The present study investigated the effect of a model urease-binding polysaccharide in combination with a histamine H 2 receptor antagonist on Helicobacter pylori colonization in vivo. Euthymic hairless mice were treated daily with dextran sulfate via drinking water and/or famotidine via intragastric gavage starting at 1 week postchallenge with a CagA ؉ VacA ؉ (type 1) strain of H. pylori. Treatment of precolonized mice for 2 weeks with dextran sulfate combined with famotidine yielded a group mean bacterial load (per 100 mg of gastric tissue) of log 10 1.04 CFU, which was significantly lower than those of the famotidine (log 10 3.35 CFU, P < 0.01) and dextran sulfate (log 10 2.45 CFU, P < 0.05) monotherapy groups and the infected nontreated group (log 10 3.64 CFU, P < 0.01). Eradication was achieved after 2 weeks of treatment in 50% or more of the test mice using drug combinations (1 or 2 weeks of famotidine plus 2 weeks of dextran sulfate) versus none in the monotherapy and positive control groups. The enhanced activity of the drug combination may be related to the daily pattern of transient acid suppression by famotidine inducing periodic bacterial convergence to superficial mucus sites penetrated by dextran sulfate from the lumen. Increased urease-dextran sulfate avidity was observed in vitro in the presence of famotidine and may partly account for the enhanced activity. With potential utility in abbreviating treatment time and eradication of antibiotic-resistant strains, the use of urease-targeted polysaccharides concurrently with a gastric acid inhibitor warrants consideration as an additional component of the standard multidrug chemotherapy of H. pylori infection.Helicobacter pylori infection is present in up to 50% of the human population (4,22) and is the most important cause of gastric ulcers and gastric malignancies in humans (6, 17). The epidemiological importance of this pathogen necessitates the development of inexpensive drugs with minimal side effects. Currently, a cost-effective approach to therapy of H. pylori infection is based on a combination of drugs largely involving a proton pump inhibitor (e.g., omeprazole) and one or two antimicrobials including antibiotics and bismuth (23). Most of the oral antimicrobials being used against H. pylori are active via the systemic route inasmuch as acidity within the luminal side of the gastric mucus either inactivates or renders them less effective. The acidic region of the mucus is the putative haven for the majority of H. pylori cells, since the presence of surfaceadsorbed urease enzyme that generates ammonia within the peribacterial space requires an acidic microenvironment. The bacterium can survive with intact metabolic function anywhere from a lower limit of pH 3.5 (19), and the presence of urea in the medium greatly enhances its acid resistance resulting from the alkalinizing effect of ammonia from urealysis. Therefore, a therapeutic agent that specifically targets H. pylori within the acidic stratum of the gastric mucus is expected to complement ot...
