Factors influencing the eradication of Helicobacter pylori with triple therapy

GASTROENTEROLOGY

1992:102:493-496

Factors Influencing the Eradication of Helicobacter pylori With Triple Therapy DAVID Y. GRAHAM, GINGER M. LEW, HODA M. MALATY, DOLORES G. EVANS, DOYLE J. EVANS, Jr., PETER D. KLEIN, LESLEY C. ALPERT,

and ROBERT M. GENTA

Departments of Medicine, Pediatrics, and Pathology, Division of Molecular Virology, and U.S. Department of Agriculture/Agricultural Research Service Children’s Nutrition Research Center, Baylor College of Medicine; and Veterans Affairs Medical Center, Houston, Texas

Helicobacter pylori infection has been associated with gastritis, duodenal ulcer, gastric ulcer, and the epidemic form of gastric carcinoma. Eradication of H. pylori infection has proven to be di5cult. Recently, combinations of antimicrobial drugs have been shown to eradicate ~0% of infections; however, the results have proven variable, and the factors influencing effectiveness of therapy are unclear. In the present study, the effectiveness of a triple therapy for eradication of H. pylori infection was evaluated. Triple therapy consisted of 2 g tetracycline, 750 mg metronidazole, and five or eight tablets of bismuth subsalicylate daily in 93 patients (70 with duodenal ulcer, 17 with gastric ulcer, and 6 with simple H. pylori gastritis). Combinations of a sensitive urea breath test, serology, culture, and histology were used to confirm the presence of infection, eradication, or relapse. Eradication was defined as inability to show H. pylori ;rl month after ending therapy. The overall eradication rate was 67%. The factors evaluated for their effect on predicting eradication included age, gender, type of disease, duration of therapy, amount of bismuth subsalicylate [five or eight Pepto-Bismol tablets daily (Procter & Gamble, Cincinnati, OH)], and compliance with the prescribed medications. Stepwise regression showed that compliance was the most important factor predicting success: the success rate was 96% for patients who took >60% of the prescribed medications and 69% for patients who took less. For those taking >60% of the prescribed therapy, the eradication rates were similar (a) for patients receiving therapy for 14 days or when tetracycline and bismuth subsalicylate were taken for an additional 14 days: (b) for patients with duodenal ulcer, gastric ulcer, and simple H. pylori gastritis; and (c) whether five or eight bismuth subsalicylate tablets were taken. It is concluded that triple therapy is effective for eradication of H. pyZori and that future studies need to take compliance into account for comparisons between regimens.

H

elicobacter pylori infection has been associated with gastritis, duodenal ulcer, gastric ulcer, and the epidemic form of gastric carcinoma.‘,’ Eradication of H. pylori infections has proven to be difficult.3-Q Therapy with a single or with two antimicrobials has proven ineffective, as evidenced by eradication rates much below 50%.3Recently, combinations of three antimicrobial drugs have been shown to eradicate >5O% of H. pylori infections. Despite these apparent successes, the results have been variable, and the factors influencing effectiveness of therapy remain unclear.3~8~QIn the current study, we evaluated the effectiveness of a three antimicrobial drug combination (triple therapy) for eradication of H. pylori infection with special emphasis on the factors that might predict good vs. poor responses. Materials and Methods The patients in this study had participated in five different clinical protocols, each of which also included therapy to eradicate H. pylori infection. The studies were duodenal ulcer healing, gastric ulcer healing, and effect of eradication of H. pylori on (a) meal-stimulated gastrin release, (b) bombesin-stimulated gastrin release, and (c) on gastric structure and function. Antimicrobial triple therapy consisted of tetracycline hydrochloride (500 mg q.i.d.), metronidazole (250 mg t.i.d.), and bismuth subsalicylate tablets [ISO mg bismuth per tablet (Pepto-Bismol; Procter & Gamble, Cincinnati, OH)] (Table 1). Bismuth subsalicy-

late tablets were administered one with each meal and two at bedtime (70 patients) or two with each meal and two at bedtime (30 patients). For patients with active peptic ulcers, antiulcer therapy (ranitidine, 300 mg after the evening meal) was administered for the initial 14 days of triple therapy. Assessment of compliance with antimicrobial therapy was performed by pill count. The H. pylori status was confirmed by the [13C]urea breath testlO*” and a sensitive, specific enzyme-linked imThis is a U.S. government its use.

work. There are no restrictions

on

494

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ET AL.

