In Korea, clarithromycin resistance varies regionally, and therefore, the efficacies of H. pylori eradication regimens depend on areas studies. Thus, we sought to determine the prevalence of clarithromycin resistance in the Incheon area, which abuts western Seoul. In this region the clarithromycin resistance rate was previously reported to be 37.4%, but it was included patients who were eradicated H. pylori infection, and thus, clarithromycin resistance may have been overestimated.16 In the present study, clarithromycin resistance was 21.9% (39/178). This result indicates Incheon is a region of high clarithromycin resistance and that empirical clarithromycin triple therapy is not a suitable first-line regimen for H. pylori eradication in the region.
According to the Maastricht V guidelines, in a setting with high clarithromycin resistance (> 15%), choice of therapy should be based on the frequencies of metronidazole and of combined clarithromycin and metronidazole resistance. However, antimicrobial susceptibility testing by culture and antibiogram is difficult and time-consuming, and not available in all institutions. In addition, the success rate of H. pylori culture is relatively low at 55-73%.17 Furthermore, if empirical bismuth-based quadruple therapy is expected to be used, it is not advisable to perform antimicrobial susceptibility testing because the risk of tetracycline resistant strains is extremely low and metronidazole resistance has little effect on eradiation rate.18 Therefore, empirical BQT provides a good alternative first-line eradication therapy in areas of high clarithromycin resistance.
Based on the results of previous studies, we considered tailored therapy would have a higher eradication rate than empirical BQT.8,15 However, we found the eradication rates of BQT and TT were not significantly different (88.8 vs 81.4, p = 0.07). In particular, in patients with clarithromycin-sensitive H. pylori in the TT group, the eradication rate of clarithromycin triple therapy was only 79.4% (94/118), which was lower than that previously reported in a Korean study.8 Although DPO-PCR can diagnose A2142G and A2143G variants, it does not provide a comprehensive view of clarithromycin resistance and cannot identify resistance to other antibiotics. Nevertheless, point mutation of 23S rRNA, which usually involves the substitution of guanine with adenine at nucleotides 2142 and 2143 is detected by DPO-PCR and is known to be associated with clarithromycin resistance. Substitution of adenine with cytosine at position 2142 is also less frequently observed.19 Other point mutations in 23S rRNA, such as of A2115G, G2141A, T2117C, T2182C, T2289C, G224A, C2245T and C2611A, have also been reported, but their clinical significances are unknown. Macrolide resistance caused by the efflux pump system also plays an important role in promoting multidrug H. pylori resistance.19 Thus, despite the absence of A2142G or A2143G mutations, it can be inferred the eradication rate was lower than expected in the present study because of other point mutations or the involvements of efflux pump systems.
Maastricht V guideline suggests that the eradication rate should be over 80% by ITT analysis and over 90% by PP analysis. In our study, we use only BQT therapy and clarithromycin based triple therapy as a first line therapy. So the eradication rate was below the Maastricht V guideline. We should study further to improve eradication rate, and efficacy in aspect to complication and medical cost. And recently, fluoroquinolone resistance has increased in our region. In the present study, RUT was used in the BQT group and DPO-PCR in the TT group to diagnose H. pylori infection, and thus, H. pylori diagnostic rates may have differed in the two groups. Originally, we intended to test all participants using RUT and DPO-PCR, regardless of treatment regimen. However, our IRB committee determined that it was unethical to select an eradication regimen irrespective of clarithromycin resistance results, and thus, we modified the study design. Rapid urease testing is reliable and its sensitivity and specificity are 90% and 95-100%20,21. False-negatives are more common than false positives, and thus, negative results do not exclude the possibility of H. pylori infection, but false positive are uncommon. The Seeplex® ClaR-H. pylori ACE detection kit has been reported to have a sensitivity of 97.7% and a specificity of 83.1% for the diagnosis of H. pylori versus culture testing,22 and thus, our diagnostic method is not likely to have biased diagnosis or eradication rates due to false positive results.
In this study, levofloxacin-based triple therapy was used as second-line therapy following failed first-line treatment. In the Maastricht V consensus, fluoroquinolone-containing triple therapy, such as levofloxacin, is recommended as second-line treatment after failure of first-line clarithromycin-based and second-line bismuth quadruple therapy. According to a meta-analysis, the eradication rate of levofloxacin-based triple therapy as a second-line treatment was 74.8-79.6%.23 In the present study, the eradication rate of levofloxacin-based triple therapy was 61.8% by PP analysis, which is lower rate than those reported previously. This may have been related to a rapid increase in fluoroquinolone resistance over recent years. A recent Korean study reported a resistance rate for levofloxacin of 5.7% for 2003-2005, but a rate of 34.6% for 2009-2012.24 This rapid increase in levofloxacin resistance may be due to cross-resistance to other fluoroquinolones such as ciprofloxacin or moxifloxacin. Also, BQT is recommended as 2nd line eradication regimen after failure of triple therapy. But, in this study, patients took levofloxacin based triple therapy after failure of clarithromycin based triple therapy. In our study, we tried to compare the compliance and medical cost between BQT and TT group. So we used same 2nd line regimen in failure group.
According to recently published guidelines, the recommended duration for H. pylori eradication therapy is 14 days,4,14 whereas we used a 7-day regimen. When we planned this study, the 14-day regimen was not recommended because the eradication rates of 7- and 14-day regimens were believed to be similar, and thus, Korean medical insurance only covered 7 day regimens. However, metronidazole resistance can be overcome by long-duration treatment. Therefore, the eradication success rate of BQT can be improved after 14 days treatment of BQT.
In terms of medical cost, the rapid urease test was less expensive than the DPO-PCR in diagnostic test, and the 7-day BQT regimen was less expensive than the 7-day clarithromycin triple therapy regimen, and thus, based on diagnostic and therapeutic costs, empirical BQT was preferred. However, in a recent study, conducted in Incheon city, it was reported that DPO-PCR guided target therapy was equivalent or superior to empirical clarithromycin triple therapy in terms of cost effectiveness.16
Our research has several limitations. First, it was conducted at a single center in Incheon, and thus, it is difficult to generalize our results. Second, as mentioned above, different H. pylori diagnostic methods were used in the two groups, and thus, group diagnosis rates may have different results. However, since the sensitivities of both diagnostic methods are high, we believe it is unlikely that this greatly influenced our results. Third, H. pylori culture along with real antibiotic resistance test had not been performed. And validation study for DPO-PCR was not performed in our institution. Fourth, we think because of small sample size, BQT showed somewhat higher eradication rate than TT in despite of the other previous study.