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Randomized trial of omeprazole and clarithromycin combined with either metronidazole or amoxycillin in the treatment of Helicobacter pylori (HP) in metronidazole resistant or sensitive patients
April 1998
Apoptosis in situ was examined by the methods of terminal uridine deoxynucleotidyl nick end-labelling (TUNEL). We compared the apoptotic indices in the patients infected with Helicobacter pylori with those of uninfected patients, and evaluated the relationship of the gastric juice ammonia level, cagA and vacA protein according to the apoptotic indices. All the patients infected by Helicobacter pylori had been treated with triple therapy of omeprazole, amoxacillin, and clarithromycin for two weeks, and if they showed eradication after four weeks, the reevaluation with the above studies were performed. Results: 15 out of 24 patients were infected with Helicobacter pylori. Among the 15 infected patients, six harbored cagA+vacA+ strains and seven were infected with cagA+vacA- strains. Also, two patients were infected cagA-vacA- strains. Ammonia level of gastric juice in infected patients (96.45-+54.16mmol/L) by Helicobacter pylori was significantly higher than those in both uninfected patients (13.85 -+ 6.05mmol/L) and the patients after eradication therapy. (17.61 +_.11.94mmol/L) (p < 0.01) Apoptotic indices in infected patients (11.96_+3.02) by Helicobacter pylori were higher than those in both uninfected patients(7.56 -+ 2.09) and the patients(8.32 -+ 3.78) after eradication therapy.(p < 0.05) The difference in apoptotic indices between the patients haboring cagA+vacA+ strains (n=6) (12.35 -+ 2.97) and cagA+vacA- strins (n=7) (12.14 -+ 2.98) was not statistically significant. Apoptotic indices and ammonia concentration in the gastric juice showed a slightly positive correlation (R=0.26). Conclusions: Helicobacter pylori induces epithelial apoptosis in vivo. Apoptotic indices in persons infected with vacA+ strains did not differ significantly from those with vacA- strains. Apoptotic indices were slightly correlated with the ammonia level in the gastric juice. • G0626 POST-ERADICATION EVALUATION OF H. PYLORI (HP) STATUS: THE '3C Urea LASER ASSISTED RATIO ANALYZER (LARA) BREATH TEST. M.H.M.G. Hnuben, E.F. Hensen, P. Stare, B.W.M. van 't Hoff, R.W.M. van der Hulst, A van der Ende, F.J.W. ten Kate, G.N.J. Tytgat. Department of Gastroenterology,Academic Medical Center, Amsterdam,The Netherlands Introduction: The combination of histology and culture of multiple endoscopic biopsies is the gold standard for evaluation of Hp status, before and after eradication therapy. However, this is costly, inconvenient for patients and bears a risk of sampling error. Breath testing may overcome these problems, and could be a good alternative, especially for evaluation of Hp status after eradication therapy. Aim: Establish the sensitivity and specificity of the 13C LARA Breath Test to prove successfull Hp eradication. Methods: Gastric biopsies from antrum and corpus for histology, culture and rapid urease (CLO) test were taken from patients who were referred for endoscopic examination because of dyspeptic symptoms. Patients were asked to undergo the LARA breath test when the CLO test was positive. Hp positive patients received various eradication regimens. A second endoscopy with 8 biopsies for histology, culture and rapid urease test, as well as the LARA breath test were repeated 5-7 weeks after cessation of eradication therapy. No proton pump inhibitors, antibiotics nor bismuth were allowed during 28 days prior to the breath tests. Results of the breath test were compared with the results of histology, culture and rapid urease test. For this study we used a cut off value of 5 delta units at 60 minutes after urea ingestion. Results: 100 patients were eligible for post-therapy analysis. Breath samples of 2 patients could not be processed due to low CO2 in breath sample (n=l) and technical problems (n=l). Eight patients were lost to follow-up.
