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Is there a role for honey in the treatment of Helicobacter pylori infection?
April 1998 adenocarcinoma. In an attempt to differentiate Barrett's esophagus (BE) from intestinal metaplasia of the gastric mucosa (IGM), cytokeratin (CK) 7 and 20 expression was evaluated by immunohistochemistry. Fifteen gastroesophagectomy specimens with BE (n=10) and IGM (n=5) were immunostained with monoclonal antibodies directed against CK7 and CK20. Cytoplasmic staining for CK7 was present in the superficial and deep glands in BE while CK20 was present only superficially. Conversely, IGM showed CK20 positivity in the superficial and deep glands with minimal to no CK7 staining. Nonmetaplastic fundic mucosa showed minimal surface CK7 positivity while CK20 stained the surface and foveolar regions. These staining patterns were consistent from case to case. CK subsets can be used to distinguish BE from IGM. This may prove especially useful in the evaluation of endoscopic biopsies in which the location of the gastroesophageal junction is uncertain. • G1021 PHYSIOLOGIC AND SYMPTOMATIC RESPONSES TO CISAPRIDE TREATMENT IN OLDER ADULTS WITH GERD;. W.C. Orr, J. McClanahan, M. Zhang, LD.Z. Chen, Lynn Health Science Institute, Oklahoma City, OK Cisapride is prokinetic drug which has been demonstrated to increase LES pressure, facilitate esophageal motility, and enhance gastric emptying. Both esophageal dysfunction and delayed gastric emptying are frequent characteristics of patients with GERD, and delayed gastric emptying as well as esophageal motor disorders have been shown to be more frequent in older adults. The present study reports on 18 older adults (mean=71 years, 12F) with symptoms suggestive of GERD who were treated in a single blind placebo controlled cross-over trial with cisapride 10mg q.i.d. All subjects underwent 24-hour esophageal pH monitoring, and fasting and postprandial electrogastrography (EGG) under baseline and placebo conditions and at the end of 4 weeks of treatment with cisapride, pH measurements were taken 5cm proximal to the manometrically determined LES. Computerized spectral analysis was performed to calculate the percentage of 2-4 cycles/min waves, the power of the EGG dominant frequency and the instability coefficient (minute-by-minute variation of the slow wave frequency). RESULTS: Heartburn episodes showed a significant reduction with cisapride (c) vs placebo (p) treatment (mean=16/week (p) vs 11/week (c) p < .05). Similarly, heartburn intensity (scale of 0-10) was reduced significantly for both daytime (mean=2.0 (p) vs 1.0 (c)) and at night (.96 (p) vs .26 (c)). In addition reports of postprandial fullness were significantly reduced (p < .02). There were no significant differences in 24-hour acid contact time (ACT) with cisapride treatment (8.6% (p) vs 7.2% (c)), upright ACT (12% (p) vs 10% (c)) or supine (3% (p) vs 2% (c)). The percent 2-4 cpm activity was significantly (p < .005) increased with cisapride treatment under fasting conditions. This was not significantly changed postprandial. The instability coefficient was significantly diminished with cisapride under both fasting and postprandial conditions (p < .03, .01 respectively). The power in the dominant frequency was not altered under any condition by cisapride. CONCLUSIONS: 1. Cisapride treatment significantly normalized parameters of gastric myoelectric functioning and significantly reduced symptoms of postprandial fullness. 2. Cisapride is an effective treatment for older adults with symptoms of GERD, and symptom reduction appears to be related to the normalization of gastric myoelectric functioning rather than esophageal acid contact time. 3. Although there were no significant changes in ACT there was significant reduction in symptoms related to gastroesophageal refux. • G1022 DEVELOPMENT OF CLARITHROMYCIN RESISTANCE IS 2.7 TIMES LESS LIKELY WITH RANITIDINE BISMUTH CITRATE THAN WITH OMEPRAZOLE. M. Osato z, D.Y. Graham 1, N Vakil 2, S.H. Gordon 3, C.S. Kleoudis3, M.T. Silver3, R.H. Murdock 3, 1VAMC, Houston, TX, 2University of Wisconsin, Milwaukee, Wl, 3Glaxo Wellcome Inc., Research Triangle Park, NC. Background: Antibiotic resistance is an increasing problem in the treatment of H. pylori infection. Purpose: To investigate whether clarithromycin (CLARI) resistance develops less frequently when ranitidine bismuth citrate (RBC) is used with CLARI compared to omeprazole (OME) plus CLARI in the treatment of H. pylori infection. Methods: Patients were enrolled in two identically designed, randomized double-blind, double-dummy multicenter trials involving patients with endoscopically diagnosed duodenal ulcer and H. pylori. Therapy consisted of RBC 400mg BID plus CLARI 500mg TID for 14 days followed by RBC 400mg BID alone for 14 days or OME 40mg QD plus CLARI 500mg TID for 14 days followed by OME 20mg QD alone for 14 days. Culture and susceptibility testing was done on antral and corpus specimens both before and after treatment. CLARI susceptibility was by E-test, with resistance defined as an MIC > 2~ag/mL. Acquired resistance was calculated in patients who had CLARI susceptible organisms at baseline and evaluable posttreatment culture results. Results: 512 patients had H pylori data at baseline and post-treatment culture results; 466 had CLARI susceptible H. pylori at baseline. Acquired CLARI resistance was significantly less common with RBC than with OME: RBC +
