| Background and Aims:Helicobacter pylori(H. pylori) infection is closely related to a variety of gastrointestinal and extra-gastrointestinal diseases, which has been a serious threat to human health. Hence, it is extremely important to eradicate H. pylori for preventing H. pylori related diseases. However, due to the fact of broad application of antibiotics, the rate of antibiotic resistance is increasing, yet the eradication rate of existing scheme is declining year by year. Therefore, Consensus opinion at home and abroad all recommend not use an antibiotic when its resistance rate of an area reaches to a certain level. At the same time, it is also proposed individualized precision scheme based on different antibiotic resistance of H. pylori. Therefore, it is critical to develop an effective eradication scheme if known various characteristics of drug resistance of H. pylori. As we all know, antibiotics resistance of H. pylori will affect its eradication rates, but how and what it influence? Whether we can overcome the negative influence on H. pylori eradication rate for drug resistance by improved programs and prolonged treatment? But all these have yet to be confirmed. So this paper aims to analyze characteristics of antibiotics resistance of H. pylori by studying different H. pylori isolates resistance to nine antibiotics including metronidazole, clarithromycin, levofloxacin, tetracycline, amoxicillin, rifampicin, furazolidone, moxifloxacin and azithromycin, from 14 hospitals of nine regions in China. Meanwhile, we have a systematical evaluation of the currently published literature describing antibiotics resistance of H. pylori, thus to explore the effect of antibiotics resistance on H. pylori eradication rate and degree of influence that different eradication schemes have on H. pylori infection from the perspective of evidence-based medicine, so as to provide guidance for clinical drug use. Method: The characteristic of antibiotic resistance of H.pylori in china:1.Strains sources: 810 clinical isolates were stored in institution of gastroent- erology of Jiangxi province, which came from 14 hospitals of nine regions of China.2.Antibiotic susceptibility tests: E-test to detect the susceptibility of metronidazole, clarithromycin, levofloxacin, tetracycline, amoxicillin, rifampicin, moxifloxacin, azithromycin. And Kirby-Bauer disk diffusion method to detect the susceptibility of furazolidone.3.Analysis measure: comparing the resistance rate of H. pylori for nine kinds of antibiotics; comparing the difference among various age, sex, time and region. As well as the different resistance rates among those antibiotics belong to same kind.4.Statistical analysis: all data were categorical data, we compared the difference of antibiotic resistance of H.pylori among different ages, sex and time using ?2 statistics or Fisher’s exact test or non-parametric tests. And SPSS software version 17.0 was performed to produce statistical outputs. Systematic review: the effect of antibiotic resistance on the eradication rate of H.pylori :1.Search databases: Pub Med, EMBASE, the Cochrane Central Register of Controlled Trials, Science Citation Index, China National Knowledge Infrastructure(CNKI), Wanfang databases and Chinese Biomedical Literature databases(CBM) were searched, and abstract books of major conference proceedings were also manual searched and their authors were contacted when necessary to ask them to provide details of the study and unpublished literature.2.The main search terms: Helicobacter pylori, resistance, treatment, therapy, clinical trials.3.Outcome: the eradication rates of antibiotic resistance or sensitive H. pylori strain.4.Treatment schemes containing effect of antibiotic resistance on eradication rate of H.pylori were fully retrieved and the literature eligible for inclusion criteria were included at last. We had a systematic review of efficacy and safety of them.5.Statistical analysis: Statistical analysis was performed using Comprehensive Meta-Analysis Software version 2.0, and subgroup analysis was also performed. Results: The characteristic of helicobacter pylori on antibiotic resistance in china:1.The resistance rates of 9 antibiotic of 810 clinical isolates the resistance rates of metronidazole, clarithromycin, levofloxacin, amoxicillin, azithromycin, moxifloxacin, rifampicin, furazolidone, tetracycline were 78.4%, 20.99%, 17.89%,4.69%, 18.96%, 12.28%,1.87%,0%,2.54%, respectively.2.The rates of single resistance, double resistances, and multiple resistances of clinical isolate strains: we classified clarithromycin and azithromycin as the group of macrolide antibiotic and levofloxacin and moxifloxacin as the group of quinolones. we found the rates