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Effectiveness of ranitidine bismuth citrate, clarithromycin, and metronidazole therapy for treating Helicobacter pylori
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 1999 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 94, No. 4, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00048-9
Effectiveness of Ranitidine Bismuth Citrate, Clarithromycin, and Metronidazole Therapy for Treating Helicobacter pylori Duane T. Smoot, M.D., Tanya Hinds, R.D., M.S., Hassan Ashktorab, Ph.D., Jyoti Jagtap, M.B.B.S., Kyung S. Kim, Ph.D., and Victor F. Scott, M.D. Gastroenterology Division, Department of Medicine and Cancer Center, Howard University, Washington, D.C.
OBJECTIVE: There are limited data available from the United States on the effectiveness of ranitidine bismuth citrate (RBC) plus two antibiotics to treat Helicobacter pylori. Therefore, the following study was undertaken to evaluate RBC with two antibiotics, which have been used successfully in combination, to treat H. pylori. METHODS: Adults with and without abdominal symptoms, who had never received H. pylori eradication therapy, were tested for the presence of H. pylori infection either by in-office rapid serology assays or histology. Positive subjects were administered the 13C-urea breath test. Subjects who had a positive urea breath test were then treated with RBC 400 mg b.i.d., clarithromycin 500 mg b.i.d., and metronidazole 500 mg b.i.d. for 10 days. Four to 6 wk after completing antibiotics all subjects were asked to return for a second urea breath test to assess treatment success. RESULTS: Forty-seven of the 50 subjects enrolled into this study completed the antibiotic regimen and returned for a repeat urea breath test. Thirty-seven subjects were negative for H. pylori by urea breath test and 10 were positive, resulting in a 79% eradication rate. Seven subjects (14%) stopped their medication because of side effects. When analysis was performed on the 40 subjects who took $ 80% of their medication (per-protocol), the eradication rate was 90%. CONCLUSIONS: The combination of RBC with clarithromycin and metronidazole successfully treated H. pylori infection after only 10 days of therapy. The per-protocol eradication rate from this study was similar to that seen with Food and Drug Administration (FDA)-approved regimens. In conclusion, RBC plus clarithromycin and metronidazole should be considered as a first-line treatment regimen for H. pylori infection, and may only need to be taken for a period of 10 days, as opposed to 14 days for FDA-approved regimens. (Am J Gastroenterol 1999;94:955–958. © 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION Helicobacter pylori (H. pylori) infection causes an active chronic gastritis and is an important etiological factor in the development of peptic ulcers. Successful treatment of this infection heals ulcers and significantly reduces the risk of duodenal and gastric ulcer relapse (1– 4). Treatment of this infection within the gastric lumen has been relatively difficult, requiring two to four drugs given multiple times a day for up to 2 wk. Dual therapies were initially approved for treatment of this infection by the Food and Drug Administration (FDA) with successful treatment rates ranging from 64 – 84% (Product Information, Abbott Laboratories, North Chicago, IL; Product Information, Glaxo Wellcome Inc., Research Triangle Park, NC). Although the dual-therapy regimens have good compliance with low incidence of side effects, they have less than desirable eradication rates. Ranitidine bismuth citrate (RBC) is a relatively new antimicrobial agent that was developed for the purpose of treating H. pylori infection (5, 6). RBC has been shown in vitro to have both inhibitory and bactericidal activity against H. pylori (5). RBC has approximately a twofold greater anti-H. pylori activity than an equivalent mixture of ranitidine with bismuth citrate, which is possibly due to the greater solubility of RBC even at lower pH values (5). The dual-therapy regimen including RBC had on average a higher rate of treatment success than the dual therapy regimen, including proton pump inhibitors, when using treatment trials presented to the FDA. Laine et al. have shown that the combination of RBC with amoxicillin and clarithromycin does significantly increase the treatment success rate over that of the combination of RBC with clarithromycin alone (7). Our study was designed to determine if the addition of metronidazole to clarithromycin and RBC would also significantly increase the treatment success rate, while reducing the treatment duration from 14 to 10 days.
