Amoxicillin-resistant mutations in the pbp1 gene of Helicobacter pylori in children with peptic ulcers

Do Thi Minh Phuong, Nguyen Thi Viet Ha, Le Huu Phương Anh, Nguyen Hai Anh, Nguyen Van Tinh, Chu Thi Phuong Mai, Tran Thi Huyen Trang

Main Article Content

Abstract

Amoxicillin is the primary antibiotic used to eradicate Helicobacter pylori (H. pylori) in children. The emergence of amoxicillin resistance in Vietnam is of significant concern. Mutations in the pbp1 gene can lead to changes in the structure of PBP1 and the development of AMO resistance. Objective: This study aims to evaluate the frequency of mutations in the pbp1 gene and their correlation with antibiotic resistance in H. pylori among children with peptic ulcers. Subjects and methods: A cross-sectional analysis was conducted to study 43 pediatric patients diagnosed with peptic ulcers and confirmed H. pylori infection. The E-test method was employed to determine the minimum inhibitory concentration, while Sanger sequencing was utilized to detect gene mutations. Results: All strains carried three or more mutations in the pbp1 gene. The data indicate a significant prevalence of the mutations F366L (90.7%), S414R (81.4%), Ins 464-465 (88,4%), F473V (88.4%), and D534N (95.3%) among strains. Notably, the mutations F366L, S414R, and F473V were significantly associated with amoxicillin resistance (p < 0.05), and the combination of mutations F366L/S414R/F473V correlated with an increased minimum inhibitory concentration. In conclusion, the high frequency of pbp1 gene mutations is a major contributing factor to the elevated rate of amoxicillin resistance in children with peptic ulcers.

Article Details

References

1. Shashidhar H, Flomenhoft D, Tolia V. Helicobacter pylori & beyond: pediatric peptic ulcer disease. Therapy. 2009;6(1):65-73. doi:10.2217/14750708.6.1.65
2. Kato S, Nishino Y, Ozawa K, et al. The prevalence of Helicobacter pylori in Japanese children with gastritis or peptic ulcer disease. J Gastroenterol. 2004;39(8):734-738. doi:10.1007/s00535-004-1381-2
3. Malfertheiner P, Megraud F, Rokkas T, et al. Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut. Published online August 8, 2022:gutjnl-2022-327745. doi:10.1136/gutjnl-2022-327745
4. Homan M, Jones NL, Bontems P, et al. Updated joint ESPGHAN/NASPGHAN guidelines for management of Helicobacter pylori infection in children and adolescents (2023). Journal of Pediatric Gastroenterology and Nutrition. 2024 Sep;79(3):758-785.. doi:10.1002/jpn3.12314
5. Nguyễn Hữu Hiếu, Nguyễn Thị Việt Hà. Đặc điểm lâm sàng, cận lâm sàng và tình trạng kháng kháng sinh của trẻ em bị loét dạ dày tá tràng có nhiễm Helicobacter pylori. Tạp chí Nghiên cứu Y học. 2021;143(7):134-141. doi:10.52852/tcncyh.v143i7.248
6. Le LTT, Nguyen TA, Nguyen NA, et al. Antibiotic Resistance of Helicobacter pylori in Children with Gastritis and Peptic Ulcers in Mekong Delta, Vietnam. Healthcare (Basel). 2022;10(6):1121. doi:10.3390/healthcare10061121
7. Kim BJ, Kim JG. Substitutions in penicillin-binding protein 1 in amoxicillin-resistant Helicobacter pylori strains isolated from Korean patients. Gut Liver. 2013;7(6):655-660. doi:10.5009/gnl.2013.7.6.655
8. Kwon YH, Kim JY, Kim N, et al. Specific mutations of penicillin-binding protein 1A in 77 clinically acquired amoxicillin-resistant Helicobacter pylori strains in comparison with 77 amoxicillin-susceptible strains. Helicobacter. 2017;22(6). doi:10.1111/hel.12437
9. Okamoto T, Yoshiyama H, Nakazawa T, et al. A change in PBP1 is involved in amoxicillin resistance of clinical isolates of Helicobacter pylori. J Antimicrob Chemother. 2002;50(6):849-856. doi:10.1093/jac/dkf140
10. Gerrits MM, Godoy APO, Kuipers EJ, et al. Multiple mutations in or adjacent to the conserved penicillin-binding protein motifs of the penicillin-binding protein 1A confer amoxicillin resistance to Helicobacter pylori. Helicobacter. 2006;11(3):181-187. doi:10.1111/j.1523-5378.2006.00398.x
11. Tran TT, Nguyen AT, Quach DT, et al. Emergence of amoxicillin resistance and identification of novel mutations of the pbp1A gene in Helicobacter pylori in Vietnam. BMC Microbiol. 2022;22:41. doi:10.1186/s12866-022-02463-8
12. Rimbara E, Noguchi N, Kawai T, et al. Correlation between Substitutions in Penicillin-Binding Protein 1 and Amoxicillin Resistance in Helicobacter pylori. Microbiology and Immunology. 2007;51(10):939-944. doi:10.1111/j.1348-0421.2007.tb03990.x
13. Eucast: Clinical breakpoints and dosing of antibiotics. Accessed July 4, 2024. https://www.eucast.org/clinical_breakpoints
14. Nguyen TVH, Bengtsson C, Yin L, et al. Eradication of Helicobacter pylori in children in Vietnam in Relation to Antibiotic Resistance. Helicobacter. 2012;17(4):319-325. doi:10.1111/j.1523-5378.2012.00950.x
15. Nguyễn Thị Út, Hoàng Thị Bích Ngọc, Nguyễn Hồng Phúc. Kháng kháng sinh tiên phát của Helicobacter pylori ở trẻ em loét dạ dày tá tràng tại Bệnh Viện Nhi Trung ương năm 2023. Tạp chí Y học Việt Nam. 2023;533(1B). doi:10.51298/vmj.v533i1B.7842
16. Cimuanga-Mukanya A, Tshibangu-Kabamba E, Kisoko P de JN, et al. Synergistic effects of novel penicillin-binding protein 1A amino acid substitutions contribute to high-level amoxicillin resistance of Helicobacter pylori. mSphere. 9(8):e00089-24. doi:10.1128/msphere.00089-24