The role of antisecretory drugs in the treatment of Helicobacter pylori infection

Aliment Pharmacol Ther 1997; 11 (Suppl. 1): 21 25. The role of antisecretory drugs in the treatment of Helicobacter pylori infection W. L. PETERSON Department of Internal Medicine, University of Texas Southwestern Medical School and Medical Service, Dallas Department of Veterans Affairs Medical Center, Dallas, USA SUMMARY The efficacy of antibiotics against Helicobacter pylori is enhanced by the co-administration of antisecretory drugs. While proton pump inhibitors appear to have some direct effect on H. pylori and extreme hypochlorhydria has a deleterious effect on the organism, the most likely mechanism by which antisecretory drugs as a class provide this effect is by improving the efficacy of the antibiotics themselves. Although proton pump inhibitors are the most widely used antisecretory agents, H receptor antagonists also enhance antibiotic effects. INTRODUCTION Antisecretory drugs have assumed a role in the treatment of Helicobacter pylori infection for several reasons. First, early studies of patients with active peptic ulcers simply added anti-h. pylori regimens such as bismuth triple therapy to standard antisecretory therapy. Only later was it recognized that H. pylori therapy alone could heal ulcers without concomitant antisecretory therapy., Such studies suggest that although addition of an antisecretory agent reduces ulcer pain more rapidly than with H. pylori therapy alone, the rates of ulcer healing are comparable., Second, it was recognized early on, and has since been confirmed by many studies, that antibiotics alone yield inadequate cure rates for H. pylori infection. Even a combination of three antibiotics (clarithromycin, amoxicillin, and metronidazole) eradicates H. pylori only about 60% of the time. Because the efficacy of some antibiotics are diminished at low ph, antisecretory agents were added. Third, it has been noted that proton pump Correspondence to: Professor W. L. Peterson, Dallas VAMC (111B1), 4500 S. Lancaster Road, Dallas, TX 75216, USA inhibitors have direct in vitro inhibitory effects against H. pylori. H. PYLORI CURE RATES WITH AND WITHOUT ANTISECRETORY DRUGS There are few studies in which direct comparisons have been made between antibiotics alone and antibiotics plus an antisecretory drug. Therefore, most of the cure rates noted in this section represent amalgamated data from the literature and from review articles. Inherent in this approach is a substantial lack of precision due to the wide difference in study design and analysis. On the other hand, precise values are less important for this exercise than establishing the concept that addition of an antisecretory drug enhances the effect of antibiotics in curing H. pylori infection. The antibiotics best studied as single agents are amoxicillin and clarithromycin. As shown in Table 1, cure rates with these antibiotics alone are approximately 20%, and 40%, respectively. The nitroimidazoles (metronidazole, tinidazole) alone have virtually no effect as monotherapy owing to the rapid development of resistance by H. pylori. Addition of standard doses of ranitidine to amoxicillin or clarithromycin results in cure rates about 15% higher than with the antibiotic alone, 1997 Blackwell Science Ltd 21

22 W. L. PETERSON Table 1. Approximate cure rates of H. pylori infection with antibiotic regimen alone or combined with an H receptor antagonist (H RA) or proton pump inhibitor (PPI) Cure rate (%) Antibiotic(s) Alone H RA PPI Amoxicillin 20 35 60 Clarithromycin 40 55 70 Amoxicillin 60 70 80 nitromidazole Clarithromycin 60 80 90 nitromidazole Bismuth triple 80 90 95 therapy although published data are limited (pers comm, Glaxo Wellcome). Addition of higher doses of ranitidine or, better studied, omeprazole to amoxicillin or clarithromycin give cure rates of approximately 60%,, and 70%,,,, respectively. Dual antibiotic therapy has most frequently consisted of amoxicillin or clarithromycin plus a nitroimidazole, with eradication rates of approximately 60%.,, Concomitant use of an H receptor antagonist results in cure rates 10 20% higher (Table 1)., Even better results have been found with the addition of a proton pump inhibitor, giving eradication rates of 80% with amoxicillin plus a nitroimidazole and 90% with clarithromycin plus a nitroimidazole.,, Triple therapy with bismuth, metronidazole, and amoxicillin or tetracycline without antisecretory therapy results in cure rates of approximately 80%, which increases to 90% and 95% with the addition of an H receptor antagonist or proton pump inhibitor, respectively., Two studies have recently been published directly comparing bismuth triple therapy alone to bismuth