Triple Therapy of Helicobacter pylori Infection in Peptic Ulcer A 12-Month Follow-up Study of 93 Patients
Scand J Gastroenterol Downloaded from informahealthcare.com by University Of South Australia on 08/31/15 For personal use only.
K. SEPPALA, M. FARKKILA, H . NUUTINEN, K. HAKALA, H. VAANANEN, H. RAUTELIN & T. U. KOSUNEN Second Dept. of Medicine, Helsinki University Central Hospital, and Dept. of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland Seppala K , Farkkila M , Nuutinen H, Hakala K, Vaananen H , Rautelin H, Kosunen T U . Triple therapy of Helicobacter pylori infection in peptic ulcer. A 12-month follow-up study of 93 patients. Scand J Gastrocnterol 1902;27:973-976 This study was undertaken to evaluate the success of triple therapy in peptic ulcer patients and ulcer relapses. One hundred and one Consecutive Helicobacter pylori-positive peptic ulcer patients were assigned to an open trial with 2 weeks of treatment with colloidal bismuth subcitrate, arnoxicillin, and metronidazole. At the (,-week follow-up only 1 duodenal ulcer was unhealed of 57 active ulcers, and H. pvlori was found to be eradicated in 84% of thc 100 subjects. The sensitivity to metronidazole was determined from 71 pretreatment strains of H . pylori. Eradication of H. pylori succeeded in 89% of the patients with metronidazole-susceptible strains and in 61 5% of patients with metronidazole-resistant strains ( p < 0 . 0 3 ) . All 16 patients i n whom the treatment failed to eradicate the organism had metronidazole-resistant strains after treatment. The ulcer relapse rate was low. At the 12-month follow-up of 03 patients only 1 of the 84 H. pylori-negative patients (including 4 patients after new successful therapy) had relapsing ulcers (2 asymptomatic episodes), and 1 had H. pylori reinfection. whereas 3 of the 9 bacteria-positive patients relapsed ( p = 0.002); at the 2-year control 2 more patients had ulcer relapses. The eradication of H. pylori infection clearly prevents relapses of peptic ulcer, but the success of triple therapy depends on the frequency of pretrcatmcnt metronidazole-resistant H. pylori strains. Key words: Helicohucter py/or;; metronidazole resistance; peptic ulcer; treatment
Prof. Kuri Seppala, M . D., Gaslroenrerologicul Unit, Second Dept. of’Medicine, University of Helsinki, SF-00290 Hetsinki, Finland
Helicobacter pylori infection is associated with chronic gas-
tritis and peptic ulcer. Active gastritis has healed after H . pylori eradication ( I ) , and the number of duodenal ulcer relapses has decreased to one-fourth (2). Further interest in the eradication of H. p y l o r i infection has arisen after studies in which triple therapy has been successfully applied (3-6). The aim of this study was t o evaluate the use of triple therapy in peptic ulcer patients and their ulcer relapses and to define possible causes of treatment failures. MATERIALS AND M E T H O D S The material consists of 101 consecutive endoscopically diagnosed peptic ulcer patients (53 men and 48 women) who received triple therapy. Seventy-two patients had duodenal ulcer (DU), 13 prepyloric ulcer (PPU), and 16 gastric ulcer (GU). The mean age of the patients was 53.5 years (range, 34-84 years). H . p y l o r i infection was verified only by histology in 12 patients and by both H . p y l o r i culture and histology in 89 patients. Patients were symptomatic, and the first endoscopy was made because of gastric complaints. Fifty-seven patients had active ulcer at endoscopy C-I4 days before the start of the triple therapy. The time between the triple therapy and the last verified ulcer before treatment
was a mean of 2 weeks (median, 23.7 weeks; range, &6 years). Before the triple therapy two patients (without active ulcer) were receiving maintenance therapy and nine patients on-demand therapy with H, blocker. Study design
At the first visit gastric histology was studied in two body, antral, and duodenal biopsy specimens for mucosal changes and H. p y l o r i status, using hematoxylin-eosin and modified Giemsa staining. H . pylori was cultured from samples taken separately from antrum and body. The susceptibility to metronidazole was studied by disk diffusion test for H . p y l o r i pretreatment strains from 71 patients (7). The follow-up endoscopy was done at 6 weeks and 6 and 12 months after the beginning of therapy. Gastric histology and bacteriologic test for H . p y l o r i were done during followup studies as for the first visit. 7ieatment
All patients received triple therapy for 2 weeks. The daily oral treatment consisted of 120 mg colloidal bismuth subcitrate four times daily, 500 mg metronidazole three times daily, and 500 mg amoxitillin four times daily. Fifty-seven patients with active ulcer received Hzblockers for 4 weeks
974
K . Seppala et al.