MATERIALS AND METHODS Subject Population This study was conducted on adult outpatients, with and without abdominal symptoms, who had never received H.
956
Smoot et al.
pylori eradication therapy. Fifty subjects were recruited for this study at Howard University Hospital between March 1, 1997 and October 31, 1997. Subjects were excluded from this study if they had a chronic infectious disease, severe cardiac or pulmonary disease, allergy to any of the study medications, pregnancy or breastfeeding, recent antibiotic therapy within the prior 2 months, or did not provide informed consent. Also, subjects were excluded if the serum creatinine was . 2.0 mg/dl, or the aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, or bilirubin were greater than twice the upper limit of normal. This research study was approved by the Howard University Human Subject Institutional Review Board. Study Designs Subjects enrolled in this study had either a positive blood test for H. pylori or H. pylori present on gastric histology from biopsies taken at upper endoscopy. Before being started on study medication all subjects gave informed consent and were administered a 13C-urea breath test (Meretek Diagnostics, Houston, TX) to confirm current H. pylori infection. Within 1 wk of confirming current H. pylori infection by urea breath testing, subjects were started on a 10-day regimen consisting of ranitidine bismuth citrate 400 mg b.i.d., clarithromycin 500 mg b.i.d., metronidazole 500 mg b.i.d. At the completion of the 10-day treatment regimen, subjects were contacted by phone to assess compliance, and were asked about adverse advents from taking the medication. Four to 6 wk after completion of the triple drug therapy subjects were asked to return for a repeat 13C-urea breath test to assess treatment success. At this return visit, subjects were asked to bring in any remaining medication for pill counts. Subjects whose urea breath test became negative after therapy were considered to be successfully treated for their H. pylori infection. Data Analysis Intention-to-treat analysis for eradication was defined to include all subjects who began taking the study medication. The per-protocol analysis for eradication was defined as subjects who took at least 80% of the study medications as prescribed and returned for the repeat urea breath test. Descriptive statistics including means and 95% confidence intervals (CI) for eradication rates were used to describe the study results.
AJG – Vol. 94, No. 4, 1999
Table 1. Characteristics of Study Population Characteristics
Number
Number of subjects Mean age, yr (range) Male/female Ethnic/racial group Black White East Indian Asian
50 42 (26–72) 34/16 41 (82%) 6 (12%) 2 (4%) 1 (2%)
(46%), seven subjects (14%) reported heartburn or upper abdominal burning, four subjects (8%) complained of excessive gas, and two subjects (4%) reported nausea and intermittent vomiting. Forty-nine of the 50 subjects enrolled in this study started the treatment regimen. One subject traveled out of the country immediately after receiving and before starting the medication. Forty-seven of the 49 subjects who began the treatment regimen returned for the follow-up visit and were administered the second 13C urea breath test to assess treatment success. Thirty-seven subjects were negative for H. pylori by the urea breath test and 10 were positive, resulting in an overall 79% eradication rate. Treatment success by intent-to-treat and per-protocol analysis was 75.5% (95% CI 61– 86%) and 90% (95% CI 75–97%), respectively (Table 2). Only mild to moderate side effects were reported during the study. A total of 21 of the 49 subjects who took the regimen reported side effects (Table 1). Six of the 10 subjects who were not successfully treated stopped their medication (four after 1 day, one after 3 days, one after 5 days) and one of the 37 subjects who were successfully treated stopped the medication (after 6 days) because of side effects. The patients who stopped medication within the first 3 days complained of nausea and vomiting, the patients who stopped medication after 5 and 6 days complained of diarrhea and headaches. The two patients who did return for the repeat breath test reported taking all medication without side effects, and both of them reported marked improvement in their abdominal complaints.
