SUMMARY

Background: Standard anti-Helicobacter pylori therapy may not achieve a satisfactory eradication rate. Fluoroquinolones, such as moxifloxacin, are safe and promising agents for H. pylori eradication. Aim: To compare the efficacy of two 1-week moxifloxacin-based H. pylori eradication regimens with two standard treatments. Methods: Three hundred and twenty H. pylori-positive subjects were randomized into four groups to receive: moxifloxacin, amoxicillin, esomeprazole (Group MAE); moxifloxacin, tinidazole and esomeprazole (Group MTE); standard triple therapies with clarithromycin, amoxicillin and esomeprazole (Group CAE) or tinidazole (Group CTE) for 7 days. H. pylori status was re-assessed 6 weeks after the end of therapy by 13C urea breath test.

Results: Three hundred and twenty patients completed the efficacy analysis per protocol; H. pylori eradication rate in group MTE was 90% (72 of 80) and 92% (72 of 78), in group MAE was 88% (70 of 80) and 89%, (70 of 79) in Group CAE was 73% (58 of80) and 78% (58 of 74), and in Group CTE was 75% (60 of 80) and 79% (60 of 76), respectively, in intention-to-treat and in per protocol analyses. Eradication rates of moxifloxacin-based triple therapies were significantly higher than that observed using standard triple schemes. The incidence of side effects was significantly lower in moxifloxacin groups than in control groups. Conclusions: Seven-day moxifloxacin-based triple therapies provide optimal eradication rates with a good compliance when compared with the standard triple therapy schemes.

INTRODUCTION

Helicobacter pylori infection is the main pathogenic factor in the development of chronic gastritis, peptic ulcer and gastric malignancies. Considering the worldwide diffusion of H. pylori and the possible severe complications of chronic infection, the availability of efficacious treatment options is essential.

Correspondence to: Prof. A. Gasbarrini, Catholic University, Gemelli Hospital, Largo A Gemelli 8, 00168 Rome, Italy. E-mail: angiologia@rm.unicatt.it Ó 2005 Blackwell Publishing Ltd

The guidelines established by several International Consensus Conference suggest the use of a first-line therapy based on two antibiotics, clarithromycin (500 mg b.d.) and amoxicillin (1 g b.d.) or nitroimidazole (500 mg b.d.) associated with a proton pump inhibitor (b.d.) for 7 days. The eradication rate of this scheme is variable in different studies ranging from 70 to 85%.1, 2 Patients’ compliance and bacterial resistance are some of thefactors involved in treatment’s failure.3 For this reason new antibiotic associations and simpler eradication regimens are needed. However, in western country the major cause of treatment failure remains the resistance to clarithromycin. The wide use
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of such antibiotic for community acquired upper and lower respiratory diseases and for otitis probably can explain the increasing resistance of H. pylori in general population. To overcome this problem different classes of antibiotics such as fluoroquinilones, rifabutin and newer macrolides have been used with variable rates of success.4–6 In particular, some studies have evaluated the efficacy and tolerability of new fluoroquinolones, such as levofloxacin, that could provide a valid alternative to standard antibiotics and, more interesting, a useful way to overcome the occurrence of primary resistance to macrolides and nitroimidazoles.7 Among antibacterial agents currently under investigation there is moxifloxacin, a 8-methoxy-fluoroquinolone with a broad spectrum of activity, an improved coverage of Gram-positive and anaerobic bacteria, compared with first generation fluoroquinolones, and a retained good activity against Gram-negative bacteria.8–10 As with other fluoroquinolones, the antibacterial effect of moxifloxacin is based on the inhibition of bacterial topoisomerase II, the enzyme responsible for DNA superspiralized rolling and unrolling.11 Moxifloxacin is characterized by rapid absorption afteroral administration with an absolute bioavailability of 89% and a wide penetration in tissues and fluids. It has a predominant renal excretion with a mean elimination half-life of 9–16 h that allows a single daily administration. Dosage adjustment is not required in old patients or in those with renal or mild hepatic impairment. In contrast with other fluoroquinolones this antibiotic shows a low drug interactions and a low incidence of adverse events. The most common side effects are gastrointestinal disturbances like nausea and diarrhoea.12, 13 Finally, in vitro studies have shown that bacterial resistance was less common with moxifloxacin than with other fluoroquinolones. In patients with community acquired pneumonia or bronchitis the efficacy of a single dose of moxifloxacin (400 mg once

daily) reached a bacteriological and clinical success rate higher than 90%.9, 14 In these patients moxifloxacin was at least as effective as clarithromycin. Moreover, it has been shown that several clarithromycin-resistant bacteria are sensible to moxifloxacin. Moxifloxacin has been used in association with clarithromycin15 for H. pylori eradication in first line therapy with excellent results. Aim of this study was to compare the efficacy and tolerability of two new moxifloxacin based regimens with two standard triple therapies in first line H. pylori eradication.
PATIENTS AND METHODS

