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We would like to thank Georgopoulos et al for their kind remarks on our manuscript.1Molina-Infante J. et al.Gastroenterology. 2013; 145: 121-128Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar In a similar line of work, these authors have recently demonstrated that 10-day concomitant therapy is a highly effective therapy (>90%) in Greece, where the clarithromycin resistance rate is around 40%.2Georgopoulos S.D. et al.Helicobacter. 2013; 18: 459-467Crossref PubMed Scopus (50) Google Scholar Notwithstanding the fact that in our manuscript we found a 14-day optimized concomitant therapy not to be impaired by dual resistance to clarithromycin and metronidazole (only in 3 patients), the authors are right to point out that evolving evidence, including ours3Molina-Infante J. et al.Helicobacter. 2012; 17: 269-276Crossref PubMed Scopus (69) Google Scholar and theirs,2Georgopoulos S.D. et al.Helicobacter. 2013; 18: 459-467Crossref PubMed Scopus (50) Google Scholar is showing that the Achilles heel of concomitant therapy, albeit to a much lesser extent than that observed with sequential therapy, is dual resistance.4Graham D.Y. et al.Clin Gastroenterol Hepatol. 2013 Jun 7; ([Epub ahead of print])Google ScholarIn this regard, the recent article published by Graham et al is a must for Helicobacter pylori researchers.4Graham D.Y. et al.Clin Gastroenterol Hepatol. 2013 Jun 7; ([Epub ahead of print])Google Scholar Graham et al elegantly provide the formula for predicting outcome of therapies based on the effectiveness of the regimen against susceptible and resistant strains along with knowledge of the prevalence of resistance. As for concomitant therapy, the efficacy of 14-day therapy is not impaired by either clarithromycin or metronidazole resistance, but it is expected to fall below 90% when the prevalence of dual clarithromycin–metronidazole resistant strains is >15%. Therefore, the authors state that it cannot be recommended in settings where metronidazole resistance is >60% (ie, China, India, Iran, or Central or South America) or in populations at high risk of dual resistance (ie, after clarithromycin or metronidazole treatment failures). Accordingly, the failure of 14-day concomitant therapy has been lately documented as a first-line therapy in Turkey (75%)5Toros A.B. et al.Helicobacter. 2011; 16: 225-228Crossref PubMed Scopus (27) Google Scholar and Korea (80%),6Lim J.H. et al.Helicobacter. 2013; 18: 180-186Crossref PubMed Scopus (54) Google Scholar and with a length of 10 days as a second-line therapy (60.6%) by Georgopoulos et al.2Georgopoulos S.D. et al.Helicobacter. 2013; 18: 459-467Crossref PubMed Scopus (50) Google Scholar There are such differences susceptibility patterns for H pylori infection that one size cannot fit all; it is true that we currently lack a valid nonbismuth recipe for everyone. However, 14-day concomitant therapy seems to be the best nonbismuth choice, at least for most European countries, some Asian countries, and possibly the United States, seeing as clarithromycin resistance rates are steadily increasing in these settings, whereas metronidazole resistance remains in relatively low (<30%–40%).7Megraud F. et al.Gut. 2013; 62: 34-42Crossref PubMed Scopus (665) Google ScholarFrom a microbiological standpoint, the most reliable way to overcome antibiotic resistance would be the use of a combination of drugs for which resistance does not seem to be a problem. In this context, bismuth quadruple therapy seems to be an attractive alternative treatment, especially in its most recent galenic formulation, bismuth subcitrate potassium, metronidazole, and tetracycline (BMT, sold under license as Pylera).8Megraud F. Therap Adv Gastroenterol. 2012; 5: 103-109Crossref PubMed Scopus (110) Google Scholar Nonetheless, bismuth salts are not widely available, many countries are currently experiencing a general unavailability of tetracycline, and the launch of Pylera onto the market has proved troublesome. As such, nonbismuth quadruple therapies remain in the front line to tackle H pylori infection in many settings worldwide.It took a decade to understand that the efficacy of sequential therapy was undermined by metronidazole and dual resistance,4Graham D.Y. et al.Clin Gastroenterol Hepatol. 2013 Jun 7; ([Epub ahead of print])Google Scholar as efficiently shown by Georgopoulos et al in their table. At the present, we are aware that concomitant therapy may not work in settings with high rates of dual clarithromycin and metronidazole resistance, in which bismuth quadruple therapy would be the best choice. As such, concomitant therapy should be validated out of Taiwan, Thailand, Japan, China, Spain, and Greece, where it has accomplished cure rates of >90%. Trials should include fair comparators (ie, hybrid sequential-concomitant therapy or bismuth quadruple therapy, but not triple therapy), to avoid exposure of subjects to ineffective therapies. Likewise, antimicrobial resistance data will be key, as Georgopoulos et al emphasize, to promptly decipher the best quadruple therapy, either bismuth- or nonbismuth-based, for each and every geographical area. We would like to thank Georgopoulos et al for their kind remarks on our manuscript.1Molina-Infante J. et al.Gastroenterology. 2013; 145: 121-128Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar In a similar line of work, these authors have recently demonstrated that 10-day concomitant therapy is a highly effective therapy (>90%) in Greece, where the clarithromycin resistance rate is around 40%.2Georgopoulos S.D. et al.Helicobacter. 