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. 2022 Jul 12;11(7):786. doi: 10.3390/pathogens11070786

Primary Antibiotic Resistance of Helicobacter pylori in Different Regions of China: A Systematic Review and Meta-Analysis

Jinnan Chen 1,†, Puheng Li 2,†, Yu Huang 1, Yixian Guo 1, Zhaohui Ding 1, Hong Lu 1,*
Editors: Emad M El-Omar, Guillermo I Perez-Perez
PMCID: PMC9316315  PMID: 35890031

Abstract

Aim: Understanding the prevalence of antibiotic resistance can provide reliable information for selecting treatment options. The goal of this meta-analysis was to observe the primary antibiotic resistance of Helicobacter pylori (H. pylori) in different regions and time periods of China. Method: We searched PubMed, EMBASE, Chinese Biomedical databases and the China National Knowledge Infrastructure from inception to 20 February 2022. Data on the prevalence of H. pylori primary resistance at various time points were included. A random-effect model was established to calculate the pooled antibiotic resistance. Results: In total, 2150 articles were searched, with 70 meeting the inclusion criteria. The resistance to clarithromycin, metronidazole, levofloxacin amoxicillin, tetracycline and furazolidone in 2016–2020 were 34% (95% CI: 30–39%), 78% (95% CI: 73–84%), 35% (95% CI: 30–40%), 3% (95% CI: 1–5%), 2% (95%CI: 1–4%) and 1% (95% CI: 0–4%), respectively. Clarithromycin showed regional difference, as the resistance was higher in northern (37%, 95% CI: 32–41%) and western China (35%, 95% CI: 17–54%) than that in southern (24%, 95% CI: 17–32%) and eastern China (24%, 95% CI: 20–28%). Conclusion: The resistance of H. pylori to clarithromycin and metronidazole was high and increased over time, whereas resistance to levofloxacin, amoxicillin, tetracycline and furazolidone remained stable.

Keywords: Helicobacter pylori, primary resistance, amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline

1. Introduction

Though decreasing in developed countries, the prevalence of Helicobacter pylori (H. pylori) is still high in China, causing a major health burden due to peptic ulcer disease complications and gastric cancer [1,2]. As an infectious disease, antibiotics-based therapies play a leading role in the treatment [3,4]. However, we face the serious challenge of high antimicrobial resistance because of the previous use of these antibiotics [5]. The primary antibiotic resistance decreases the efficiency of first-line treatment. The overall effect is dependent on both the cure rate with resistant strains and the proportion with resistance, especially clarithromycin and levofloxacin-containing regimen [6,7]. Empirical anti-H. pylori therapy is commonly used in current clinical practice instead of susceptibility-guided therapy which is unavailable in most of China. Therefore, obtaining high-quality local data and the antibiotic resistance pattern is needed to get good clinical outcomes [8]. In this study, we reviewed and analyzed primary antibiotic resistance rates of H. pylori in different regions and time periods in China over two decades to provide some guidance for selecting the first-line antibiotics.

2. Method

2.1. Search Strategy and Select Criteria

A search focused on the primary antibiotic resistance of H. pylori in the Chinese mainland population was done on Pubmed, Embase, the Chinese Biomedical (CBM) and the China National Knowledge Infrastructure (CNKI) from inception to 20 February 2022. The study was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [9]. The search terms included were as follows: “Helicobacter pylori” and “China”, these search terms were combined with “Antibiotic resistance” and each individual antibiotic serially (“clarithromycin”, “metronidazole”, “levofloxacin”, “amoxicillin”, “furazolidone” and “tetracycline”).