The study is a single centre, prospective, open label trial performed at the Gastroenterology and Internal Medicine DayHospital of Gemelli Hospital of Rome, Italy. This trial is reported according to the recommendations of the Consort Statement for the quality of reports of parallel group, randomized trial.16 Eligibility criteria Three hundred and twenty H. pylori positive patients with dyspeptic symptoms were enrolled from March 2003 to March 2004. Patients were considered eligible for the study if they underwent upper gastrointestinal endoscopy and H. pylori infection was diagnosed through histological examination (Giemsa stain) of antral and body bioptic samples (two from the antral mucosa and two from the corpus) and 13C urea breath test. Patients were considered infected by H. pylori if both tests resulted positive. Demographic and clinical data are summarized in Table 1. All patients were requested to sign an informed consent form before beginning the protocol, after a full explanation by the investigator.

Gender (male/female) MTE MAE CTE CAE 43/37 44/36 44/36 43/37

Age (mean ± s.d.) 48 47 49 48 ± ± ± ± 8.4 9.4 9.9 11.1

Ulcer-like dyspepsia (%) 37.5 42.5 38.7 45 (30/80) (34/80) (31/80) (36/80)

Dismotility-like dyspepsia (%) 32.5 30 31.25 28.7 (26/80) (24/80) (25/80) (23/80)

Reflux-like dyspepsia (%) 30 27.5 30 26.2 (24/80) (22/80) (24/80) (21/80)

Table 1. Demographic and clinical characteristics of patients randomized according to Rome I criteria

MTE, moxifloxacin, tinidazole, esomeprazole; MAE, moxifloxacin, amoxicillin, esomeprazole; CTE, clarithromycin, tinidazole,esomeprazole; CAE, clarithromycin, amoxicillin, esomeprazole.




Dyspepsia was classified as ulcer-like, dysmotility-like and reflux-like according to the Rome I criteria.17 Exclusion criteria were: previous eradication therapy, recent (within the previous 3 months) use of antimicrobial agents, bismuth compounds, proton pump inhibitors and H2 receptor antagonists, laxatives, antidiarrhoeals, probiotic preparations, alcohol and/or addictive drugs abuse. Patients with acute or chronic gastrointestinal diseases, subjects with major concomitant diseases, including psychic disorders, and pregnant or lactating women were excluded from the study. Patients under chronic drug treatments were considered suitable if they had been receiving such treatments for more than 3 months. Outcomes Primary end point of this study was to evaluate the eradication rate of 7 days moxifloxacin-based therapies compared with standard first line schemes. Helicobacter pylori eradication was assessed using the 13C urea breath test performed with citric acid and 75 mg of 13C urea, 6 weeks after the end of therapy. The cut-off for positivity was delta value >3.5 units. Patients were asked to avoid anti-acid treatment and antibiotics for 2 weeks and 1 month respectively, before performing 13C-urea breath test. We also evaluated the patients’ compliance and the occurrence of side effects in different groups oftreatment. Compliance was assessed both by an interview (administered by a trained physician) performed after the end of therapy and by a pill count of the drug boxes returned at the same interview. Low compliance was defined as more then 20% of pills returned at time of the interview. At enrolment the patients were informed of the common side effects expected from the studied therapies. All patients were asked to fill in a validated questionnaire (modified DeBoer) in order to report therapyrelated side effects (diarrhoea, taste disturbance, nausea, bloating, loss of appetite, vomiting, abdominal pain, constipation, headache, skin rash).18 Each symptom was graded from absent (0) to severe (interruption of treatment, 3) based on the intensity. The questionnaire was administered at enrolment and diary cards in the same format (Likert scales) were completed by the patients during the treatment period and then returned at the post-therapy interview.

