Aliment. Phavmacol. Ther. (1992) 6 , 751-758.
Short report : omeprazole plus antibiotic combinations for the eradication of rnetronidazole-resistant Helicobacter pylori
G. D. BELL", K. U. POWELL", S. M. BURRIDGE", G. SPENCER", G. BOLTONS, K. PURSERS, S. BROOKSg, S. PROSSERg, G. H A R R I S O N t , P. W. G A N T 11, P. H. J O N E S 11 & J. E. TROWELL* Departments of *Medicine, t Medical Physics, Histopafhology, 5 Pharmacy and I I the PHLS, The Ipswich Hospital, Ipswich, UK and Europa Scientific, Scope House, Wesfon Road, Crewe, UK
+
Accepted for publication 29 July 1992
SUMMARY
Twenty-eight Helicobacter pylori-positive patients with metronidazoleresistant isolates and 25 with metronidazole-sensitive isolates were treated for 14 days with 40 rng omeprazole nocte plus 500 mg amoxycillin t.d.s. Eradication of H.pylori, defined as absence of the organism one month after cessation of treatment, was assessed using the [14C]ureabreath test. The eradication rate in patients with metronidazoleresistant isolates was 14/28 (50%)while that in patients was metronidazole-sensitive isolates was 12/25 (48 %). In contrast to these encouraging eradication rates, very poor results were obtained with a 7day course of omeprazole (40 mg nocte) in combination with erythromycin ethylsuccinate (500 mg q.d.s.) and tripotassium dicitrato bismuthate tablets (120 mg q.d.s.). The latter eradication rates were 3/20 (15%)in patients taking erythromycin tablets and 3/19 (16%)in those taking a liquid formulation of erythromycin. All treatment regimens were well tolerated and all patients completed the prescribed course of therapy. Correspondence to: Dr G. D. Bell, Department of Medicine, The Ipswich Hospital, Heath Road Wing, Ipswich, Suffolk IP4 5PD, UK. 75 1
752
G. D. B E L L et al.
INTRODUCTION To facilitate comparison with our previous study16 we gave the omeprazole at bedtime rather than as the now more standard single dose in the morning. Helicobacter pylori is now considered to be a major factor in the multi-factorial disease that is peptic ulcer.' It has been shown that the gastric antrum of more than 90% of patients with duodenal ulcer is colonized by this organism1" and several independent studies from different parts of the world have shown that eradication of H. pylori markedly reduces duodenal ulcer relapse rates.' Unfortunately, at present, there is no uniformly satisfactory medication for eradicating H. pylovi.',' Proton pump inhibitors such as omeprazole, lansoprazole and pantoprazole, have demonstrated in-vitro activity against H. p y l ~ r i . ~However, -~ in patients treated with omeprazole monotherapy, H.pylori appears to be only temporarily cleared rather than eradicated.'-'' O n the other hand, more encouraging results have been reported on the use of omeprazole in combination with various antibiotic~.'~ However, ~'~ we have previously reported that 20 mg omeprazole daily for 28 days in combination with 250 mg amoxycillin t.d.s. for the first 14 days resulted in only a 31.3 % H. pylori eradication rate." De Koster et a l l 5 evaluated the efficacy of a 7-day course of erythromycin (500 mg q.d.s.) in combination with tripotassium dicitrato bismuthate (120 mg q.d.s.) and omeprazole (40 mg once daily). They have reported an eradication rate of 9/18 (50.0%) without development of erythromycin resistance after the treatment, indicating that if this treatment regimen initially fails, it can be repeated. The authors concluded that the combination of omeprazole, erythromycin and bismuth might be a valid treatment option for those with metronidazole resistance. The aims of the present open, non-randomized study were (a) to investigate the claims of De Koster ef aLz3 that the erythromycin/bismuth/omeprazole combination was effective in patients with metronidazole-resistant H.pylovi isolates and (b)in a separate study, to determine whether higher doses of both omeprazole and amoxycillin than we had previously used'' would confirm the findings of other authors who reported that relatively high eradication rates ( > 50%) could be achieved with such To facilitate comparison with our previous studyI6 we gave the omeprazole at bedtime rather than as the now more standard single dose in the morning.