of single resistance, double resistance, multiple resistance and full sensitive were 49.13%, 25.5%, 10.41% and 13.89% respectively.3.The rates of single resistance or simultaneously resistance for levofloxacin, moxifloxacin, clarithromycin, azithromycin: the rates of simultaneous resistance for levofloxacin and moxifloxacin were 7.88%, single resistance for levofloxacin and moxifloxacin were 17.89%,12.28% respectively.; the rates of simultaneous resistance for clarithromycin and azithromycin were 9.75%, single resistance for levofloxacin and moxifloxacin were 18.02%,18.96% respectively.4.The rates of antibiotic resistance for infected patients in various ages: Statistic showed significant difference among these two groups(P<0.05). For patients whose age were between 40-60 year old, the resistance rates of clarithromycin, levofloxacin, azithromycin were 18.75%, 18.75% and 19.05% respectively. For patients whose age were between 20-40 year old, the resistance rate of metronidazole was 77.52%. There were no significant difference among these single resistance, double resistance and multiple resistances groups.5.The rates of antibiotic resistance for infected patients in different gender: in female patients, the rates of antibiotic resistance for metronidazole and moxifloxacin were 82.83% and 15.82% respectively, higher than that of male patients(76.55% and 9.96% for metronidazole and moxifloxacin respectively). Statistic showed significant difference between these two groups.6.The rates of antibiotic resistance for infected patients in difference time For metronidazole, the resistance rate in 2010, 2011, 2013 were 75.52%, 75.76%, 81.69% respectively. For clarithromycin, the resistance rate in 2010, 2011, 2013 were 16.21%, 18.18%, 19.25% respectively. For levofloxacin, the resistance rate in 2010, 2011, 2013 were 19.31%, 27.27%, 16.2% respectively. There were significant difference when comparing the multiple resistance rates in 2010 with 2013(P<0.05). And comparing the whole sensitive rates in 2010 with 2011 also showed a significant difference.7.The rates of antibiotic resistance for infected patients in different regions: the highest resistance rate for amoxicillin was 14.58% from shanghai. The highest resistance rates for metronidazole, levofloxacin, azithromycin were 94.74%, 21.05%, 57.89% from xi’an. The highest resistance rates for clarithromycin, tetracycline, moxifloxacin and rifampicin were 45.45%, 13.67%, 22.73%, 22.73% from anhui. The highest resistance rate for single antibiotic resistance was 64.71% from Guangzhou. The highest resistance rate for double antibiotic resistance was 47.37% from in xi’an. The highest resistance rate for multiple antibiotic resistance was 36.36% from anhui. The highest resistance rate for full antibiotic sensitive was 18.75% from shanghai. Systematic review: the effect of antibiotic resistance on the eradication rate of H.pylori:1. Finally, a total of 87 studiesincluding15815 patients were enrolled in the system review.2. Effect of single clarithromycin resistance on eradication rate of H. pylori:(1)As to the effect of single clarithromycin resistance in the triple therapy on eradication rate of H. pylori, the total eradication rate of pooled drug resistance groups was 52.90%, the total eradication rate of pooled antibiotics sensitive groups was 88.39%, the total pooled OR was 0.118(95% CI:0.073-0.192),and the difference was statistically significant(P<0.05). Subgroup analysis showed that, for GAC therapy subgroup, the pooled eradication rate of drugs groups was 54.63%, the antibiotics sensitive groups was 89.15%, and total pooled OR was 0.113(95%CI: 0.062-0.206); for GCM therapy subgroup, the pooled eradication rate of drugs groups was 40.79%, the antibiotics sensitive groups was 83.81%, the total pooled OR was 0.144(95%CI:0.085-0.244) and the differences of both groups above were statistically significant(P<0.05).For the course of GAC treatment subgroup, the pooled OR of 7d, 10 d and 14 d was 0.134(95%CI: 0.062-0.289), 0.040(95% CI: 0.013-0.125) and 0.158(95% CI: 0.084-0.298), respectively, and differences of three group were all statistically significant(P<0.05).However, because the number of articles searched were too few, we neither performed subgroup of GBC therapy nor subgroup of treatment course for GCM therapy..(2)As to the effect of single clarithromycin resistance in the quadruple bismuth therapy on eradication rate of H. pylori, the total eradication rate of pooled drug resistance groups was 75.69%, the total eradication rate of pooled antibiotics sensitive groups was 95.25%, the total pooled OR was 0.157(95% CI: 0.081-0.303),and the difference was statistically significant(P<0.05). Subgroup analysis showed that, for GBAC therapy subgroup, the pooled eradication rate of drugs groups was 74.16%, the antibiotics sensitive groups was 95.28%, and total pooled OR was 0.074(95% CI: 0.017-0.314), and the difference was statistically significant(P<0.05). GBCM therapy subgroup analysis cannot be performed because of too few articles included.