Table I. Responses of men and women to Helicobacter pylori triple therapy 6 weeks after the beginning of therapy H . pylori eradication
Men Women Total
Successful
Failed
Total
49 (92%) 35 (74%) 84 (84%)
4 (8%) 12 (26%) 16 (16%)
53
At the 6-week follow-up H . pylori-negative H . pylori-positive
DU+PPU
GU
72 8
12* 1
Relapses lPPUt
3 (2DU + 1 PPU)$
(chi-square; cor-
* At 12 months one patient had Helicobacter pylori reinfection; later H . pytori eradication. Difference of relapse rates between successfully treated and treatment failure patients, p = 0.002 (chisquare; corrected). t NSAID user; twice asymptomatic PPU. $ At 24 months two more patients relapsed.
with the triple therapy. Patients received pretreatment information about the importance of taking medicines regularly and were advised to contact their physicians about problems during therapy. The study was accepted by the ethical committee of the Second Dept. of Medicine of the University Hospital of Helsinki.
cated ( p = 0.03). Eleven (19%) of responders and seven (54%) of the non-responders had metronidazole-resistant strains before treatment.
Male-female eradication difference, p rected).
Scand J Gastroenterol Downloaded from informahealthcare.com by University Of South Australia on 08/31/15 For personal use only.
47
Table 11. Ulcer relapses at 12-month follow-up in 6Y duodenal ulcer (DU), 11 prepyloric ulcer (PPU), and 13 gastric ulcer (GU) patients
= 0.03
100
Statistical methods Statistical analysis was performed by using the chi-square test with Yates’s correction.
RESULTS The 4-week fullow-up Six weeks after the beginning of the therapy 100 patients had the first endoscopy control. All except 1 of the 51 active ulcers were healed. An 84-year-old woman with bleeding DU had no endoscopy control. She was treated at home because of a leg fracture, and 10 months later she was without gastric symptoms with normalized anti-Hi. pylori IgG . H. pylori eradication was successful in 84 patients (84%) in both histologic and bacteriologic studies. Sixteen patients (16%) were treatment failures (non-responders) with positive H. pylori status. Women showed a lower response rate to therapy than men ( p = 0.03) (Table I). Side effects of triple therapy The side effects were not registered by the patients. Two patients had self-limiting diarrhea, and there were some other minor adverse effects during the triple therapy period (metal taste in the mouth, nausea, and so forth). Only one patient stopped taking medicines after 1 week’s treatment. Metrunidazule re.ristance The sensitivity to metronidazole could be determined from pretreatment strains isolated from 71 patients. In 58 of them the bacteria were eradicated, but in 13 patients the infection persisted. The treatment was more often successful when the bacteria were sensitive t o metronidazole; 89% of the sensitive strains and 61% of the resistant strains were eradi-
Treatment failures All 16 non-responders had metronidazole-resistant posttreatment H . pylori strains. They received a new antimicrobial therapy at least once. Five of them had successful eradication; at 12-month follow-up four patients participated, and they are included in the group of successfully treated patients. These five patients received a modified triple therapy; four of them had 500 mg erythromycin three times daily (three of them instead of amoxicillin, two with extra 500 mg tetracyclin four times daily and 20 mg omeprazole, and one instead of metronidazole). One received 20 mg omeprazole extra. The 6-month follow-up Ninety-five patients participated in the 6-month followup; 86 of them were H . pylori-negative, and 9 were H . pylori-positive. Two of the patients died of non-gastric diseases before the 6-month follow-up visit; they had been bacteria-negative at the 6-week visit. The 12-month follow-up The 12-month follow-up results are presented in Table 11. Ninety-three subjects participated in this follow-up; 83 were H. pylori-negative and 10 H . pylori-positive. One patient had died of non-gastric disease. Reinfection One gastric ulcer patient was reinfected at the 12-month follow-up. H e received a new triple therapy and was H . pyhri-negative 1 year later. Ulcer relapses One of the 84 H. pylori-negative patients had 2 asymptomatic ulcer relapses, and 3 of 9 treatment failures had ulcer relapses during the 12-month follow-up ( p = 0.002). (Two more patients had ulcer relapses during 24 months.)
