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We read with great interest the article by Sherwood and colleagues (Gut 2002;51:490–5) evaluating the role of acid secretion and gastric luminal pH on the gastric transfer rate of amoxycillin, clarithromycin, and metronidazole. The study showed that metronidazole and clarithromycin but not amoxicillin transfer was increased by acid secretion. Gastric acid suppression, induced by the use of omeprazole, produced the fall in clarithromycin and metronidazole transfer.
These data may help to clarify preliminary results of our study on Helicobacter pylori eradication in a population of 120 H pylori infected dyspeptic patients (63 males and 57 females; mean age 53.2 (12.31) years).1 None of the patients received prior antibiotic treatment with nitroimidazoles or macrolides, or H pylori eradication therapy, nor was there a history of gastrointestinal surgery, alcohol use, or smoking.
Our population was divided in two groups of 60 patients who underwent two different 14 day triple eradicating regimens based on either ranitidine 300 mg twice daily and clarithromycin and metronidazole 500 mg twice daily (RCM group) or omeprazole 20 mg twice daily and clarithromycin and metronidazole 500 mg twice daily (OCM group).
A higher H pylori eradication rate was obtained in the RCM group. In fact, 54 of 60 patients had H pylori eradicated in the first group compared with 42 patients in the OCM group (p<0.025), suggesting an important impact of the antisecretory drug on the therapeutic result. Incomplete gastric acid suppression, caused by H2 receptor antagonists, may be responsible for the difference.
While omeprazole inhibits gastric acid secretion with irreversible block of the parietal cell H+/K+ ATPase, the pump responsible for HCl secretion, ranitidine does not abolish gastric secretory activity completely. Ranitidine affects only the pathway mediated by activation of H2 parietal cell receptors, thus the “acid trapping” mechanism and active secretion of clarithromycin and metronidazole to the gastric lumen are maintained.2,3
In fact, metronidazole, which is a weak base, may passively diffuse from gastric capillaries into the acid compartments (tubulovescicles and canaliculi) of parietal cells and into the gastric lumen, in accordance with the pH partition hypothesis.4 In the acidic environment, this antibiotic becomes ionised and as such is trapped and concentrated both in the acidic compartments of the parietal cells and in the gastric lumen. Therefore, metronidazole may both passively diffuse across the gastric mucosa and be secreted to the gastric lumen with gastric acid, performing its topical anti-H pylori activity.
Sherwood et al reported that clarithromycin may also be secreted with HCl. The lower acid inhibition mediated by H2 receptor antagonists not only maintains clarithromycin secretion with gastric acid but also contributes to the molecular stability of this antibiotic.5
Despite the fact that proton pump inhibitors are usually preferred as adjuvants for antibiotic therapy against H pylori, because of their greater effectiveness on acid suppression and the additional antibacterial effect, recent meta-analytical papers have shown no difference between proton pump inhibitors and H2 receptor antagonists in improving Helicobacter eradication rates.6
In conclusion, our clinical results support the hypothesis that inhibition of gastric acid decreases gastric clearance of metronidazole and clarithromycin, reducing the therapeutic effectiveness of triple eradicating regimens.
We thank Dr Pellegrini et al for their interest in our article (Gut 2002;51:490–5).
As they correctly point out, the very effective inhibition of acid secretion may interfere with acid trapping and thus decrease antibiotic transfer into the gastric juice. However, the final antibiotic concentration in gastric juice depends on both the rate of secretion and the rate of degradation. Although metronidazole and amoxycillin are stable in gastric juice, clarithromycin is not,1 hence more effective inhibition of acid secretion will tend overall to increase the concentration of undegraded clarithromycin. The acid degradation product has some antibacterial effect which also needs to be considered.
As can be seen, there are so many variables that we feel there is no substitute for actually measuring antibiotic concentrations in gastric juice on ranitidine and omeprazole, and comparing them in patients before any definite conclusions can be drawn on their relative pharmacological merits.
It is interesting that there have been relatively few clinical trials of proton pump inhibitors versus H2 receptor antagonists for Helicobacter eradication, with conflicting results from the two meta-analyses.2,3 One conclusion could be that the convention for using proton pump inhibitors has more to do with the large number of trials of proton pump inhibitor based regimens in the 1990s and the perhaps erroneous assumption that more reliable ulcer healing equates to better antibiotic drug delivery, rather than adequate evidence that proton pump inhibitors are superior.