Question

DESCRIPTION TOTA POS 4. A 40-year-old woman with a Helicobacter pylori-positive gastric ulcer dose not respond to standard therapy with clarithromycin, amoxicillin, and omeprazole? What is the most likely reason for therapeutic falure? Provide an alternative treatment regimen and describe the mechanism of each component (2 Points)

Answer 1

Eradication of Helicobacter pylori from the gastric and duodenal mucosa of infected patients is the most important goal in the management of peptic ulcer disease and other conditions associated with H pylori.¹The survival capabilities of H pylori in the stomach make it difficult to eradicate, and effective treatment requires multidrug regimens consisting of two antibiotics

combined with acid suppressants and bismuth compounds.²A significant proportion of patients do not respond to treatment, and adverse treatment outcome is associated with advanced age, smoking, high intragastric bacterial load before treatment, bacterial genotype, and host genetic polymorphisms of the cytochrome-P450 isoenzymes that are specifically involved in the metabolism of proton pump inhibitors.³ Adherence to the drug regimen is particularly important for successful eradication of infection and can be improved by education of patients and programmes to improve compliance.⁴ But as in many other infectious diseases, antibiotic resistance is the major cause of treatment failure. Meta-analyses have established beyond doubt that resistance to either the macrolide or 5-nitroimidazole component of the regimen is an important predictor of eradication failure.^5–7The extent to which resistance compromises efficacy is related to the other components of the drug regimen and is less pronounced for metronidazole than clarithromycin.

Widespread use of antimicrobial drugs has resulted in a worldwide increase in the prevalence of antibiotic resistance in H pylori; 11-70% of clinical strains isolated in western Europe are resistant to metronidazole, and up to 15% are resistant to clarithromycin. Although tetracycline resistance seems rare, resistance to amoxicillin is an emerging and possibly under-recognised problem.

PPI, amoxicillin and metronidazole: After failure of a combination of PPI, amoxicillin and clarithromycin, a theoretically correct alternative would be the use, as second option, of other PPI-based triple therapy including amoxicillin (which does not induce resistance) and metronidazole (an antibiotic not used in the first trial), and several authors have reported encouraging results with this strategy[37-44]. However, in our experience, when this therapy has been administered twice-daily for one week, eradication rates lower than 50% have been obtained[45]; the subsequent use of higher (three times per day) antibiotic doses was followed only by a mild increase in eradication rate (58%), which was still unacceptable[45]. However, if ranitidine bismuth citrate (RBC) is used instead of PPI, also plus amoxicillin and nitroimidazole, encouraging results have been reported (81% cure rate), although in this protocol antibiotics were administered for 14 d instead of 7 d[46]. In this same study, the readministration of clarithromycin, even when co-prescribed with RBC, was associated with poor eradication rates. In the same way, Nagahara et al[47] studied a group of patients who, after failure of first-line PPI-clarithromycin-amoxicillin therapy, had received second-line therapy with the same regimen (for 14 d) or had received PPI-amoxicillin-metronidazole (for 10 d). The eradication rates for second-line therapy with the same regimen (thus readministering clarithromycin) was only 53%, while it was 81% with PPI-amoxicillin-metronidazole. These observations underlie the idea that antibiotics, and specifically clarithromycin, should not be readministered in successive treatments.

Quadruple therapy: Another alternative, the use of a quadruple regimen (i.e. PPI, bismuth, tetracycline and metronidazole), has been generally used as an optimal second-line therapy after PPI-clarithromycin-amoxicillin failure, and has been the recommended rescue regimen in several guidelines[3,48-50]. Several studies have obtained relatively good results with this quadruple regimen, and the results are summarized in Table ​Table11[45,51-71]. Thus, the weighted mean eradication rate with this rescue therapy, calculated from the studies included in the table, is 77%. In this combination regimen, PPI should be prescribed in the usual dose for twice a day, colloidal bismuth subcitrate 120 mg four times per day, tetracycline 500 mg four times per day, and metronidazole is probably best prescribed at high doses (i.e. 500 mg three times per day). The study with the lowest efficacy[57] administered metronidazole at low doses (250 mg four times per day). Limited experience suggests that quadruple therapy may also be effective when the first (failed) regimen included RBC instead of PPI. Thus, Beales et al[72] reported that four of the five patients initially failing RBC-clarithromycin-amoxicillin therapy were successfully treated with quadruple therapy. Seven-day treatment duration seems to be sufficient when quadruple therapy is used after a failed first regimen, as quite similar eradication rates with 7, 10 and 14 d have been reported (mean figures, calculated from Table ​Table1,1, of 74%, 72% and 81%, respectively). Furthermore, in a recent retrospective study, patients who failed the standard triple therapy (PPI, amoxicillin, clarithromycin) received 1 or 2 wk quadruple therapy, and the eradication rate was similar between the two regimens[54]. These results are in agreement with those reported previously with quadruple therapy as a first-line regimen, where 1-wk therapy appeared sufficient, and prolonging treatment did not increase efficacy[73]. Finally, although PPIs are generally prescribed as the antisecretors in quadruple therapy, some authors have shown, in a randomized study, that omeprazole 20 mg b.i.d. and ranitidine 300 mg b.i.d. were equally effective as antisecretory agents combined in a second-line quadruple eradication regimen after failure with previous regimens without metronidazole[62]. Nevertheless, these regimens were administered over 14 d and, therefore, it remains to be demonstrated whether the equivalence between both antisecretors-PPIs and H₂-blockers- is also observable with 7 d regimens.