triple therapy with omeprazole., Using an intention to treat analysis, the eradication rate rose from 83.3% with bismuth triple therapy alone to 98.1% with triple therapy plus omeprazole in one and from 80% to 86% in the other. The reasons for the discrepant results in these two studies are not known. Recognizing the limitations of the above data, it nevertheless appears clear that addition of an antisecretory agent enhances the H. pylori eradication rates of whichever antibiotic regimen it is added to. Less clear are the mechanisms by which antisecretory agents accomplish these results. POSSIBLE MECHANISMS BY WHICH ANTISECRETORY DRUGS ENHANCE THE EFFECTS OF ANTIBIOTICS The antisecretory drug has a direct effect on H. pylori The antimicrobial effects of antisecretory agents against H. pylori have been studied in vitro and in vivo (Table 2). In vitro. H receptor antagonists have no effect on survival of H. pylori in standard culture media. Omeprazole, on the other hand, when added to culture media causes a substantial decrease in survival at ph levels 6.0 and below, but not at ph 7.0. For example, the addition of 100 µg ml of omeprazole at ph 4.0 resulted in a 5 6 log reduction of survival. A similar, but less pronounced, decrease in survival was noted for Escherichia coli, Proteus mirabilis, and Staphylococcus typhimurium (Table 3). In vivo, omeprazole is converted in the acidic milieu of the parietal cell to its active form, a sulphenamide. This would theoretically also occur in the gastric lumen at acidic ph levels but not at ph 7. Such a phenomenon might explain why omeprazole was effective at lower ph levels but had no inhibitory effect at ph 7.0. Therefore, survival studies were repeated using omeprazole that had been preactivated at ph 5.0 for 20 min. With pre-activation, omeprazole now reduced survival at ph 7 as well. Thus, when omeprazole is in an acidic milieu or is pre-activated with acid, it effectively inhibits survival of H. pylori and other enteric bacteria in vitro. Table 2. Effects of antisecretory therapy alone on H. pylori Agent In vitro In vivo H receptor antagonist No effect No effect Omeprazole Decreased Suppression survival Table 3. Effect of omeprazole (100 µg ml) on survival of H. pylori and other enteric pathogens at ph 4.0 Bacterium H. pylori 6.07 Escherichia coli 3.88 Proteus mirabilis 2.58 Staphyloccocus typhimurium 3.30 Log decrease survival after 60 min

ANTISECRETORY AGENTS AND TREATMENT OF H. PYLORI INFECTION 23 In vivo. In vivo results of H receptor antagonists and omeprazole are shown in Table 2. Not surprisingly, H receptor antagonists have no effect. Administration of omeprazole alone results in the inability to detect H. pylori immediately after therapy in up to 50% of subjects, but when diagnostic tests are conducted at least 4 weeks after cessation of therapy, eradication is confirmed 5% of the time.,, The phenomenon of temporary inability to detect the presence of H. pylori is termed suppression and may simply reflect a decrease in the number of organisms below the limits of detection of standard diagnostic tests. One mechanism by which omeprazole may suppress H. pylori is, as shown from in vitro studies, by a direct antimicrobial effect of the compound. However, two observations cast doubt on this mechanism. First, omeprazole is manufactured as an enteric-coated drug and would not be found in an acidic stomach. Second, in an alkaline environment, such as would be present after several days of therapy with omeprazole, the drug could be released from its enteric coating but might not be acid-activated to its active form, the sulphenamide. To resolve this issue, studies are needed to determine if omeprazole and or its sulphenamide can be recovered from gastric juice. Another mechanism by which omeprazole might effect survival of H. pylori is through hypochlorhydria. Antisecretory drug-induced hypochlorhydria is deleterious to survival of H. pylori H. pylori survives with difficulty at very high ph. The formation of ammonia from urease-induced hydrolysis of urea, which allows the organism to survive at low ph, may serve to suffocate the organism at high ph., This might also be the reason why organisms tend to migrate from the more alkaline antrum to the less alkaline corpus during antisecretory therapy, although not all investigators believe this phenomenon occurs. It is further possible that high ph levels promote the overgrowth of other bacteria which might compete with H. pylori for survival or that secreted immunoglobulin is degraded to a lesser degree at lower levels of acidity. As proton pump inhibitors produce ph levels higher than with H receptor antagonists, this might explain why the former suppress H. pylori in