Therapy of H. pylori in Peptic Ulcer
Scand J Gastroenterol Downloaded from informahealthcare.com by University Of South Australia on 08/31/15 For personal use only.
DISCUSSION
H . pylori eradication has changed the profiles of chronic gastritis and duodenal ulcer. Of DU patients treated with H2 blockers 7@80% had yearly relapses (2,5,8). Today it is obvious that permanent H . pylori eradication will prevent the great majority of duodenal ulcer relapses. In practice, it is important to know that endoscopic control of the success of H . pylori eradication is not necessary in asymptomatic patients, since previously elevated H . pylori IgG antibody titers decrease more than 50% within 6 months. This indicates the success of eradication (9), which can also be estimated without endoscopy by the I3C-urea breath test (10). In the present study only 1 of 84 successfully treated ulcer patients had two asymptomatic prepyloric ulcer relapses during the 12-month follow-up. She took NSAID regularly. None of the 16 patients with gastric ulcers had relapses. None of 55 H . pylori-negative patients had a relapse At the 24-month control. The low number of relapses in treatment failure patients (three of nine at 12 months and two more at 24 months) may have been influenced by several antimicrobial courses given to these patients during the followup period. Patients were usually happy to receive triple therapy because it made them clinically symptomless without any need to continue further ulcer therapy. At the 12-month follow-up only some patients with gastroesophageal reflux occasionally took antacids for symptomatic relief, and two had H2 blockers on demand. Bismuth preparations combined with antimicrobials give the best eradication rates (80-90%) observed. This was also confirmed in our study. Occurrence of metronidazoleresistant H . pylori strains has been reported to be related to earlier use of nitroimidazoles but also after H . pylori treatment with nitroimidazoles (11-14). This has a clear influence on the success of H . pylori eradication. In Finland metronidazole resistance was 26% in a study of 559 H. pylori-positive patients (7). Women harbored metronidazole-resistant strains more than twice as often as men. The pretreatment metronidazole resistance had a clear effect on our eradication results. Pretreatment metronidazole resistance was more than twice as common among patients who remained culture-positive in spite of the therapy (54%) compared with patients who were later treated successfully (19%) ( p < 0.03). The percentage of women in therapeutic failures was greater than one would have expected on the basis of their proportion in all treated patients (p = 0.03). Younger women are more likely to have a metronidazoleresistant organism, perhaps related to previous use of antibiotic for gynecologic complaints (7, 14). Unfortunately, in the present material information about previous use of metronidazole could not be obtained. In the absence of pretreatment metronidazole sensitivity testing a carefully compiled drug history is useful (14). The high eradication rate of H . pylori infection is important, but for the stability of successful H. pylori eradication
975
it is important that the reinfection rate of H . pyfori remains low. The yearly reinfection rate was 1% in our material, in comparison with 4% in Australia (15) and more than 20% in 18 months in Brazil (16). We conclude that in developed countries triple therapy should be given to all patients with chronic recurrent duodenal ulcer. The therapy needs good follow-up to find treatment failures, patients who are at high risk of relapsing ulcer. On the other hand, when H . pylori infections are treated with antimicrobial drugs, it is important to consider that frequent resistance to nitroimidazoles will decrease the eradication rate in schemes using these drugs. Another important factor will be the rate of reinfection in the population treated, which, if high, may ruin the results of eradication therapy.