Table 2. Compliance, Side Effects, and Eradication Rates Treatment Results
RESULTS The initial characteristics of our study population are listed in Table 1. H. pylori was diagnosed by serology in 46 subjects and by histology on upper endoscopic biopsy in four subjects before the initial urea breath test. Only one of the four subjects who underwent upper endoscopy had a peptic (duodenal) ulcer. Thirty-five (70%) of the subjects had gastrointestinal symptoms at the time of enrollment. Dyspepsia was reported as the main symptom in 23 subjects
Compliant (took $ 80% of meds.) No. of subjects with side effects Diarrhea Nausea Metallic taste Headache Stopped medication due to side effects Eradication rates Intent-to-treat Per-protocol * One person never started taking the antibiotics.
42/49 (85.7%) 21 (42.9%) 10 9 6 2 7/49 (14.3%) 37/49 (75.5%)* 36/40 (90.0%)
AJG – April, 1999
DISCUSSION Numerous antibiotic combinations have been shown to be effective in treating H. pylori infection. Many of the initial antibiotic regimens shown to effectively treat H. pylori included bismuth. The actions of bismuth on H. pylori are complex and include inhibition of protein and cell wall synthesis, membrane function, and ATP synthesis (8). In addition to these antibacterial actions, investigators have postulated that bismuth-containing regimens may also decrease the development of antibiotic resistance by H. pylori. RBC, the newest bismuth-containing compound, has antimicrobial activity against H. pylori similar to that of colloidal bismuth subcitrate and bismuth subsalicylate (8). In combination with clarithromycin, RBC was shown in a large study in the U.S. to effectively treat H. pylori infection, with an eradication rate of 82% (9). However, in other countries the combination of RBC and clarithromycin has yielded much better results, with eradication rates up to 94% (10, 11). In the U.S., it has taken the addition of another antibiotic for treatment success rates . 90% when using RBC (7). The combination of RBC with clarithromycin and amoxicillin for 2 wk has been shown in the U.S. to have a per-protocol eradication rate of 96% (7). Our study has shown that the combination of RBC with clarithromycin and metronidazole for 10 days will give a per-protocol eradication rate of 90%. Laine et al. showed that in the U.S., using twice-daily triple therapies of 10 –14 days in duration increased efficacy over 7 days of therapy and achieved eradication rates $ 90% (12). Side effects are common with triple drug regimens for H. pylori eradication (13–16). However, most regimens are well tolerated, with only mild to moderate side effects reported. Wyeth et al. randomized 100 dyspeptic patients to receive ranitidine bismuth citrate in combination with one or two antibiotics; overall drug-related events occurred in 19% of subjects but only 4% of subjects withdrew because of side effects (6). In one U.S. study, the regimen of RBC plus metronidazole and tetracycline was associated with a dropout rate of 12% because of side effects, whereas RBC plus amoxicillin and clarithromycin was associated with a 6% dropout rate from side effects (7). RBC alone is well tolerated and, even when given with clarithromycin, is unlikely to produce such side effects as to cause a subject to discontinue the medication (9 –11). The side effects associated with the treatment regimen used in this study are probably due to either clarithromycin or metronidazole, or both. The use of these two antibiotics together is likely to cause a relatively higher drop-out rate because of side effects, compared with regimens using amoxicillin with either clarithromycin or metronidazole. So far, the best therapies for H. pylori eradication in the United States include three to four medications to be taken twice a day for 10 –14 days. There are currently three FDA-approved triple therapies that have excellent eradication rates and should be considered as first-line treatment:
10-Day RBC Triple Therapy for H. pylori
957
omeprazole 20 mg b.i.d. or lansoprazole 30 mg b.i.d. with amoxicillin 1 gm b.i.d. and clarithromycin 500 mg b.i.d., or tetracycline 500 mg q.i.d., pepto bismol 2 tabs q.i.d., and flagyl 250 mg q.i.d. with ranitidine 150 mg b.i.d. These therapies should be taken for 10 –14 days; in the U.S. we have not had good success with these regimens when taken for only 7 days. This study shows that twice-daily triple therapy with ranitidine bismuth citrate in combination with metronidazole and clarithromycin for 10 days is an effective treatment regimen for H. pylori infection. Triple therapies, given twice daily, have similar costs to that of FDA-approved dual therapies. These data support the use of ranitidine bismuth citrate in combination with two antibiotics as an effective first-line therapy for H. pylori infection.