N= 90 H.p.+ (n) H.P.- (n) Sens. (%) 8pec. (%) PPV (%) NPV(%) Histology + Culture + CLO 6 84 100 100 100 100 Histology 7 83 100 99 86 100 6 84 100 100 100 100 Culture LARA 7 83 100 99 86 100 Condusinn: The LARA breath test proves to be a reliable alternative for posttherapy evaluation of Hp status. These encouraging data need to be confirmed in the ongoing multicentre study. Supported by Alimenterics Inc. Morris Plains, NJ, USA G0627 PPI-TRIPLE THERAPY FAILURE: RE-TREATMENT WITH PPITRIPLE THERAPY OR QUADRUPLE THERAPY? M.H,M.G. Houben, D. van de Beek, B.W.M. van "t Hoff, R.W.M. van der Hulst, E.A.J. Ranws, A. van der Ende, F.J.W. ten Kate, G.N.J. Tytgat. Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands.
Triple therapy with proton pump inhibitors (PPIs) in combination with two antibiotics for one week eradicates Helicobacter pylori (Hp) in around 90% of the patients. It is unclear how PPI triple therapy failures should be retreated. PPI triple therapy or quadruple therapy? Aim: To compare one week PPI-triple with quadruple therapy for Hp eradication in patients with previous PPI-triple therapy failure in relation to metronidazole and clarithromycin resistance. Methods: 19 consecutive patients (M/F 9/10) with persisting Hp infection after one week treatment with omeprazole 20 mg bid, metronidazole 400 mg bid and clarithromycin 250 mg bid (OMC) or omeprazole 20 mg bid, amoxycillin 1000 mg bid and clarithromycin 500 mg bid (OAC) were
Esophageal, Gastric, and Duodenal Disorders A153
randomly allocated to one of the following treatment schemes for 7 days each. Eight patients were retreated with OMC and 11 patients were treated with omeprazole 20 mg bid, bismuth subcitrate 120 mg qid, tetracycline 500 qid, metronidazole 500 mg tid (OBTM). Other PPI, bismuth compounds or antibiotics were not allowed during the study period At each endoscopy 6 biopsies were taken: 2 for histology and 1 for culture from both antrum and corpus. Hp eradication was considered successful when both histology and culture were negative at least 4 weeks after the last dose of eradication therapy. Antibiotic resistance was determined by E-test. Metronidazole resistance (MR) was defined as a MIC > 8 pg/ml, clarithromycin resistance (CR) as MIC _>1 pg/ml. Results: ITT eradication rates are presented in the table. In one patient in the OBTM-group the antibiotic sensitivity pattern was not available. None of the patients were both MS and CR. N = 90 H.p.+ (n) H.P.- (n) Sens. (%) Spec. (%) PPV (%) NPV (%) Histology + Culture + CLO 6 84 100 100 100 100 Histology 7 83 100 99 86 100 Culture 6 84 100 100 100 100 LARA 7 83 100 99 86 100 The difference in overall eradication rate between OMC and OBTM is 0.75. (95% confidence interval: 0.32-0.98); p=0.003 (exact p value). Conclusions: In failures of PPI triple therapy, one week OBTM is superior to one week OMC, especially in metronidazole resistant patients. We recommend quadruple therapy in PPI-triple therapy failure. • G0628
RANDOMIZED TRIAL OF OMEPRAZOLE AND CLARITHROMYCIN COMBINED WITH EITHER METRONIDAZOLE OR AMOXYCILLIN IN THE TREATMENT OF HELICOBACTER PYLORI (HP) IN METRONIDAZOLE RESISTANT OR SENSITIVE PATIENTS. M.H.M.G. Houben, E.F. Hensen, B.W.M. van 't Hoff, R.W.M. van der Hulst, E.A.J. Rauws, A. van der Ende, F.J.W. ten Kate, G.N.J. Tytgat. Department of Gastroenterology, Academic Medical Hospital, Amsterdam, The Netherlands. Omeprazole and clarithromycin combined with either amoxycillin or metronidazole are effective therapies against Hp infections but the effect of metronidazole resistance on these regimens is unclear. Up to now, no studies have been designed to study whether Hp eradication rates of OMC or OAC are equal in patients harbouring resistant or sensitive strains for metronidazole. Aim: To assess if