In order to minimize selection bias, inclusion and exclusion criteria were established as follows: (1) the diagnosis of H. pylori infection must be based on at least one of the routine diagnostic methods (13C or 14C urea breath test, histology examination, rapid urease test or in vitro culture); (2) the patients had no use of Proton pump inhibitor, antibiotic or herbal medicine within the previous 2 weeks; (3) the patients did not receive H. pylori eradication therapy, which could exclude the influence of secondary drug resistance; (4) drug susceptibility was tested using the Agar dilution method, Epsilometer test (E-test), Polymerase Chain Reaction (PCR) or Kirby–Bauer (KB) disk diffusion method; (5) the patients were older than 18 years old; (6) the patients were mainland residents; (7) the articles must be original articles, not reviews or letters to editors. The inclusion of the article and data extraction were conducted by two authors. The disagreements were resolved by discussion between the two authors.

2.2. Data Extraction

Two authors (JN Chen and PH Li) extracted relevant information including: publication year, study period, source area, drug susceptibility method, number of patients enrolled and those with resistance of different antibiotics independently according to a standardized data extraction form. Yu Huang was responsible for the discordant results.

2.3. Statistics Analysis

Meta-analysis was performed for the primary antibiotic resistance of H. pylori in Chinese patients. In some studies, the H. pylori resistance rates were close to 0%. Therefore, Freeman–Tukey double arcsine transformation was used to process the data. Heterogeneity was tested by Cochran’s Q test and I² test (I2 < 25%, 25–75%, and I2 > 75% represents low, moderate and high heterogeneity, respectively). The DerSimonian and Laird random effect model was used to calculate the pooled rate and 95% confidence interval (CI). We used Egger’s test and Funnel plot to examine the potential heterogeneity. We calculated the mean annual percentage change and its confidence interval by calculating resistance rates between the earliest and most recent study periods available. For time period analysis, we divided the sample year into 4 groups based on their study period: before 2005, 2006–2010, 2011–2015 and 2016–2020. If the article spanned two time periods, we included it in its closest time periods. If the article included two or more time periods, we classified them separately. If the year of sample collection was not indicated in the study, 2 years before the publication of the article was defined as the study period [8]. For the region analysis, we divided China into four regions based on their geographical characteristics and matched each study, except the multicenter study, according to its urban location. All of the data analyses were performed using R version 4.1.0.

3. Results

We searched 2150 articles, and 70 articles were enrolled in the study (Figure 1). Among the included studies, 21 were from northern China, 27 were from eastern China, 8 were from southern China, 7 from western China and 7 studies were multicenter studies (Table 1).

Figure 1.

Figure 1

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Study selection.

Table 1.

Characteristics of the enrolled studies on resistance rate of H. pylori to antibiotics.