ACKNOWLEDGMENTS This research was funded by an investigator-initiated grant from Glaxo Wellcome, Inc. Reprint requests and correspondence: Duane T. Smoot, M.D., G.I. Division, Department of Medicine, Howard University Hospital, 2041 Georgia Avenue, N.W., Washington, D.C. 20060. Received May 19, 1998; accepted Nov. 30, 1998.
REFERENCES 1. Graham DY, Lew GM, Evans DG, et al. Effect of triple therapy (antibiotics plus bismuth) on duodenal ulcer healing. Ann Int Med 1991;115:226 – 69. 2. Smoot DT, Scott VF. The role of Helicobacter pylori in the pathogenesis of acid-peptic disease. J Assoc Acad Minor Phys 1992;3:46 –9. 3. Rauws EA, Tytgat GN. Cure of duodenal ulcers associated with eradication of Helicobacter pylori. Lancet 1990;335:1233–5. 4. Marshall BJ, Goodwin CS, Warren JR, et al. Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet 1988;2:1439 – 42. 5. McColm AA, McLaren A, Klinkert G, et al. Ranitidine bismuth citrate: A novel anti-ulcer agent with different physicochemical characteristics and improved biological activity to a bismuth citrate-ranitidine admixture. Aliment Pharmacol Ther 1996;10:241–50. 6. Wyeth JW, Pounder RE, Duggan AE, et al. The safety and efficacy of ranitidine bismuth citrate in combination with antibiotics for the eradication of Helicobacter pylori. Aliment Pharmacol Ther 1996;10:623–30. 7. Laine L, Estrada R, Trujillo M, et al. Randomized comparison of ranitidine bismuth citrate-based triple therapies for Helicobacter pylori. Am J Gastroenterol 1997;92:2213–5. 8. Lambert JR, Midolo P. The actions of bismuth in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther 1997;11(suppl 1):27–33. 9. Peterson WL, Ciociola AA, Sykes DL, et al. Ranitidine bismuth citrate plus clarithromycin is effective for healing duodenal ulcers, eradicating H. pylori and reducing ulcer recurrence. RBC H. pylori Study Group [see comments]. Aliment Pharmacol Ther 1996;10:251– 61. 10. Bardhan KD, Dallaire C, Eisold H, et al. Ranitidine bismuth citrate with clarithromycin for the treatment of duodenal ulcer. Gut 1997;41:181– 6. 11. Axon AT, Ireland A, Smith MJ, et al. Ranitidine bismuth
958
Smoot et al.
citrate and clarithromycin twice daily in the eradication of Helicobacter pylori. Aliment Pharmacol Ther 1997;11:81–7. 12. Laine L, Estrada R, Trujillo M, et al. Randomized comparison of differing periods of twice-a-day triple therapy for the eradication of Helicobacter pylori. Aliment Pharmacol Ther 1996; 10:1029 –33. 13. Lerang F, Moum B, Ragnhildstveit E, et al. A comparison between omeprazole-based triple therapy and bismuth-based triple therapy for the treatment of Helicobacter pylori infection: A prospective randomized 1-yr follow-up study. Am J Gastroenterol 1997;92:653– 8. 14. Lerang F, Moum B, Haug JB, et al. Highly effective twice-
AJG – Vol. 94, No. 4, 1999
daily triple therapies for Helicobacter pylori infection and peptic ulcer disease: Does in vitro metronidazole resistance have any clinical relevance? Am J Gastroenterol 1997;92:248 –53. 15. Lazzaroni M, Bargiggia S, Porro GB. Triple therapy with ranitidine or lansoprazole in the treatment of Helicobacter pylori-associated duodenal ulcer. Am J Gastroenterol 1997; 92:649 –52. 16. Labenz J, Tillenburg B, Weismuller J, et al. Efficacy and tolerability of a one-week triple therapy consisting of pantoprazole, clarithromycin and amoxycillin for cure of Helicobacter pylori infection in patients with duodenal ulcer. Aliment Pharmacol Ther 1997;11:95–100.
