Alarming resistance to Helicobacter pylori antibiotics in Southeast China’s children over 6 years old

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success of H.pylori eradication depends mainly on the use of sensitive antibiotics15. However, antimicrobial susceptibility testing for H.pylori is not universally available. Therefore, the choice of an effective empirical eradication therapy is based on region-specific and population-specific antibiotic resistance patterns. In the present single-center study, we conducted a large patient-based survey to assess resistance rates of the six most common antibiotics for H.pylori eradication in Southeast China from 2015 to 2020. Our study indicated that the resistance rates of H.pylori at CLA, MTZ and LEV were extremely high from 2015 to 2020 and saw a linear increase in most resistance patterns over the past 9 years.

The primary concern is the rapid development of high rates of CLA resistance, which is an important component of first-line treatment regimens. In our study, overall resistance to CLA increased by 11.1% in 2012ten to 43.1% in 2020 in our center, by 2.8% each year, and remained permanently above 15% from 2013 to 2020, threshold of resistance rate to CLA for standard triple therapy in the Maastricht IV consensus report /Florence5. It was higher than most parts of the world16 but similar in other parts of China17. CLA resistance has been reported to be correlated with treatment failure18.19. Among patients who received CLA-containing regimens, CLA-resistant strains were significantly higher in those whose eradication failed18. Unfortunately, the effects of antibiotic resistance on H.pylori the efficacy of eradication could not be assessed because treatment regimens and outcomes were not fully obtained in this study. In the future, we will monitor subsequent treatment regimens and the effectiveness of eradication.

The prescription of ALC in children during the last decade for respiratory tract infections could contribute to a high resistance rate of H.pylori at CLA20. There is statistical significance between the consumption of macrolides and quinolones in the community and the H.pylori resistance in European countries21.22. Nationwide population-level data revealed a significant upward trend in the consumption of antibiotics, including macrolides, in Chinese tertiary hospitals from 2011 to 2015, then the overall consumption of macrolides slightly increased. decreased from 2015 to 2017.23.24. It seems consistent with the trend in the resistance rate of H.pylori at CLA from 2012 to 2018 (Fig. 1A).

MTZ is also one of the oldest and most commonly used antibiotics for H.pylori eradication. However, the prevalence of resistance to MTZ was high worldwide, particularly in China due to the increased prescription of MTZ, especially for dental infections and parasitic infections. Additionally, many clinicians mistakenly believe that in vitro resistance cannot prevent the use of MTZ because increasing the dosage and duration of treatment will help increase the eradication rate. These could lead to an extremely high resistance rate of MTZ in our region (81.7%), which has remained at a high level since 2014 (Fig. 1). In addition, dual resistance to CLA + MTZ was greater (16.4%) than 15%, and 77.3% (416/538) of strains were resistant to MTZ in the CLA-resistant isolates. According to updated consensus reports, bismuth-containing quadruple therapies with a proton pump inhibitor, bismuth and a combination of two antibiotics, among FZD, TET, MTZ and AML, are the recommended first-line treatment in regions with high (> 15%) double resistance CLA and MTZ5.6. But TET and FZD which are used for H.pylori eradication in adults are relatively contradicted in children due to potential side effects and the evidence supporting this regimen in children and adolescents is limited25. The use of TET may be considered instead of AMO in children over 8 years of age if the strain is resistant to ALC in case of penicillin allergy in the updated ESPGHAN/NASPGHAN guidelineseven. However, TET and FZD are not permitted for use in children in China and Japan.8.26.

LEV is generally contraindicated in children under 18 due to potential serious side effects, although it has been widely studied to eradicate H.pylori and has been shown to be effective in adults. The overall resistance rate of H.pylori at LEV also increased over time in our studies, although it was lower than in adults27. As H.pylori the infection is generally acquired in childhood mainly by intrafamilial transmission, the high resistance to LEV in children could be explained by the transmission of strains resistant to LEV from parents to children.

There was no strain resistant to AML in our study, indicating a low incidence of this antibiotic resistance of H.pyloriwhich was in agreement with previous studies10,17,28. Some AML-resistant strains of H.pylori show a strong decrease in resistance to LAM after freezing linked to the downregulation of genes involved in membrane structure and transport function29. Our gastric mucosa samples are preserved in brain-heart infusion broth and transported for isolation and susceptibility testing at 4°C, which can exclude underestimation of resistance caused by cryopreservation.

There was no significant difference in resistance rates between different sex and age groups in our previous study.tenconsistent with results in different regions of China17.28but differently with the same areas28. Dual resistance to CLA and MTZ increased significantly in the 7–12 and 13–18 year groups compared to the 1–6 year group in our current study, whether or not the 2012–2014 data were implicated (Table 3, Fig. 2). Next, we checked for dual resistance to CLA + MTZ in different age groups from 2012 to 2014 and found that it did increase with age but was not statistically significant, with 8.8% (9/ 102) in the 1-6 year old group, 12.0% (35/291) in the 7-12 year old group and 13.2% (20/152) in the 13-18 year old group. The number of patients enrolled in Li’s study was also relatively small, which may be why he was unable to detect the difference in resistance between different age groups.

Secondary resistance rates were higher than primary resistance in the same population in different regions, especially the resistance rate to CLA17,19,30,31. In our study, the rate of primary resistance to CLA in 1513 children with no history H.pylori treatment was 31.9%, while the rate of secondary resistance among the 125 children who received prior treatment was significantly higher (44.8%, P 19but lower than different regions reported in recent years, including southeast China17,30,31.

Multi-drug resistance was also a significant problem. 37.7% of strains were resistant to more than one antibiotic from 2015 to 2020, 28.7% double resistant and 9.0% triple resistant, almost two to three times compared to that of 2012 to 2014 (19.6%, 16.7% and 2.9% respectively)ten. The rate of primary resistance to CLA, MTZ, and LEV was 8.8%, and the rate of secondary resistance increased significantly to 15.2% (P17. Double and triple resistances were the very important reasons for the increase in resistance rates (Fig. 1).

With the growing prevalence of antibiotic resistance around the world H.pylori infection, antibiotic susceptibility testing is becoming increasingly necessary to guide decisions about appropriate therapies in individuals and treatment policies in populations. However, culture-based antibiotic susceptibility testing for H.pylori , according to upper gastrointestinal endoscopy, is not universally available for children in China. On the one hand, pediatric endoscopists and specialized hospitals where gastrointestinal endoscopy is not performed in all hospitals in China. On the other hand, H.pylori culture is difficult and culture-based antimicrobial susceptibility testing is not routinely performed in the majority of hospitals. H.pylori resistance rates are not systematically monitored by relevant institutions and are not yet taken into account by the drug administration department of our hospital. Nowadays, advances in understanding the basic molecular aspects of drug resistance in H.pyloriand the development of molecular techniques (such as PCR, next-generation sequencing) have enabled several molecular methods for the rapid detection of resistance in clinical infections32. We compared partial results of culture-based analyzes H.pyloridiagnosis and antimicrobial susceptibility testing with molecular methods (sequencing and gene chip technology) from 2015 to 201633.34. Our results confirm that the sensitivity and accuracy of molecular methods are superior to culture-based ones, although challenges remain. It is important to note that most molecular tests can be culture-based when performed on cultured isolates or culture-free when directly applied to various types of biological specimens such as fresh gastric biopsy specimens. , frozen or embedded in paraffin, stool samples and gastric juice. Future studies should target the latter and are needed for the standardization and implementation of easy-to-use computational tools to detect resistance-related genetic determinants. These should be more effective in adopting eradication therapies in the future through frontline antimicrobial susceptibility testing.

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