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Novel bismuth–metronidazole–tetracycline triple-layer tablet for treatment of helicobacter pyloriAliment Pharmacol Ther 2005; 21: 165–168.
Novel bismuth–metronidazole–tetracycline triple-layer tabletfor treatment of Helicobacter pylori D . Y . G R A H A M * , A . R . O P E K U N * , G . B E L S O N * , H . M . T . E L - Z I M A I T Y * & M . R . C A R L S O N àDepartments of *Medicine and Pathology, VA Medical Center and Baylor College of Medicine, Houston, TX, USA;àPrometheus Labs, San Diego, CA, USA cure rate among metronidazole-susceptible strains was Background: Current anti-Helicobacter pylori treatment 100% (22 of 22) (95% confidence interval 84–100%) regimens are costly and because of the increasing compared with 55% (five of nine intention-to-treat) antibiotic resistance, are becoming ineffective.
(95% confidence interval 21–86%) among metronidaz- Aim: To evaluate a triple-layer tablet containing ole-resistant strains. In four cases, therapy was trun- 100 mg bismuth subcitrate, 250 mg metronidazole, cated at 4–7 days because of side-effects; yet the and 250 mg tetracycline in a single triple-layer tablet.
treatment was effective in three. The three metronidaz- Methods: H. pylori-infected adult patients received bis- ole-susceptible but clarithromycin-resistant infections muth–metronidazole–tetracycline (two tablets, t.d.s.) and ranitidine (300 mg) once daily for 14 days. Efficacy Conclusion: This novel triple-layer tablet combination was determined using 13C-urea breath testing.
therapy was effective in all patients with metronidazole- Results: Thirty-three of 35 enrolled patients were susceptible H. pylori and many of those with resistant available for evaluation; using the protocol-specified organisms. A greater degree of acid suppression may modified intention-to-treat analysis, five failed treat- ment, two were lost to follow-up (cure rate per- the presence of metronidazole resistance unless the dose and duration of metronidazole is increased. One prob- Eradication therapy is recommended for those with lem with BMT triple or quadruple therapy is the need to confirmed Helicobacter pylori infection. Current proton- take a large number of tablets every day. This pilot pump inhibitor containing triple-therapy regimens are study evaluated a new combination therapy (Helidac costly and the eradication rate in large population Triple-Layer BMT; Prometheus, San Diego, CA, USA) studies is typically in the range of 60 to 80% in part consisting of 600-mg triple-layer tablets containing because of an increasing prevalence of clarithromycin 100 mg colloidal bismuth subcitrate (B), 250 mg resistance.1–4 The traditional bismuth–metronidazole– metronidazole (M), and 250 mg tetracycline (T) in a tetracycline (BMT) therapy retains its effectiveness in single tablet in patients with active H. pylori infection.
the face of clarithromycin resistance, is less effective in The ability of combined medications into a multi-layertablet markedly reduced the need to take a largenumber of pills every day. The cure rates were compared Correspondence to: Dr D. Y. Graham, Veterans Affairs Medical Center, RM among those with and without metronidazole-resistant 3A-320 (111D), 2002 Holcombe Boulevard, Houston, TX 77030, USA.
E-mail: dgraham@BCM.TMC.edu who were pregnant or lactating, allergy to any of the study medications, participation in a clinical trial within This was a pilot study to evaluate the efficacy of the the last 30 days and/or previous treatment with BMT, triple-layer BMT tablet administered three times a day unwillingness to refrain from alcohol-containing bever- for 2 weeks. The antisecretory drug, ranitidine, was ages for the duration of the study, use of proton-pump used as an adjuvant. Potentially eligible patients inhibitors within 15 days of the study enrollment.
underwent endoscopy where gastric mucosal biopsies Outcome of therapy was assessed at least 4 weeks after were obtained using jumbo biopsy forceps (Radial the end of antimicrobial therapy by 13C-urea-breath test JawTM 3; MicroVasive, Watertown, MA, USA); two testing (Prometheus) determined by gas isotope ratio antral and one corpus biopsy were taken for histology5 mass spectrometry. Cure was defined as negative urea- and one antral and one corpus biopsy were taken for breath test (enrichment delta over baseline [DOB] <2.4 culture. Pretherapy H. pylori status was defined by a positive culture and/or H. pylori gastritis as determinedby Genta triple stain of the gastric mucosal biopsies.