Randomization Using a computer generated number sequence, eligible patients were randomized to receive one of four first-line treatment schemes, all given for 7 days. The treatment groups were: (A) moxifloxacin 400 mg od, amoxicillin 1 g b.d., esomeprazole 20 mg b.d. (MAE group, n Œ 80); (B) moxifloxacin 400 mg od, tinidazole 500 mg b.d., esomeprazole 20 mg b.d. (MTE group, n Œ 80); (C) clarythromicin 500 b.d., amoxicillin 1 g b.d., esomeprazole 20 mg b.d. (CAE group, n Œ 80); (D) claythromicin 500 b.d., tinidazole 500 mg b.d., esomeprazole 20 mgb.d. (CTE group, n Œ 80). Sample size An estimated sample size of 60 subjects per group would give an 80% power to detect a difference of 15% in the eradication rate between the moxifloxacin-based therapies and the standard triple therapies (assumed to have an eradication rate of 75%), with and a two-sided alpha Œ 0.05. Thus, we aimed to recruit at least 80 patients per group. Statistical analysis Both per protocol (pp) and intention-to-treat (ITT) analyses were performed. For the purpose of the analysis, the incidence of side effects was considered as a binomial variable (present–absent). Any ‘side effect’ was considered absent if the subject reported the same complaint at baseline visit, as assessed by the questionnaire. To detect differences in H. pylori eradication rates and the incidence of side effects, the v-square and the Fisher exact tests were used. Odds ratio (OR) for achieving H. pylori eradication with 95% confidence intervals (95% CI) were calculated. The statistical analysis was performed using STATA 6.0 (College Station, TX, USA).

RESULTS

Study flow and overall compliance Figure 1 summarizes the trial flow. Three hundred and twenty patients (172 males, aged 18–65 years) with non-ulcer dyspepsia were enrolled. Drug compliance was excellent: 307 of 320 patients (95.9%) completed the studied therapeutic regimens. One





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320 H.pylori positive patients

7 daysMoxifloxacin 400 mg od Tinidazole 500 mg bid Esomeprazole 20 mg bid (n = 80)

7 days Moxifloxacin 400 mg od Amoxicillin 1 g bid. Esomeprazole 20 mg bid (n = 80)

7 days Clarithromycin 500 mg bid Tinidazole 500 mg bid Esomeprazole 20 mg bid (n = 80)

7 days Clarithromycin 500 mg bid Amoxicillin 1 g bid. Esomeprazole 20 mg bid (n = 80

Drops out



Eradication rate (ITT)

72/80 patients (90%)

70/80 patients (87.5%)

60/80 patients (75%)

58/80 patients (72.5%)

Figure 1. Study flow chart.

drop-out occurred in the MAE group (because of sideeffects self-rated as mild: nausea). Two drops-out occurred in the MTE group (because of side-effects self-rated as moderated: one case for nausea and the other for diarrhoea). Six patients interrupted therapy in the CAE group (one for low compliance and five because of side effects self-rated as severe: four patients for taste disturbance, one for skin rash). No cardiac dysrhythmias were observed during the eradication therapies. Four drops-out occurred in the CTE group (because of side-effects self-rated as severe: two cases for taste disturbance and two for abdominal pain). Eradication of H. pylori infection The eradication rate in moxifloxacin-based regimens was: 87.5% (70 of 80 patients) and 88.6% (70 of 79

in MAE group in ITT and PP analysis, respectively; 90% (72 of 80) and 92.3% (72 of 78) in MTE group in ITT and PP analysis, respectively. When we consider the control groups, H. pylori eradication wasachieved in 72.5% (58 of 80) and 78.4% (58 of 74) in CAE group and 75% (60 of 80) and 78.9% (60 of 76) in CTE group in ITT and PP analysis, respectively (Table 2). In particular, the eradication rates of moxifloxacin-based therapies were significantly higher than these observed using standard triple therapies for 7 days in ITT analysis (Table 2). Considering PP analysis only the association between moxifloxacin and tinidazole resulted in higher eradication rate when compared with standard triple therapies (Table 2). No significant differences were found among moxifloxacin-amoxicillin based therapy with standard triple therapies in PP analysis (Table 2).