(3)As to the effect of single clarithromycin resistance in the quadruple sequential therapy on eradication rate of H. pylori, the total eradication rate of pooled drug resistance groups was 80.85%, the total eradication rate of pooled antibiotics sensitive groups was 94.81%, the total pooled OR was 0.239(95% CI: 0.095-0.599),and the difference was statistically significant(P<0.05). Subgroup analysis showed that, for GA/GCM therapy subgroup, the pooled eradication rate of drugs groups was 76.47%, the antibiotics sensitive groups was 95.81%, and total pooled OR was0.121(95% CI: 0.031-0.469) and the difference was statistically significant(P<0.05); for GA/GCT therapy subgroup, the pooled eradication rate of drugs groups was 83.33%, the antibiotics sensitive groups was 93.59%,the total pooled OR was 0.426(95% CI: 0.122-1.484),and the difference was no statistical significance(P>0.05). In addition, both of two groups discussed above didn’t be performed subgroup analysis of treatment course because of too few articles included.(4)As to the effect of single clarithromycin resistance in the quadruple concomitant therapy on eradication rate of H. pylori, the total eradication rate of pooled drug resistance groups was 82.29%, the total eradication rate of pooled antibiotics sensitive groups was 93.33%, the total pooled OR was 0.417(95%CI:0.077-2.257),and the difference was not statistically significant(P>0.05). Subgroup analysis showed that, for GACM therapy subgroup, the pooled eradication rate of drugs groups was 92.11%, the antibiotics sensitive groups was 92.59%, the total pooled OR was 0.587(95% CI: 0.030-11.575), and the difference was not statistically significant(P>0.05).Because of too few articles included, we didn’t perform subgroup of GACM treatment course and subgroup of GACN, GACT therapy groups.3.Effect of single metronidazole resistance on eradication rate of H. pylori:(1)As to the effect of single metronidazole resistance in the triple therapy on eradication rate of H. pylori, the total eradication rate of pooled drug resistance groups was 68.53%, the total eradication rate of pooled antibiotics sensitive groups was 90.04%, the total pooled OR was 0.248(95% CI: 0.183-0.338),and the difference was statistically significant(P<0.05). Subgroup analysis showed that, for GAM therapy subgroup, the pooled eradication rate of drugs groups was 65.20%, the antibiotics sensitive groups was 92.90%, and the pooled OR was 0.146(95% CI: 0.105-0.203); for BAM therapy subgroup, the pooled eradication rate of drugs groups was 50%, the antibiotics sensitive groups was 83.10%, and pooled OR was 0.192(95% CI: 0.066-0.561); for BTM therapy subgroup, the pooled eradication rate of drugs groups was 64.84%, the antibiotics sensitive groups was 80.54%, and pooled OR was 0.341(95% CI: 0.136-0.854); for GCM therapy subgroup, the pooled eradication rate of drugs groups was 75.17%, the antibiotics sensitive groups was 89.19%, and pooled OR was 0.455(95% CI: 0.260-0.795), the differences of all groups above were statistically significant(P<0.05).For the course of GAM treatment subgroup, the pooled OR of 7d, 10 d and 14 d was 0.120(95% CI: 0.081-0.178), 0.400(95% CI: 0.164-0.975), 0.145(95% CI: 0.066-0.316), respectively, and differences of three group were all statistically significant(P<0.05). For the course of BMT treatment subgroup, the pooled OR of 7d and 14 d was 0.083(95%CI: 0.013-0.545),0.340(95%CI:0.134-0.864),and differences were both statistically significant(P<0.05).For the course of GCM treatment subgroup, the pooled OR of 7d was 0.452(95% CI: 0.260-0.785) and the difference was statistically significant(P <0.05); however, the pooled OR of 10 d and 14 d was 0.208(95% CI: 0.006-7.444) and 0.514(95% CI: 0.011-24.904),respectively, and both treatment courses had no statistic difference(P>0.05). because the number of articles searched were too little, we didn’t perform subgroup of BCM therapy and subgroup of treatment course for BAM,BTM therapy.