Pre-treatment biopsies were cultured and antibiotic susceptibility testing (metronidazole, clarithromycin, Compliance was assessed by pill count if the patient and amoxicillin) was performed as previously described returned medication containers, self-kept diary and/or using the E-test (AB Biodisk, Solna, Sweden) method.6 questioning if the patient failed to return medication The presence of metronidazole resistance in those with E-test result suggesting resistance [minimum inhibitoryconcentration (MIC) >8 lg/mL] was reconfirmed by agar dilution which was used as the final arbiter ofinfection with a susceptible or resistant strain.6, 7 Side-effects were evaluated using a by patient interview, Isolates were considered metronidazole resistant if the review of self-reporting diaries, before and after therapy MIC was >8 lg/mL by agar dilution or >1 lg/mL for physical and laboratory evaluations.
Inclusion criteria were: male and female patients between the ages of 18 and 75 years (inclusive) whoprovided written informed consent to participate in the This was an open-label pilot study with a goal of enrolling study. Female patients of childbearing potential, defined between 30 and 40 evaluable patients. The primary as not surgically sterile or at least 2 years postmeno- efficacy endpoint was H. pylori eradication assessed pausal, must have agreed to use one of the following 4 weeks or more after completion of treatment using forms of contraception from screening to 30 days the 13C-urea breath test. The secondary endpoint was following the last dose of study drug: hormonal (oral, assessment of effectiveness in patients infected with H.
implant, or injection), barrier (condom, diaphragm pylori resistant to metronidazole (defined by agar dilu- with spermicide), intrauterine device, or vasectomized tion). The success rate was determined as the percentage partner (6 months minimum). Presence of an active of patients whose H. pylori infection was cured. Data was H. pylori infection as shown by positive histology or tabulated using a MS-Access database (A. Opekun, Baylor positive culture within 30 days of enrollment in study.
College of Medicine, Houston, 2004). Exact confidence Exclusion criteria were: previous surgery of the stom- intervals (CI) were calculated,8 otherwise categorical data ach, such as partial gastrectomy or gastroplasty, use of were analysed using SigmaStat (SPSS, Chicago, IL, USA).
antibiotics within the preceding 30 days, regular use of Safety parameters were also assessed including adverse bismuth compounds (more than three times per week) experiences, physical examination, and laboratory in the 30 days before enrollment, presence of serious parameters including hemogram, blood urea nitrogen, medical condition(s) precluding participation or con- glucose, hepatic transaminases, uric acid, and urinalysis.
comitant medication known to interact with the study The study was approved by the Institutional Review medications (warfarin), presence of Zollinger–Ellison Boards at Baylor College of Medicine for the VA Medical syndrome, chronic nonsteriodal antiinflammatory drug Center, Houston. All patients signed an informed use, except aspirin at a dose of £ 325 mg/day, women Ó 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 165–168 T R I P L E - L AY E R B M T F O R H . P YL O R I resistant H. pylori. The success with metronidazole- resistant organisms was approximately 50% with the Thirty-five eligible H. pylori-infected adult patients upper 95% CI reaching about 90%. We used agar (26 males, nine females, age 22–76 years, mean dilution to assess the presence of metronidazole resist- 50 years) were enrolled. Both culture and histology ance whereas others have used E-test.7 The cure rate were positive in 100%. Thirty-two patients had out- among resistant strains by E-test was 61%.