2013; 18: 459-467Crossref PubMed Scopus (50) Google Scholar Notwithstanding the fact that in our manuscript we found a 14-day optimized concomitant therapy not to be impaired by dual resistance to clarithromycin and metronidazole (only in 3 patients), the authors are right to point out that evolving evidence, including ours3Molina-Infante J. et al.Helicobacter. 2012; 17: 269-276Crossref PubMed Scopus (69) Google Scholar and theirs,2Georgopoulos S.D. et al.Helicobacter. 2013; 18: 459-467Crossref PubMed Scopus (50) Google Scholar is showing that the Achilles heel of concomitant therapy, albeit to a much lesser extent than that observed with sequential therapy, is dual resistance.4Graham D.Y. et al.Clin Gastroenterol Hepatol. 2013 Jun 7; ([Epub ahead of print])Google Scholar In this regard, the recent article published by Graham et al is a must for Helicobacter pylori researchers.4Graham D.Y. et al.Clin Gastroenterol Hepatol. 2013 Jun 7; ([Epub ahead of print])Google Scholar Graham et al elegantly provide the formula for predicting outcome of therapies based on the effectiveness of the regimen against susceptible and resistant strains along with knowledge of the prevalence of resistance. As for concomitant therapy, the efficacy of 14-day therapy is not impaired by either clarithromycin or metronidazole resistance, but it is expected to fall below 90% when the prevalence of dual clarithromycin–metronidazole resistant strains is >15%. Therefore, the authors state that it cannot be recommended in settings where metronidazole resistance is >60% (ie, China, India, Iran, or Central or South America) or in populations at high risk of dual resistance (ie, after clarithromycin or metronidazole treatment failures). Accordingly, the failure of 14-day concomitant therapy has been lately documented as a first-line therapy in Turkey (75%)5Toros A.B. et al.Helicobacter. 2011; 16: 225-228Crossref PubMed Scopus (27) Google Scholar and Korea (80%),6Lim J.H. et al.Helicobacter. 2013; 18: 180-186Crossref PubMed Scopus (54) Google Scholar and with a length of 10 days as a second-line therapy (60.6%) by Georgopoulos et al.2Georgopoulos S.D. et al.Helicobacter. 2013; 18: 459-467Crossref PubMed Scopus (50) Google Scholar There are such differences susceptibility patterns for H pylori infection that one size cannot fit all; it is true that we currently lack a valid nonbismuth recipe for everyone. However, 14-day concomitant therapy seems to be the best nonbismuth choice, at least for most European countries, some Asian countries, and possibly the United States, seeing as clarithromycin resistance rates are steadily increasing in these settings, whereas metronidazole resistance remains in relatively low (<30%–40%).7Megraud F. et al.Gut. 2013; 62: 34-42Crossref PubMed Scopus (665) Google Scholar From a microbiological standpoint, the most reliable way to overcome antibiotic resistance would be the use of a combination of drugs for which resistance does not seem to be a problem. In this context, bismuth quadruple therapy seems to be an attractive alternative treatment, especially in its most recent galenic formulation, bismuth subcitrate potassium, metronidazole, and tetracycline (BMT, sold under license as Pylera).8Megraud F. Therap Adv Gastroenterol. 2012; 5: 103-109Crossref PubMed Scopus (110) Google Scholar Nonetheless, bismuth salts are not widely available, many countries are currently experiencing a general unavailability of tetracycline, and the launch of Pylera onto the market has proved troublesome. As such, nonbismuth quadruple therapies remain in the front line to tackle H pylori infection in many settings worldwide. It took a decade to understand that the efficacy of sequential therapy was undermined by metronidazole and dual resistance,4Graham D.Y. et al.Clin Gastroenterol Hepatol. 2013 Jun 7; ([Epub ahead of print])Google Scholar as efficiently shown by Georgopoulos et al in their table. At the present, we are aware that concomitant therapy may not work in settings with high rates of dual clarithromycin and metronidazole resistance, in which bismuth quadruple therapy would be the best choice. As such, concomitant therapy should be validated out of Taiwan, Thailand, Japan, China, Spain, and Greece, where it has accomplished cure rates of >90%. Trials should include fair comparators (ie, hybrid sequential-concomitant therapy or bismuth quadruple therapy, but not triple therapy), to avoid exposure of subjects to ineffective therapies. Likewise, antimicrobial resistance data will be key, as Georgopoulos et al emphasize, to promptly decipher the best quadruple therapy, either bismuth- or nonbismuth-based, for each and every geographical area. Is There a Nonbismuth Quadruple Therapy That Can Reliably Overcome Bacterial Resistance?GastroenterologyVol. 145Issue 6PreviewIn the July issue of Gastroenterology Molina–Infante et al reported acceptable (grade B) and high (grade A) Helicobacter pylori eradication rates using optimized hybrid and concomitant nonbismuth quadruple therapies, in populations with relatively high rates of antibiotic resistances (ie, Spain and Southern Italy).1,2 This is a very important study because as yet most data concerning the efficacy of these first-line treatments were coming from low clarithromycin resistance areas.3,4 The authors used antimicrobial susceptibility data to conclude that dual antibiotic resistance (ie, to both clarithromycin and metronidazole) did affect cure rates with the hybrid but not with the concomitant regimen. Full-Text PDF