PATIENTS A N D M E T H O D S Ethical approval and informed patient consent were obtained before the start of the study. All patients had positive cultures for H. pylori obtained from endoscopic biopsies of gastric mucosa. The techniques utilized for the histological examination ' ~ the method of testing the organisms for metronidazoleand culture of H.p y l o ~ i and resistance'' have been described elsewhere. With the exception of the 25 patients in
E R A D I C A T I O N OF RESISTANT H E L I C O B A C T E R P Y L O R I
753
Group I11 B (see below), all patients were infected with metronidazole-resistant organisms. Twenty patients were treated with 40 mg omeprazole nocte plus erythromycin ethylsuccinate tablets (500 mg q.d.s.) and tripotassium dicitrato bismuthate tablets (120 mg q.d.s.) for 7 days (Group I). Nineteen patients received omeprazole (40 mg nocte) plus erythromycin ethylsuccinate liquid preparation (500 mg q.d.s.) plus tripotassium dicitrato bismuthate tablets (120 mg q.d.s.) for 7 days (Group 11). Fiftythree patients received omeprazole (40 mg nocte) plus amoxycillin (500 mg t.d.s.) for 14 days; of these, 28 patients had metronidazole-resistant H.pylori isolates (Group I11 A) and 25 had metronidazole-sensitive isolates (Group I11 B). All patients were encouraged to complete the entire course of anti-H. pylori therapy and to report any significant side effects to one of us (K.U.P.). Patients in treatment groups I and I1 had a [13C]urea breath test performed as previously described" one month after completion of therapy. Any change of < 5 parts/1000 above baseline values was considered to be negative, i.e. to indicate successful H. pylovi e r a d i c a t i ~ n .Patients ~ ~ , ~ ~in Groups I11 A and I11 B underwent a [14C]ureabreath test as previously described21*22 one month after completing therapy. A 2-h area under the curve (AUC) of < 40 was considered to represent successful H.pylovi eradicati~n.~~,'~,~~ RESULTS
Of the 15 male and five female patients in Group I (40 mg omeprazole nocte, erythromycin tablets 500 mg q.d.s. and tripotassium dicitrato bismuthate tablets 120 mg q.d.s. for 7 days), 14 had duodenal ulcers, two had gastric ulcers and four had non-ulcer dyspepsia; these patients had a median age of 55 years (range 28-79 years). Treatment was well tolerated and all 20 patients completed therapy without reporting any significant side-effects. The success rate in terms of H. pyluri eradication was only 3/20 (15.0%).Of the 16 male and three female patients (12 with duodenal ulcers, one with a gastric ulcer and six with non-ulcer dyspepsia) in Group I1 (40 mg omeprazole nocte, erythromycin liquid 500 mg q.d.s. and tripotassium dicitrato bismuthate tablets 120 mg q.d.s. for 7 days), 13 had previously failed (in Group I) on the same combination of drugs. These patients had a median age of 53 years (range 31-79 years) and all 19 tolerated treatment well and completed the course of therapy without reporting any significant side-effects. The H.pylori eradication rate was only 3/19 (15/8%); two of the three apparent successes occurred in patients who were previously treated unsuccessfulIy in Group I. The 19 male and nine female patients (14 with duodenal ulcers, three with gastric ulcers and 11 with non-ulcer dyspepsia) with metronidazole-resistant H. pylori isolates in Group I11 A (omeprazole 40 mg nocte plus amoxycillin tablets 500 mg t.d.s. for 14 days) had a median age of 54years (range 36-79 years). All 28 patients completed the course of therapy and the only side-effects reported were looseness of stool in one patient and vomiting in a second patient on Days 1and 2
754
ERADICATION OF RESISTANT H E L I C O B A C T E R PYLORI
of therapy; the vomiting subsided despite continuation of therapy for the full 14day treatment period. The success rate in terms of H. pylori eradication was 14/28 (50.0%). All 25 patients (20 male and five female; 16 with duodenal ulcers, two with gastric ulcers and seven with non-ulcer dyspepsia) with metronidazole-sensitive H. pylori isolates in Group 111 B (40 mg omeprazole nocte plus amoxycillin tablets 500 mg t.d.s. for 14 days) completed the course of therapy. These patients had a median age of 57 years (range 48-78 years). Side-effects were reported in three patients (diarrhoea, vaginal thrush and vomiting, respectively). The H. pylori eradication rate at one month post-treatment was 12/25 (48.0%).
