Antibiotic-resistant H. pylori strains in the last ten years in Japan

An increase in the prevalence of antibiotic-resistant H. pylori strains has been reported. We tested the sensitivity of H. pylori strains to antibiotics before and after the eradication treatment to determine primary and secondary resistance by E-test. A total of 336 H. pylori strains from 1987 to 1998 were tested for sensitivity to clarithromycin (CAM), amoxicillin (AMPC), and metronidazole (MNZ). Primary resistance of H. pylori to CAM, MNZ, and AMPC were found in 9.5%, 26.8%, and 0.3% strains, respectively. The resistant strains to CAM and MNZ were gradually increasing in the last few years. The cure rates of triple therapy with MNZ and CAM for CAM-susceptible and CAM-resistant H. pylori isolates were 83.3% (40/48) and 30.0% (3/10) respectively, and the cure rates of triple therapy with CAM and AMPC for CAM-susceptible and CAM-resistant H. pylori isolates were 79.3% (69/87) and 12.5% (1/8) respectively. After triple therapy, secondary resistant strains to CAM and MNZ were found in 42.1% (8/19) and 31.6% (6/19) of the cases.     

Importance of drug selection and the use of sensitivity tests for the eradication therapy for Helicobacter pylori

Drug selection for eradication therapy of H. pylori, considering their drug resistance was evaluated. The measurement of resistant colonies was performed in blood agar plates using the MIC method and the criteria for resistance was as follows: MIC > 1 mg/l with AMPC, MIC > 2 mg/l with CAM and MIC > 8 mg/l with MNZ. Primary resistant colonies were found in 0% with AMPC, 8.9% with CAM and 5.9% with MNZ. Secondary resistant colonies were found in 0% with AMPC, 50.0% with CAM and 54.5% with MNZ. CAM and MNZ showed high resistance rate and among them, colonies resistant to CAM were also highly resistant to MNZ. But colonies resistant to MNZ (acquired after CAM) were all sensitive to AMPC. Considering this issue and the absence of resistance to AMPC, we considered the triple therapy with AMPC, MNZ and a PPI as the best option for the eradication of H. pylori.     

Helicobacter pylori eradication therapy for gastric ulcer in elderly

Sixty-five-years or older person accounts for 23% of the population in Japan. Hence, Helicobacter pylori (H. pylori) eradication therapy is performed in many elderly patients. Urea breath test and H. pylori stool antigen test for diagnosis of H. pylori infection before and after eradication therapy are recommended from the point of being a noninvasive test and providing accurate diagnosis. H. pylori eradication therapy in Japan consists of the PPI/AMPC/CAM as the first therapy, and PPI/AMPC/MNZ as the second therapy. Eradication therapy rate and adverse effect rate of H. pylori eradication therapy for elderly patients are the same as for young people. It is not necessary to avoid H. pylori eradication therapy merely because of high age in elderly patients. However, it is necessary to be careful regarding drug interactions in patients who are taking multiple drugs.     

Eradication effect of lansoprazole-based triple therapy against H. pylori

Eradication of H. pylori provides a potential cure in the majority of patients with gastric ulcer as well as duodenal ulcer. Two proton pump inhibitor(PPI)-based triple therapy, combining with clarithromycin(CAM), amoxicillin(AMPC) or metronidazole have been established as standard regimens worldwide. In Japan, lansoprazole(LPZ)-based triple therapy combined with CAM and AMPC for 1 week was firstly investigated on eradication effect against H. pylori and determination of the optimal dose of CAM in multicenter, double-blind trial. Patients with active gastric ulcer or duodenal ulcer were enrolled in this study. The eradication rate of H. pylori in patients with gastric ulcer were 0%, 87.5% and 89.2% and those in patients with duodenal ulcer were 4.4%, 91.1% and 83.7% in LPZ(60 mg/d) alone, LPZ(60 mg/d) with CAM(400 mg/d) and AMPC(1,500 mg/d), LPZ(60 mg/d) with CAM(800 mg/d) and AMPC(1,500 mg/d), respectively, in the full set analysis. LPZ-based triple therapy demonstrated a high eradication rate and was safe. In addition, the combination regimens with lower or higher dose of CAM were equivalent in Japanese patients.     

