For treatment of Helicobacter pylori infection, 1-week proton pump inhibition (PPI)–based triple therapy is still the first choice, which has been used under different guidelines for both adults and children (1–5). However, the success of triple therapy has been hampered by the wide use of antibiotics, which has led to a dramatic increase in H pylori strains resistant to metronidazole and particularly clarithromycin, or both of them (6–12). Clarithromycin resistance is highly predictive of treatment failure if clarithromycin is part of the regimen (13,14). In contrast, in vitro metronidazole resistance may be overcome in vivo by longer treatment (14 days) and/or higher doses (15). Eradication rates may still reach up to 75%, depending on minimal inhibitory concentration (MIC) values (16,17).
The sequential therapy is a novel, promising approach that deserves consideration as a treatment strategy for H pylori infection. However, because most of the published studies failed to evaluate clarithromycin and nitroimidazole (metronidazole) resistance, there is, at present, insufficient information to truly judge this antimicrobial regimen according to its applicability in populations with high and/or low antimicrobial resistance (18).
Data on 1233 H pylori–infected children living in 14 different European countries and collected during a 4-year period (1999–2002) revealed the following resistance rates before the first therapy (n = 1037 children): 23% of H pylori strains were resistant to metronidazole, 20% to clarithromycin and 5.3% to both antibiotics. After at least 1 treatment failure (n = 196 children), 35% of H pylori strains were resistant to metronidazole, 42% to clarithromycin, and 15.3% to both antibiotic agents (19). The increasing number of pediatric patients with multiresistant H pylori strains calls for evaluation of treatment regimens in children with antibiotic components to which H pylori is not resistant. Second-line antibiotics such as tetracycline or quinolones (levofloxacin/moxifloxacin) are not approved for use in the pediatric age group or may even be contraindicated below a certain age. Bismuth salts are not available in most European countries for use in either children or adults. Rifabutin has been successfully used in adults, but may cause resistance problems in the treatment of tuberculosis, which would support limiting the use of rifabutin in this population. Because H pylori–infected children in Europe often belong to lower socioeconomic classes or live in developing countries, they have a higher long-term risk for tuberculosis, prohibiting the wide use of rifabutin in this population.
For lack of alternatives, we and other members of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Working Group on H pylori Infection have treated children infected with a strain resistant to both metronidazole and clarithromycin with a normal dose 1- or 2-week triple therapy containing amoxicillin (∼50 mg/kg/day), metronidazole (∼15–20 mg/kg/day), and omeprazole (∼1 mg/kg/day). The eradication in a pilot study was successful in 12/16 children (75%) (unpublished data). So far, no prospective treatment trials have been published with respect to treatment of children harbouring a double-resistant H pylori strain. Therefore, we wanted to evaluate prospectively the success rate and side effects of a triple therapy using high-dose amoxicillin, metronidazole, and esomeprazole in children with H pylori double-resistance strain and to document the safety of this regimen.
PATIENTS AND METHODS
This is a registered open investigator-initiated study that was conducted following good clinical practice (EudraCT number 2006-002639-26), approved by the ethical committee of the Ludwig Maximilian University of Munich. Written informed consent was obtained from all of the participants. Patients were recruited at 22 centres in Belgium, Germany, Poland, Italy, Spain, Greece, France, Czech Republic, and the Netherlands between March 2007 and March 2009.
Patients of both sexes were prospectively recruited if they were younger than 18 years of age, had a body weight above 15 kg, and had positive culture for H pylori with proven resistance to metronidazole and clarithromycin. MIC values were determined by E-test in all but 1 centre, which used the agar diffusion technique. Breakpoints for resistance were defined as follows: metronidazole ≥16 μg/mL, clarithromycin ≥1.0 μg/mL, and amoxicillin ≥0.5 μg/mL. Patients were not eligible for the study if they did not fulfil the inclusion criteria and/or harboured a strain resistant to amoxicillin, or had a complicated peptic ulcer disease such as bleeding or perforation, had a contraindication for any of the study drugs, or were taking nonsteroidal anti-inflammatory drugs, antibiotics, or bismuth compounds within 4 weeks before inclusion or had a history of partial gastrectomy or other severe concomitant diseases.
Patients were treated with doses chosen according to weight groups (Table 1). Esomeprazole, amoxicillin, and metronidazole were prescribed for 14 days according to the local conditions and regulations. It was recommended to take esomeprazole tablet at least 10 minutes before the meal. If the child was not able to swallow tablets, then the parents were advised to dissolve the multiple-unit pellet system tablets on a teaspoon with apple juice or water and immediately give the child the micropellet suspension. The 2 antibiotics were administered after or with meals either as tablets or—if not possible—in liquid form (suspension).