metronidazole resistance affects the Hp eradication rates in patients treated for one week with either omeprazole 20 mg bid, metronidazole 400 mg bid and clarithromycin 250 nag bid (OMC) or omeprazole 20 mg bid, amoxycillin 1000 mg bid and clarithromycin 500 mg bid (OAC). Design: A randomized, single-blind, single centre study with parallel groups. Patients were stratified for rnetronidazole resistance. Whithin the strata patients were randomised to either OAC or OMC. Methods: 122 patients who were culture positive for Hp were enrolled into a metronidazole resistant (MIC > 8 pg/ml) and a metronidazole sensitive group (MIC < 4 pg/ml). Resistance was determined by E-test. Repeat endoscopy was performed at least 28 days after the last dose of study medication. At each endoscopy 6 biopsies were taken: 2 for histology and 1 for culture from both antrum and corpus. Cure of Hp infection was defined as absence of Hp in culture and histology in all biopsies. Results: 122 patients were included ((18-75 years; 40 past or present ulcer, 82 NUD). Twelve patients were excluded from the PP analysis due to violation of the protocol (i.e. non compliance, lost to follow up, non-allowed medication). All 4 clarithromycin resistant patients (3%) were also metronidazole resistant and were all failures of therapy.
ITT PP
Metronidazole sensitive OAC OMC 23/26 (89%) 21/26 (81%) 22/25 (88%) 19/22(85%)
Metronidazole resistant OAC OMC 29/35 (83%) 29/35 (83%) 27/30 (90%) 27/33 (82%)
CONCLUSIONS: Based on the PP-analysis we conclude that OAC is equally effective in patients with metronidazole-sensitive or resistant strains. In no other groups equivalence, nor significant differences could be shown. However not significant, OMC has a slighly lower eradicationrate in all groups. We recommend OAC as first line therapy, especially if metronidazole resistance is unknown. Supported by ASTRA, Zoetermeer, The Netherlands.
Apoptosis in situ was examined by the methods of terminal uridine deoxynucleotidyl nick end-labelling (TUNEL). We compared the apoptotic indices in the patients infected with Helicobacter pylori with those of uninfected patients, and evaluated the relationship of the gastric juice ammonia level, cagA and vacA protein according to the apoptotic indices. All the patients infected by Helicobacter pylori had been treated with triple therapy of omeprazole, amoxacillin, and clarithromycin for two weeks, and if they showed eradication after four weeks, the reevaluation with the above studies were performed. Results: 15 out of 24 patients were infected with Helicobacter pylori. Among the 15 infected patients, six harbored cagA+vacA+ strains and seven were infected with cagA+vacA- strains. Also, two patients were infected cagA-vacA- strains. Ammonia level of gastric juice in infected patients (96.45-+54.16mmol/L) by Helicobacter pylori was significantly higher than those in both uninfected patients (13.85 -+ 6.05mmol/L) and the patients after eradication therapy. (17.61 +_.11.94mmol/L) (p < 0.01) Apoptotic indices in infected patients (11.96_+3.02) by Helicobacter pylori were higher than those in both uninfected patients(7.56 -+ 2.09) and the patients(8.32 -+ 3.78) after eradication therapy.(p < 0.05) The difference in apoptotic indices between the patients haboring cagA+vacA+ strains (n=6) (12.35 -+ 2.97) and cagA+vacA- strins (n=7) (12.14 -+ 2.98) was not statistically significant. Apoptotic indices and ammonia concentration in the gastric juice showed a slightly positive correlation (R=0.26). Conclusions: Helicobacter pylori induces epithelial apoptosis in vivo. Apoptotic indices in persons infected with vacA+ strains did not differ significantly from those with vacA- strains. Apoptotic indices were slightly correlated with the ammonia level in the gastric juice. • G0626 