helicobacter 17(5):382–390. https://doi.org/10.1111/j.1523-5378.2012.00962.x
Liang X, Xu X, Zheng Q, Zhang W, Sun Q, Liu W, Xiao S, Lu H (2013) Efficacy of bismuth-containing quadruple therapies for clarithromycin-, metronidazole-, and fluoroquinolone-resistant Helicobacter pylori infections in a prospective study. Clin Gastroenterol Hepatol 11(7):802–807 e801. https://doi.org/10.1016/j.cgh.2013.01.008
Chen MJ, Wu MS, Chen CC, Chen CC, Fang YJ, Bair MJ, Chang CY, Lee JY, Hsu WF, Luo JC, Lin JT, Liou JM, Taiwan Gastrointestinal D, Helicobacter C (2017) Impact of amoxicillin resistance on the efficacy of amoxicillin-containing regimens for Helicobacter pylori eradication: analysis of five randomized trials. J Antimicrob Chemother 72(12):3481–3489. https://doi.org/10.1093/jac/dkx320
CLSI (ed) (2016) Methods for antimicrobial dilution and disk susceptibility testing of infrequently isolated or fastidious bacteria. 3rd ed. CLSI guideline M45. Clinical and Laboratory Standards Institute, Wayne
The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 10.0, 2020. http://www.eucast.org
Lee BH, Kim N, Hwang TJ, Lee SH, Park YS, Hwang JH, Kim JW, Jeong SH, Lee DH, Jung HC, Song IS (2010) Bismuth-containing quadruple therapy as second-line treatment for Helicobacter pylori infection: effect of treatment duration and antibiotic resistance on the eradication rate in Korea. Helicobacter 15(1):38–45. https://doi.org/10.1111/j.1523-5378.2009.00735.x
Tursi A, Di Mario F, Franceschi M, De Bastiani R, Elisei W, Baldassarre G, Ferronato A, Grillo S, Landi S, Zamparella M, De Polo M, Boscariolo L, Picchio M (2017) New bismuth-containing quadruple therapy in patients infected with Helicobacter pylori: a first Italian experience in clinical practice. Helicobacter 22(3). https://doi.org/10.1111/hel.12371
Chen Q, Zhang W, Fu Q, Liang X, Liu W, Xiao S, Lu H (2016) Rescue therapy for Helicobacter pylori eradication: a randomized non-inferiority trial of amoxicillin or tetracycline in bismuth quadruple therapy. Am J Gastroenterol 111(12):1736–1742. https://doi.org/10.1038/ajg.2016.443
Gisbert JP, Perez-Aisa A, Rodrigo L, Molina-Infante J, Modolell I, Bermejo F, Castro-Fernandez M, Anton R, Sacristan B, Cosme A, Barrio J, Harb Y, Gonzalez-Barcenas M, Fernandez-Bermejo M, Algaba A, Marin AC, McNicholl AG, Association HpSGotSG (2014) Third-line rescue therapy with bismuth-containing quadruple regimen after failure of two treatments (with clarithromycin and levofloxacin) for H. pylori infection. Dig Dis Sci 59(2):383–389. https://doi.org/10.1007/s10620-013-2900-x
Graham DY, Osato MS, Hoffman J, Opekun AR, Anderson SY, Kwon DH, El-Zimaity HM (2000) Metronidazole containing quadruple therapy for infection with metronidazole resistant Helicobacter pylori: a prospective study. Aliment Pharmacol Ther 14(6):745–750. https://doi.org/10.1046/j.1365-2036.2000.00770.x
Miehlke S, Kirsch C, Schneider-Brachert W, Haferland C, Neumeyer M, Bastlein E, Papke J, Jacobs E, Vieth M, Stolte M, Lehn N, Bayerdorffer E (2003) A prospective, randomized study of quadruple therapy and high-dose dual therapy for treatment of Helicobacter pylori resistant to both metronidazole and clarithromycin. Helicobacter 8(4):310–319. https://doi.org/10.1046/j.1523-5378.2003.00158.x
Graham DY, Lee SY (2015) How to effectively use bismuth quadruple therapy: the good, the bad, and the ugly. Gastroenterol Clin N Am 44(3):537–563. https://doi.org/10.1016/j.gtc.2015.05.003
Wu DC, Hsu PI, Tseng HH, Tsay FW, Lai KH, Kuo CH, Wang SW, Chen A (2011) Helicobacter pylori infection: a randomized, controlled study comparing 2 rescue therapies after failure of standard triple therapies. Medicine 90(3):180–185. https://doi.org/10.1097/MD.0b013e31821c9d1c
Anoushiravani M, Falsafi T, Niknam V (2009) Proton motive force-dependent efflux of tetracycline in clinical isolates of Helicobacter pylori. J Med Microbiol 58(Pt 10):1309–1313. https://doi.org/10.1099/jmm.0.010876-0
Chen C, Hooper DC (2018) Effect of Staphylococcus aureus Tet38 native efflux pump on in vivo response to tetracycline in a murine subcutaneous abscess model. J Antimicrob Chemother 73(3):720–723. https://doi.org/10.1093/jac/dkx432
Scott DR, Sachs G, Marcus EA (2016) The role of acid inhibition in Helicobacter pylori eradication. F1000Research 5:F1000 faculty Rev-1747. https://doi.org/10.12688/f1000research.8598.1
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This study was supported by the National Cheng Kung University Hospital clinical bacterial database.
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MT Hsieh and WL Chang conceived the study and contributed equally. Patients were enrolled from all authors. MT Hsieh and WL Chang reviewed all the medical records, analyzed the data, and interpreted the results. MT Hsieh and WL Chang prepared the initial draft of the manuscript. BS Sheu coordinated the study design and improved the subsequent drafts of the manuscript. The final draft was approved for submission.
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Hsieh, MT., Chang, WL., Wu, CT. et al. Optimizing the MIC breakpoints of amoxicillin and tetracycline for antibiotic selection in the rescue therapy of H. pylori with bismuth quadruple regimen. Eur J Clin Pharmacol 76, 1581–1589 (2020). https://doi.org/10.1007/s00228-020-02938-5
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DOI: https://doi.org/10.1007/s00228-020-02938-5