REFERENCES 1. Rauws EAJ, Langenberg W, Houthoff HJ, Zanen HC, Tytgat GNJ. Campylobacter pyloridis-associated chronic active antral gastritis. A prospective study of its prevalence and the effects of antibacterial and antiulcer treatment. Gastroenterology 1988;94:33-40. 2. Marshall BJ, Goodwin CS, Warren JR, et al. Prospective double-blind trial of duodenal ulcer relapse after eradication of Carnpylobacter pylori. Lancet 1988;2:1437-42. 3. Borody T, Cole P, Noonan S, et al. Long-term Campylobacter pylori recurrence post-eradication, Gastroenterology 1988; 94:A43. 4. Bdrsch G , Mai U , Opferkuch W. Oral triple-therapy (Om) may effectively eradicate Campylobacter pylori (C.P.) in man: a pilot study. Gastroenterology 1988;94:A44. 5. Rauws EAJ, Tytgat GNJ. Cure of duodenal ulcer associated with eradication of H . pylori. Lancet 1990;225:1233-5. 6. Valle J, Seppala K, Sipponen P, Kosunen TU. Disappearance of gastritis after eradication of Helicobacter pylori. A morphometric study. Scand J Gastroenterol 1991;26: 1057-65. 7. Rautelin H, Seppala K, Renkonen 0 - V . Vainio U. Kosunen TU. Role of in vitro rnetronidazole resistance in Helicobacter pylori infections. Antimicrob Agents Chemother 1092;36:16.T 6. 8. Wormsley KG. Relapse of duodenal ulcer. Br Med J 1986; 293:1501. 9. Seppala K, Kosunen T , Sipponen P, Valtonen V. Decrease of Helicobacter pylori antibodies reflects successful eradication therapy [abstract]. 9th World Congress of Gastroenterology; 1990:917. 10. Bell G D , Weil J, Harrison G , et al. 14 C-urea breath analysis, a non-invasive test for Campylobacter pylori. Lancet 1987;l: 1367-8. 11. Goodwin CS, Marshall BJ, Blincow ED, Wilson DH, Blackbourne S, Phillips M. Prevention of nitroimidazolc resistance in Campylobacter pylori by coadrninistration of colloidal bismuth subcitrate; clinical and in vitro studies. J Clin Pathol 1988;41: 207-10. 12. Becx MCJM, Janssen AJHM, Clasener HAL. dc Koning RW. Metronidazole-resistant Helicobacter pylori [letter]. Lancet 1990;11539-40. 13. Glupczynski Y,Burette A, de Koster E, et al. Metronidazole resistance in Helicobacter pylori [letter]. Lancet 1990;335:97& 7. 14. Bell GD, Weil J , Powell K , et al. Hclicobacter pylori treated with combinations of tripotassiurn dicitrato and metronidazolc: efficacy of different treatment regimens and some observations on the emergence of metronidazole resistance. Eur J Gastroenterol Hepatol 1991;3:819-22.
916
K. Seppiilii et al.
15. Lian JX, Carrick J , Lee A, Daskalopoulos G. Long term recurrence of Helicobacter pylori infection after successful eradication with 'triple therapy'. Gastroenterology 1991;DDW abstract 412.
Scand J Gastroenterol Downloaded from informahealthcare.com by University Of South Australia on 08/31/15 For personal use only.
Received 13 January 1992 Accepted 7 July 1992
16. Coelho LGV, Passos MCF, Chausson Y, Castro LP. Duodenal ulcer and eradication of H. pylori in a developing country-an 18-month follow-up study. Eur J Gastroenterol Hepatol 1991;3 Suppl 1.