Authors Regions Year Method Clarithromycin Metronidazole Levofloxacin Amoxicillin Tetracycline Furazolidone
Patients(n) Prevalence(%) Patients(n) Prevalence(%) Patients(n) Prevalence(%) Patients(n) Prevalence(%) Patients(n) Prevalence(%) Patients(n) Prevalence(%)
North China - -
Gao et al. [10] Beijing 2000 E-test 47 12.8 47 34.0 - - 47 2.13 - - - -
2001 63 12.7 63 31.75 - - 63 0.00 - - - -
2002–2003 22 9.09 22 54.55 - - 22 0.00 - - - -
2004–2005 24 20.83 24 70.83 - - 24 0.00 - - - -
2006–2007 71 38.03 71 80.28 40 25.00 71 0.00 41 0.00 - -
2008 39 38.46 39 66.67 39 46.15 39 0.00 39 0.00 - -
2009 24 25.00 24 66.67 24 41.67 24 0.00 24 4.17 - -
Zhang [11] Beijing 2009–2010 E-test 371 39.89 371 66.85 371 34.50 371 6.74 371 4.85 - -
2013–2014 E-test 950 52.63 950 63.37 950 54.84 950 4.42 950 7.26 - -
Liu [12] Beijing 2012–2013 PCR 130 37.69 - - - - - - - - - -
Bai [13] Beijing 2013 E-test 144 25.69 144 55.56 - - - - - - - -
Zhang [14] Beijing 2013–2014 E-test 700 50.14 700 63.86 700 54.43 700 3.71 700 7.29 - -
Song [15] Beijing 2013–2015 E-test 58 39.66 58 60.34 58 36.21 58 3.45 58 3.45 - -
Li [16] Beijing 2013–2020 E-test 74 51.35 74 58.11 74 28.38 - - - - - -
Song [17] Beijing 2014–2015 E-test 147 44.90 147 67.35 - - 147 2.04 - - - -
Suo [18] Beijing 2014–2018 E-test 96 37.50 96 62.50 96 37.50 96 4.17 96 4.17 - -
Suo [19] Beijing 2014–2018 E-test 100 38.00 100 62.00 100 39.00 100 4.00 100 5.00 - -
Fu [20] Beijing 2015 E-test 324 43.21 324 63.89 324 45.37 324 4.32 324 7.10 - -
Ma [21] Beijing 2015–2016 E-test 56 28.57 56 69.64 56 0.00 56 0.00 - - 56 8.93
Song [22] Beijing 2015–2017 E-test 65 38.46 65 63.08 65 40.00 65 3.08 65 6.15 - -
Fan [23] Beijing 2015–2018 PCR 270 51.85 - - - - - - - - - -
Song [24] Beijing 2017–2018 E-test 650 33.54 650 58.46 650 33.69 650 2.92 650 4.15 - -
Cui [25] Beijing 2017–2018 E-test 506 38.74 506 57.31 506 31.03 506 2.57 506 6.32 - -
Gao [26] Beijing - PCR 111 42.34 - - 111 41.44 111 5.41 111 12.61 - -
Meng [27] Hebei 2012–2013 KB 155 21.29 155 94.19 155 5.81 155 2.58 - - 155 3.00
Wang [28] Shandong 2011–2014 ADM 134 67.16 134 62.69 134 56.72 - - - - - -
Wang [29] Liaoning 1998–1999 E-test 23 39.13 23 86.96 23 47.83 23 4.35 23 13.04 - -
2002–2004 E-test 50 14.00 50 66.00 50 46.00 50 2.00 50 14.00 - -
2016–2017 E-test 27 55.56 27 92.59 27 81.48 27 25.93 27 18.52 - -
Wang [30] Shandong 2012–2014 ADM - - 101 43.56 - - - - - - - -
East China
Gu [31] Shanghai 2005–2006 E-test 36 8.33 36 44.44 - - 36 2.78 - - - -
Lin [32] Shanghai 2008–2009 KB 137 18.25 137 77.37 137 29.93 137 2.19 - - 137 2.19
Zheng [33] Shanghai 2008–2009 ADM 77 20.78 77 41.56 - - 77 0.00 77 0.00 - -
Sun [34] Shanghai - ADM 133 18.05 133 42.11 - - - - - - - -
Tan [35] Shanghai 2009–2010 KB 120 36.67 120 82.50 120 41.67 120 22.50 - - 120 0.83
Zhou [36] Shanghai 2009 KB 248 15.32 248 42.74 - - - - - - - -
Xu [37] Shanghai 2010–2011 ADM 120 24.17 120 48.33 - - 120 0.00 - - - -
Liao [38] Shanghai 2012 ADM 112 18.75 - - 112 30.36 - - - - - -
Hu [39] Shanghai 2013–2015 E-test 132 14.39 132 63.64 132 30.30 132 0.00 - - - -
Zhang [40] Shanghai 2014 ADM 200 26.50 200 45.50 - - 200 1.50 - - - -
Shen [41] Shanghai 2016 ADM 105 33.33 105 70.48 105 32.38 105 2.86 105 0.95 - -