vivo while the latter do not. It might also explain why the eradication rates shown in Table 1 are uniformly higher when antibiotics are combined with proton pump inhibitors than when they are combined with H receptor antagonists. Finally, this might explain why several studies using a fixed dose of amoxicillin combined with increasing doses of omeprazole have found higher eradication rates with higher doses of omeprazole. On the other hand, there are several lines of evidence against the hypothesis that hypochlorhydria per se is the most important (or only) mechanism by which antisecretory drugs enhance eradication rates of H. pylori. First, not all investigators have found that there is a dose response of omeprazole when combined with amoxicillin., Second, the data shown in Table 1 are not from direct comparative studies. A recent study has directly compared amoxicillin plus either omeprazole or ranitidine. Although gastric acidity was lower with omeprazole, cure rates of H. pylori did not differ. Furthermore, a meta-analysis of parallel group trials comparing H receptor antagonists and omeprazole found similar eradication results (76.5% and 78.6%, respectively). Thus, there is reasonable doubt that proton pump inhibitors are more effective than H receptor antagonists in combination with antibiotics or that greater degrees of acid suppression provide higher rates of eradication. The antisecretory drug has an effect on the antibotics A third means by which antisecretory drugs might enhance the efficacy of antibiotics in eradicating H. pylori is by affecting the antibiotics themselves. This could occur in several ways. There is evidence that antibiotic activity (i.e. minimum inhibitory concentrations) and stability are greater at higher ph, especially with amoxicillin. In one study, the activity of clarithromycin against H. pylori decreased almost 16-fold when the ph of the medium was changed from 7.2 to 5.5. Another possibility is that antisecretory drugs alter the pharmacokinetics or tissue distribution of antibiotics. For example, omeprazole increases blood and gastric tissue concentrations of clarithromycin and gastric juice concentrations of amoxicillin. Increased levels of antibiotics in gastric juice and tissue are likely a result of less tissue washout of antibiotics from the secretion of gastric juice and decreased gastric juice volume. CONCLUSION It is possible to cure H. pylori infection with regimens that do not include anti-secretory drugs. However, the addition of anti-secretory drugs enhances the efficacy of almost all such regimens and, in patients with active

24 W. L. PETERSON peptic ulcers, speeds the relief of symptoms. The mechanisms by which anti-secretory drugs enhance antimicrobial efficacy have not been clearly determined but are probably multiple. REFERENCES 1 Graham DY, Lew GM, Evans DG, Evans DJ, Klein PD. Effect of triple therapy (antibiotics plus bismuth) on duodenal ulcer healing. Ann Intern Med. 1991; 115: 266 9. 2 Hosking SW, Ling TKW, Chung SCS, et al. Duodenal ulcer healing by eradication of Helicobacter pylori without anti-acid treatment: randomised controlled trial. Lancet. 1994; 343: 508 10. 3 Lam SK, Ching CK, Lai KC, et al. Does treament of Helicobacter pylori (Hp) with antibiotics alone heal duodenal ulcer (DU)? A randomised double-blind placebo controlled study. Gastroenterology 1996; 110: A169 (Abstract). 4 Penston JG. Review article: clinical aspects of Helicobacter pylori eradication therapy in peptic ulcer disease. Aliment Pharmacol Ther 1996; 10: 469 86. 5 Unge P, Gad A, Gnarpe H, Olsson J. Does omeprazole improve antimicrobial therapy directed towards Campylobacter pylori in patients with antral gastritis? Scand J Gastroenterol 1989; 24: 49 54. 6 McGowan CC, Cover TL, Blaser MJ. The proton pump inhibitor omeprazole inhibits acid survival of Helicobacter pylori by a urease-independent mechanism. Gastroenterology. 1994; 107: 1573 8. 7 Chiba N, Rao B, Rademaker JW, Hunt RH. Meta-analysis of the efficacy of antibiotic therapy in eradicating Helicobacter pylori. Am J Gastroenterol. 1992; 87: 1716 27. 8 Dixon JS. Helicobacter pylori eradication: unravelling the facts. Scand J Gastroenterol. 1995; 30 (Suppl. 212): 48 62. 9 Chiba N, Wilkinson J, Hunt RH. Omeprazole and clarithromycin in Helicobacter pylori eradication: a meta-analysis. Gastroenterology 1996; 110: A80 (Abstract). 10 Goodwin CS, Marshall BJ, Blincow ED, et al. Prevention of nitroimidazole resistance in Campylobacter pylori by coadministration of colloidal bismuth subcitrate: clinical and in vitro studies. J Clin Pathol 1988; 41: 207 10. 11 Pentson JG. Review article: Helicobacter pylori eradication understandable caution but no excuse for inertia. Aliment Pharmacol Ther 1994; 8: 369 90. 