Efficacy of 5-Day Levofloxacin- Containing Concomitant Therapy in Eradication of Helicobacter pylori Infection Your Logo Gastroenterology, Volume 143, Issue 1, July 2012, Pages Alessandro Federico et al

Helicobacter pylori is a transmissible human pathogen that causes symptomatic diseases, including adenocarcinoma of the distal stomach, in approximately 20% of infected subjects. Therefore, this infection should be cured whenever it is diagnosed. H pylori infection has proven challenging to cure because the prevalence of bacterial strains resistant to the most commonly used antimicrobials, in particular clarithromycin (CLA), increases. Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of Helicobacter pylori Infection

As a result, currently recommended first-line therapies both in the United States and Europe achieve a 75%– 80% eradication rate, which is not acceptable. Because of this, the Maastricht III and Maastricht IV Consensus Conferences recommended bismuth- containing quadruple therapy (ie, proton pump inhibitor [PPI] plus bismuth, tetracycline [TET], and metronidazole [MET]) as a first-line strategy in areas with a high (ie, >15%) prevalence of CLA resistance, even though compliance with this regimen is low. Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of Helicobacter pylori Infection

We have recently shown that in an area of high prevalence (ie, >15%) of CLA and dual (ie, CLA plus MET) resistance, a levofloxacin (LEV)-containing ST is more effective than a CLA-containing ST regimen, achieving eradication rates higher than 95%. ST is actually a quadruple therapy with 3 antimicrobials (ie, AMO, a macrolide/quinolone, and an imidazole) and an acid suppressive agent given in sequence over a 10-day period. Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of Helicobacter pylori Infection

Based on the hypothesis that the use of 3 antimicrobials rather than the sequential scheme of drug administration plays a major role in the efficacy of ST, we designed a study to assess whether the concomitant administration of a PPI, AMO, LEV, and TIN for 5 days might be as effective as the 10-day sequential administration of the same drugs at the same total dose of antimicrobials in H pylori–infected patients naïve to treatment. Secondary end points were to assess the influence of antimicrobial resistance on the outcome of eradication treatments, the incidence of adverse events, and the costs related to either regimen. Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of Helicobacter pylori Infection

A total of 468 consecutive patients with dyspepsia who were referred to our gastroenterology units for consultation between January and December 2011 were asked to participate in the study. H pylori–infected patients who were at least 18 years of age. Diagnosis of H pylori infection was based on positivity to 13C urea breath test (13C-UBT) or on positivity to both rapid urease test and histology in those patients who underwent endoscopy because of age older than 45 years and/or presence of alarm symptoms. Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of Helicobacter pylori Infection Methods

In patients undergoing endoscopy, 5 biopsy specimens were taken for histologic assessment according to the Sydney system and 2 more specimens (1 from the antrum and 1 from the body) were taken for rapid urease test. Two additional biopsy samples were obtained from the antrum for bacterial culture and antimicrobial susceptibility testing. Biopsy samples were sent to our microbiology laboratory within 24 hours and stored at −70°C. Isolated strains were tested for in vitro susceptibility to AMO, TET, CLA, LEV, and MET by E-test. Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of Helicobacter pylori Infection

Exclusion criteria : previous treatment for H pylori infection; use of inhibitors of acid secretion and/or antibiotics during the 6 weeks before the study; gastrointestinal malignancy; previous gastroesophageal surgery; severe concomitant diseases; hematologic disorders; history of allergy to any of the drugs used in the study; pregnancy or lactation; alcohol abuse; drug addiction; severe neurologic or psychiatric disorders; and long-term use of corticosteroids or anti-inflammatory drugs. Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of Helicobacter pylori Infection

To assess whether the infection had been eradicated, H pylori status was reevaluated by 13C-UBT performed by nonmedical personnel unaware of the eradication regimen of each patient at 6 and 10 weeks after completion of therapy. Infection was considered eradicated if patients had a negative test result on both occasions. 13C-UBT was performed after an overnight fast. A baseline breath sample was obtained, and 100 mg of 13C urea with citric acid (1.4 g) was administered as an aqueous solution.Another breath sample was collected 30 minutes later.

The test result was considered positive if the difference between the baseline sample and the 30-minute sample exceeded 5.0 parts/1000 of 13co2. All treated patients discontinued treatment with PPIs at least 2 weeks before undergoing 13C-UBT.

Each group consisted of 90 patients. One group was treated with a 5-day quadruple concomitant therapy (5d- QCT) (ie, esomeprazole 40 mg twice daily plus AMO 1 g twice daily plus LEV 500 mg twice daily plus TIN 500 mg twice daily for 5 consecutive days). The second group was treated with 10-day sequential therapy (10d-ST) (ie, esomeprazole 40 mg twice daily plus AMO 1 g twice daily for 5 days followed by esomeprazole 40 mg twice daily plus LEV 500 mg twice daily plus TIN 500 mg twice daily for 5 more days). Therapeutic Regimens

Patients who failed to eradicate the infection were re- treated with a quadruple therapy consisting of esomeprazole 40 mg twice daily plus MET 500 mg 3 times daily plus TET 500 mg 4 times a day plus bismuth subcitrate 240 mg twice daily and underwent a new 13C- UBT after 6 weeks.