(2)As to the effect of single metronidazole resistance in the quadruple bismuth therapy on eradication rate of H. pylori, the total eradication rate of pooled drug resistance groups was 80.22%, the total eradication rate of pooled antibiotics sensitive groups was 92.05%, the total pooled OR was 0.214(95% CI: 0.134-0.342),and the difference was statistically significant(P<0.05). Subgroup analysis showed that, for GBAM therapy subgroup, the pooled eradication rate of drugs groups was 76.92%, the antibiotics sensitive groups was 92.55%, and total pooled OR was 0.167(95% CI: 0.020-1.428), and the difference was statistically significant(P<0.05); For GBTM therapy subgroup, the pooled eradication rate of drugs groups was 78.87%, the antibiotics sensitive groups was 91.89%, and total pooled OR was 0.221(95% CI: 0.131-0.373), and the difference was statistically significant(P<0.05); For the course of GBMT treatment subgroup, the pooled OR of 7d, 10 d and 14 d was 0.236(95% CI: 0.118-0.471), 0.238(95% CI: 0.099-0.573), 0.092(95% CI: 0.013-0.642), respectively, and the differences were all statistically significant(P <0.05). In addition, GBCM therapy cannot be performed subgroup analysis and GBAM therapy cannot be performed treatment course subgroup analyzes because of too few articles included.(3)As to the effect of single metronidazole resistance in the quadruple sequential therapy(GA/GCM)on eradication rate of H. pylori, the total eradication rate of pooled drug resistance groups was 82.30%, the total eradication rate of pooled antibiotics sensitive groups was 92.31%,the total pooled OR was 0.489(95% CI: 0.192-1.245),and the difference was not statistically significant(P >0.05).(4)As to the effect of single metronidazole resistance in the quadruple concomitant therapy(GACM) on eradication rate of H. pylori, the total eradication rate of pooled drug resistance groups was 89.29%, the total eradication rate of pooled antibiotics sensitive groups was 94.74%, the total pooled OR was 0.514(95% CI: 0.033-8.079),and the difference was not statistically significant(P>0.05).4. Meta-analysis of single levofloxacin resistance on eradication rate of H. pylori:As to the effect of single levofloxacin resistance in the triple therapy(GAL) on eradication rate of H. pylori, the total eradication rate of pooled drug resistance groups was 75%, the total eradication rate of pooled antibiotics sensitive groups was 89.25%, the total pooled OR was 0.186(95% CI: 0.021-1.682),and the difference was not statistically significant(P>0.05).5.Effect of metronidazole and clarithromycin dual resistance on eradication rate of H. pylori:(1)As to the effect of clarithromycin and metronidazole dual resistance in the triple therapy on eradication rate of H. pylori, the total eradication rate of pooled drugs resistance groups was 38.18%, the total eradication rate of pooled antibiotics sensitive groups was 92.76%, the total pooled OR was 0.043(95% CI: 0.019-0.100),and the difference was statistically significant(P<0.05).(2)As to the effect of clarithromycin and metronidazole dual resistance in the quadruple bismuth therapy on eradication rate of H. pylori, the total eradication rate of pooled drug resistance groups was 62.5%, the total eradication rate of pooled antibiotics sensitive groups was 99%, the total pooled OR was 0.039(95% CI:0.004-0.345), and the difference was statistically significant(P<0.05).(3)As to the effect of clarithromycin and metronidazole dual resistance in the quadruple concomitant therapy on eradication rate of H. pylori, the total eradication rate of pooled drug resistance groups was71.43%, the total eradication rate of pooled antibiotics sensitive groups was 94.83%, the total pooled OR was 0.139(95%CI:0.019-0.989),and the difference was statistically significant(P<0.05). Conclusion:1.The resistance rates of amoxicillin, furazolidone, tetracycline, rifampicin for H. pylori keep in a low level in our country, suggest the former three antibiotic could be considered as the first choice for eradication of H.pylori.and rifampicin could be used in rescue therapy due to the low resistance rate. However,the resistance rates of metronidazole, quinolones and macrolides were still higher, and should be used under the guideline of susceptibility tests.2.There exists great regional differences in antibiotic resistance of H.pylori in China, so we should take into consideration various characteristics of antibiotic resistance of different regions when formulating a treatment scheme.3.The antibiotic resistance,especially double resistance of H.pylori is the main reason that induce a declining eradication rate, whereas we cannot completely overcome the negative effect by prolonging the duration of treatment. Therefore, it is proposed individualized precision scheme based on different antibiotic resistance of H. pylori.4.The quadruple concomitant therapy can overcome the phenomenon of declining eradication rate of H. pylori caused by a single antibiotic resistance, but cannot overcome the unsatisfactory effects caused by dual resistance of antibiotics. |
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