Getting to the route of Helicobacter pylori treatment.

In over little more than a decade, the status of Helico bacter pylori has risen from that of unimportant gastric commensal to that of one of the most studied pathogens in the world. This has culminated in the recent publication of the complete genome of one strain, only the seventh bacterium for which this has been achieved. During this time antimicrobial treatment has also advanced, albeit at a slower pace, achieving successful eradication of the infection in 85–90% of patients. Unfortunately this therapeutic advance has been rather empirical and lacking in scientific basis, so that, when treatment fails (in a significant minority of patients), the underlying reasons remain unclear. Patient compliance and antimicrobial resistance are undoubtedly important and much research has been focused on these aspects. Failure of drug delivery, on the other hand, despite being clearly shown to be important for the treatment of other bacterial infections, has only received scant attention. Recently though, the ‘pharmacology of the gastric mucosa’ has received renewed interest and provided further insight into the mechanisms behind treatment failure of H. pylori infection. Interest in the movement of drugs across gastric mucosa is by no means recent and was present before the antibiotic era, when the stomach was felt to be an important site of drug absorption. These studies (predominantly in animal models) showed that both basic and acidic drugs penetrated gastric mucosa when given systemically but with different limitations. Basic drugs became ‘trapped’ by ionization within gastric juice, dependent upon their dissociation constant, and thus achieved higher concentrations in gastric juice than in plasma. Furthermore, some bases failed to achieve their predicted very high concentrations within gastric juice, the concentrations being limited by gastric blood flow. Acidic drugs, on the other hand, did not undergo ‘trapping’ and, therefore, achieved lower concentrations in gastric juice, concentrations that were also shown to be limited by protein binding. Much more recently, studies in human volunteers, animal models (chiefly in guinea pigs and rats), and, to a lesser extent, patients, have demonstrated the distribution of the commonly used antibiotics against H. pylori within the gastric mucosa. Metronidazole has been studied most extensively, and appears to cross the gastric mucosa easily in both directions by simple diffusion; once within the gastric lumen, it dissociates into ionized and unionized forms depending upon the pH. This results in the concentration of metronidazole being higher in acidic gastric juice than in plasma. Metronidazole is very stable in gastric juice (its half-life is 800 h at pH 2) and this, together with its rapid distribution across gastric mucosa, probably explains why, despite its relatively high in-vitro MIC for H. pylori, it is so effective in the clinical setting. Amoxycillin also appears to cross gastric mucosa by simple diffusion, but does so very poorly although it is fairly stable in gastric juice at low pH. Unlike metronidazole, no ‘trapping’ occurs within gastric juice because it is a weak acid. Interestingly, the addition of omeprazole to suppress gastric acid (increasing pH and reducing gastric juice volume) results in increased intra-gastric concentrations of amoxycillin, which may partly explain why acidsuppression is required for this antibiotic to be effective in vivo. Clarithromycin, perhaps the most useful antibiotic against H. pylori, has been studied relatively little. Like metronidazole it is concentrated in gastric juice compared with plasma, but unlike metronidazole, this cannot be explained by acid trapping (its pKa is too high). It seems likely that an active transport process underlies its transfer across gastric mucosa from blood to lumen, although this remains to be proven. Clarithromycin is very unstable in gastric acid and acid-suppression should, therefore, always be used concurrently. These data on metronidazole, amoxycillin and clarithromycin go some way to explaining the enigma of why antimicrobials that are highly effective against H. pylori in vitro, fail to be useful in the clinical setting. For example, H. pylori is extremely sensitive to many penicillins in vitro (with MICs 0.003 mg/L) but even if combined with