Table 2. Comparison between eradication rate of moxifloxacin based triple therapies and standard therapies. Data are presented as percentages Analysis Intention-to-treat Therapies MTE vs. CTE MTE vs. CAE MAE vs. CTE MAE vs. CAE MTE vs. CTE MTE vs. CAE MAE vs. CTE MAE vs. CAE % 90 90 87.5 87.5 92.3 92.3 88.6 88.6 (72/80) (72/80) (70/80) (70/80) (72/78) (72/78) (70/79) (70/79) vs. vs. vs. vs. vs. vs. vs. vs. 75 (60/80) 72.5 (58/80) 75 (60/80) 72.5 (58/80) 78.9 (60/76) 78.4 (58/74) 78.9 (60/76) 78.4 (58/74) OR [95% CI] 1.91 2.08 1.62 1.75 2.00 2.03 1.50 1.52 [1.23–7.30] [1.42–8.23] [1.01–5.37] [1.16–6.06] [1.18–8.69] [1.22–9.00] [0.85–5.03] [0.88–5.21] P-value 0.01 0.005 0.04 0.02 0.02 0.01 ns ns

Per protocol

MTE, moxifloxacin, tinidazole, esomeprazole; MAE, moxifloxacin, amoxicillin, esomeprazole; CTE, clarithromycin, tinidazole,esomeprazole; CAE, clarithromycin, amoxicillin, esomeprazole; OR, odds ratio for H. pylori eradication; ns, not significant.


MOXIFLOXACIN AND H. PYLORI ERADICATION

Side effects profile Data on the prevalence and severity of investigated side effects are described in Tables 3 and 4. The overall prevalence of side effects was significantly lower in the MAE and MTE groups than in the CAE and CTE groups. The incidence of taste disturbance was significantly higher in the CTE group than in the moxifloxacin based groups. Moreover, diarrhoea was more frequent in the CAE group than in MAE and MTB group. Other side effects reported by patients were constipation, bloating, abdominal pain, nausea and headache.
DISCUSSION

This study showed that 7-day therapies based on moxifloxacin in association with amoxicillin or tinidazole and esomeprazole are more effective and tolerated than standard triple therapies (clarithromycin, amoxicillin or tinidazole and esomeprazole) in first line eradication of H. pylori. Moreover, compliance was slightly better in moxifloxacin then in clarithromycin groups. The regimens currently recommended as first line treatment for H. pylori eradication involve 7-day triple therapy based on the use of a proton pump inhibitor and two different antibiotics among clarithromycin, amoxicillin and nitroimidazole.19 However, these schemes fail to eradicate H. pylori in up to 20% of patients because of bacterialresistance and poor patients’ compliance related to side effects, treatment duration and number
Table 3. Detail of incidence and severity of side effects during the study. Data are reported as percentages at ITT analysis Symptom Skin rash Taste disturbance Bloating Abdominal pain Nausea Vomiting Headache Constipation Diarrhoea Overall

of pills administered per day.3 Clarithromycin and metronidazole resistances are the most common causes of standard first line therapies failure. The primary resistance to macrolides in Western countries varies from 2 to 12%. In the same areas H. pylori resistance to nitroimidazoles ranges from 2 to 50% with a prevalence of 12–15% in Italy.20, 21 For this reason, alternative regimens that overcome bacterial resistance to standard antibiotics and reduce incidence of side effects have been evaluated. In particular, in the last years new therapeutic schemes based on fluoroquinolones (levofloxacin or moxifloxacin plus an antibiotic and a proton pump inhibitor) are under investigation either as first line or rescue therapies.22, 23 First generation fluorquinolones such as norfloxacin and pefloxacin did not show satisfactory eradication rate;24, 25 on the contrary two studies from our group have evaluated, the efficacy of two different levofloxacin based triple therapies (associated with rabeprazole and amoxicillin or nitroimidazole) showing an eradication rate up then 90%7, 22 in first line treatment. The same fluoroquinolone was also successfully used in associationwith different antibiotics22, 26 even in second line treatment, with high eradication rates (63–94%), probably overcoming, at least in a percentage of the patients, clarithromycin resistance. The absence of an antibiotic susceptibility test in these studies did not allow to have a conclusive response on this issue. Moxifloxacin is a second generation fluoroquinolones, whose antibacterial spectrum covers all major upper and lower respiratory tract pathogens, including betaMAE (%) – 4/80 3/80 1/80 2/80 – 2/80 3/80 2/80 10/80 (5) (3.7) (1.2) (2.5) (2.5) (3.7) (2.5) (12.5) MTE (%) – 5/80 4/80 2/80 1/80 1/80 1/80 2/80 2/80 11/80 (6.2) (5) (2.5) (1.2) (1.2) (1.2) (2.5) (2.5) (13.7) CAE (%) 1/80 9/80 8/80 4/80 5/80 1/80 2/80 5/80 10/80 26/80 (1.2) (11.2) (10) (5) (6.2) (1.2) (2.5) (6.2) (12.5)  (32.5)§ CTE (%) – 13/80 7/80 5/80 7/80 2/80 3/80 6/80 7/80 29/80 (16.2)* (8.7) (6.2) (8.7) (2.5) (3.7) (7.5) (8.7) (36.2)à