Long [42] Shanghai 2016–2017 ADM 66 24.24 66 74.24 - - - - - - - -
Chen [43] Shanghai 2017–2018 ADM 382 35.08 382 82.72 382 46.86 - - - - - -
Yu [44] Shanghai 2018 ADM 145 31.72 145 81.38 145 40.69 145 0.00 - - - -
Luo [45] Shanghai 2018–2019 E-test 37 32.43 37 81.08 37 45.95 - - - - - -
Xu [46] Shanghai 2018–2019 ADM 100 32.00 100 64.00 - - 100 0.00 - - - -
Luo [47] Shanghai 2018–2019 ADM 207 30.92 207 75.85 207 42.03 207 0.97 - - - -
Cao [48] Zhejiang 2005–2006 KB 85 20.00 85 96.47 - - 85 37.65 - - 85 21.18
Pan [49] Zhejiang 2014 ADM 467 26.12 467 96.79 467 28.69 467 0.00 - - 467 0.00
Liu [50] Zhejiang 2016 ADM 398 12.56 398 80.15 398 38.69 398 0.00 398 0.00 398 0.00
Sun [51] Zhejiang 2017 ADM 127 33.86 127 91.34 127 44.88 127 0.00 127 0.00 127 0.00
Xu [52] Zhejiang 2018 ADM 56 23.21 - - - - - - - - - -
Su [53] Jiangsu 2013 PCR 159 19.50 - - 159 30.82 - - - - - -
Jiang [54] Jiangsu 2017–2019 ADM 1204 38.62 1204 78.57 1204 27.41 1204 1.83 1204 0.33 1204 0.58
Jiang [55] Jiangsu 2017–2019 KB 553 33.82 553 82.64 553 18.63 553 2.53 553 0.72 553 0.72
Liu [56] Jiangxi 2010–2017 E-test 804 19.03 804 58.29 804 23.26 804 1.24 804 2.24 - -
Hong [57] Jiangxi 2014 E-test 374 13.90 374 78.36 374 12.57 - - - - - -
South China
Zhang [58] Guangdong 2000 ADM 164 6.10 164 51.83 - - 164 0.61 - - - -
Yang [59] Guangdong 2015–2017 PCR 244 22.95 - - 244 5.33 - - - - - -
Wang [60] Guangdong 2016–2017 KB 39 20.51 39 71.79 39 5.13 39 2.56 - - - -
Lu [61] Guangdong 2016–2018 ADM 557 34.11 557 92.46 557 42.37 557 1.26 557 0.00 529 0.00
Zhang [62] Guangdong 2017–2019 ADM 315 32.70 315 83.17 - - 231 0.00 - - - -
Ruan [63] Fujian 2001 ADM 47 10.64 47 34.04 - - 47 0.00 - - - -
2004 ADM 54 25.93 54 55.56 - - 54 0.00 - - - -
2006 ADM 102 28.43 102 47.06 - - 102 1.96 - - - -
He [64] Fujian 2019 - - - - 262 32.44 - - - - - -
Luo [65] Guangxi 2011–2012 KB 300 40.33 300 87.33 300 6.67 300 8.00 300 0.00 300 0.00
West China
Zhou [66] Chongqing 2009 KB - - - - 100 4.00 - - - - - -
2013 KB - - - - 100 12.00 - - - - - -
Yang [67] Chongqing 2017 ADM 232 29.74 232 96.55 232 37.93 232 0.00 232 0.00 232 0.00
Zhou [68] Chongqing 2012–2016 KB 150 21.33 150 54.00 150 4.00 150 2.00 - - 52 0.00
Tang [69] Sichuan 2017–2019 E-test 117 44.44 117 90.60 117 28.21 117 7.69 117 0.85 117 0.85
He [70] Sichuan 2019–2020 KB 200 15.50 200 70.00 200 38.50 200 1.00 - - 200 1.00
Hu [71] Yunnan 2000–2001 E-test - - 109 67.89 - - - - - - - -
Zhang [72] Yunnan 2015–2016 KB 196 66.33 196 98.47 196 41.33 196 34.69 - - 196 31.12
Multicenter
Zhou [73] 2008–2010 E-test 280 40 280 66.79 - - 280 4.64 - - - -
Qi [74] 2008–2010 E-test 128 41.41 - - - - 128 5.47 - - - -
Song [75] 2008–2012 E-test 600 37.50 600 67.20 600 33.50 600 6.80 600 3.50 - -
Xie [76] 2013–2014 E-test 288 18.40 - - - - 288 4.51 288 0.69 - -
Xie [77] 2013–2014 E-test 206 33.98 206 80.10 - - - - - - - -
Zhou [78] 2013–2014 E-test 950 48.84 950 66.84 - - 950 2.00 - - - -
Liu [79] 2010–2016 E-test 1117 22.11 1117 78.25 1117 19.16 1117 3.40 1117 1.88 1117 0.00
Overall 18301 30.00 17013 70.00 14230 31.00 15448 3.00 10614 3.00 6045 1.00
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3.1. Primary Resistance of H. pylori to Clarithromycin