come data available for evaluation; using the protocol- Quadruple therapy consistent of a similar combination specified modified intention-to-treat analysis (ITT), five of antibiotics and a proton-pump inhibitor has repeat- failed eradication therapy and three patients were lost to edly been shown to be effective despite the presence of follow-up. The ITT cure rate was 77.4% (27 of 35) (95% metronidazole resistance provided that attention was CI 59.8–89.5%). The per-protocol (PP) cure rate was given to the dose of metronidazole (e.g. 400 or 500 mg 84.3% (27 of 32) (95% CI 67–95%). Resistance to three times daily) and duration of therapy of approxi- metronidazole was present in 13 by E-test and was mately 14 days.9–14 We previously attempted to sim- confirmed by agar dilution in nine. The cure rate among plify quadruple therapy by using twice-a-day quadruple susceptible strains was 22 of 22 (100%) (95% CI therapy and giving the drugs at breakfast and with the 84–100%). Among resistant strains, it was five of nine evening meal. That approach also resulted in <50% (55.5%, ITT) (95% CI 21–86%). Four of the five patients success rate among those with metronidazole-resistant (80%) with treatment failure had metronidazole- H. pylori.6 Subsequently, a study of twice-a-day quad- resistant organisms. In four cases, therapy was trun- ruple therapy given at the mid-day and with the cated after 6, 7, 7, and 7.5 days because of side-effects; evening meal administration and yielded excellent the treatment was effective in three (the one failure was eradication rates even among those who had repeatedly a metronidazole-resistant case). There were three cases failed eradication therapy in the past.15, 16 Those with metronidazole-susceptible and clarithromycin- two studies varied both in the timing of administration resistant strains and all were cured.
of the drugs and in the form of bismuth with themorning–evening protocol using bismuth subsalicylateand the mid-day–evening protocol using bismuth subcitrate. To examine whether those results were due Adverse event data are available for 34 patients who to the difference in timing or to differences in the took at least one dose of the BMT study medication.
bismuth used, we examined the bismuth subsalicylate Twenty-two patients (65%) reported at least one at the morning and evening meals. In that study, the adverse event. The most frequently reported solicited cure rate was >95% for those with metronidazole- adverse event was abdominal cramps or pain (22 susceptible strains and 83.3% for those with metroni- patients, for which 23% of those were graded mild, dazole-resistant H. pylori.17 These data suggested that 63% moderate, and 14% marked). This was followed by bismuth subcitrate may offer a slight advantage over change in stools consistency [19 patients (56%); unformed stools (68%) or liquid stools (32%)]. Other This study used three times a day therapy and thus events reported include headache (17 patients or 50%); encompassed the timing of administration of both prior belching (16 patients or 47%); nausea (15 patients studies. The combination tablet used had similar doses or 44%); dizziness or light headedness (12 patients or of antibiotics to traditional quadruple therapy as it 35%); anorexia (11 patients or 32%); muscle aches or contained bismuth subcitrate and the dose of metroni- cramps (nine patients or 26%); vomiting (15 patients dazole was 1.5 g. The exception was that the antise- or 15%); chills (four patients or 12%) and rash or cretory drug used was a single dose of 300 mg of ranitidine rather than twice a day proton-pump inhib-itor. The result in the presence of metronidazole-susceptible strains was excellent but were unsatisfactory in the presence of metronidazole resistance such that This novel triple-layer tablet BMT combination therapy the convenience of the triple-layer tablet was offset by was effective in all patients with metronidazole-suscept- the lower level of effectiveness in patients with met- ible H. pylori including those with clarithromycin- ronidazole-resistant H. pylori. Excellent results have Ó 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 165–168 been repeatedly shown for treatment of metronidazole- 7 Osato MS, Graham DY. Etest for metronidazole susceptibility resistant H. pylori with quadruple-therapy regimens in H. pylori: use of the wrong standard may have led to thewrong conclusion. Am J Gastroenterol 2004; 99: 769.
containing either bismuth subcitrate or subsalicy- 8 Fagan T. Quickbasic program for exact and mid-P confidence late.17–19 These excellent results with BMT quadruple intervals for a binomial proportion. Comput Biol Med 1996; therapy using a proton-pump inhibitor suggests that use of a more potent antisecretory regimen (e.g. a ranitidine 9 de Boer W, Driessen W, Jansz A, Tytgat G. Effect of acid twice a day or a proton-pump inhibitor) would likely suppression on efficacy of treatment for Helicobacter pylori have produced more favourable results as adjuvants infection. Lancet 1995; 345: 817–20.
10 de Boer WA, Driessen WM, Potters VP, Tytgat GN. Random- for the triple-layer BMT. Such studies are needed.
ized study comparing 1 with 2 weeks of quadruple therapy foreradicating Helicobacter pylori. Am J Gastroenterol 1994; 89:1993–7.