DISCUSSION Triple therapy, consisting of a bismuth salt plus metronidazole in combination with either amoxycillin or tetracycline, has been reported to be successful in more than ~~-~~ 90 % of patients with metronidazole-sensitive H. pyEori i n f e ~ t i o n . Unfortunately, significant side-effects are reported in a large proportion of patients receiving triple the rap^',^^,^^ and the overall success rate is adversely affected by poor patient c o m p l i a n ~ e .Triple ~ ~ , ~ ~therapy is disappointing in patients with metronidazoleresistant o r g a n i s r n and, ~ ~ ~therefore, ~ ~ ~ ~ there ~ ~ ~is~a need for a safe and effective therapeutic regimen for this group of patients. We have estimated that, in the UK where only approximately 20 YO of H. pylori isolates are metronidazole-resistant,30triple therapy might be expected to eradicate the organism successfully in about 80 % of patients. In contrast, in developing countries where more than 80 % of H.pylori isolates are metronidazole-resistant, triple therapy would be successful in only approximately 40% of patients. Consequently, there is an urgent need to develop safe and effective H. pylovi eradication regimens to treat patients with metronidazole-resistant organisms. We were unable to confirm the recommendation of De Koster ef 61.'' that the combination of omeprazole, erythromycin and tripotassium dicitrato bismuthate would provide a valid alternative therapy for H.pylori eradication in patients with metronidazole-resistant isolates or in those with amoxycillin allergy. Using the omeprazole/erythromycin combination, our eradication rates of 3/20 (15.0%) in patients taking erythromycin tablets and 3/19 (15.8%)in those taking the liquid erythromycin formulation were considerably lower than the 9 118 (50.0 %) reported by the Belgian group.15 The reason for this difference in eradication rates is not clear. In patients with metronidazole-resistant H. pylori isolates, we have previously reported that omeprazole (20 mg nocte for 28 days) plus amoxycillin (250 mg t.d.s. for the first 14 days of treatment) gave an eradication rate of 31.3 %.16 In the present study, we have shown that by increasing the dose of omeprazole to 40 mg nocte and that of amoxycillin to 500 mg t.d.s., we were able to obtain an eradication rate of 49.1 YO in patients with both metronidazole-resistant and sensitive H. pylori
ERADICATION OF RESISTANT H E L I C O B A C T E R PYLORI
755
Table I. Published eradication rates for H. pylori using omeprazole in combination with amoxycillin Eradication rate Daily dosage regimen Omeprazole/amoxycillin
Duration of therapy (days)
No.
%
Reference
~
20 mg/0.75 g 20 mg/2.0 g 20 mg/2.0 g 40 mg/1.5 40 mg/1.5 40 mg/1.5 40 mg/2.0 40 mg/2.0 40 mg/2.0 80 mg/2 g
g g g g g g
28/14" 28 28 28/14t 14 14 7 14 7 7
5/16 4/13 9/17 84/157 5/8 26/53 8/12 46/56 19/31
31.3 30.8 53.0
16 31 13
54.0 62.5 49.1 66.7 82.1 61.3
32 12
29/47
61.7
14
*33
35 14
20 mg omeprazole daily for 28 days and 0.75 g amoxycillin daily from Days 1 to 14. 15 to 28. Present study: Groups I11 A (metronidazole-resistant H.pylori isolates) and 111 B (metronidazolesensitive H. pylori isolates) combined.
t 40 mg omeprazole daily for 28 days and 1.5 g amoxycillin daily from Days
+
isolates. Other groups have used similar or even higher doses of omeprazole and/or amoxycillin with comparable or better results'2-14,16,31-35 and these are summarized in Table 1. Although we used the [13C]ureabreath test in Groups I and I1 and the ['4C]urea breath test in Groups 111 A and 111 B, this is unlikely to account for the differences observed as we have previously demonstrated a 100% agreement between the two tests in H. pylori-positive patients both pre-therapy and at least one month post-therapy." The omeprazole/amoxycillin combination used in our study was associated with a much lower incidence of side effects than we had previously observed with standard triple therapy.23 Amoxycillin-resistant H.pylori isolates appear to be extremely rare36and, in contrast to metronidazole therapy, amoxycillin resistance does not seem to develop following a failed course of treatment. Consequently, pre-therapy culture of the infecting organism and antibiotic sensitivity testing become less important with the omeprazole/amoxycillin combination than with triple the rap^.^^-'^ It seems probable that if a course of omeprazole/amoxycillin therapy fails to eradicate the organism, it is worth repeating the treatment. However, further studies are necessary before any firm conclusions can be made. O n the other hand it seems likely that in parts of the world where approximately 80% of H. pylori isolates are metronidazole-resistant, one can achieve as good or better results with omeprazole 40 mg once daily plus 500 mg amoxycillin t.d.s. for 14 days than with triple therapy for a similar duration.
756
G. D. B E L L et al.
Amoxycillin appears to have a largely luminal effect and, in theory, higher doses of the drug than those used in the present study may be still more effective. At present, one of the highest reported H. pylori eradication rates in patients with metronidazole-resistant isolates was obtained by Logan et al.37 In this study, a 14day eradication regimen consisted of omeprazole (40 mg mane for 14 days), amoxycillin (500 mg t.d.s. for 14 days), tripotassium dicitrato bismuthate (120 mg q.d.s. from Days 1-7) and ciprofloxacin (750 mg b.d. from Days 7-14). H. pylovi eradication, determined using the ["CIurea breath test, showed a one-month post-treatment eradication rate of 14/19 (73.7%); all patients remained negative when retested at 3 and 5 months post-therapy. Unfortunately, resistance to ciprofloxacin developed and the overall results indicate that this difficult and rather complex treatment regimen is not optimal. Previous studies using ciprofloxacin in combination with omeprazole have given disappointing results, as in the study of Labenz ef a/. (omeprazole 40 mg mane and ciprofloxacin 1 g t.d.s. for 7 days), in which an eradication rate of only 3/20 (15.0%) was obtained.38
CONCLUSIONS In patients with metronidazole-resistant H. pylori infections, 40 mg omeprazole in combination with 500 mg amoxycillin t.d.s. for 14 days will eradicate approximately 50% of the infections. Unlike standard triple therapy, the incidence of side effects with omeprazole/amoxycillin is low and the treatment is equally effective in metronidazole-resistant and metronidazole-sensitive infections. With the combination of omeprazole 40 mg nocte, 500 mg erythromycin (tablets or liquid) q.d.s. and 120 mg tripotassium dicitrato bismuthate for 7 days we achieved an eradication rate of only approximately 15 YO.