Vol. 94, No. 4, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00048-9
Effectiveness of Ranitidine Bismuth Citrate, Clarithromycin, and Metronidazole Therapy for Treating Helicobacter pylori Duane T. Smoot, M.D., Tanya Hinds, R.D., M.S., Hassan Ashktorab, Ph.D., Jyoti Jagtap, M.B.B.S., Kyung S. Kim, Ph.D., and Victor F. Scott, M.D. Gastroenterology Division, Department of Medicine and Cancer Center, Howard University, Washington, D.C.
OBJECTIVE: There are limited data available from the United States on the effectiveness of ranitidine bismuth citrate (RBC) plus two antibiotics to treat Helicobacter pylori. Therefore, the following study was undertaken to evaluate RBC with two antibiotics, which have been used successfully in combination, to treat H. pylori. METHODS: Adults with and without abdominal symptoms, who had never received H. pylori eradication therapy, were tested for the presence of H. pylori infection either by in-office rapid serology assays or histology. Positive subjects were administered the 13C-urea breath test. Subjects who had a positive urea breath test were then treated with RBC 400 mg b.i.d., clarithromycin 500 mg b.i.d., and metronidazole 500 mg b.i.d. for 10 days. Four to 6 wk after completing antibiotics all subjects were asked to return for a second urea breath test to assess treatment success. RESULTS: Forty-seven of the 50 subjects enrolled into this study completed the antibiotic regimen and returned for a repeat urea breath test. Thirty-seven subjects were negative for H. pylori by urea breath test and 10 were positive, resulting in a 79% eradication rate. Seven subjects (14%) stopped their medication because of side effects. When analysis was performed on the 40 subjects who took $ 80% of their medication (per-protocol), the eradication rate was 90%. CONCLUSIONS: The combination of RBC with clarithromycin and metronidazole successfully treated H. pylori infection after only 10 days of therapy. The per-protocol eradication rate from this study was similar to that seen with Food and Drug Administration (FDA)-approved regimens. In conclusion, RBC plus clarithromycin and metronidazole should be considered as a first-line treatment regimen for H. pylori infection, and may only need to be taken for a period of 10 days, as opposed to 14 days for FDA-approved regimens. (Am J Gastroenterol 1999;94:955–958. © 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION Helicobacter pylori (H. pylori) infection causes an active chronic gastritis and is an important etiological factor in the development of peptic ulcers. Successful treatment of this infection heals ulcers and significantly reduces the risk of duodenal and gastric ulcer relapse (1– 4). Treatment of this infection within the gastric lumen has been relatively difficult, requiring two to four drugs given multiple times a day for up to 2 wk. Dual therapies were initially approved for treatment of this infection by the Food and Drug Administration (FDA) with successful treatment rates ranging from 64 – 84% (Product Information, Abbott Laboratories, North Chicago, IL; Product Information, Glaxo Wellcome Inc., Research Triangle Park, NC). Although the dual-therapy regimens have good compliance with low incidence of side effects, they have less than desirable eradication rates. Ranitidine bismuth citrate (RBC) is a relatively new antimicrobial agent that was developed for the purpose of treating H. pylori infection (5, 6). RBC has been shown in vitro to have both inhibitory and bactericidal activity against H. pylori (5). RBC has approximately a twofold greater anti-H. pylori activity than an equivalent mixture of ranitidine with bismuth citrate, which is possibly due to the greater solubility of RBC even at lower pH values (5). The dual-therapy regimen including RBC had on average a higher rate of treatment success than the dual therapy regimen, including proton pump inhibitors, when using treatment trials presented to the FDA. Laine et al. have shown that the combination of RBC with amoxicillin and clarithromycin does significantly increase the treatment success rate over that of the combination of RBC with clarithromycin alone (7). Our study was designed to determine if the addition of metronidazole to clarithromycin and RBC would also significantly increase the treatment success rate, while reducing the treatment duration from 14 to 10 days.