Esophageal, Gastric, and Duodenal Disorders A249 CLARI---19/230 (8%) compared to OME+CLARI=41/236 (17%), p <0.01. Looked at another way, of those patients whose infection was not cured, OME co-therapy was 2.7 times (odds ratio) more likely to result in acquired resistance to CLARI compared to co-therapy with RBC. Conclusion: Development of resistance to CLARI is significantly less likely with RBC compared to OME. These data are consistent with the hypothesis that ranitidine bismuth citrate co-therapy is associated with a reduced frequency of antimicrobial resistance. This study was funded by Glaxo Wellcome Inc., Research Triangle Park, NC. • G1023 IS THERE A ROLE FOR HONEY IN THE TREATMENT OF HELICOBACTER PYLOR1 INFECTION? M. Osato, S. Reddy. D.Y. Graham, Department of Medicine, Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX. Background: It has been observed that honey from New Zealand and Saudi Arabia at concentrations approximating 20% (v/v) can inhibit the growth of H. pylori in vitro. The mechanism of the anti-H, pylori effect is conjectured to involve hydrogen peroxide mediated killing. This study was designed to determine whether regional differences in honey production (honey from Texas and Iowa) could be detected with regard to the anti-H, pylori-inhibiting activity and to determine whether this activity was due to the presence of hydrogen peroxide in the honey. Methods: Broth dilution susceptibility tests were performed using solutions of honey prepared in BHI broth ranging in concentration from 5-35% (v/v) in 5% increments. Control solutions containing glucose, fructose and combined glucose/fructose solutions in ratios of 1:1.23 were also prepared. A catalase control was also included. Eighteen clinical isolates of 11. pylori were tested. Inoculated plates were placed at 37C under 12% CO2 for 3 days. After 3 days, 10 uL aliquots from each well were transferred to Mueller-Hinton agar plates and incubated under 12% CO2 for an additional 3 days. Growth was determined on the basis of plus/minus grading. Results: All of the solutions containing either fructose, glucose, glucose/fructose combinations, or honey were equally effective in inhibiting the growth of H. pylori. All of the isolates were inhibited by solutions containing 15% (w/v) carbohydrate. Honey solutions, with or without catalase, inhibited 14/18 isolates at a concentration of 10%, and 18/18 isolates at a concentration of 15%. Condnsion: Regional differences in honey activity against H. pylori were not detected, nor was the effect of killing found to be related to the presence of hydrogen peroxide in the honey. Osmotic effects were shown to be the most important parameter for killing H. pylori as all carbohyrate solutions >__15% (v/v) inhibited 100% of the H. pylori. It would seem impossible to obtain this high concentration at the sites of H. pylori growth in vivo. • GI024 COMPARATIVE EFFICACIES OF ANTIMICROBIAL AGENTS AGAINST CLARITHROMYCIN-RESISTANT HELICOBACTER PYLOR1. M.S. Osato, S.G. Reddy, D.Y. Graham, Department of Medicine, Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX; A.A. Piergies, Evanston Northwestern Healthcare, Clinical Pharmacology Unit, Evanston, IL; W. Bochenek, R. Testa, Wyeth-Ayerst, Philadelphia, PA. Background: Emergence of antibiotic resistant H. pylori has necessitated the identification of alternate therapies for the treatment of this infection. Aim: To assess the in vitro efficacies of eight antibiotics as compared to clarithrumcyin against clarithromycin-resistant isolates of 11. pylori. Included in the evaluation were clarithromycin, azithromycin, minocycline, tetracycline, ofloxacin, ciprofloxacin, cefixime and two investigational agents: DMG-MINO CL 344 (a minocycline derivative), and a cyclic carbonate of erythromycin A. Methods: Testing was performed using agar dilution methods currently being evaluated by the NCCLS subcommittee on antimicrobial susceptibility testing. Under these guidelines, Mueller-Hinton agar containing 5% aged sheep blood was used. All incubations were done under CampyPak Plus conditions for 72 hours at 37 C. The drug concentrations in the agar ranged from 0.016 to 16 pg/mL. Twenty-one clarithromycin-resistant clinical isolates of H. pylori obtained from patients with duodenal ulcer were used. H. pylori ATCC 43504 was used as the control in all determinations. Results: The MICsJMIC,, o values show that the tetracyclines were the most efficacious agents, followed by cefixime. Although the quinolones had MICso values of 1 or 2, the MICgovalues were 16 pg/mL. Macrolide cross-resistance was detected.