The clarithromycin resistance sharply increased from 15% (95% CI: 9–22%) before 2005 to 34% (95% CI: 22–48%) in 2016–2020 (p < 0.001, Figure 2 and Figure S1). Meanwhile, the prevalence of clarithromycin resistance in different regions was also detected. The clarithromycin resistance in northern (37%, 95% CI: 32–41%) and western China (34%, 95% CI: 17–54%) were higher than that in eastern (24%, 95% CI: 20–28%) and southern China (24%, 95% CI: 17–32%) (p = 0.0004, Figure S2).

Figure 2.

Figure 2

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Primary clarithromycin (A), metronidazole (B), levofloxacin (C), amoxicillin (D), tetracycline (E) and furazolidone (F) resistance of H. pylori in China.

Subsequent time period analysis of northern and eastern China showed an upward trend of clarithromycin resistance in both regions over the past 20 years, from 16% to 42% (p < 0.0001, Figure 3 and Figure S3) and from 20% to 30% (p = 0.008, Figure 3 and Figure S4), respectively.

Figure 3.

Figure 3

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Time trends of primary clarithromycin (A), metronidazole (B) and levofloxacin (C) resistance in different regions of China.

3.2. Primary Resistance of H. pylori to Metronidazole

The resistance rate of H. pylori to metronidazole steadily increased from 55% (95% CI: 44–65%) before 2005 to 78% (95% CI: 73–84%) in 2016–2020 (p = 0.0003, Figure 2 and Figure S5). Western China had the highest metronidazole resistance (83%, 95% CI: 65–95%), followed by eastern China (72%, 95% CI: 65–78%), southern China (68%, 95% CI: 54–82%) and northern China (64%, 95% CI: 60–68%). However, the difference did not reach statistical significance (p = 0.054, Figure S6).

Time period analysis was also performed. Despite the fact that no statistical difference was found in northern China (p = 0.279, Figure 3 and Figure S7), the metronidazole resistance showed a decreasing trend in the last 10 years, from 71% (95% CI: 63–78%) in 2006–2010 to 62% (95% CI: 57–67%) in 2016–2020. Similarly, no discrepancy was observed in eastern China within periods. However, the metronidazole resistance had increased from 63% (95% CI: 44–81%) to 79% (95% CI: 76–82%) numerically (p = 0.107, Figure 3 and Figure S8).

3.3. Primary Resistance of H. pylori to Levofloxacin

The levofloxacin resistance in China had decreased from 47% (95% CI: 35–58%) before 2005 to 24% (95% CI: 16%, 33%) in 2011–2015 but increased to 35% in 2016–2020 (95% CI: 30–40%) (p = 0.0186, Figure 2 and Figure S9). Regional variation had not been found with resistance estimates from northern (38%, 95% CI: 31–45%), eastern (32%, 95% CI: 27–37%), southern (21%, 95% CI: 10–36%) and western China (16%, 95% CI: 3–35%) (p = 0.087, Figure S10).

Further subgroup analysis showed there was no statistical difference of the levofloxacin resistance in northern China (p = 0.364, Figure 3 and Figure S11) and eastern China (p = 0.052, Figure 3 and Figure S12) during the same time periods.