MATERIALS AND METHODS Subject Population This study was conducted on adult outpatients, with and without abdominal symptoms, who had never received H.
956
Smoot et al.
pylori eradication therapy. Fifty subjects were recruited for this study at Howard University Hospital between March 1, 1997 and October 31, 1997. Subjects were excluded from this study if they had a chronic infectious disease, severe cardiac or pulmonary disease, allergy to any of the study medications, pregnancy or breastfeeding, recent antibiotic therapy within the prior 2 months, or did not provide informed consent. Also, subjects were excluded if the serum creatinine was . 2.0 mg/dl, or the aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, or bilirubin were greater than twice the upper limit of normal. This research study was approved by the Howard University Human Subject Institutional Review Board. Study Designs Subjects enrolled in this study had either a positive blood test for H. pylori or H. pylori present on gastric histology from biopsies taken at upper endoscopy. Before being started on study medication all subjects gave informed consent and were administered a 13C-urea breath test (Meretek Diagnostics, Houston, TX) to confirm current H. pylori infection. Within 1 wk of confirming current H. pylori infection by urea breath testing, subjects were started on a 10-day regimen consisting of ranitidine bismuth citrate 400 mg b.i.d., clarithromycin 500 mg b.i.d., metronidazole 500 mg b.i.d. At the completion of the 10-day treatment regimen, subjects were contacted by phone to assess compliance, and were asked about adverse advents from taking the medication. Four to 6 wk after completion of the triple drug therapy subjects were asked to return for a repeat 13C-urea breath test to assess treatment success. At this return visit, subjects were asked to bring in any remaining medication for pill counts. Subjects whose urea breath test became negative after therapy were considered to be successfully treated for their H. pylori infection. Data Analysis Intention-to-treat analysis for eradication was defined to include all subjects who began taking the study medication. The per-protocol analysis for eradication was defined as subjects who took at least 80% of the study medications as prescribed and returned for the repeat urea breath test. Descriptive statistics including means and 95% confidence intervals (CI) for eradication rates were used to describe the study results.
AJG – Vol. 94, No. 4, 1999
Table 1. Characteristics of Study Population Characteristics
Number
Number of subjects Mean age, yr (range) Male/female Ethnic/racial group Black White East Indian Asian
50 42 (26–72) 34/16 41 (82%) 6 (12%) 2 (4%) 1 (2%)
(46%), seven subjects (14%) reported heartburn or upper abdominal burning, four subjects (8%) complained of excessive gas, and two subjects (4%) reported nausea and intermittent vomiting. Forty-nine of the 50 subjects enrolled in this study started the treatment regimen. One subject traveled out of the country immediately after receiving and before starting the medication. Forty-seven of the 49 subjects who began the treatment regimen returned for the follow-up visit and were administered the second 13C urea breath test to assess treatment success. Thirty-seven subjects were negative for H. pylori by the urea breath test and 10 were positive, resulting in an overall 79% eradication rate. Treatment success by intent-to-treat and per-protocol analysis was 75.5% (95% CI 61– 86%) and 90% (95% CI 75–97%), respectively (Table 2). Only mild to moderate side effects were reported during the study. A total of 21 of the 49 subjects who took the regimen reported side effects (Table 1). Six of the 10 subjects who were not successfully treated stopped their medication (four after 1 day, one after 3 days, one after 5 days) and one of the 37 subjects who were successfully treated stopped the medication (after 6 days) because of side effects. The patients who stopped medication within the first 3 days complained of nausea and vomiting, the patients who stopped medication after 5 and 6 days complained of diarrhea and headaches. The two patients who did return for the repeat breath test reported taking all medication without side effects, and both of them reported marked improvement in their abdominal complaints.
Table 2. Compliance, Side Effects, and Eradication Rates Treatment Results
RESULTS The initial characteristics of our study population are listed in Table 1. H. pylori was diagnosed by serology in 46 subjects and by histology on upper endoscopic biopsy in four subjects before the initial urea breath test. Only one of the four subjects who underwent upper endoscopy had a peptic (duodenal) ulcer. Thirty-five (70%) of the subjects had gastrointestinal symptoms at the time of enrollment. Dyspepsia was reported as the main symptom in 23 subjects
Compliant (took $ 80% of meds.) No. of subjects with side effects Diarrhea Nausea Metallic taste Headache Stopped medication due to side effects Eradication rates Intent-to-treat Per-protocol * One person never started taking the antibiotics.