REFERENCES 1 Tytgat G N J, Axon A T R, Dixon M F ,
4 Megraud F, Bouchard S, Larnouliatte H.
Graham D Y, Lee A, Marshall B J. Helicobactev pylori: causal agent in peptic ulcer disease? Working Party Report. World Congresses of Gastroenterology; 26-31 August 1990, Sydney, Australia; Blackwell Scientific Publications, 1990: 36-45. 2 Axon A R. Duodenal ulcer: the villain unmasked? Br Med J 1991; 302: 919-20. 3 Suerbaum S, Leying H, Hemmerle B, Klernm K, Opferkuch W. Antibacterial activity of pantoprazole, orneprazole, and other (H+/K+) ATPase inhibitors against Helicobacter pylori. Third Workshop of the Helicobacfev pylovi Study Group. Rev Esp Enf Digest 1990; 78: P256. (Abstract.)
Proton pump inhibitors have an antimicrobial activity against Helicobacter pylovi. Gastroenterology 1991; 100: ,4123. (Abstract.) 5 Suerbaurn S, Leying H, Hemmerle B, Klemm K, Opferkuch W. Antibacterial activity of pantoprazole and omeprazole against Helicobacfev pylari. Eur J Clin Microbiol Infect Dis 1991; 10: 92-3. 6 Megraud F, Boyanova L, Larnouliatte H. Activity of lansoprazole against Helicobactev pylori. Lancet 1991; 3 3 7 : 1486. (Letter.) 7 Iwahi T, Satoh H, Nakao M, et al. Lansoprazole, a novel benzimidazole proton pump inhibitor, and its related compounds have
E R A D I C A T I O N OF RESISTANT H E L I C O B A C T E R PYLORI selective activity against Helicobacter pylori. Antimicrob Agents Chemother 1991; 35: 490-6. 8 Weil J, Bell G D, Powell K, et al. Omeprazole
and Helicobacter pylori: temporary suppression rather than true eradication. Aliment Pharmacol Ther 1991; 5 : 309-13. 9 Daw MA, Deegan P, Leen E, O’Moriin C. Short report: the effect of omeprazole on Helicobacter pylori and associated gastritis. Aliment Pharmacol Therp 1991; 5 : 435-9. 10 Sharp J, Logan R P H , Walker M M , Gummett P A , Misiewicz J J, Baron J H. Effect of omeprazole on Helicobacter pylori. Gut 1991; 32: A565. (Abstract.) 11 Wagner S, Varrentrapp M, Haruma K, et al. The role of omeprazole (40 mg) in the treatment of gastric Helicobacter pyluri infection. Z Gastroenterol 1991; 29: 595-8. 12 Unge P, Gad A, Gnarpe H, Olsson J. Does omeprazole improve antimicrobial therapy directed towards gastric Campylobacter pylori in patients with antral gastritis? A pilot study. Scand J Gastroenterol 1989; 24:
combination. Aliment Pharmacol Ther 1990; 4: 651-7. 19 Bell G D, Powell K, Weil J, Harrison G. 13C-
urea breath test for Helicobacter pylori infection. Gut 1991; 32: 551-2. (Letter.) 20 Logan R P H, Dill S, Bauer F E, et al. The European I3C-urea breath test for the detection of Helicobacterpylori. Eur J Gastroenterol Hepatol 1991; 3: 915-21. 21 Bell G D, Weil J, Harrison G. I4C-ureabreath analysis: a non-invasive test for Campylobacter pylori in the stomach. Lancet 1987; i: 1367-8. 22 Weil J, Bell G D, Harrison G. I4C-ureabreath test for Campylobacter pylori. Gut 1989; 30: 1656-7. 23 Bell G D, Powell K, Burridge S M, et al.