All of the patients/parents were asked to fill out a diary during the 2 weeks of treatment to document the daily intake of study medication, gastrointestinal symptoms, and possible adverse events. At the end of the first and the second week, the local investigator called the patient and asked for adverse events and compliance in a standardized format. At follow-up 6 weeks (42 to a maximum of 56 days) after the end of therapy, the diaries were collected. A patient was considered as compliant when at least 80% of the drugs had been taken (per protocol analysis).
Definition of H pylori Eradication
A 13C-urea breath test (UBT) was performed after 6 (–8) weeks as previously described and validated (20) to monitor the success of therapy. After a fasting period of at least 4 hours, 75 mg 13C-urea was ingested with cold apple juice. Breath samples were taken at baseline and at 30 minutes. A delta over baseline value >5‰ indicated a positive test result and therefore treatment failure. Six months after treatment, a second UBT was offered to the patient, but was not compulsory.
H pylori cure rates were calculated by both intention-to-treat (ITT) and per-protocol (PP) analyses. For ITT analysis, all of the recruited patients who filled in the prescription and took at least 1 dose were included. For PP analysis, all of the protocol violators (taking <80% of the study medication, not filling out the diary, no UBT after treatment) were excluded (Fig. 1). For statistical analysis, 95% confidence interval (CI) was used. Rates of eradication were calculated as the percentage of patients with a negative UBT 6 weeks after treatment.
The study cohort included 64 children (28 girls) with a median age of 11.6 years (range 5.4–16.9 years); patients' characteristics are given in Table 2. Twenty-three patients had previously received 1 and the rest 2 or more eradication attempts. Two patients were excluded because they never filled in their prescription or took any drugs. Of the remaining 62 patients, 5 did not return for a UBT posttreatment, and for 12 children compliance with drug intake and/or reporting was insufficient. Thus, 62 patients were eligible for the ITT analysis and 45 for the PP analysis (Fig. 1). All 62 patients had chronic active gastritis upon histology. Macroscopic findings included nodularity in 52 patients, including 1 child with duodenal peptic ulcer and 3 patients with gastric and/or duodenal erosions. In 10 cases, endoscopic findings were completely normal.
Eradication rates after 6 weeks were 66% (41/62 patients; CI 54.2–77.8) by ITT analysis and 73% (33/45 patients; CI 59.7–86.3) by PP analysis. There was no trend observed for better success of treatment even in higher doses per kilogram body weight for all 3 drugs (depicted for metronidazole in Fig. 2). The median dose of amoxicillin was 65 mg/kg body weight (range 39–100 mg/kg), the median dose for metronidazole was 23 mg/kg body weight (range 13–34 mg/kg) and the median dose for esomeprazole was 1.5 mg/kg body weight (range 0.8–2.7 mg/kg). Six months after the end of treatment, UBT was repeated in 37 children. None of them received further anti–H pylori treatment. Results showed 100% concordance with the UBT after 6 weeks (26/37 with negative results).
Adherence and Adverse Events
Adherence as assessed by the diary and telephone contacts on days 7 and 14 of treatment revealed that only 69% of the patients reported an intake of ≥80% of any of the study drugs.
Of 45 patients who maintained the daily diary, 21 had an adverse event: common symptoms were nausea (n = 6; 10.8%), diarrhoea (n = 5; 8.9%), vomiting (n = 4; 7.1%), abdominal pain (n = 3; 5.4%), headache (n = 2; 3.6%), and dry skin/pruritus (n = 1; 1.8%). Only in 1 case, treatment had to be stopped due to severe diarrhoea and vomiting.
This was the first prospective treatment trial in children infected with a double-resistant H pylori strain. Our results indicate that 2-week treatment with high-dose amoxicillin, metronidazole, and esomeprazole is a well-tolerated option in those patients. The treatment was successful in 3 of 4 children who took at least 80% of the prescribed drugs.
This study was conducted as an investigator-initiated trial. Due to limitation of financial support, lack of other treatment options in children, and ethical considerations, it was not possible to perform a controlled trial with placebo or other drug combinations as controls.
In adults, new prospective, randomized multicentre trials have been conducted to investigate the efficacy of different treatment regimens for eradication of H pylori resistant to metronidazole and clarithromycin. Quadruple therapy and dual therapy with high-dose omeprazole/amoxicillin have been used successfully (21). Also, in adults 1-week once-daily therapy with esomeprazole, moxifloxacin, and rifabutin seems to be a promising modality for rescue treatment of H pylori infection and may serve as an alternative to quadruple therapy, particularly in patients with intolerance to amoxicillin (22,23). No study on sequential therapy has thus far been performed on patients with double-resistant strains. However, a recent systematic review identified 2 randomized controlled trials on adult patients that provided data on antibiotic-susceptibility testing (24). In these trials, only 26 patients harboured strains resistant to both clarithromycin and metronidazole; 14 were treated with sequential therapy and 12 with standard triple therapy. The eradication rate was 57% (95% CI 32.6–78.6) for sequential therapy and 33% (95% CI 13.8–60.9) for triple therapy. In light of the poor performance of alternative treatment options in children, the eradication rate in our study with 66% (95% CI 54–78) in the intention-to-treat analysis and 73% (95% CI 60–86) in the PP analysis is good.