12 van der Hulst RWM, Keller JJ, Rauws EAJ, Tytgat GNJ. Treatment of Helicobacter pylori infection: a review of the world literature. Helicobacter 1996; 1: 6 19. 13 Axon ATR, Moayyedi P. Eradication of Helicobacter pylori: omeprazole in combination with antibiotics. Scand J Gastroenterol. 1996; 31 (Suppl. 215): 82 9. 14 Bazzoli F, Zagari RM, Fossi S, et al. Short-term low-dose triple therapy for the eradication of Helicobacter pylori: a randomized, double-blind, controlled study. Gastroenterology 1996; 110: A61 (Abstract). 15 Yousfi MM, El-Zimaity HMT, Cole RA, Genta RM, Graham DY. Metronidazole, ranitidine and clarithromycin combination for treatment of Helicobacter pylori infection (modified Bazzoli s triple therapy). Aliment Pharmcol Ther 1996; 10: 119 22. 16 Lind T, Veldhuyzen van Zanten S, Unge P, et al. Eradication of Helicobacter pylori using one week triple therapies combining omeprazole with two antimicrobials the MACH 1 study. Helicobacter 1996; 1: 138 44. 17 Yousfi MM, El-Zimaity HM, Al-Assi MT, et al. Metronidazole, omeprazole and clarithromycin: an effective combination therapy for Helicobacter pylori infection. Aliment Pharmacol Ther 1995; 9: 209 12. 18 deboer W, Driessen W, Jansz A, Tytgat G. Effect of acid suppression on efficacy of treatment for Helicobacter pylori infection. Lancet 1995; 345: 817 20. 19 Goodwin CS, Blake P, Blincow E. The minimum inhibitory and bactericidal concentrations of antibiotics and anti-ulcer agents against Campylobacter pyloridis. J Antimicrob Chemother 1986; 17: 309 14. 20 Graham DY, Klein PD, Opekun AR, et al. In vivo susceptibility of Campylobacter pylori. Am J Gastroenterol 1989; 84: 233 8. 21 Weil J, Bell GD, Powell K, et al. Omeprazole and Helicobacter pylori: temporary suppresion rather than true eradication. Aliment Pharmacol Ther 1991; 5: 309 13. 22 Daw MA, Deegan P, Leen E, O Morain C. Short report: the effect of omeprazole on Helicobacter pylori and associated gastritis. Aliment Pharmacol Ther 1991; 5: 435 9. 23 Clyne M, Labigne A, Drumm B. Helicobacter pylori requires an acidic environment to survive in the presence of urea. Infect Immun 1995; 63: 1669 73. 24 Neithercut WD, Greig MA, Hossack M, McColl KEL. Suicidal destruction of Helicobacter pylori: metabolic consequence of intracellular accumulation of ammonia. J Clin Pathol 1991; 44: 380 4. 25 Logan RPH, Walker MM, Misiewicz JJ, et al. Changes in the intragastric distribution of Helicobacter pylori during treatment with omeprazole. Gut 1995; 36: 12 6. 26 Graham DY, Genta R, Evans DG, et al. H. pylori does not migrate from the antrum to the corpus in response to omeprazole. Am J Gastroenterol. 1996; 91: 2120 4. 27 Bayerdorffer E, Miehlke S, Mannes GA, et al. Double-blind trial of omeprazole and amoxicillin to cure Helicobacter pylori in patients with duodenal ulcers. Gastroenterology 1995; 108: 1412 7. 28 van der Hulst RWM, Weel JFL, Verheul SB, et al. Treatment of Helicobacter pylori infection with low- or high-dose omeprazole combined with amoxicillin and the effect of retreatment: a prospective, randomized, double-blind study. Aliment Pharmacol Ther 1996; 10: 165 72. 29 Malaty H, El-Zimaity HMT, Genta RM, Cole RA, Graham DY. High-dose proton pump inhibitor plus amoxicillin for the treatment or retreatment of Helicobacter pylori infection. Aliment Pharmacol Ther 1996; 10: 1001 4. 30 Adamek RJ, Labenz J, Opferkuch W, et al. Ranitidine amoxicillin vs omeprazole amoxicillin for cure of H. pyloripositive gastric ulcer: Role of acid suppression. Gastroenterology. 1995; 108: A44 (Abstract). 31 Holtmann G, Layer P, Goebell H. Proton pump inhibitors or H - receptor antagonists for H. pylori eradication. Meta-analysis of

ANTISECRETORY AGENTS AND TREATMENT OF H. PYLORI INFECTION 25 parallel group studies. Gastroenterology. 1996; 110: A136 (Abstract) 32 Cederbrant G, Kahlmeyer G, Schalen C, Kamma C. Additive effect of clarithromycin combined with 14-OH clarithromycin, erythromycin, amoxicillin, metronidazole, or omeprazole against H. pylori. J Antimicrob Chemother 1994; 34: 1025 9. 33 Hunt RH. Hp and ph: implications for the eradication of Helicobacter pylori. Scand J Gastroenterol 1993; 28 (Suppl. 196): 12 6. 34 Axon ATR. The role of acid inhibition in the treatment of Helicobacter pylori infection. Scand J Gastroenterol 1994; 29 Suppl. 201: 16 23. 35 Gustavson LE, Kaiser JF, Edmonds AL, et al. Effect of omeprazole on concentrations of clarithromycin in plasma and gastric tissue at steady state. Antimicrob Agents Chemother 1995; 39: 2078 83. 36 Goddard AF, Jessa MJ, Barrett DA, et al. Effect of omeprazole on the distribution of metronidazole, amoxicillin, and clarithromycin in human gastric juice. Gastroenterology 1996; 111: 358 67.