3.4. Primary Resistance of H. pylori to Amoxicillin, Tetracycline and Furazolidone

The primary resistance of H. pylori to amoxicillin (3%), tetracycline (2%) and furazolidone (1%) were low (Figures S13–S15) and have remained relatively stable in the past two decades (Figure 3)

3.5. Influence of Gender on the Primary Resistance of H. pylori to Clarithromycin, Levofloxacin and Metronidazole

The level of resistance depending on the gender of patients was shown in Table S1. The results showed no difference in the resistance rates of clarithromycin (p = 0.5459), levofloxacin (p = 0.6522) or metronidazole (p = 0.2311) between male and female (Figures S16–S18).

3.6. Meta-Regression Analysis of Antibiotics Resistance of H. pylori

Meta-regression analysis including regions, time periods and method was performed (Table 2) and indicated that compared with northern China and western China, eastern China (Difference: −0.23; 95% CI: −0.32, −0.14; p < 0.0.0001) and southern China (Difference: −0.17; 95% CI: −0.29, −0.05; p = 0.0066) had a lower risk of clarithromycin resistance. Southern China had the lowest levofloxacin resistance (Difference: −0.22; 95% CI: −0.40, −0.04; p = 0.0174).

Table 2.

Multivariate meta-analysis of antibiotics resistance of H. pylori in China.

Clarithromycin Metronidazole Levofloxacin Amoxicillin Tetracycline Furazolidone
Difference
(95% CI)		 Difference
(95% CI)		 Difference
(95% CI)		 Difference
(95% CI)		 Difference
(95% CI)		 Difference
(95% CI)
p Value p Value p Value p Value p Value p Value
Period
Before 2005 Reference Reference Reference Reference Reference NA
2006–2010 0.22 (0.10 to 0.34) 0.0005 0.05 (−0.10 to 0.20) −0.07 (−0.33 to 0.20) 0.07 (−0.03 to 0.16) −0.19 (−0.31 to −0.07) 0.0019 Reference
2011–2015 0.22 (0.11 to 0.33) <0.0001 0.11 (−0.02 to 0.24) −0.17 (−0.41 to 0.08) −0.01 (−0.10 to 0.08) −0.13 (−0.25 to −0.01) 0.0357 −0.18 (−0.46 to 0.11)
2016–2020 0.28 (0.17 to 0.39) <0.0001 0.22 (0.09 to 0.35) 0.0009 −0.04 (−0.29 to 0.21) 0.04 (−0.05 to 0.13) −0.15 (−0.27 to −0.03) 0.012 −0.08 (−0.35 to 0.19)
Method
Agar dilution Reference Reference Reference Reference Reference Reference
E-test −0.08 (−0.18 to 0.02) 0.01 (−0.11 to 0.12) −0.07 (−0.20 to 0.06) 0.11 (0.01 to 0.20) 0.0269 0.07 (0.01 to 0.13) 0.0264 0.09 (−0.21 to 0.39)
Disk diffusion −0.04 (−0.14 to 0.06) 0.13 (0.00 to 0.25) 0.0417 −0.21 (−0.36 to −0.06) 0.007 0.23 (0.15 to 0.30) <0.0001 0.01 (−0.04 to 0.06) 0.12 (−0.08 to 0.32)
PCR −0.07 (−0.20 to 0.06) NA −0.14 (−0.34 to 0.06) 0.15 (−0.05 to 0.35) 0.20 (0.08 to 0.31) 0.0006 NA
Regions
North Reference Reference Reference Reference Reference Reference
East −0.23 (−0.32 to −0.14) <0.0001 0.03 (−0.08 to 0.15) −0.07 (−0.19 to 0.06) −0.01 (−0.10 to 0.08) −0.11 (−0.16 to −0.06) <0.0001 −0.17 (−0.50 to 0.16)
South −0.17 (−0.29 to −0.05) 0.0066 0.03 (−0.14 to 0.19) −0.22 (−0.40 to −0.04) 0.0174 0.00 (−0.11 to 0.11) −0.15 (−0.22 to −0.08) <0.0001 −0.20 (−0.54 to 0.13)
West −0.12 (−0.26 to 0.02) 0.0876 0.10 (−0.05 to 0.26) −0.11 (−0.28 to 0.05) 0.05 (−0.06 to 0.16) −0.13 (−0.20 to −0.07) 0.0001 −0.10 (−0.40 to 0.20)
Multicenter −0.05 (−0.15 to 0.07) 0.11 (−0.04 to 0.26) −0.10 (−0.32 to 0.12) 0.02 (−0.06 to 0.11) −0.08 (−0.13 to −0.03) 0.0032 −0.20 (−0.57 to 0.17)
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A positive correlation could be found between time periods and clarithromycin resistance based on multivariate analysis (p < 0.0001). Metronidazole resistance was higher in 2016–2020 (Difference: 0.22; 95% CI: 0.09, 0.35; p = 0.0009) than that before 2005.