MTE, moxifloxacin, tinidazole, esomeprazole; MAE, moxifloxacin, amoxicillin, esomeprazole; CTE, clarithromycin, tinidazole, esomeprazole; CAE, clarithromycin, amoxicillin, esomeprazole; ITT, intention-to-treat analysis; PP, per protocol analysis; OR, odds ratios. * vs. MAE: P < 0.05, OR: 0.44 (0.08–0.87) and vs. MTE: P < 0.05, OR: 0.53 (0.12–1.01).   vs. MAE and MTE: P < 0.05, OR: 0.32 (0.04–0.85). vs. MAE: P < 0.0005, OR: 0.44 (0.11–0.56) and vs. MTE: P Œ 0.001, OR: 0.48 (0.13– 0.61). § vs. MAE: P < 0.005, OR: 0.49 (0.13–0.67) and vs. MTE: P < 0.005, OR: 0.53 (0.15–0.73). Ó2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 1241–

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Table 4. Intensity of side effects between therapies: percentages at ITT analysis Intensity MAE MTE CAE CTE

Mild 9/80 (11.2) 8/80 (10) 16/80 (20) 17/80 (21.2) Moderate – 1/80 (1.2) 3/80 (3.7) 4/80 (5) Severe – – 2/80 (2.5) 4/80 (5) Caused 1/80 (1.2) 2/80 (2.5) 5/80 (6.2) 4/80 (5) drop-out
MTE, moxifloxacin, tinidazole, esomeprazole; MAE, moxifloxacin, amoxicillin, esomeprazole; CTE, clarithromycin, tinidazole, esomeprazole; CAE, clarithromycin, amoxicillin, esomeprazole; ITT, intentionto-treat analysis.

lactamase and macrolide resistant pneumococci. In ‘in vitro’ studies, the emergence of bacterial resistance seems to be less common with moxifloxacin then with other fluoroquinolones. Only one study has evaluated the effectiveness of moxifloxacin in first line treatment in association with clarithromycin.15 In our study we administered moxifloxacin associated with amoxicillin or tinidazole with an excellent eradication rate. Our observations show that moxifloxacin may be a promising alternative to antiH. pylori schemes.27–29 Moxifloxain based schemes may improve patient’s compliance for the low occurrence of side effects, and for the administration of only one pill daily. In particular, a lower incidence of diarrhoea and taste disturbance was observed in moxifloxacin groups than in clarithromycin groups. Diarrhoea is probably due to antibiotic effect on the normal intestinal microflora.Strengths of the study are the high number of patients enrolled, the homogeneous geographical origin (all from the city of Rome), gender distributions and age of included patients and the use of two standard triple therapies (in according to International Consensus Conferences) for control groups. In control groups we used two standard clarithromycin based schemes to sort out differences in eradication rate, incidence of side effects and compliance that could be related to the different antibiotics used (amoxicillin or tinidazole). We found slight differences in side effects profile between CAE and CTE groups. A slight higher incidence of taste disturbance and lower incidence of diarrhoea was found in CTE group when compared with CAE. Eradication rate of CAE was not statistically different from CTE group (72.5% vs. 75%) and similar to data published in previous studies. This results are in accordance to the

evidence that clarithromycin resistance is the major determinant of H. pylori eradication. A limitation of the study is the lack of the evaluation of clarithromycin and tinidazole resistance so that we cannot exclude the presence of baseline differences in resistance to nitroimidazole and macrolides among groups. The clinical validity of this study is not affected by the absence of an antibiotic susceptibility test, by the fact that it is not routinely performed in gastroenterologic units. However, the high number of subjects included in the study makes it difficult and expensive toperform the susceptibility test in all patients. Moreover, further studies that evaluate primary and secondary resistance of H. pylori to nitroimidazole, clarithromycin and moxifloxacin are needed. In conclusion, a 7-day moxifloxacin-based triple therapies are more effective and tolerated than standard triple therapies for H. pylori eradication in first line attempt and could be suggested in clinical practice.
ACKNOWLEDGEMENTS

This study was not supported by pharmaceutical company.
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