42/49 (85.7%) 21 (42.9%) 10 9 6 2 7/49 (14.3%) 37/49 (75.5%)* 36/40 (90.0%)
AJG – April, 1999
DISCUSSION Numerous antibiotic combinations have been shown to be effective in treating H. pylori infection. Many of the initial antibiotic regimens shown to effectively treat H. pylori included bismuth. The actions of bismuth on H. pylori are complex and include inhibition of protein and cell wall synthesis, membrane function, and ATP synthesis (8). In addition to these antibacterial actions, investigators have postulated that bismuth-containing regimens may also decrease the development of antibiotic resistance by H. pylori. RBC, the newest bismuth-containing compound, has antimicrobial activity against H. pylori similar to that of colloidal bismuth subcitrate and bismuth subsalicylate (8). In combination with clarithromycin, RBC was shown in a large study in the U.S. to effectively treat H. pylori infection, with an eradication rate of 82% (9). However, in other countries the combination of RBC and clarithromycin has yielded much better results, with eradication rates up to 94% (10, 11). In the U.S., it has taken the addition of another antibiotic for treatment success rates . 90% when using RBC (7). The combination of RBC with clarithromycin and amoxicillin for 2 wk has been shown in the U.S. to have a per-protocol eradication rate of 96% (7). Our study has shown that the combination of RBC with clarithromycin and metronidazole for 10 days will give a per-protocol eradication rate of 90%. Laine et al. showed that in the U.S., using twice-daily triple therapies of 10 –14 days in duration increased efficacy over 7 days of therapy and achieved eradication rates $ 90% (12). Side effects are common with triple drug regimens for H. pylori eradication (13–16). However, most regimens are well tolerated, with only mild to moderate side effects reported. Wyeth et al. randomized 100 dyspeptic patients to receive ranitidine bismuth citrate in combination with one or two antibiotics; overall drug-related events occurred in 19% of subjects but only 4% of subjects withdrew because of side effects (6). In one U.S. study, the regimen of RBC plus metronidazole and tetracycline was associated with a dropout rate of 12% because of side effects, whereas RBC plus amoxicillin and clarithromycin was associated with a 6% dropout rate from side effects (7). RBC alone is well tolerated and, even when given with clarithromycin, is unlikely to produce such side effects as to cause a subject to discontinue the medication (9 –11). The side effects associated with the treatment regimen used in this study are probably due to either clarithromycin or metronidazole, or both. The use of these two antibiotics together is likely to cause a relatively higher drop-out rate because of side effects, compared with regimens using amoxicillin with either clarithromycin or metronidazole. So far, the best therapies for H. pylori eradication in the United States include three to four medications to be taken twice a day for 10 –14 days. There are currently three FDA-approved triple therapies that have excellent eradication rates and should be considered as first-line treatment:
10-Day RBC Triple Therapy for H. pylori
957
omeprazole 20 mg b.i.d. or lansoprazole 30 mg b.i.d. with amoxicillin 1 gm b.i.d. and clarithromycin 500 mg b.i.d., or tetracycline 500 mg q.i.d., pepto bismol 2 tabs q.i.d., and flagyl 250 mg q.i.d. with ranitidine 150 mg b.i.d. These therapies should be taken for 10 –14 days; in the U.S. we have not had good success with these regimens when taken for only 7 days. This study shows that twice-daily triple therapy with ranitidine bismuth citrate in combination with metronidazole and clarithromycin for 10 days is an effective treatment regimen for H. pylori infection. Triple therapies, given twice daily, have similar costs to that of FDA-approved dual therapies. These data support the use of ranitidine bismuth citrate in combination with two antibiotics as an effective first-line therapy for H. pylori infection.