Clinical Application of the DiversiLab Microbial Typing System Using Repetitive Sequence‐Based PCR for Characterization of Helicobacter pylori in Japan

We evaluated the DiversiLab (DL) system with universal primers, a semiautomated repetitive extragenic palindromic sequence‐based polymerase chain reaction (PCR) (rep‐PCR) system, for the characterization of Helicobacter pylori in Japan. All 135 isolates from Japanese patients with gastric cancer (GC, n = 55) or non‐GC (n = 80) were used and subjected to the drug susceptibility examinations (amoxicillin, AMPC; metronidazole, MNZ; and clarithromycin, CAM) by E‐test. There were 28 MNZ‐resistant (20.7%), 35 CAM‐resistant (25.9%), and 16 MNZ/CAM‐resistant (11.9%) isolates. DL rep‐PCR fingerprinting analysis at the level of 95% similarity revealed five major groups (A–E) and the other including 45 isolates. The occupation rates of GC‐derived isolates in groups B (54.2%) and E (58.8%) were higher than in the other groups: A (26.7%), C (28.6%), D (30.0%), and the other (40.0%). Relative higher occupation rates of drug resistants, such as MNZ‐, CAM‐ and double MNZ/CAM‐resistant isolates, were observed in groups B (45.8%), C (42.6%), and D (40%). Five of eight GC‐derived isolates with MNZ/CAM resistance were significantly assigned to group B (P = 0.0312, χ²‐test). These results suggest that the isolates classified in group B have a potential to contribute to the development of severe gastric disorders. The DL system, rapid and high sensitive technology, would be widely available in clinical laboratory for pathological and epidemiological analyses even in H. pylori.     

Indication of H. pylori eradication therapy--who should be treated?

With increased evidence of H. pylori infection being deeply related with various gastric diseases, its curative therapy will be approved by social security foundation soon also in Japan. Japanese Society of Helicobacter reported a guideline for H. pylori diagnosis and treatment in July 2000. In the guideline, only peptic ulcers and low grade MALT lymphomas are recommended as an indication of H. pylori eradication and other diseases such as atrophic gastritis, post EMR state for early gastric cancer and post-operated stomach due to gastric cancer, hyperplastic polyps and non-ulcer dyspepsia, were not included. It is speculated that while benefit of eradication therapy for peptic ulcers and low grade MALT lymphomas has been supported by much clinical evidence, that for other diseases was judged not to be enough. Especially as to atrophic gastritis, eradication therapy might be considered in aspect of decreasing gastric cancer risk in Japan. Since accumulated epidemiological and experimental data strongly support its positive correlation with cancer risk, patients in high risk group for gastric cancer could be included for a target eradication therapy. In present, indication of the therapy should be clinically and socially decided according to individual patient.     

Effect of sucralfate on antibiotic therapy for Helicobacter pylori infection in mice

It has been documented that sucralfate, a basic aluminum salt, enhances the efficacies of antibiotics against Helicobacter pylori, resulting in eradication rates comparable to those associated with the use of proton pump inhibitors. However, its mechanism of action remains unclear. The aim of the present study was to investigate sucralfate's ability to complement antibiotic treatment of H. pylori infection in vivo. Four weeks following induced H. pylori infection, clarithromycin (CAM) and amoxicillin (AMPC) were administered orally to C57BL/6 mice for 5 days, both with and without sucralfate or lansoprazole. When sucralfate was concurrently given with CAM and AMPC at the maximum noninhibitory doses for the treatment of H. pylori infection, the bacterial clearance rates were comparable to those achieved by treatment with lansoprazole plus those antibiotics. The results of pharmacokinetic studies showed that lansoprazole delayed gastric clearance and accelerated the absorption of CAM, whereas sucralfate suppressed both gastric clearance and absorption. AMPC was undetectable in all samples. Scanning electron microscopy with a microscope to which a energy dispersive spectrometer was attached revealed that aluminum-containing aggregated substances coated the mucosa surrounding H. pylori in mice receiving sucralfate plus antibiotics, whereas the gastric surface and pits where H. pylori had attached were clearly visible in mice receiving lansoprazole plus antibiotics. The addition of sucralfate to the antibiotic suspension resulted in a more viscous mixture that bound to the H. pylori-infected mucosa and that inhibited the loss of CAM bioavailability in the acidic environment. Sucralfate delays gastric clearance of CAM and physically captures H. pylori through the creation of an adherent mucus, which leads to bacterial clearance.     

Guidelines in the management of Helicobacter pylori infection in Japan--in comparison with the guidelines published in other countries

Helicobacter pylori(H. pylori) is a causative agent for chronic gastritis and is an important risk factor for peptic ulcers, gastric carcinomas, and gastric MALT lymphomas. In 2000, the Japanese Society for Helicobacter Research published a guideline on the diagnosis and treatment of H. pylori infection for physicians in routine medical practice. In this guideline, H. pylori eradication therapy is recommended in gastric or duodenal ulcer patients. H. pylori eradication is also recommended in gastric MALT lymphoma patients but the guideline says it should be done at specialist institutions. Considering the high prevalence of gastric carcinomas in Japan. H. pylori eradication for the prevention of gastric carcinomas should be discussed urgently.     