The aim of the study was to choose drugs that are most likely to be successful and available in the participating countries to have the most homogeneous regimen. Amoxicillin forms an important constituent for any therapy regimen and achieves maximum plasma concentration between 1 and 3 hours following oral ingestion. For this reason, coprescription of a PPI capable of achieving a faster optimal intragastric pH may be desirable for maximum antibacterial effect (25). We chose esomeprazole (20 mg Nexium multiple-unit pellet system tablets, AstraZeneca) as PPI because it is available in all of the participating countries and the application of the micropellets is easy even in young children (26). Tinidazole was initially chosen in the pilot study because it has been used to successfully treat H pylori infection in adults (27) and children (28–30) without any serious side effects. However, the manufacturer has decided to take the drug off the market. Therefore, metronidazole was chosen, but in higher doses (20–30 mg/kg body weight/day) compared to the pilot study. Following oral administration of metronidazole, peak serum levels also occur in 1 to 2 hours after ingestion (31).
Because neither metronidazole nor esomeprazole was available in liquid form at the beginning of the study, it was unrealistic to suggest the dose at milligram/kilogram body weight. Although in previous studies an milligram/kilogram body weight was reported, the authors did not describe how this could be achieved with tablets (32). We decided to divide the children into 3 different groups with respect to body weight (Table 1), which is a common practice for most medications, and instructions by manufacturers reflect the real-life situation. This implied that there was a range of doses within each group. It was agreed that the doses per kilogram body weight should be highest in the youngest age group because the metabolic rate is higher compared with older children (33). This is the case not only for the antibiotics used but also for PPI (34). Although numbers within the 3 weight groups were too small to perform a statistical analysis, there was no trend observed for treatment failure within this dose range (Fig. 2).
It was decided that the duration of the treatment should be 2 weeks. A recent prospective randomized head-to-head trial compared 1-week and 2-week triple therapy and found significant eradication advantages for the 2-week regimen (35). A meta-analysis comparing treatment trials with the same drugs of different duration showed that a 7-day therapy was significantly less likely to cure H pylori infection in adults than a 14-day therapy (15). A meta-analysis of studies in children confirmed that metronidazole-based treatment regimens are superior if given for 2 weeks compared with 1 week (36). Although the adherence was expected to be lower in the longer-duration treatment because it was believed that in children infected with double-resistant strains and often after several failed treatments, every opportunity for a better cure should be explored.
Apart from the impact of pharmacokinetics of therapy constituents, other factors play a significant role in determining the success of an eradication regimen. In particular, the adherence of patients has been identified as an important factor contributing to treatment failure (25). The medication adherence in our study seemed to be unsatisfactory. Only 67% were considered to be adhering, taking at least 80% of the study medication. As a possible explanation except for the 2-week duration, most of our patients were children from immigrant populations with a low socioeconomic background and/or language problems.
The study regimen was well tolerated, and most of the adverse events were mild and transient. Therapy had to be discontinued due to severe diarrhoea, nausea and vomiting in 1 patient.
The high-dose therapy with amoxicillin, metronidazole, and esomeprazole given for 14 days is a good alternative treatment in children infected with a double-resistant H pylori strain. The increase in resistance against different antibiotics, especially metronidazole and clarithromycin, in children within European countries and the United States should be recognized both by paediatric gastroenterologists and by general paediatricians. Eradication of H pylori with a well-chosen regimen should follow only when susceptibility in geographic areas is established or populations with a high resistance rate are identified by tests. Further studies are needed to evaluate new treatment regimen in children with H pylori double-resistant strains.
The following physicians were also involved in the process of the study or helped to recruit patients: Prof G. Oderda (Novara, Italy), Prof F. Megraud (France), Prof M. Kist (Freiburg, Germany), Dr J. Sykora (Pilsen, Czech Republic), Dr A. Kindermann (Amsterdam, the Netherlands), Dr A. Pappas (Aachen, Germany), Dr M. Richter (Erlangen, Germany), Dr G. Kliemann (Giessen, Germany), Priv-Doz Dr A. Schmidt-Choudhury (Bochum, Germany), Dr Handrick (Görlitz, Germany), Dr Wegner (Düren, Germany), Dr Hanrath (Hof, Germany), Dr Jedwilayties (Friedrichshafen, Germany), and Dr Knoll (Worms, Germany).
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