GASTROENTEROLOGY

Table 1. Summary of the Therapies Used in an Attempt to Eradicate H. pylori Infections Drugs

Therapy 1 Metronidazole Tetracycline Pepto-Bismol Therapy 2 Metronidazole Tetracycline Pepto-Bismol Therapy 3 Metronidazole Tetracycline Pepto-Bismol Therapy 4 Metronidazole Tetracycline Pepto-Bismol

Dosage

Duration (days)

250

mg t.i.d. 500 mg q.i.d. 5 tablets daily

14 14 14

250 mg q.i.d. 500 mg q.i.d. 8 tablets daily

14 14 14

250 mg q.i.d. mg q.i.d. 5 tablets daily

14

500

250 mg

q.i.d. 500 mg q.i.d. 5 tablets daily

10 10

14

28 28

munosorbent assay (ELISA)” in all. The majority (82%) had pretreatment gastric antral mucosal biopsies for H. pylori culture and/or histological evaluation with WarthinStarry stain. Breath tests were repeated at the time of ulcer healing, 1 month later. The routine follow-up for all patients was endoscopy with antral mucosal biopsies, breath test, and serum sample at s-month intervals, and whenever symptoms occurred. Eradication was defined as inability to show H. pylori 21 month after ending therapy. The protocol was approved by Institutional Review Boards for Human Studies at Baylor College of Medicine, the Methodist Hospital, and the Veterans Affairs Medical Center, Houston, Texas. Statistical

Methods

The data were analyzed by x2 test and stepwise regression analysis using the SAS program (SAS Institute, Cary, NC). We categorized patients into groups: three groups according to the diagnosis (duodenal ulcer, gastric ulcer, or simple gastritis); three groups according to the duration of therapy (10 days, 14 days, and 28 days); two groups according to the number of bismuth subsalicylate tablets taken per day (5 or 8 tablets); and two groups according to the percentage of medication taken. The stepwise regression was also repeated using only the patients in whom accurate assessment of compliance was available by actual pill count. The Mantel-Haenszel x2 test was used to examine the relationship between the eradication rate and the type of ulcer, duration of therapy, number of bismuth tablets, and the percentage of prescribed medications taken.

Results One hundred eight patients received triple therapy. There were 106 men and 2 women. The median age was 62 years (range, 28-86 years). Fifteen patients were excluded from analysis because they did not return at least 1 month after ulcer healing so

Vol. 102, No. 2

that evaluation of the effectiveness of therapy could be assessed. The evaluable patients included 70 with duodenal ulcer, 17 with gastric ulcer, and 6 with H. pylori gastritis not associated with ulcer disease (Table 2). The median follow-up for those in whom the infection was eradicated was 29 weeks (mean, 33 weeks; range, 4-79 weeks). Overall, the eradication rate was 87%. The eradication rate varied between 70% and 100% among the different treatment groups, but the differences were not significant (Table 3). The eradication rates in relation to duration of therapy was 77% for lo-day therapy, 91% for 14-day therapy, and 86.6% for 28-day therapy (P = NS). Data on compliance with the prescribed medications were available for 75 patients; no information was available on 18 patients in the gastrin studies, because the patients were not instructed to return their medications. Definite pill counts were available on 59 patients; 16 patients did not return their medications for pill count despite repeated attempts to have them do so. Patients who failed to return their medications had an eradication rate of 70% compared with 69% for patients who took ~60%; these two groups were combined into the “~60%” group. Stepwise regression was used to identify the most important factor(s) predicting eradication of the H. pylori infection, and compliance with taking antimicrobial therapy was the most important predictor (P < 0.001) (Table 4). The eradication rate for those who took 260% of their medications (median for the group was 90%) was 96% compared with 69% of those who took <60% (P = 0.001). The result did not change whether we analyzed the data as two groups (those who took > or ~60% of the prescribed medications), whether we restricted the evaluation to the 59 patients in whom pill counts were available, or whether we eliminated the patients in whom we did not have a combination of breath test and culture or histology to confirm the presence of H. pylori infection pretreatment. For patients taking >60% of the prescribed therapy, the eradication rates were similar for (a) patients receiving therapy for 14 days or when tetracycline and bismuth subsalicylate were

Table 2. Summary of the Study Populations No. of patients in each category Therapy duration (days)

Ulcer Duodenal

Gastric

Gastritis

10

21

1

-

14

44

12

-

28

5 70

4 17

Total

6 6

February 1992

Table 3. Summary

ERADICATION

of Eradication

Results in Relation to

Compliance With Medications

Group

Group eradication rate (%)