Ulcers and gastritis

This article reviews recently published reports on ulcers and gastritis. Helicobacter pylori is known to be an important pathogen involved in gastroduodenal inflammation and peptic ulcers. Conventional endoscopy is of limited usefulness in the evaluation of gastritis, but magnifying endoscopy is evidently helpful in the diagnosis of chronic atrophic gastritis, intestinal metaplasia, and H. pylori infection. A significant reduction in the incidence of refractory ulcers and the prevalence of H. pylori infection in patients with peptic ulcer disease followed the introduction of H. pylori eradication treatment. Chronic H. pylori infection is associated with gastric cancer, and the effect of H. pylori eradication on the prevention of gastric cancer is an important issue that is still a matter of controversy. Endoscopic hemostasis and intravenous proton-pump inhibitor (PPI) infusion represent a widely accepted approach to the treatment of peptic ulcer bleeding. In clinical practice, it is important to prevent recurrent bleeding and to treat patients who do not respond to endoscopic therapy or PPI treatment. Laparoscopic repair for peptic ulcer perforations, with postoperative eradication treatment, has gradually met with acceptance in patients with H. pylori infection. H. pylori infection and its treatment continue to be interesting problems in this field.     

Role of Helicobacter pylori eradication in the prevention of peptic ulcer in NSAID users

Helicobacter pylori (H. pylori) and non-steroidal anti-inflammatory drug (NSAID) are independent risk factors for peptic ulcers and ulcer complications and they have additive or synergistic effects. A meta-analysis showed that the OR for the incidence of peptic ulcer was 61.1 in patients infected with H. pylori and also taking NSAID when compared to patients uninfected with H. pylori and not taking NSAID. H. pylori eradication may prevent NSAID-induced ulcers in NSAID naive patients. In patients receiving long-term NSAID, proton pump inhibitor(PPI) is more effective in the prevention of ulcer recurrence and bleeding. However, H. pylori eradication should be considered in patients receiving long -term PPI maintenance treatment to prevent the development of corpus gastritis and gastric atrophy.     

Effect of the eradication of Helicobacter pylori on peptic ulcer healing

Acid suppressive therapy with H2 receptor antagonist or proton pump inhibitor can hardly shift peptic ulcers to S2 stage (white scar). As a result, judgement of ulcer healing has been made at S1 stage (red scar). However, it has been a problem that many ulcer scars relapse. Helicobacter pylori eradication therapy can prevent peptic ulcers from relapsing. The eradication therapy shifted 92% gastric ulcers from all stages to S2 stage after 24 months. We has divided S1 stage categorized by conventional endoscopy into H3-C stage (with small defect of mucosa) and S1-C stage by dye contrast method. The ulcers at H3-C stage relapse more frequently than those at S1-C stage. The acid suppressive therapy shifted only 7%, 15% gastric ulcers at H3-C stage, S1-C stage to S2-C stage after 6 months, respectedly. On the other hand, the eradication therapy shifted 56%, 65% gastric ulcers at H3-C stage, S1-C stage to S2-C stage, respectedly. It may be one reason why the eradication therapy prevents peptic ulcers from relapsing that the therapy shifts almost peptic ulcers to S2 stage.     

Current state and measures of NSAIDs induced ulcer

In recent years, the incidence of Helicobacter pylori (H. pylori) infection has been decreasing and the incidence of peptic ulcer and bleeding ulcer induced by NSAIDs, especially low-dose aspirin (LDA), have been increasing. PPI and PG are useful for treatment and prevention of ulcers in patients receiving continuous administration of NSAIDs and/or LDA. H. pylori eradication is effective if performed before the start of NSAIDs administration, but a beneficial effect of H. pylori eradication performed during NSAIDs treatment cannot be expected. The incidence of ulcers is lower when administering COX-2-selective inhibitor than when administering non-selective NSAIDs, but attention must be given to cardiovascular events as side effects when administering COX-2-selective inhibitor.     