The method of the susceptibility test might also affect the results. Sub-analysis showed (Figures S19–S24) the choice of susceptibility test method might affect the resistance rate of levofloxacin (p = 0.0013), amoxicillin (p < 0.0001), tetracycline (p < 0.0001) and furazolidone (p = 0.0293) rather than that of clarithromycin (p = 0.4019) and metronidazole (p = 0.0565). Further multivariate regression analysis demonstrated that compared with the agar dilution method, the disk diffusion method might overestimate the resistance rate of metronidazole (Difference: 0.13; 95% CI: 0.00, 0.25; p = 0.0417) and amoxicillin (Difference: 0.23, 95% CI: 0.15, 0.30; p < 0.0001) but underestimate that of levofloxacin (Difference: −0.21; 95%CI: −0.36, −0.06; p = 0.007). Meanwhile, E-test might overestimate the resistance rate of amoxicillin (Difference: 0.11; 95% CI: 0.01, 0.20; p = 0.0269) and tetracycline (Difference: 0.07; 95% CI: 0.01, 0.13; p = 0.0264) when compared with the agar dilution method.

4. Discussion

Supervising the prevalence of primary antibiotic resistance in a region can provide reliable information for the choice of treatment options [8].

In our study, we showed the mean overall resistance of H. pylori in China to clarithromycin, metronidazole and levofloxacin was 30.0%, 70.0% and 31.0% and increased over time, but that of amoxicillin, tetracycline and furazolidone was 3.0%, 3.0% and 1.0%, respectively, and remained low during these years.

H. pylori has similar characteristics of clarithromycin and levofloxacin resistance with a clear mechanism by some certain gene mutation (23S rRNA and gyrA, respectively), which has an all-or-none effect on the efficacy. That means that the efficacy of treatment does not improve by increasing dose and duration [80,81,82]. Our study showed that the clarithromycin resistance in China has now reached 34%, while it seemed lower in eastern (24%) and southern China (24%). The levofloxacin resistance rate is currently 31%. Lower resistance could be found in the western China. In contrast, an increasing trend could be observed in eastern China, from 25% in 2011–2015 to 37% in 2016–2020. The resistance of clarithromycin and levofloxacin are both above the threshold of empirical use of these antibiotics.

Metronidazole, a class of nitroimidazole compound, is different from clarithromycin and levofloxacin, and the mechanism of resistance is not completely clarified at present. Meanwhile, different susceptibility methods or culture methods also affected the results as our previous work demonstrated that the resistance might be overestimated by E-test when compared with agar dilution in the area with high-level metronidazole resistance [83]. Previous studies have demonstrated that the resistance can be overcome by a high dose and long duration [80,84]. Our data showed that the resistance of metronidazole was 70%, ranging from 64 to 83% in different regions. It was noticeable that the metronidazole resistance in northern China had decreased from 71% to 62% in these years.