Scand J Gastroenterol Downloaded from informahealthcare.com by University Of South Australia on 08/31/15 For personal use only.
K. SEPPALA, M. FARKKILA, H . NUUTINEN, K. HAKALA, H. VAANANEN, H. RAUTELIN & T. U. KOSUNEN Second Dept. of Medicine, Helsinki University Central Hospital, and Dept. of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland Seppala K , Farkkila M , Nuutinen H, Hakala K, Vaananen H , Rautelin H, Kosunen T U . Triple therapy of Helicobacter pylori infection in peptic ulcer. A 12-month follow-up study of 93 patients. Scand J Gastrocnterol 1902;27:973-976 This study was undertaken to evaluate the success of triple therapy in peptic ulcer patients and ulcer relapses. One hundred and one Consecutive Helicobacter pylori-positive peptic ulcer patients were assigned to an open trial with 2 weeks of treatment with colloidal bismuth subcitrate, arnoxicillin, and metronidazole. At the (,-week follow-up only 1 duodenal ulcer was unhealed of 57 active ulcers, and H. pvlori was found to be eradicated in 84% of thc 100 subjects. The sensitivity to metronidazole was determined from 71 pretreatment strains of H . pylori. Eradication of H. pylori succeeded in 89% of the patients with metronidazole-susceptible strains and in 61 5% of patients with metronidazole-resistant strains ( p < 0 . 0 3 ) . All 16 patients i n whom the treatment failed to eradicate the organism had metronidazole-resistant strains after treatment. The ulcer relapse rate was low. At the 12-month follow-up of 03 patients only 1 of the 84 H. pylori-negative patients (including 4 patients after new successful therapy) had relapsing ulcers (2 asymptomatic episodes), and 1 had H. pylori reinfection. whereas 3 of the 9 bacteria-positive patients relapsed ( p = 0.002); at the 2-year control 2 more patients had ulcer relapses. The eradication of H. pylori infection clearly prevents relapses of peptic ulcer, but the success of triple therapy depends on the frequency of pretrcatmcnt metronidazole-resistant H. pylori strains. Key words: Helicohucter py/or;; metronidazole resistance; peptic ulcer; treatment
Prof. Kuri Seppala, M . D., Gaslroenrerologicul Unit, Second Dept. of’Medicine, University of Helsinki, SF-00290 Hetsinki, Finland
Helicobacter pylori infection is associated with chronic gas-
tritis and peptic ulcer. Active gastritis has healed after H . pylori eradication ( I ) , and the number of duodenal ulcer relapses has decreased to one-fourth (2). Further interest in the eradication of H. p y l o r i infection has arisen after studies in which triple therapy has been successfully applied (3-6). The aim of this study was t o evaluate the use of triple therapy in peptic ulcer patients and their ulcer relapses and to define possible causes of treatment failures. MATERIALS AND M E T H O D S The material consists of 101 consecutive endoscopically diagnosed peptic ulcer patients (53 men and 48 women) who received triple therapy. Seventy-two patients had duodenal ulcer (DU), 13 prepyloric ulcer (PPU), and 16 gastric ulcer (GU). The mean age of the patients was 53.5 years (range, 34-84 years). H . p y l o r i infection was verified only by histology in 12 patients and by both H . p y l o r i culture and histology in 89 patients. Patients were symptomatic, and the first endoscopy was made because of gastric complaints. Fifty-seven patients had active ulcer at endoscopy C-I4 days before the start of the triple therapy. The time between the triple therapy and the last verified ulcer before treatment
was a mean of 2 weeks (median, 23.7 weeks; range, &6 years). Before the triple therapy two patients (without active ulcer) were receiving maintenance therapy and nine patients on-demand therapy with H, blocker. Study design
At the first visit gastric histology was studied in two body, antral, and duodenal biopsy specimens for mucosal changes and H. p y l o r i status, using hematoxylin-eosin and modified Giemsa staining. H . pylori was cultured from samples taken separately from antrum and body. The susceptibility to metronidazole was studied by disk diffusion test for H . p y l o r i pretreatment strains from 71 patients (7). The follow-up endoscopy was done at 6 weeks and 6 and 12 months after the beginning of therapy. Gastric histology and bacteriologic test for H . p y l o r i were done during followup studies as for the first visit. 7ieatment
All patients received triple therapy for 2 weeks. The daily oral treatment consisted of 120 mg colloidal bismuth subcitrate four times daily, 500 mg metronidazole three times daily, and 500 mg amoxitillin four times daily. Fifty-seven patients with active ulcer received Hzblockers for 4 weeks
974
K . Seppala et al.