Experience with ’triple’ anti-Helicobacfer pylori eradication therapy: side-effects and the importance of testing the pre-treatment bacterial isolate for metronidazole resistance. Aliment Pharmacol Ther 1992; 6: 327-33. 24 Logan R P H, Gummett P A, Misiewicz J ,
49-54. 13 Lamouliatte H, de Mascarel A, Megraud F,
14
15
16
17
et al. Omeprazole improves amoxycillin therapy directed towards Helicobacter pylori associated chronic gastritis. Gastroenterology 1990; 98: A75. (Abstract.) Labenz J, Gyenes F, Ruhl G H, Bursch G. Amoxycillin-omeprazole treatment for eradication of Helicobacter pylori. Eur J Gastroenterol Hepatol 1991; 3: 38. (Abstract.) De Koster E, Burette A, Nyst J F, et al. HP treatment : bismuth, omeprazole, antibiotics. 1991; 100: A52. Gastroenterology (Abstract.) Bell G D, Powell K, Weil J, et al. Experience with omeprazole in combination with either amoxycillin or colloidal bismuth subcitrate in patients with metronidazole-resistant Helicobacter pylori. Eur J Gastroenterol Hepatol 1991; 3: 923-6. Trowel1 J E, Yoong A K H, Saul K J, Gant P W, Bell G D. A simple half-Gram stain for demonstrating Campylobacter pyloridis in sections. J Clin Pathol 1987; 41: 207-
10. 18 Weil J, Bell G D, Powell K, et al. Helicobacter
pylori infection treated with a tripotassium dicitrato bismuthate and metronidazole
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25
26
27
28 29
30
31
Karim Q N, Walker M M, Baron J H. One week eradication regimen for Helicobacter pylori. Lancet 1991; 338: 1249-52. Glupczynski Y, Burette A. Eradicating Helicobacter pylori. Lancet 1992; 339: 54-5. (Letter.) Rautelin H, Kosunen T U , Seppda K. Eradicating Helicobacter pylori. Lancet 1992; 339: 54-5. (Letter.) Veldhuyzen van Zanten S J 0. Helicobacter pylori, causation, change in natural history, and why Helicobacter-positive duodenal ulcers should not be routinely treated. Scand J Gastroenterol 1991; 26: 98-104. Katelaris P. Eradicating Helicobacter pylori. Lancet 1992; 339: 54-5. (Letter.) Graham D Y, Lew G M, Malaty H M, et al. Factors influencing the eradication of Helicobacter pylori with triple therapy. Gastroenterology 1992; 102: 493-6. Weil J, Bell G D, Powell K, et al. Helicobacfer pylori and metronidazole resistance. Lancet 1990; 336: 1445. (Letter.) activity against Helicobacter pylori. Antimicrob Agents Chemother 1991; 35 : 490-6. Lamouliatte H, Megraud F, de Mascarel A. Does omeprazole improve amoxycillin therapy directed towards C. pylori associated chronic gastritis? Proceedings of the Second
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Meeting of the European Campylobacter pylori Study Group. Klin Wochenschr 1989; 67: P37. (Abstract.) 32 Unge P, Eriksson K, Bergman B, et al. Omeprazole and amoxycillin in patients with duodenal ulcer : Helicobacter pylori eradication and remission of ulcers and symptoms during a 6-month follow-up. A double-blind comparative study. Gastroenterology 1992; 102: ,4183. (Abstract.) 33 Labenz J, Gyenes F, Riihl G H, Biirsch G. Amoxycillin-omeprazole treatment for eradication of Helicobacter pylori. Third Workshop of the Helicobacfer pylori Study Group. Rev Esp Enf Digest 1990; 78: P219. (Abstract.) 34 Labenz J. So klappt die Eradikation! Therapiewoche 1991; 41: 2532-6. 35 Labenz J, Gyenes E, Ruhl G H, Borsch G. Zweiwochige Amoxycillin/Omeprazole-
Therapie zur Helicobacter pylori-Eradikation. Klin Wochenschr 1992; 69: P37. (Abstract.) 36 FamerCe D, Ramdani B, Lamy V. Assessment of Helicobacter pylori’s sensitivity to tinidazole, amoxycillin and tetracycline among 472 patients. Third Workshop of the Helicobacter pylori Study Group. Rev Esp Enf Digest 1990; 78: P219. (Abstract.) 37 Logan R P H, Gummett P A, Karim N Q, Walker M M, Baron J H, Misiewicz J J. A two-week eradication regime for metronidazole-resistant Helicobacfev pylori. Gut 1991; 32: A1227-8. (Abstract.) 38 Labenz J, Gyenes E, Peitz U, Borsch G. Ciprofloxacin-omeprazole treatment for eradication of Helicobacfer pylori. Third Workshop of the Helicobacter pylori Study Group. Rev Esp Enf Digest 1990; 78: P224. (Abstract.)