Duodenal ulcer

90.3

Gastric ulcer

70.1

Medication taken (%)b

>60%

Factor PC

Id-day therapy (%)

(X2;&

0.01

28-day therapy (%)

,2?%,

0.01

5 bismuth

tablets (%)

100

1.00

8 bismuth

tablets (%)

(*O;:l) 100

100

WI

14-day therapy

91

28-day therapy

86.6

(4/4) (&

0.058

(6;:1

0.155

(40;:2j 100 (7/7)

(12& 5 bismuth 8 bismuth

tablets tablets

81.6

(zs;;O) 100

96.1

(68;)

(lo;:l] 100

(3/3)

(2/2)

0.093

“Data were available on only four patients in the lo-day protocol; these were not included. bIncludes the group of patients who refused to return their medications. “Comparison of the results for those taking > or ~60% of the prescribed antimicrobials.

continued for an additional 14 days; (b) patients with duodenal ulcer, gastric ulcer, and simple H. pylori gastritis; and (c) whether five or eight bismuth subsalicylate tablets were taken (Table 3). The importance of compliance can also be shown in those with duodenal ulcer, the largest group (Table 5); similar results were present for gastric ulcer patients. Complications to triple therapy were experienced by 20 patients (18.5%), 19 of whom were patients in whom follow-up was obtained. Nausea was the most common side effect (45%); the majority of complications were minor (Table 6). Discussion H. pylori infections have proven to be difficult to eradicate.2-g The best eradication rates have been reported with combinations of antimicrobials with most combinations using a bismuth salt, metronidazole or tinidazole, and amoxicillin or tetracycline.2-g

Variable

Regression coefficient

Compliance Amount of bismuth Duration of therapy

0.039 0.009

0.004

&9) 100

(7pl)

(17/17)

(5K

NOTE. The patients with duodenal ulcer with accurate pill counts in the lo-day therapy group were excluded because of the small number, which precluded meaningful analysis.

0.008

(19/19)

Table 4. Results of Stepwise Regression

<60%

96.5 (32/33) 100

(35;;6]

Gastritis

495

Table 5. Effect of Various Treatment Parameter on Eradication of H. pylori Infection in Patients With Duodenal Ulcer

<60%

>60%

OF H. PYLORI INFECTION

Analysis F

P

12.66 2.41 2.38

0.0007 0.124 0.127

NOTE. The factor, age, and type of disease did not meet the level of significance of co.15 for any model tested.

Our results are consistent with these observations because our overall eradication rate was 87%. Our study was the first to examine the factors responsible for a poor rate of eradication of H. pylori; we found that failure to take the prescribed medications was the variable that best predicted a poor result. This study showed that triple therapy using bismuth subsalicylate tablets is as effective as has been previously reported for triple therapy protocols for the eradication of H. pylori using colloidal bismuth subcitrate. This observation suggests that there are no special properties of colloidal bismuth subcitrate as an antimicrobial to eradicate H. pylori. This is in contrast to data from studies on experimental ulcers suggesting that colloidal bismuth subcitrate has ulcer-healing properties not shared with bismuth subsalicylate, bismuth subcarbonate, or bismuth subnitrate.‘3s’4 For example, histochemical staining of experimental ulcers showed that only colloidal bismuth subcitrate (compared with bismuth subnitrate, bismuth subcarbonate, and bismuth subsalicylate) coated experimental gastric ulcers in rats.14 Subsequent studies also showed important differences between different formulation of bismuth sub-

Table 6. Complications

Reported During Triple Theravv No. of patients

Complication Nausea/queasy feelings Dry mouth Diarrhea Rash Dizziness Disorientation Constipation Sore throat (Monilia) Monilia vaginitis “One severe. bBoth severe; one was an exacerbation “Patient also had dry mouth.

9” 2 2 2b 2

1 1 lo lC of psoriasis.

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GRAHAM ET AL.

citrate; colloidal bismuth subcitrate is effective in preventing ulceration in Shay rats but noncolloidal bismuth subcitrate is not.15 It is not clear whether other triple therapies using a bismuth and two other antimicrobials would achieve the same excellent results, because a number of other variables were not examined. One possibly important variable that we did not test is the timing of medications in relation to meals. This may be important, especially in relation to bismuth administration, because administration with meals tends to allow a longer contact time and possibly better intragastric distribution than administration fasting.‘” This hypothesis is also consistent with data that tablet formulations of antacids have a longer duration of action than that of antacid liquids.17 A previous study has shown that administration of the swallow tablet of bismuth subcitrate was more effective if given four times daily than when given twice daily; in that study bismuth subcitrate was administered before meals.” Additional studies are required to examine whether liquid formulations of bismuth subsalicylate are equally effective to tablet formulations.