The overall primary resistance rate of H. pylori to amoxicillin, tetracycline and furazolidone remained low, and all of them were lower than 5%, with the exception of a few studies that reported higher rates of resistance.

Other studies from Asia, Europe and Latin America have also reported primary resistance of H. pylori, which was lower than that in China, as these data showed that clarithromycin resistance ranged from 12 to 21.4%, levofloxacin resistance ranged from 15 to 18% and metronidazole resistance ranged from 38.9 to 53% with an increasing trend over time.

The increasing resistance to clarithromycin, levofloxacin and metronidazole might be contributed to by the increasing consumption of these antibiotics and cross resistance to the corresponding antibiotics. Megraud et al. reported that the community consumption of these antibiotics was associated with its corresponding H. pylori resistance in European countries [5]. Similarly, Yang et al. found that the macrolide and quinolones ranked third and fourth in consumption of antibiotics, respectively, in China during 2018–2020 [85]. There are no definitive data on imidazole consumption in China. However, since metronidazole was produced in the 1960s, it had been widely used in the treatment of anaerobic infections in China. Compared with macrolide and quinolone, imidazole has been present in the community for a longer time, which has led to a high metronidazole resistance in China.

The success rate of clarithromycin-containing triple therapy has been reported less than 80% in China [86]. The addition of bismuth to the triple therapy, which has been recommended as a first-line therapy, improves cure rates despite a high prevalence of antimicrobial resistance. The effect of bismuth is to attain an additional 30–40% in the success with resistant infections [87]. The rising resistance to clarithromycin and levofloxacin can severely reduce the efficacy of this modified quadruple therapy failing to reach a 90% success rate. For metronidazole, resistance has no clinical significance since it can be overcome after increasing the dosage and prolonging the duration [80]. At present, amoxicillin is widely used in clinical practice, as long as patients have no allergic reaction. Despite the poor accessibility in China, tetracycline combined with metronidazole is often used as a first-line therapy in areas with high clarithromycin and levofloxacin resistance [3]. Furazolidone is a special drug, which is widely used in China due to its low resistance rate. Although it may be accompanied by adverse reactions such as peripheral neuritis, the treatment success rate is high [88].

There are still limitations in our review. Firstly, since it was a single rate meta-analysis, there was obvious heterogeneity among different studies. Second, most of the enrolled studies were from northern and eastern China and data from other regions was lacking, thus causing potential publication bias.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/pathogens11070786/s1, Figure S1: Clarithromycin [By period]; Figure S2: Clarithromycin [By region]; Figure S3: Clarithromycin [North China]; Figure S4: Clarithromycin [East China]; Figure S5: Metronidazole [By period]; Figure S6: Metronidazole [By region]; Figure S7: Metronidazole [North China]; Figure S8: Metronidazole [East China]; Figure S9: Levofloxacin [By period]; Figure S10: Levofloxacin [By region]; Figure S11: Levofloxacin [North China]; Figure S12: Levofloxacin [East China]; Figure S13: Amoxicillin [By period]; Figure S14: Tetracycline [By period]; Figure S15: Furazolidone [By period]; Figure S16: Clarithromycin [By gender]; Figure S17: Levofloxacin [By gender]; Figure S18: Metronidazole [By gender]; Figure S19: Clarithromycin [By method]; Figure S20: Levofloxacin [By method]; Figure S21: Metronidazole [by method]; Figure S22: Amoxicillin [by method]; Figure S23: Tetracycline [by method]; Figure S24: Furazolidone [by method]; Table S1: Characteristics of the enrolled studies on resistance rate of H. pylori to antibiotics based on Gender.

Click here for additional data file. (9.6MB, zip)

Author Contributions

H.L. conceived the study. J.C. and P.L. wrote the protocol and collected data. J.C. and Y.H. performed the systematic review. P.L., Z.D. and Y.G. did the statistical analysis. J.C. and P.L. wrote the article, which was revised by H.L. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Funding Statement

This work was supported by a grant from the National Natural Science Foundation of China (grant number 81970497).

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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