Short report : omeprazole plus antibiotic combinations for the eradication of rnetronidazole-resistant Helicobacter pylori
G. D. BELL", K. U. POWELL", S. M. BURRIDGE", G. SPENCER", G. BOLTONS, K. PURSERS, S. BROOKSg, S. PROSSERg, G. H A R R I S O N t , P. W. G A N T 11, P. H. J O N E S 11 & J. E. TROWELL* Departments of *Medicine, t Medical Physics, Histopafhology, 5 Pharmacy and I I the PHLS, The Ipswich Hospital, Ipswich, UK and Europa Scientific, Scope House, Wesfon Road, Crewe, UK
+
Accepted for publication 29 July 1992
SUMMARY
Twenty-eight Helicobacter pylori-positive patients with metronidazoleresistant isolates and 25 with metronidazole-sensitive isolates were treated for 14 days with 40 rng omeprazole nocte plus 500 mg amoxycillin t.d.s. Eradication of H.pylori, defined as absence of the organism one month after cessation of treatment, was assessed using the [14C]ureabreath test. The eradication rate in patients with metronidazoleresistant isolates was 14/28 (50%)while that in patients was metronidazole-sensitive isolates was 12/25 (48 %). In contrast to these encouraging eradication rates, very poor results were obtained with a 7day course of omeprazole (40 mg nocte) in combination with erythromycin ethylsuccinate (500 mg q.d.s.) and tripotassium dicitrato bismuthate tablets (120 mg q.d.s.). The latter eradication rates were 3/20 (15%)in patients taking erythromycin tablets and 3/19 (16%)in those taking a liquid formulation of erythromycin. All treatment regimens were well tolerated and all patients completed the prescribed course of therapy. Correspondence to: Dr G. D. Bell, Department of Medicine, The Ipswich Hospital, Heath Road Wing, Ipswich, Suffolk IP4 5PD, UK. 75 1
752
G. D. B E L L et al.
INTRODUCTION To facilitate comparison with our previous study16 we gave the omeprazole at bedtime rather than as the now more standard single dose in the morning. Helicobacter pylori is now considered to be a major factor in the multi-factorial disease that is peptic ulcer.' It has been shown that the gastric antrum of more than 90% of patients with duodenal ulcer is colonized by this organism1" and several independent studies from different parts of the world have shown that eradication of H. pylori markedly reduces duodenal ulcer relapse rates.' Unfortunately, at present, there is no uniformly satisfactory medication for eradicating H. pylovi.',' Proton pump inhibitors such as omeprazole, lansoprazole and pantoprazole, have demonstrated in-vitro activity against H. p y l ~ r i . ~However, -~ in patients treated with omeprazole monotherapy, H.pylori appears to be only temporarily cleared rather than eradicated.'-'' O n the other hand, more encouraging results have been reported on the use of omeprazole in combination with various antibiotic~.'~ However, ~'~ we have previously reported that 20 mg omeprazole daily for 28 days in combination with 250 mg amoxycillin t.d.s. for the first 14 days resulted in only a 31.3 % H. pylori eradication rate." De Koster et a l l 5 evaluated the efficacy of a 7-day course of erythromycin (500 mg q.d.s.) in combination with tripotassium dicitrato bismuthate (120 mg q.d.s.) and omeprazole (40 mg once daily). They have reported an eradication rate of 9/18 (50.0%) without development of erythromycin resistance after the treatment, indicating that if this treatment regimen initially fails, it can be repeated. The authors concluded that the combination of omeprazole, erythromycin and bismuth might be a valid treatment option for those with metronidazole resistance. The aims of the present open, non-randomized study were (a) to investigate the claims of De Koster ef aLz3 that the erythromycin/bismuth/omeprazole combination was effective in patients with metronidazole-resistant H.pylovi isolates and (b)in a separate study, to determine whether higher doses of both omeprazole and amoxycillin than we had previously used'' would confirm the findings of other authors who reported that relatively high eradication rates ( > 50%) could be achieved with such To facilitate comparison with our previous studyI6 we gave the omeprazole at bedtime rather than as the now more standard single dose in the morning.