11 de Boer WA, Tytgat GN. 90% cure: which anti-Helicobacter This material is based upon work supported in part by therapy can achieve this treatment goal?. Am J Gastroenterol1995; 90: 1381–2.
the Office of Research and Development Medical 12 de Boer WA, van Etten RJ, Lai JY, Schneeberger PM, van de Research Service Department of Veterans Affairs and Wouw BA, Driessen WM. Effectiveness of quadruple therapy by Public Health Service grant DK56338 which funds using lansoprazole, instead of omeprazole, in curing Helico- the Texas Gulf Coast Digestive Diseases Center, by the bacter pylori infection. Helicobacter 1996; 1: 145–50.
Hilda Schwartz G.I. Endowment, and from a grant from 13 de Boer WA. How to achieve a near 100% cure rate for H. pylori infection in peptic ulcer patients. A personal view-point. J Clin Gastroenterol 1996; 22: 313–6.
14 de Boer WA, van Etten RJ, van de Wouw BA, Schneeberger PM, Van Oijen AH, Jansen JB. Bismuth-based quadrupletherapy for Helicobacter pylori – a single triple capsule plus 1 Dore MP, Leandro G, Realdi G, Sepulveda AR, Graham DY.
lansoprazole. Aliment Pharmacol Ther 2000; 14: 85–9.
Effect of pretreatment antibiotic resistance to metronidazole 15 Dore MP, Graham DY, Mele R, Marras L, Nieddu S, Manca A, and clarithromycin on outcome of Helicobacter pylori therapy: Realdi G. Colloidal bismuth subcitrate-based twice-a-day a meta-analytical approach. Dig Dis Sci 2000; 45: 68–76.
quadruple therapy as primary or salvage therapy for Heli- 2 Gisbert JP, Khorrami S, Calvet X, Gabriel R, Carballo F, Pajares cobacter pylori infection. Am J Gastroenterol 2002; 97: 857– JM. Meta-analysis: proton pump inhibitors vs. H2-receptor antagonists – their efficacy with antibiotics in Helicobacter pylori 16 Dore MP, Marras L, Maragkoudakis E, Nieddu S, Manca A, eradication. Aliment Pharmacol Ther 2003; 18: 757–66.
Graham DY, Realdi G. Salvage therapy after two or more prior 3 Laheij RJ, Rossum LG, Jansen JB, Straatman H, Verbeek AL.
Helicobacter pylori treatment failures: the super salvage regi- Evaluation of treatment regimens to cure Helicobacter pylori infection – a meta-analysis. Aliment Pharmacol Ther 1999; 17 Graham DY, Belson G, Abudayyeh S, Osato MS, Dore MP, El-Zimaity HM. Twice daily (mid-day and evening) quadruple 4 Broutet N, Tchamgoue S, Pereira E, Lamouliatte H, Salamon therapy for H. pylori infection in the United States. Dig Liver R, Megraud F. Risk factors for failure of Helicobacter pylori therapy – results of an individual data analysis of 2751 18 van der Wouden EJ, Thijs JC, van Zwet AA, Sluiter WJ, patients. Aliment Pharmacol Ther 2003; 17: 99–109.
Kleibeuker JH. The influence of in vitro nitroimidazole 5 El-Zimaity HM, Al-Assi MT, Genta RM, Graham DY. Confir- resistance on the efficacy of nitroimidazole-containing anti- mation of successful therapy of Helicobacter pylori infection: Helicobacter pylori regimens: a meta-analysis. Am J Gastro- number and site of biopsies or a rapid urease test. Am J 19 Graham DY, Osato MS, Hoffman J, Opekun AR, Anderson S, 6 Graham DY, Hoffman J, El-Zimaity HM, Graham DP, Osato M.
Kwon DH, El-Zimaity HM. Metronidazole containing quad- Twice a day quadruple therapy (bismuth subsalicylate, ruple therapy for infection with metronidazole resistant tetracycline, metronidazole plus lansoprazole) for treatment Helicobacter pylori: a prospective study. Aliment Pharmacol of Helicobacter pylori infection. Aliment Pharmacol Ther Ó 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 165–168
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