Gastric Transitional Zones, Areas whereHelicobacterTreatment Fails: Results of a Treatment Trial Using the Sydney Strain Mouse Model

Abstract

Current combination therapies cure Helicobacter pylori infection in 75 to 85% of cases. However, many treatment failures are not explained by antibiotic resistance. Our goal was to explore treatment failures under in vivo conditions by using the H. pylori Sydney strain (SS1) mouse model. Mice infected with H. pylori (SS1) were treated with monotherapies or combination therapies used in human trials. Bacterial levels and distribution of organisms within the stomach were assessed 24 h after treatment to determine clearance and location of treatment failures and 29 days after treatment to determine cure rates. Except for treatment with metronidazole, mono-and dual therapies did not cure infection but resulted in decreases in bacterial levels and differences in distribution within the stomach. In cases of treatment failure when clarithromycin was used, omeprazole and dual therapy with omeprazole and amoxicillin resulted in organisms being cleared from the antrum, but organisms remained in the antrum-body transitional zone. The triple therapies of OMC and bismuth subcitrate, metronidazole, and tetracycline were successful in eradicating infection. Except for metronidazole monotherapy and triple therapy with OAC, there was good correlation between the Sydney strain mouse model and humans with respect to the success of antimicrobial therapy. The antrum-body transitional zone was identified as a sanctuary site in treatment failure. This could result from antimicrobial agents not functioning effectively at this site or bacteria in this location expressing products that protect them against antimicrobial agents. This is the first demonstration of a possible sanctuary site as a reason for failure of therapy.

Preclinical Studies of Amixicile, a Systemic Therapeutic Developed for Treatment of Clostridium difficile Infections That Also Shows Efficacy against Helicobacter pylori

“…Thus, drugs that concentrate in areas of inflammation (serum leakage) are likely to be the most effective against H. pylori, such as MTZ, which also tends to concentrate in gastric acid (41). Our group and others have shown that MTZ is the most effective monotherapy for the treatment of mice colonized by strains of H. pylori that are susceptible to MTZ (42,43). The remarkable efficacy of amixicile as a monotherapy was unexpected, since neither amoxicillin nor clarithromycin, a mainline therapeutic used for the treatment of H. pylori in humans, shows any efficacy as a monotherapy in this model (42,43).…”

“…Our group and others have shown that MTZ is the most effective monotherapy for the treatment of mice colonized by strains of H. pylori that are susceptible to MTZ (42,43). The remarkable efficacy of amixicile as a monotherapy was unexpected, since neither amoxicillin nor clarithromycin, a mainline therapeutic used for the treatment of H. pylori in humans, shows any efficacy as a monotherapy in this model (42,43). On the basis of these results, we suggest that amixicile most likely concentrates in areas of inflammation associated with active infections.…”

Anti-Helicobacter pylori Potential of Artemisinin and Its Derivatives

“…The test sample (50 mg/kg/day) and the antibiotics were suspended in 0.5% hydroxypropylmethylcellulose. Each animal received the corresponding treatment twice daily for 7 days (46). Animals were sacrificed 36 h and 29 days, respectively, after the cessation of treatment for the assessment of H. pylori colonization for clearance and eradication profiles.…”

Transfer and distribution of amoxicillin in the rat gastric mucosa and gastric juice and the effects of rabeprazole

“…Therefore, the antibiotics used to eliminate H pylori must achieve inhibitory or bactericidal concentrations at the site of infection. The antibiotics are usually taken orally, and thus the thickness of the mucus layer, the shape and motility of the stomach, and the acidic environment may all contribute to inadequate distribution and concentration of the drugs at the surface of the gastric mucosa [6] . When treating H pylori infections by oral administration, some areas of the stomach, such as the crypts and folds of the gastric body or the transitional zones between the different gastric zones, are not sufficiently exposed to locally acting drugs [7] .…”