Table I. Responses of men and women to Helicobacter pylori triple therapy 6 weeks after the beginning of therapy H . pylori eradication
Men Women Total
Successful
Failed
Total
49 (92%) 35 (74%) 84 (84%)
4 (8%) 12 (26%) 16 (16%)
53
At the 6-week follow-up H . pylori-negative H . pylori-positive
DU+PPU
GU
72 8
12* 1
Relapses lPPUt
3 (2DU + 1 PPU)$
(chi-square; cor-
* At 12 months one patient had Helicobacter pylori reinfection; later H . pytori eradication. Difference of relapse rates between successfully treated and treatment failure patients, p = 0.002 (chisquare; corrected). t NSAID user; twice asymptomatic PPU. $ At 24 months two more patients relapsed.
with the triple therapy. Patients received pretreatment information about the importance of taking medicines regularly and were advised to contact their physicians about problems during therapy. The study was accepted by the ethical committee of the Second Dept. of Medicine of the University Hospital of Helsinki.
cated ( p = 0.03). Eleven (19%) of responders and seven (54%) of the non-responders had metronidazole-resistant strains before treatment.
Male-female eradication difference, p rected).
Scand J Gastroenterol Downloaded from informahealthcare.com by University Of South Australia on 08/31/15 For personal use only.
47
Table 11. Ulcer relapses at 12-month follow-up in 6Y duodenal ulcer (DU), 11 prepyloric ulcer (PPU), and 13 gastric ulcer (GU) patients
= 0.03
100
Statistical methods Statistical analysis was performed by using the chi-square test with Yates’s correction.
RESULTS The 4-week fullow-up Six weeks after the beginning of the therapy 100 patients had the first endoscopy control. All except 1 of the 51 active ulcers were healed. An 84-year-old woman with bleeding DU had no endoscopy control. She was treated at home because of a leg fracture, and 10 months later she was without gastric symptoms with normalized anti-Hi. pylori IgG . H. pylori eradication was successful in 84 patients (84%) in both histologic and bacteriologic studies. Sixteen patients (16%) were treatment failures (non-responders) with positive H. pylori status. Women showed a lower response rate to therapy than men ( p = 0.03) (Table I). Side effects of triple therapy The side effects were not registered by the patients. Two patients had self-limiting diarrhea, and there were some other minor adverse effects during the triple therapy period (metal taste in the mouth, nausea, and so forth). Only one patient stopped taking medicines after 1 week’s treatment. Metrunidazule re.ristance The sensitivity to metronidazole could be determined from pretreatment strains isolated from 71 patients. In 58 of them the bacteria were eradicated, but in 13 patients the infection persisted. The treatment was more often successful when the bacteria were sensitive t o metronidazole; 89% of the sensitive strains and 61% of the resistant strains were eradi-
Treatment failures All 16 non-responders had metronidazole-resistant posttreatment H . pylori strains. They received a new antimicrobial therapy at least once. Five of them had successful eradication; at 12-month follow-up four patients participated, and they are included in the group of successfully treated patients. These five patients received a modified triple therapy; four of them had 500 mg erythromycin three times daily (three of them instead of amoxicillin, two with extra 500 mg tetracyclin four times daily and 20 mg omeprazole, and one instead of metronidazole). One received 20 mg omeprazole extra. The 6-month follow-up Ninety-five patients participated in the 6-month followup; 86 of them were H . pylori-negative, and 9 were H . pylori-positive. Two of the patients died of non-gastric diseases before the 6-month follow-up visit; they had been bacteria-negative at the 6-week visit. The 12-month follow-up The 12-month follow-up results are presented in Table 11. Ninety-three subjects participated in this follow-up; 83 were H. pylori-negative and 10 H . pylori-positive. One patient had died of non-gastric disease. Reinfection One gastric ulcer patient was reinfected at the 12-month follow-up. H e received a new triple therapy and was H . pyhri-negative 1 year later. Ulcer relapses One of the 84 H. pylori-negative patients had 2 asymptomatic ulcer relapses, and 3 of 9 treatment failures had ulcer relapses during the 12-month follow-up ( p = 0.002). (Two more patients had ulcer relapses during 24 months.)