PATIENTS A N D M E T H O D S Ethical approval and informed patient consent were obtained before the start of the study. All patients had positive cultures for H. pylori obtained from endoscopic biopsies of gastric mucosa. The techniques utilized for the histological examination ' ~ the method of testing the organisms for metronidazoleand culture of H.p y l o ~ i and resistance'' have been described elsewhere. With the exception of the 25 patients in
E R A D I C A T I O N OF RESISTANT H E L I C O B A C T E R P Y L O R I
753
Group I11 B (see below), all patients were infected with metronidazole-resistant organisms. Twenty patients were treated with 40 mg omeprazole nocte plus erythromycin ethylsuccinate tablets (500 mg q.d.s.) and tripotassium dicitrato bismuthate tablets (120 mg q.d.s.) for 7 days (Group I). Nineteen patients received omeprazole (40 mg nocte) plus erythromycin ethylsuccinate liquid preparation (500 mg q.d.s.) plus tripotassium dicitrato bismuthate tablets (120 mg q.d.s.) for 7 days (Group 11). Fiftythree patients received omeprazole (40 mg nocte) plus amoxycillin (500 mg t.d.s.) for 14 days; of these, 28 patients had metronidazole-resistant H.pylori isolates (Group I11 A) and 25 had metronidazole-sensitive isolates (Group I11 B). All patients were encouraged to complete the entire course of anti-H. pylori therapy and to report any significant side effects to one of us (K.U.P.). Patients in treatment groups I and I1 had a [13C]urea breath test performed as previously described" one month after completion of therapy. Any change of < 5 parts/1000 above baseline values was considered to be negative, i.e. to indicate successful H. pylovi e r a d i c a t i ~ n .Patients ~ ~ , ~ ~in Groups I11 A and I11 B underwent a [14C]ureabreath test as previously described21*22 one month after completing therapy. A 2-h area under the curve (AUC) of < 40 was considered to represent successful H.pylovi eradicati~n.~~,'~,~~ RESULTS
Of the 15 male and five female patients in Group I (40 mg omeprazole nocte, erythromycin tablets 500 mg q.d.s. and tripotassium dicitrato bismuthate tablets 120 mg q.d.s. for 7 days), 14 had duodenal ulcers, two had gastric ulcers and four had non-ulcer dyspepsia; these patients had a median age of 55 years (range 28-79 years). Treatment was well tolerated and all 20 patients completed therapy without reporting any significant side-effects. The success rate in terms of H. pyluri eradication was only 3/20 (15.0%).Of the 16 male and three female patients (12 with duodenal ulcers, one with a gastric ulcer and six with non-ulcer dyspepsia) in Group I1 (40 mg omeprazole nocte, erythromycin liquid 500 mg q.d.s. and tripotassium dicitrato bismuthate tablets 120 mg q.d.s. for 7 days), 13 had previously failed (in Group I) on the same combination of drugs. These patients had a median age of 53 years (range 31-79 years) and all 19 tolerated treatment well and completed the course of therapy without reporting any significant side-effects. The H.pylori eradication rate was only 3/19 (15/8%); two of the three apparent successes occurred in patients who were previously treated unsuccessfulIy in Group I. The 19 male and nine female patients (14 with duodenal ulcers, three with gastric ulcers and 11 with non-ulcer dyspepsia) with metronidazole-resistant H. pylori isolates in Group I11 A (omeprazole 40 mg nocte plus amoxycillin tablets 500 mg t.d.s. for 14 days) had a median age of 54years (range 36-79 years). All 28 patients completed the course of therapy and the only side-effects reported were looseness of stool in one patient and vomiting in a second patient on Days 1and 2
754
ERADICATION OF RESISTANT H E L I C O B A C T E R PYLORI
of therapy; the vomiting subsided despite continuation of therapy for the full 14day treatment period. The success rate in terms of H. pylori eradication was 14/28 (50.0%). All 25 patients (20 male and five female; 16 with duodenal ulcers, two with gastric ulcers and seven with non-ulcer dyspepsia) with metronidazole-sensitive H. pylori isolates in Group 111 B (40 mg omeprazole nocte plus amoxycillin tablets 500 mg t.d.s. for 14 days) completed the course of therapy. These patients had a median age of 57 years (range 48-78 years). Side-effects were reported in three patients (diarrhoea, vaginal thrush and vomiting, respectively). The H. pylori eradication rate at one month post-treatment was 12/25 (48.0%).
DISCUSSION Triple therapy, consisting of a bismuth salt plus metronidazole in combination with either amoxycillin or tetracycline, has been reported to be successful in more than ~~-~~ 90 % of patients with metronidazole-sensitive H. pyEori i n f e ~ t i o n . Unfortunately, significant side-effects are reported in a large proportion of patients receiving triple the rap^',^^,^^ and the overall success rate is adversely affected by poor patient c o m p l i a n ~ e .Triple ~ ~ , ~ ~therapy is disappointing in patients with metronidazoleresistant o r g a n i s r n and, ~ ~ ~therefore, ~ ~ ~ ~ there ~ ~ ~is~a need for a safe and effective therapeutic regimen for this group of patients. We have estimated that, in the UK where only approximately 20 YO of H. pylori isolates are metronidazole-resistant,30triple therapy might be expected to eradicate the organism successfully in about 80 % of patients. In contrast, in developing countries where more than 80 % of H.pylori isolates are metronidazole-resistant, triple therapy would be successful in only approximately 40% of patients. Consequently, there is an urgent need to develop safe and effective H. pylovi eradication regimens to treat patients with metronidazole-resistant organisms. We were unable to confirm the recommendation of De Koster ef 61.'' that the combination of omeprazole, erythromycin and tripotassium dicitrato bismuthate would provide a valid alternative therapy for H.pylori eradication in patients with metronidazole-resistant isolates or in those with amoxycillin allergy. Using the omeprazole/erythromycin combination, our eradication rates of 3/20 (15.0%) in patients taking erythromycin tablets and 3/19 (15.8%)in those taking the liquid erythromycin formulation were considerably lower than the 9 118 (50.0 %) reported by the Belgian group.15 The reason for this difference in eradication rates is not clear. In patients with metronidazole-resistant H. pylori isolates, we have previously reported that omeprazole (20 mg nocte for 28 days) plus amoxycillin (250 mg t.d.s. for the first 14 days of treatment) gave an eradication rate of 31.3 %.16 In the present study, we have shown that by increasing the dose of omeprazole to 40 mg nocte and that of amoxycillin to 500 mg t.d.s., we were able to obtain an eradication rate of 49.1 YO in patients with both metronidazole-resistant and sensitive H. pylori
ERADICATION OF RESISTANT H E L I C O B A C T E R PYLORI
755
Table I. Published eradication rates for H. pylori using omeprazole in combination with amoxycillin Eradication rate Daily dosage regimen Omeprazole/amoxycillin
Duration of therapy (days)
No.