6. Gastrointestinal Physiology Working Group, Morgan DR. Kraft W, Bender M, Pearson A. Nitrofurans in the treatment of gastritis associated with Campylobacter pylori. Gastroenterology 1988;95:1178-1184. 7. Borsch G, Mai U, Muller KM. Monotherapy or polychemotherapy in the treatment of Campylobacter pylori-related gastroduodenal disease. Stand J Gastroenterol 1988;23(Suppl 142):101-106. 8. Graham DY, Borsch GMA. The who’s and when’s of therapy for Helicobacter pylori. Am J Gastroenterol 1990;85:15521555. 9. Glupczynski Y, Burette A. Drug therapy of Helicobacter pylori infection: problems and pitfalls. Am J Gastroenterol 1990; 85:1545-1551. 10. Graham DY, Klein PD, Evans DJ Jr, Evans DG, Alpert LC, Ope-

11.

12.

13. 14.

15.

References 1. Graham DY. Helicobacter

16.

105. 2. Graham

17.

pylori: its epidemiology and its role in duodenal ulcer disease. J Gastroenterol Hepatol1991;6:97-

DY. Helicobacter pylori in human populations: the present and predictions of the future based on the epidemiology of polio. In: Menge H, Gregor M, Tytgat GNS, Marshall BJ, McNulty, CAM, eds. Helicobacter pylori 1990: proceedings of the Second International Symposium on Helicobocter pylori. Berlin, Germany: Springer-Verlag, 1991:97-102. 3. Borsch GMA, Graham DY. Helicobacter pylori. In: Benjamin SB, Collen MJ, eds. Handbook of experimental pharmacology. Volume 99. Pharmacology of peptic ulcer disease. Berlin, Germany: Springer-Verlag, 1991:107-147. 4. Bayerdorffer E, Ottenjann R. The role of antibiotics in Campylobacter pylori-associated peptic ulcer disease. Stand J Gastroenterol 1988;23(Suppl 142):93-100. 5. 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.

18.

kun AR, Boutton TW. Campylobacter pylori detected rioninvasively by the ‘%-urea breath test. Lancet 1987;1:1174-1177. Klein PD, Graham DY. Campylobacter pylori detection by the ‘%urea breath test. In: Rathbone B, Heatley V, eds. Campylobacter pylori and gastroduodenal disease. Oxford, England: Blackwell Scientific, 1989:94-106. Evans DJ Jr, Evans DG, Graham DY, Klein PD. A sensitive and specific serologic test for detection of Campylobacter pylori infection. Gastroenterology 1989;96:1004-1008. Hall DWR. Review of the modes of action of colloidal bismuth subcitrate. Stand J Gastroenterol 1989;24:3-6. Koo J, Ho J, Lam SK, Wong J, Ong GB. Selective coating of gastric ulcer by tripotassium dicitrato bismuthate in the rat. Gastroenterology 1982;82:864-870. Lavy UI, Koekkoek PH, Jaitly KD. Anti-ulcer activity of colloidal bismuth subcitrate in Shay-rats. Arch Int Pharmacodyn 1976;224:291-298. Graham DY, Evans DG. Prevention of diarrhea by enterotoxigenie Escherichia coli: lessons learned with volunteers. Rev Infect Dis 1990;12:S68-S72. Barnett CC, Richardson CT. In vivo and in vitro evaluation of magnesium-aluminum hydroxide antacid tablets and liquid. Dig Dis Sci 1985;30:1049-1052. Lambert JR, Borromeo M, Eaves ER, Hansky J, Korman M. Efficacy of different dosage regimes of bismuth in eradicating Campylobacter pylori (abstr). Gastroenterology 1988;94:A248.

Received March 6, 1991. Accepted July 17, 1991. Address requests for reprints to: David Y. Graham, M.D., Veterans Affairs Medical Center (lllD), 2002 Holcombe Boulevard, Houston, Texas 77030. Supported by the Department of Veterans Affairs; by grant DK 39919 from the National Institute of Diabetes and Digestive and Kidney Diseases; by U.S. Department of Agriculture/Agricultural Research Service Children’s Nutrition Research Center: and by the generous support of Hilda Schwartz. Pepto-Bismol tablets were generously supplied by Procter & Gamble, Cincinnati, OH.