Therapy of H. pylori in Peptic Ulcer
Scand J Gastroenterol Downloaded from informahealthcare.com by University Of South Australia on 08/31/15 For personal use only.
DISCUSSION
H . pylori eradication has changed the profiles of chronic gastritis and duodenal ulcer. Of DU patients treated with H2 blockers 7@80% had yearly relapses (2,5,8). Today it is obvious that permanent H . pylori eradication will prevent the great majority of duodenal ulcer relapses. In practice, it is important to know that endoscopic control of the success of H . pylori eradication is not necessary in asymptomatic patients, since previously elevated H . pylori IgG antibody titers decrease more than 50% within 6 months. This indicates the success of eradication (9), which can also be estimated without endoscopy by the I3C-urea breath test (10). In the present study only 1 of 84 successfully treated ulcer patients had two asymptomatic prepyloric ulcer relapses during the 12-month follow-up. She took NSAID regularly. None of the 16 patients with gastric ulcers had relapses. None of 55 H . pylori-negative patients had a relapse At the 24-month control. The low number of relapses in treatment failure patients (three of nine at 12 months and two more at 24 months) may have been influenced by several antimicrobial courses given to these patients during the followup period. Patients were usually happy to receive triple therapy because it made them clinically symptomless without any need to continue further ulcer therapy. At the 12-month follow-up only some patients with gastroesophageal reflux occasionally took antacids for symptomatic relief, and two had H2 blockers on demand. Bismuth preparations combined with antimicrobials give the best eradication rates (80-90%) observed. This was also confirmed in our study. Occurrence of metronidazoleresistant H . pylori strains has been reported to be related to earlier use of nitroimidazoles but also after H . pylori treatment with nitroimidazoles (11-14). This has a clear influence on the success of H . pylori eradication. In Finland metronidazole resistance was 26% in a study of 559 H. pylori-positive patients (7). Women harbored metronidazole-resistant strains more than twice as often as men. The pretreatment metronidazole resistance had a clear effect on our eradication results. Pretreatment metronidazole resistance was more than twice as common among patients who remained culture-positive in spite of the therapy (54%) compared with patients who were later treated successfully (19%) ( p < 0.03). The percentage of women in therapeutic failures was greater than one would have expected on the basis of their proportion in all treated patients (p = 0.03). Younger women are more likely to have a metronidazoleresistant organism, perhaps related to previous use of antibiotic for gynecologic complaints (7, 14). Unfortunately, in the present material information about previous use of metronidazole could not be obtained. In the absence of pretreatment metronidazole sensitivity testing a carefully compiled drug history is useful (14). The high eradication rate of H . pylori infection is important, but for the stability of successful H. pylori eradication
975
it is important that the reinfection rate of H . pyfori remains low. The yearly reinfection rate was 1% in our material, in comparison with 4% in Australia (15) and more than 20% in 18 months in Brazil (16). We conclude that in developed countries triple therapy should be given to all patients with chronic recurrent duodenal ulcer. The therapy needs good follow-up to find treatment failures, patients who are at high risk of relapsing ulcer. On the other hand, when H . pylori infections are treated with antimicrobial drugs, it is important to consider that frequent resistance to nitroimidazoles will decrease the eradication rate in schemes using these drugs. Another important factor will be the rate of reinfection in the population treated, which, if high, may ruin the results of eradication therapy.