MICs0 MIC~
Inhibitory Concentrations (lag/mL) Clar Cyclic Azith MINO CL344 Tetra Cefix Oflox Cipro 16 > 16 > 16 0.5 0.25 1 1 2 1 > 16 > 16 > 16 0.5 0.5 1 2 16 16
Conclusion: Macrolide cross-resistance prevents use of this entire class of antimicrobials when clarithromycin resistance is present. Tetracyclines and cefixime are possible alternative agents for the treatment of H. pylori infection in these patients. Supported, in part, by Wyeth-Ayerst
Esophageal, Gastric, and Duodenal Disorders A249 CLARI---19/230 (8%) compared to OME+CLARI=41/236 (17%), p <0.01. Looked at another way, of those patients whose infection was not cured, OME co-therapy was 2.7 times (odds ratio) more likely to result in acquired resistance to CLARI compared to co-therapy with RBC. Conclusion: Development of resistance to CLARI is significantly less likely with RBC compared to OME. These data are consistent with the hypothesis that ranitidine bismuth citrate co-therapy is associated with a reduced frequency of antimicrobial resistance. This study was funded by Glaxo Wellcome Inc., Research Triangle Park, NC. • G1023 IS THERE A ROLE FOR HONEY IN THE TREATMENT OF HELICOBACTER PYLOR1 INFECTION? M. Osato, S. Reddy. D.Y. Graham, Department of Medicine, Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX. Background: It has been observed that honey from New Zealand and Saudi Arabia at concentrations approximating 20% (v/v) can inhibit the growth of H. pylori in vitro. The mechanism of the anti-H, pylori effect is conjectured to involve hydrogen peroxide mediated killing. This study was designed to determine whether regional differences in honey production (honey from Texas and Iowa) could be detected with regard to the anti-H, pylori-inhibiting activity and to determine whether this activity was due to the presence of hydrogen peroxide in the honey. Methods: Broth dilution susceptibility tests were performed using solutions of honey prepared in BHI broth ranging in concentration from 5-35% (v/v) in 5% increments. Control solutions containing glucose, fructose and combined glucose/fructose solutions in ratios of 1:1.23 were also prepared. A catalase control was also included. Eighteen clinical isolates of 11. pylori were tested. Inoculated plates were placed at 37C under 12% CO2 for 3 days. After 3 days, 10 uL aliquots from each well were transferred to Mueller-Hinton agar plates and incubated under 12% CO2 for an additional 3 days. Growth was determined on the basis of plus/minus grading. Results: All of the solutions containing either fructose, glucose, glucose/fructose combinations, or honey were equally effective in inhibiting the growth of H. pylori. All of the isolates were inhibited by solutions containing 15% (w/v) carbohydrate. Honey solutions, with or without catalase, inhibited 14/18 isolates at a concentration of 10%, and 18/18 isolates at a concentration of 15%. Condnsion: Regional differences in honey activity against H. pylori were not detected, nor was the effect of killing found to be related to the presence of hydrogen peroxide in the honey. Osmotic effects were shown to be the most important parameter for killing H. pylori as all carbohyrate solutions >__15% (v/v) inhibited 100% of the H. pylori. It would seem impossible to obtain this high concentration at the sites of H. pylori growth in vivo. • GI024 COMPARATIVE EFFICACIES OF ANTIMICROBIAL AGENTS AGAINST CLARITHROMYCIN-RESISTANT HELICOBACTER PYLOR1. M.S. Osato, S.G. Reddy, D.Y. Graham, Department of Medicine, Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX; A.A. Piergies, Evanston Northwestern Healthcare, Clinical Pharmacology Unit, Evanston, IL; W. Bochenek, R. Testa, Wyeth-Ayerst, Philadelphia, PA. Background: Emergence of antibiotic resistant H. pylori has necessitated the identification of alternate therapies for the treatment of this infection. Aim: To assess the in vitro efficacies of eight antibiotics as compared to clarithrumcyin against clarithromycin-resistant isolates of 11. pylori. Included in the evaluation were clarithromycin, azithromycin, minocycline, tetracycline, ofloxacin, ciprofloxacin, cefixime and two investigational agents: DMG-MINO CL 344 (a minocycline derivative), and a cyclic carbonate of erythromycin A. Methods: Testing was performed using agar dilution methods currently being evaluated by the NCCLS subcommittee on antimicrobial susceptibility testing. Under these guidelines, Mueller-Hinton agar containing 5% aged sheep blood was used. All incubations were done under CampyPak Plus conditions for 72 hours at 37 C. The drug concentrations in the agar ranged from 0.016 to 16 pg/mL. Twenty-one clarithromycin-resistant clinical isolates of H. pylori obtained from patients with duodenal ulcer were used. H. pylori ATCC 43504 was used as the control in all determinations. Results: The MICsJMIC,, o values show that the tetracyclines were the most efficacious agents, followed by cefixime. Although the quinolones had MICso values of 1 or 2, the MICgovalues were 16 pg/mL. Macrolide cross-resistance was detected.
MICs0 MIC~
Inhibitory Concentrations (lag/mL) Clar Cyclic Azith MINO CL344 Tetra Cefix Oflox Cipro 16 > 16 > 16 0.5 0.25 1 1 2 1 > 16 > 16 > 16 0.5 0.5 1 2 16 16
Conclusion: Macrolide cross-resistance prevents use of this entire class of antimicrobials when clarithromycin resistance is present. Tetracyclines and cefixime are possible alternative agents for the treatment of H. pylori infection in these patients. Supported, in part, by Wyeth-Ayerst