Is There a Nonbismuth Quadruple Therapy That Can Reliably Overcome Bacterial Resistance?

Abstract

In 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).1Molina-Infante J. et al.Gastroenterology. 2013; 145: 121-128Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 2Graham D.Y. et al.Helicobacter. 2007; 12: 275-278Crossref PubMed Scopus (313) Google Scholar 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.3Hsu P.I. et al.Helicobacter. 2011; 16: 139-145Crossref PubMed Scopus (141) Google Scholar, 4Wu D.C. et al.Clin Gastroenterol Hepatol. 2010; 8: 36-41Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar 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. This may be true with an optimized (14-day) regimen, but, as outlined by the same authors, the small number of patients with clarithromycin-resistant (and consequently with dual-resistant) strains precludes drawing definitive conclusions. As mentioned by Graham and Shiotani,5Graham D.Y. et al.Gastroenterology. 2012; 143: 10-12Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar to estimate the treatment efficacy in any area with a known resistance pattern it is very important to know the exact percentage of strains with different resistance patterns cured by a specific regimen. Thus, all data, especially those regarding specific resistance patterns, must be solid and based on an adequate number of patients. From this point of view, single-arm studies with availability of pretreatment H pylori cultures may be more useful to perform than randomized, controlled trials, because the former may more readily allow an adequate sample size by focusing on a single regimen. For example, in a recent study published by our group, dual resistance proved to be the only independent factor compromising the efficacy of 10-day concomitant nonbismuth quadruple regimen in a similar setting of high clarithromycin resistance. According to our data, based on 106 patients with available antibiotic susceptibility tests, this regimen eradicated H pylori in 7 of 10 patients (70%) harboring dual-resistant strains who took the regimen as first-line treatment and in only 4 of 12 (45%) of those who took it as second-line treatment after a failed standard triple therapy.6Georgopoulos S.D. et al.Helicobacter. 2013; 18: 459-467Crossref PubMed Scopus (50) Google Scholar Our findings are in line with previous relevant studies reporting on dual resistant strains of H pylori (Table 1). Overall, 5- to 14-day (mostly 10-day) concomitant treatment was successful in 23 of 31 (74%) as first-line eradication treatment. In contrast, only 9 of 27 (33%) of such strains were eradicated by the so-called sequential (10- to 14-day) nonbismuth quadruple therapy. Thus, dual resistance seems to compromise concomitant treatment but to a considerably lesser extent that the sequential one, making the former a more reasonable option in areas with a high incidence of clarithromycin and/or metronidazole resistance. Unfortunately, few data have been reported for dual-resistant strains with the hybrid therapy so far. Thus, its implementation in high resistance areas warrants further consideration.Table 1Efficacy of Concomitant and Sequential Nonbismuth Quadruple Therapies on Dual (Metronidazole and Clarithromycin)-Resistant Strains of Helicobacter pyloriStudy (first author)/JournalYearTreatment duration (d)Patients (cured/total)Eradication rate (%)Concomitant Treiber/Arch Intern Med200252/450 Okada/Aliment Pharmacol Ther199973/475 Wu/Clin Gastroenterol Hepatol2010103/475 Molina–Infante/Helicobacter2012103/475 Huang/J Dig Dis2012102/2100 Georgopoulos/Helicobacter2013107/1070 Molina–Infante/Gastroenterology2013143/3100Totals (variance of days/total patients/mean percentages)5–1423/3174Sequential Vaira/Ann Intern Med2007100/40 Romano/Gut2010100/30 Wu/Clin Gastroenterol Hepatol2010101/333 Molina–Infante/Helicobacter2012103/560 Huang/J Dig Dis2012102/450 Liou/Lancet201310–143/837.5Totals (variance of days/total patients/mean percentages)10–149/2733 Open table in a new tab Another point mentioned by the authors as a limitation of their study is the use of the Epsilometer test (E-test) for determination of antimicrobial susceptibility. The E-test tends to overestimate metronidazole resistance as opposed to the agar dilution reference method, possibly resulting in misclassification of a number of H pylori strains as metronidazole or dual resistant.7Osato M.S. et al.Am J Gastroenterol. 2004; 99: 769Crossref PubMed Scopus (8) Google Scholar In our study, we performed both tests showing very good correlation, particularly in dual-resistant strains. However, the E-test tended to overestimate metronidazole resistance, in particular when levels of drug resistance were high, but without changing the final pattern. Nevertheless, discrepancies may appear in resistance levels close to the reference point (MIC90 = 8 μg/mL), possibly requiring further confirmation by agar dilution test.8Graham D.Y. et al.Clin Gastroenterol Hepatol. 2013; http://dx.doi.org/10.1016/jcgh.2013.05.028Google Scholar Optimized Nonbismuth Quadruple Therapies Cure Most Patients With Helicobacter pylori Infection in Populations With High Rates of Antibiotic ResistanceGastroenterologyVol. 145Issue 1PreviewStrategies to eradicate Helicobacter pylori infection could be improved by suppressing acid and extending the duration of therapy (optimization). We compared the efficacy of 2 different optimized nonbismuth quadruple regimens in areas of high resistance to antimicrobial agents. Full-Text PDF ReplyGastroenterologyVol. 145Issue 6PreviewWe would like to thank Georgopoulos et al for their kind remarks on our manuscript.1 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%.2 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 ours3 and theirs,2 is showing that the Achilles heel of concomitant therapy, albeit to a much lesser extent than that observed with sequential therapy, is dual resistance. Full-Text PDF