REFERENCES 1. Rauws EAJ, Langenberg W, Houthoff HJ, Zanen HC, Tytgat GNJ. Campylobacter pyloridis-associated chronic active antral gastritis. A prospective study of its prevalence and the effects of antibacterial and antiulcer treatment. Gastroenterology 1988;94:33-40. 2. Marshall BJ, Goodwin CS, Warren JR, et al. Prospective double-blind trial of duodenal ulcer relapse after eradication of Carnpylobacter pylori. Lancet 1988;2:1437-42. 3. Borody T, Cole P, Noonan S, et al. Long-term Campylobacter pylori recurrence post-eradication, Gastroenterology 1988; 94:A43. 4. Bdrsch G , Mai U , Opferkuch W. Oral triple-therapy (Om) may effectively eradicate Campylobacter pylori (C.P.) in man: a pilot study. Gastroenterology 1988;94:A44. 5. Rauws EAJ, Tytgat GNJ. Cure of duodenal ulcer associated with eradication of H . pylori. Lancet 1990;225:1233-5. 6. Valle J, Seppala K, Sipponen P, Kosunen TU. Disappearance of gastritis after eradication of Helicobacter pylori. A morphometric study. Scand J Gastroenterol 1991;26: 1057-65. 7. Rautelin H, Seppala K, Renkonen 0 - V . Vainio U. Kosunen TU. Role of in vitro rnetronidazole resistance in Helicobacter pylori infections. Antimicrob Agents Chemother 1092;36:16.T 6. 8. Wormsley KG. Relapse of duodenal ulcer. Br Med J 1986; 293:1501. 9. Seppala K, Kosunen T , Sipponen P, Valtonen V. Decrease of Helicobacter pylori antibodies reflects successful eradication therapy [abstract]. 9th World Congress of Gastroenterology; 1990:917. 10. Bell G D , Weil J, Harrison G , et al. 14 C-urea breath analysis, a non-invasive test for Campylobacter pylori. Lancet 1987;l: 1367-8. 11. Goodwin CS, Marshall BJ, Blincow ED, Wilson DH, Blackbourne S, Phillips M. Prevention of nitroimidazolc resistance in Campylobacter pylori by coadrninistration of colloidal bismuth subcitrate; clinical and in vitro studies. J Clin Pathol 1988;41: 207-10. 12. Becx MCJM, Janssen AJHM, Clasener HAL. dc Koning RW. Metronidazole-resistant Helicobacter pylori [letter]. Lancet 1990;11539-40. 13. Glupczynski Y,Burette A, de Koster E, et al. Metronidazole resistance in Helicobacter pylori [letter]. Lancet 1990;335:97& 7. 14. Bell GD, Weil J , Powell K , et al. Hclicobacter pylori treated with combinations of tripotassiurn dicitrato and metronidazolc: efficacy of different treatment regimens and some observations on the emergence of metronidazole resistance. Eur J Gastroenterol Hepatol 1991;3:819-22.
916
K. Seppiilii et al.
15. Lian JX, Carrick J , Lee A, Daskalopoulos G. Long term recurrence of Helicobacter pylori infection after successful eradication with 'triple therapy'. Gastroenterology 1991;DDW abstract 412.
Scand J Gastroenterol Downloaded from informahealthcare.com by University Of South Australia on 08/31/15 For personal use only.
Received 13 January 1992 Accepted 7 July 1992
16. Coelho LGV, Passos MCF, Chausson Y, Castro LP. Duodenal ulcer and eradication of H. pylori in a developing country-an 18-month follow-up study. Eur J Gastroenterol Hepatol 1991;3 Suppl 1.