ACKNOWLEDGMENTS This research was funded by an investigator-initiated grant from Glaxo Wellcome, Inc. Reprint requests and correspondence: Duane T. Smoot, M.D., G.I. Division, Department of Medicine, Howard University Hospital, 2041 Georgia Avenue, N.W., Washington, D.C. 20060. Received May 19, 1998; accepted Nov. 30, 1998.
REFERENCES 1. Graham DY, Lew GM, Evans DG, et al. Effect of triple therapy (antibiotics plus bismuth) on duodenal ulcer healing. Ann Int Med 1991;115:226 – 69. 2. Smoot DT, Scott VF. The role of Helicobacter pylori in the pathogenesis of acid-peptic disease. J Assoc Acad Minor Phys 1992;3:46 –9. 3. Rauws EA, Tytgat GN. Cure of duodenal ulcers associated with eradication of Helicobacter pylori. Lancet 1990;335:1233–5. 4. Marshall BJ, Goodwin CS, Warren JR, et al. Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet 1988;2:1439 – 42. 5. McColm AA, McLaren A, Klinkert G, et al. Ranitidine bismuth citrate: A novel anti-ulcer agent with different physicochemical characteristics and improved biological activity to a bismuth citrate-ranitidine admixture. Aliment Pharmacol Ther 1996;10:241–50. 6. Wyeth JW, Pounder RE, Duggan AE, et al. The safety and efficacy of ranitidine bismuth citrate in combination with antibiotics for the eradication of Helicobacter pylori. Aliment Pharmacol Ther 1996;10:623–30. 7. Laine L, Estrada R, Trujillo M, et al. Randomized comparison of ranitidine bismuth citrate-based triple therapies for Helicobacter pylori. Am J Gastroenterol 1997;92:2213–5. 8. Lambert JR, Midolo P. The actions of bismuth in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther 1997;11(suppl 1):27–33. 9. Peterson WL, Ciociola AA, Sykes DL, et al. Ranitidine bismuth citrate plus clarithromycin is effective for healing duodenal ulcers, eradicating H. pylori and reducing ulcer recurrence. RBC H. pylori Study Group [see comments]. Aliment Pharmacol Ther 1996;10:251– 61. 10. Bardhan KD, Dallaire C, Eisold H, et al. Ranitidine bismuth citrate with clarithromycin for the treatment of duodenal ulcer. Gut 1997;41:181– 6. 11. Axon AT, Ireland A, Smith MJ, et al. Ranitidine bismuth
958
Smoot et al.
citrate and clarithromycin twice daily in the eradication of Helicobacter pylori. Aliment Pharmacol Ther 1997;11:81–7. 12. Laine L, Estrada R, Trujillo M, et al. Randomized comparison of differing periods of twice-a-day triple therapy for the eradication of Helicobacter pylori. Aliment Pharmacol Ther 1996; 10:1029 –33. 13. Lerang F, Moum B, Ragnhildstveit E, et al. A comparison between omeprazole-based triple therapy and bismuth-based triple therapy for the treatment of Helicobacter pylori infection: A prospective randomized 1-yr follow-up study. Am J Gastroenterol 1997;92:653– 8. 14. Lerang F, Moum B, Haug JB, et al. Highly effective twice-
AJG – Vol. 94, No. 4, 1999
daily triple therapies for Helicobacter pylori infection and peptic ulcer disease: Does in vitro metronidazole resistance have any clinical relevance? Am J Gastroenterol 1997;92:248 –53. 15. Lazzaroni M, Bargiggia S, Porro GB. Triple therapy with ranitidine or lansoprazole in the treatment of Helicobacter pylori-associated duodenal ulcer. Am J Gastroenterol 1997; 92:649 –52. 16. Labenz J, Tillenburg B, Weismuller J, et al. Efficacy and tolerability of a one-week triple therapy consisting of pantoprazole, clarithromycin and amoxycillin for cure of Helicobacter pylori infection in patients with duodenal ulcer. Aliment Pharmacol Ther 1997;11:95–100.