The trial was designed as a noninferiority trial. The primary outcome was the ITT H pylori eradication rates for the 2 treatments. The secondary outcomes were the PP eradication rates and the role of antimicrobial resistance in the response to treatments. Finally, we evaluated the frequency of adverse events and costs of either regimen.

Results

Patients with unsuccessful first-line therapy were treated with bismuth-containing quadruple therapy, which led to eradication of the infection in the 3 patients who had not been eradicated of the infection with 5d-QCT and in the 4 patients who had not been eradicated of the infection following 10d-ST. The 4 patients who discontinued therapy because of severe adverse events with 5d-QCT were tested by 13C- UBT, and 2 of 4 were eradicated of the infection. Also, the 2 patients who discontinued therapy in the 10d- ST group underwent 13C-UBT, and both tested positive.

Symptoms that caused discontinuation of therapy were skin rash and itching in 2 patients after 2 days of treatment and diarrhea, nausea, and vomiting after 3 days of treatment in 2 more patients in the 5d-QCT group; diarrhea and epigastric pain at the third day of the first period caused discontinuation of therapy in 2 patients in the 10d-ST group.

The cost of 5d-QCT, according to the Italian National Health System, was €33.5 ($43.50), whereas the cost of the 10d-ST was €40.2 ($52.30). Therefore, the cost of 5d-QCT was approximately €7 ($9) less compared with the cost of 10d-ST. This difference was accounted for by the lower amount of esomeprazole used in the 2 regimens

Over the past decade, a steady decline was observed in the rate of H pylori eradication following triple therapies, thus requiring a search for novel therapeutic approaches to cure H pylori infection. This randomized clinical trial involving 180 patients from 2 university hospitals shows that in an area of high prevalence (ie, >15%) of CLA-resistant H pylori strains, a 5- day LEV-containing quadruple concomitant therapy produced ITT eradication rates >90% and was safe and well tolerated by most patients. Discussion

Our results are in agreement with a recent study by Wu et al showing that concomitant and sequential therapies were equally effective in the eradication of H pylori infection in patients naïve to treatment. However, unlike our study, both treatments lasted for 10 days, and therefore patients in the concomitant arm of treatment received twice as much of antimicrobials compared with those in the sequential arm. Several randomized controlled trials and one meta- analysis have shown that nonbismuth quadruple (concomitant) therapy is more effective than and as equally tolerated as standard triple therapy.

We performed in vitro antimicrobial susceptibility testing, which confirmed the high prevalence of CLA-, MET-, and dual-resistant H pylori strains together with an approximately 8% prevalence of LEV resistance. As expected, CLA resistance did not affect the efficacy of therapy and 100% of patients infected with CLA-resistant strains were eradicated of the infection. Nine of 10 (90%) and 10 of 11 (90.9%) patients infected with a MET-resistant strain eradicated the infection in the 5d-QCT group and 10d-ST group, respectively.

In a recent study by Molina–Infante et al, a 10-day LEV- containing sequential regimen, while showing higher efficacy compared with a 10-day CLA-containing sequential regimen, achieved ITT eradication rates of approximately 85%, which is lower than that reported in our study (ie, 93%). The lower efficacy of LEV-ST compared with our study might be related to a higher prevalence of LEV-resistant H pylori strains in Spain compared with our geographical area. In this respect, one must keep in mind that the main disadvantage with use of LEV-containing therapies is the rapid emergence of resistance to this antimicrobial.

A limitation to 100% efficiency of eradication regimens is compliance to treatment, mainly due to drug-related adverse events. In our study, patients were instructed not to suspend therapy arbitrarily and to contact us in the case of the occurrence of adverse effects. Nearly all adverse events were numerically slightly higher in the 5d-QCT arm compared with the 10d-ST arm. However, this did not reach statistical significance.

A limitation of the study is that only 55% of the participants underwent endoscopy and had assessment of H pylori status at entry by 2 tests on biopsy specimens In the remaining 45%, H pylori status at entry was assessed with a single 13C-UBT. However, one must keep in mind that 13C-UBT is an excellent test to use in clinical practice with sensitivity and specificity higher than 95.

In this randomized trial showed that in an area of high (ie, >15%) prevalence of CLA-resistant H. pylori strains, a 5-day LEV-containing, nonbismuth, quadruple concomitant therapy is highly effective in the treatment of H pylori infection with an ITT eradication rate of 92% and a PP eradication rate of 96%. Also, this eradication regimen is easy to follow for the patient and well tolerated. Therefore, this regimen may represent an effective, reduced cost, and safe first-line therapeutic alternative in areas where the efficacy of triple therapy is unacceptably low. Conclusion

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