POST-ERADICATION EVALUATION OF H. PYLORI (HP) STATUS: THE '3C Urea LASER ASSISTED RATIO ANALYZER (LARA) BREATH TEST. M.H.M.G. Hnuben, E.F. Hensen, P. Stare, B.W.M. van 't Hoff, R.W.M. van der Hulst, A van der Ende, F.J.W. ten Kate, G.N.J. Tytgat. Department of Gastroenterology,Academic Medical Center, Amsterdam,The Netherlands Introduction: The combination of histology and culture of multiple endoscopic biopsies is the gold standard for evaluation of Hp status, before and after eradication therapy. However, this is costly, inconvenient for patients and bears a risk of sampling error. Breath testing may overcome these problems, and could be a good alternative, especially for evaluation of Hp status after eradication therapy. Aim: Establish the sensitivity and specificity of the 13C LARA Breath Test to prove successfull Hp eradication. Methods: Gastric biopsies from antrum and corpus for histology, culture and rapid urease (CLO) test were taken from patients who were referred for endoscopic examination because of dyspeptic symptoms. Patients were asked to undergo the LARA breath test when the CLO test was positive. Hp positive patients received various eradication regimens. A second endoscopy with 8 biopsies for histology, culture and rapid urease test, as well as the LARA breath test were repeated 5-7 weeks after cessation of eradication therapy. No proton pump inhibitors, antibiotics nor bismuth were allowed during 28 days prior to the breath tests. Results of the breath test were compared with the results of histology, culture and rapid urease test. For this study we used a cut off value of 5 delta units at 60 minutes after urea ingestion. Results: 100 patients were eligible for post-therapy analysis. Breath samples of 2 patients could not be processed due to low CO2 in breath sample (n=l) and technical problems (n=l). Eight patients were lost to follow-up.
N= 90 H.p.+ (n) H.P.- (n) Sens. (%) 8pec. (%) PPV (%) NPV(%) Histology + Culture + CLO 6 84 100 100 100 100 Histology 7 83 100 99 86 100 6 84 100 100 100 100 Culture LARA 7 83 100 99 86 100 Condusinn: The LARA breath test proves to be a reliable alternative for posttherapy evaluation of Hp status. These encouraging data need to be confirmed in the ongoing multicentre study. Supported by Alimenterics Inc. Morris Plains, NJ, USA G0627 PPI-TRIPLE THERAPY FAILURE: RE-TREATMENT WITH PPITRIPLE THERAPY OR QUADRUPLE THERAPY? M.H,M.G. Houben, D. van de Beek, B.W.M. van "t Hoff, R.W.M. van der Hulst, E.A.J. Ranws, A. van der Ende, F.J.W. ten Kate, G.N.J. Tytgat. Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands.
Triple therapy with proton pump inhibitors (PPIs) in combination with two antibiotics for one week eradicates Helicobacter pylori (Hp) in around 90% of the patients. It is unclear how PPI triple therapy failures should be retreated. PPI triple therapy or quadruple therapy? Aim: To compare one week PPI-triple with quadruple therapy for Hp eradication in patients with previous PPI-triple therapy failure in relation to metronidazole and clarithromycin resistance. Methods: 19 consecutive patients (M/F 9/10) with persisting Hp infection after one week treatment with omeprazole 20 mg bid, metronidazole 400 mg bid and clarithromycin 250 mg bid (OMC) or omeprazole 20 mg bid, amoxycillin 1000 mg bid and clarithromycin 500 mg bid (OAC) were
Esophageal, Gastric, and Duodenal Disorders A153