%
Reference
~
20 mg/0.75 g 20 mg/2.0 g 20 mg/2.0 g 40 mg/1.5 40 mg/1.5 40 mg/1.5 40 mg/2.0 40 mg/2.0 40 mg/2.0 80 mg/2 g
g g g g g g
28/14" 28 28 28/14t 14 14 7 14 7 7
5/16 4/13 9/17 84/157 5/8 26/53 8/12 46/56 19/31
31.3 30.8 53.0
16 31 13
54.0 62.5 49.1 66.7 82.1 61.3
32 12
29/47
61.7
14
*33
35 14
20 mg omeprazole daily for 28 days and 0.75 g amoxycillin daily from Days 1 to 14. 15 to 28. Present study: Groups I11 A (metronidazole-resistant H.pylori isolates) and 111 B (metronidazolesensitive H. pylori isolates) combined.
t 40 mg omeprazole daily for 28 days and 1.5 g amoxycillin daily from Days
+
isolates. Other groups have used similar or even higher doses of omeprazole and/or amoxycillin with comparable or better results'2-14,16,31-35 and these are summarized in Table 1. Although we used the [13C]ureabreath test in Groups I and I1 and the ['4C]urea breath test in Groups 111 A and 111 B, this is unlikely to account for the differences observed as we have previously demonstrated a 100% agreement between the two tests in H. pylori-positive patients both pre-therapy and at least one month post-therapy." The omeprazole/amoxycillin combination used in our study was associated with a much lower incidence of side effects than we had previously observed with standard triple therapy.23 Amoxycillin-resistant H.pylori isolates appear to be extremely rare36and, in contrast to metronidazole therapy, amoxycillin resistance does not seem to develop following a failed course of treatment. Consequently, pre-therapy culture of the infecting organism and antibiotic sensitivity testing become less important with the omeprazole/amoxycillin combination than with triple the rap^.^^-'^ It seems probable that if a course of omeprazole/amoxycillin therapy fails to eradicate the organism, it is worth repeating the treatment. However, further studies are necessary before any firm conclusions can be made. O n the other hand it seems likely that in parts of the world where approximately 80% of H. pylori isolates are metronidazole-resistant, one can achieve as good or better results with omeprazole 40 mg once daily plus 500 mg amoxycillin t.d.s. for 14 days than with triple therapy for a similar duration.
756
G. D. B E L L et al.
Amoxycillin appears to have a largely luminal effect and, in theory, higher doses of the drug than those used in the present study may be still more effective. At present, one of the highest reported H. pylori eradication rates in patients with metronidazole-resistant isolates was obtained by Logan et al.37 In this study, a 14day eradication regimen consisted of omeprazole (40 mg mane for 14 days), amoxycillin (500 mg t.d.s. for 14 days), tripotassium dicitrato bismuthate (120 mg q.d.s. from Days 1-7) and ciprofloxacin (750 mg b.d. from Days 7-14). H. pylovi eradication, determined using the ["CIurea breath test, showed a one-month post-treatment eradication rate of 14/19 (73.7%); all patients remained negative when retested at 3 and 5 months post-therapy. Unfortunately, resistance to ciprofloxacin developed and the overall results indicate that this difficult and rather complex treatment regimen is not optimal. Previous studies using ciprofloxacin in combination with omeprazole have given disappointing results, as in the study of Labenz ef a/. (omeprazole 40 mg mane and ciprofloxacin 1 g t.d.s. for 7 days), in which an eradication rate of only 3/20 (15.0%) was obtained.38
CONCLUSIONS In patients with metronidazole-resistant H. pylori infections, 40 mg omeprazole in combination with 500 mg amoxycillin t.d.s. for 14 days will eradicate approximately 50% of the infections. Unlike standard triple therapy, the incidence of side effects with omeprazole/amoxycillin is low and the treatment is equally effective in metronidazole-resistant and metronidazole-sensitive infections. With the combination of omeprazole 40 mg nocte, 500 mg erythromycin (tablets or liquid) q.d.s. and 120 mg tripotassium dicitrato bismuthate for 7 days we achieved an eradication rate of only approximately 15 YO.
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