The antimicrobial susceptibility test of Helicobacter pylori

Now that treatment of H. pylori associated disease is becoming common in Japan, drug resistant--H. pylori has emerged as a problem to be solved. There is no standard method of H. pylori drug susceptibility test in Japan yet. There are several methods available: Disk test, E-test, microplate method and agar plate dilution method. The E-test is being the standard method in European countries and USA. However the microplate method has been reported as a same accuracy as the agar dilution method, and thought as being a new standard method in Japan. In 2000, The Japanese Society of Chemotherapy proposed that drug susceptibility test be standardized and listed the break point of MIC of amoxicillin(AMPC) and clarithromycin(CAM).     

Changes in 12-Year First-Line Eradication Rate of Helicobacter pylori Based on Triple Therapy with Proton Pump Inhibitor,Amoxicillin and Clarithromycin

A triple therapy based on a proton pump inhibitor (PPI), amoxicillin (AMPC), and clarithromycin (CAM) is recommended as a first-line therapy for Helicobacter pylori (H. pylori) eradication and is widely used in Japan. However, a decline in eradication rate associated with an increase in prevalence of CAM resistance is viewed as a problem. We investigated CAM resistance and eradication rates over time retrospectively in 750 patients who had undergone the triple therapy as first-line eradication therapy at Nagoya City University Hospital from 1995 to 2008, divided into four terms (Term 1: 1997–2000, Term 2: 2001–2003, Term 3: 2004–2006, Term 4: 2007–2008). Primary resistance to CAM rose significantly over time from 8.7% to 23.5%, 26.7% and 34.5% while the eradication rate decreased significantly from 90.6% to 80.2%, 76.0% and 74.8%. Based on the PPI type, significant declines in eradication rates were observed with omeprazole or lansoprazole, but not with rabeprazole. A decrease in the H. pylori eradication rate after triple therapy using a PPI + AMPC + CAM has been acknowledged, and an increase in CAM resistance is considered to be a factor. From now on, a first-line eradication regimen that results in a higher eradication rate ought to be investigated.     

Evaluation of the efficacy and the cost-effectiveness of proton pump inhibitor-based dual and triple therapy regimens for H. pylori eradication in peptic ulcer disease

To evaluate the efficacy and the cost-effectiveness of H. pylori eradication for the treatment of peptic ulcer disease, a randomized controlled trial to compare the efficacy of proton pump inhibitor-based dual and triple regimens was conducted. A decision analysis was also performed to assess H. pylori eradication compared to the conventional maintenance strategy. Two hundred and thirty-four peptic ulcer patients suffering from H. pylori infection were randomly treated with either omeprazole 20 mg bid + amoxicillin 500 mg qid + clarithromycin 400 mg bid (OAC) or with omeprazole 20 mg bid + clarithromycin 400 mg bid (OC) for 14 days. The eradication rate with OAC was 87.6% (92/105) (95% Confidence Interval (CI): 81-94%), which was significantly higher than that with OC (61.9% (60/97) (95% CI: 52-72%)) (p < 0.001, chi 2 test). Both regimens were safe and well tolerated. H. pylori eradication was more effective and less costly than conventional strategy in a long term perspective. OAC was more cost-effective than OC. In conclusion, H. pylori eradication is a cost-effective alternative to conventional treatment. We recommend 2 weeks triple regimen with omeprazole 20 mg bid + amoxicillin 500 mg qid + clarithromycin 400 mg bid (OAC) as a first-line treatment in all patients with peptic ulcers associated with H. pylori infection.     

雷贝拉唑与兰索拉唑三联疗法治疗幽门螺杆菌阳性消化性溃疡疗效比较

目的:比较雷贝拉唑三联疗法与兰索拉唑三联疗法治疗幽门螺杆菌阳性消化性溃疡的疗效。方法:将幽门螺杆菌阳性的消化性溃疡83例分为两组:治疗组(雷贝拉唑三联疗法组)41例,以雷贝拉唑10mg,阿莫西林1000mg及甲硝唑400mg每日2次口服,治疗1周后单独服用雷贝拉唑10mg,连服7d;对照组(兰索拉唑三联疗法组)42例:以兰索拉唑30mg,阿莫西林1000mg及甲硝唑400mg,每日2次口服,治疗1周后单独服用兰索拉唑30mg,连服7d。治疗期间每周门诊随诊,记录临床症状改善情况,用药结束1个月后复查胃镜并检测幽门螺杆菌结果。结果:治疗组和对照组1d的临床症状缓解率分别为80%、60%,差异有统计学意义(P<0.05);1周后症状缓解率均为98%。治疗组和对照组的溃疡愈合率分别为93%和76%,差异有统计学意义(P<0.05);治疗组和对照组的总有效率分别为98%和96%,差异无统计学意义(P>0.05)。治疗组和对照组的幽门螺杆菌根除率分别85%和81%,差异无统计学意义(P>0.05)。结论:两组方案均能有效治疗消化性溃疡和缓解临床症状,并能有效地根除幽门螺杆菌。但雷贝拉唑三联疗法在改善临床症状和促进溃疡愈合方面优于兰索拉唑三联疗法。     