randomly allocated to one of the following treatment schemes for 7 days each. Eight patients were retreated with OMC and 11 patients were treated with omeprazole 20 mg bid, bismuth subcitrate 120 mg qid, tetracycline 500 qid, metronidazole 500 mg tid (OBTM). Other PPI, bismuth compounds or antibiotics were not allowed during the study period At each endoscopy 6 biopsies were taken: 2 for histology and 1 for culture from both antrum and corpus. Hp eradication was considered successful when both histology and culture were negative at least 4 weeks after the last dose of eradication therapy. Antibiotic resistance was determined by E-test. Metronidazole resistance (MR) was defined as a MIC > 8 pg/ml, clarithromycin resistance (CR) as MIC _>1 pg/ml. Results: ITT eradication rates are presented in the table. In one patient in the OBTM-group the antibiotic sensitivity pattern was not available. None of the patients were both MS and CR. N = 90 H.p.+ (n) H.P.- (n) Sens. (%) Spec. (%) PPV (%) NPV (%) Histology + Culture + CLO 6 84 100 100 100 100 Histology 7 83 100 99 86 100 Culture 6 84 100 100 100 100 LARA 7 83 100 99 86 100 The difference in overall eradication rate between OMC and OBTM is 0.75. (95% confidence interval: 0.32-0.98); p=0.003 (exact p value). Conclusions: In failures of PPI triple therapy, one week OBTM is superior to one week OMC, especially in metronidazole resistant patients. We recommend quadruple therapy in PPI-triple therapy failure. • G0628
RANDOMIZED TRIAL OF OMEPRAZOLE AND CLARITHROMYCIN COMBINED WITH EITHER METRONIDAZOLE OR AMOXYCILLIN IN THE TREATMENT OF HELICOBACTER PYLORI (HP) IN METRONIDAZOLE RESISTANT OR SENSITIVE PATIENTS. M.H.M.G. Houben, E.F. Hensen, B.W.M. van 't Hoff, R.W.M. van der Hulst, E.A.J. Rauws, A. van der Ende, F.J.W. ten Kate, G.N.J. Tytgat. Department of Gastroenterology, Academic Medical Hospital, Amsterdam, The Netherlands. Omeprazole and clarithromycin combined with either amoxycillin or metronidazole are effective therapies against Hp infections but the effect of metronidazole resistance on these regimens is unclear. Up to now, no studies have been designed to study whether Hp eradication rates of OMC or OAC are equal in patients harbouring resistant or sensitive strains for metronidazole. Aim: To assess if metronidazole resistance affects the Hp eradication rates in patients treated for one week with either omeprazole 20 mg bid, metronidazole 400 mg bid and clarithromycin 250 nag bid (OMC) or omeprazole 20 mg bid, amoxycillin 1000 mg bid and clarithromycin 500 mg bid (OAC). Design: A randomized, single-blind, single centre study with parallel groups. Patients were stratified for rnetronidazole resistance. Whithin the strata patients were randomised to either OAC or OMC. Methods: 122 patients who were culture positive for Hp were enrolled into a metronidazole resistant (MIC > 8 pg/ml) and a metronidazole sensitive group (MIC < 4 pg/ml). Resistance was determined by E-test. Repeat endoscopy was performed at least 28 days after the last dose of study medication. At each endoscopy 6 biopsies were taken: 2 for histology and 1 for culture from both antrum and corpus. Cure of Hp infection was defined as absence of Hp in culture and histology in all biopsies. Results: 122 patients were included ((18-75 years; 40 past or present ulcer, 82 NUD). Twelve patients were excluded from the PP analysis due to violation of the protocol (i.e. non compliance, lost to follow up, non-allowed medication). All 4 clarithromycin resistant patients (3%) were also metronidazole resistant and were all failures of therapy.
ITT PP
Metronidazole sensitive OAC OMC 23/26 (89%) 21/26 (81%) 22/25 (88%) 19/22(85%)
Metronidazole resistant OAC OMC 29/35 (83%) 29/35 (83%) 27/30 (90%) 27/33 (82%)
CONCLUSIONS: Based on the PP-analysis we conclude that OAC is equally effective in patients with metronidazole-sensitive or resistant strains. In no other groups equivalence, nor significant differences could be shown. However not significant, OMC has a slighly lower eradicationrate in all groups. We recommend OAC as first line therapy, especially if metronidazole resistance is unknown. Supported by ASTRA, Zoetermeer, The Netherlands.