Eradication therapy of Helicobacter pylori for elderly patients in Japan

In Japan, an eradication therapy of Helicobacter pylori(H. pylori) for peptic ulcers of stomach and duodenum was approved by a health insurance since November 1, 2000. A method of an eradication therapy is as follows. Adult patients are received lansoprazole 30 mg, amoxicillin 750 mg, clarithromycin 200-400 mg at the same time twice daily for seven days. This therapy is based on a guideline of a Japanese association of Helicobacter Research. Many elderly patients have complications such as hypertension, cerebral vascular disturbance, heart failure and so on. Moreover, they often take a several medicine including NSAIDs(non-steroidal anti-inflammatory drugs). Therefore, you should pay attention especially to interaction of drugs when planning an eradication therapy of H. pylori for elderly patients.     

The present status and problems of Helicobacter pylori eradication therapy with a special reference to gastric cancer

Since the eradication therapy of Helicobacter pylori(H. pylori) for peptic ulcer was covered by Japanese health insurance at 2000 November, this therapy has been generalized in Japan. However, some problems have cropped up at the time, for example, emergence of clarithromycin resistant bacterium etc. On the other hand, investigation of relation between H. pylori and gastric cancer is making progress. Uemura, et al. demonstrated H. pylori had an important role for gastric carcinogenesis by the elegant prospective study in 2001. Under the present circumstances, the Japanese society of Helicobacter Research has to reconsider the guideline for eradication therapy. In this paper, we would like to state the present status and problems of eradication therapy of the current guideline for eradication therapy, especially focusing on gastric cancer.     

雷贝拉唑与奥美拉唑三联疗法治疗幽门螺杆菌阳性消化性溃疡疗效比较--附40例分析

目的 :比较雷贝拉唑三联疗法与奥美拉唑三联疗法治疗幽门螺杆菌阳性消化性溃疡的疗效。方法 :将幽门螺杆菌阳性的消化性溃疡 85例分为两组 :治疗组 (雷贝拉唑三联疗法组 ) 4 0例 ,以雷贝拉唑 10mg、阿莫西林 10 0 0mg及甲硝唑 4 0 0mg每日 2次口服 ,治疗 1周后单独服用雷贝拉唑 10mg ,连服 7日 ;对照组 (奥美拉唑三联疗法组 ) 4 5例 :以奥美拉唑 10mg、阿莫西林 10 0 0mg及甲硝唑 4 0 0mg ,每日 2次口服 ,治疗 1周后单独服用奥美拉唑 10mg ,连服 7日。治疗期间每周门诊随诊 ,记录临床症状改善情况 ,用药结束 1个月后复查胃镜并检测幽门螺杆菌结果。结果 :治疗组和对照组治疗 1日的临床症状缓解率分别为 83%、 6 2 % ,差异有统计学意义 (P <0 0 5 ) ;1周后的症状缓解率均为 98%。治疗组和对照组的溃疡愈合率分别为 93%和 76 % ,差异有统计学意义 (P <0 0 5 ) ;治疗组和对照组的总有效率分别为 98%和 96 % ,差异无统计学意义 (P >0 0 5 )。治疗组和对照组的幽门螺杆菌根除率分别为 88%和 78% ,差异无统计学意义 (P >0 0 5 )。结论 :两组方案均能有效治疗消化性溃疡和缓解临床症状 ,并能有效地根除幽门螺杆菌。但雷贝拉唑三联疗法在快速改善临床症状和促进溃疡愈合方面优于奥美拉唑三联疗法。     

In a view of international consensus conference for the treatment of H. pylori infection

The first guideline of the treatment of H. pylori infection was reported by the working party of the World Congresses of Gastroenterology in 1990. Subsequently, many international consensus statements for the indication and the methods of eradication therapy for H. pylori infection were reported. And, now the standard regimens have been developed in European countries and U.S.A. The other hand, in Japan, the Ministry of Welfare has never been to approve the both of testing and treatment of H. pylori. One of the reasons is that there is a few scientific evidence for the benefit of the treatment of H. pylori infection in Japan. Since the resistant strains of H. pylori against antimicrobial agents are increasing in our country, we have to develop a strong and safety therapeutic regimen in Japan.