Abstract and Introduction

Abstract

Helicobacter pylori infection is the main known cause of gastritis, gastroduodenal ulcer disease and gastric cancer. After more than 20 years of experience in H. pylori treatment, however, the ideal regimen to treat this infection has still to be found. Nowadays, apart from having to know well first-line eradication regimens, we must also be prepared to face treatment failures. Therefore, in designing a treatment strategy we should not focus on the results of primary therapy alone, but also on the final (overall) eradication rate. The choice of a 'rescue' treatment depends on which treatment is used initially. If a first-line clarithromycin-based regimen was used, a second-line metronidazole-based treatment (quadruple therapy) may be used afterwards, and then a levofloxacin-based combination would be a third-line 'rescue' option. Alternatively, it has recently been suggested that levofloxacin-based 'rescue' therapy constitutes an encouraging second-line strategy, representing an alternative to quadruple therapy in patients with previous PPI-clarithromycin-amoxicillin failure, with the advantage of efficacy, simplicity and safety. In this case, quadruple regimen may be reserved as a third-line 'rescue' option. Finally, rifabutin-based 'rescue' therapy constitutes an encouraging empirical fourth-line strategy after multiple previous eradication failures with key antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin. Even after two consecutive failures, several studies have demonstrated that H. pylori eradication can finally be achieved in almost all patients if several 'rescue' therapies are consecutively given. Therefore, the attitude in H. pylori eradication therapy failure, even after two or more unsuccessful attempts, should be to fight and not to surrender.

Introduction

Helicobacter pylori infection is the main known cause of gastritis, gastroduodenal ulcer disease and gastric cancer. After more than 20 years of experience in H. pylori treatment, however, the ideal regimen to treat this infection has still to be found [Vakil, 2009]. Consensus conferences have recommended therapeutic regimens that achieve H. pylori cure rates higher than 80% on an intention-to-treat basis [Malfertheiner et al. 2007, 2002; Howden et al. 1998]. However, several large clinical trials and meta-analyses have shown that the most commonly used first-line therapies – including proton-pump inhibitors (PPIs) plus two antibiotics – may fail in up to 20% of patients [Gisbert et al. 2007d, 2000b], and in the clinical routine setting, the treatment failure rate might be even higher. Moreover, during the last few years, the efficacy of PPI-based regimens seems to be decreasing, and several studies have reported intention-to-treat eradication rates lower than 75% [Paoluzi et al. 2006; Calvet et al. 2005; Gisbert et al. 2005b; Vakil et al. 2004; Hawkey et al. 2003; Veldhuyzen Van Zanten et al. 2003; Laine et al. 2000, 1998] and even lower than 50% [Altintas et al. 2004; Gumurdulu et al. 2004; Della Monica et al. 2002]. Antibiotic resistance to clarithromycin has been identified as one of the major factors affecting our ability to cure H. pylori infection, and the rate of resistance to this antibiotic seems to be increasing in many geographical areas [Egan et al. 2008; Megraud, 2004; Vakil et al. 1998].

Papers dealing with retreatment of H. pylori after failure are difficult to analyze due to several reasons [Axon, 2000]. Firstly, patients who fail with their first treatment probably include a higher percentage of individuals who are unreliable tablet takers, others who have resistant organisms and also the 'constitutional' group, where failure will be inevitable. On the other hand, some patients submitted for 'rescue' therapy have already had more than one previous treatment for H. pylori, and this circumstance is not always clarified in the protocols. Furthermore, the original primary treatments vary among the different studies, not only with respect to the antibiotic type, but also in respect to the dose and duration of the regimen. Finally, only a few studies have directly compared, in the same protocol, two or more second-line therapies [Gisbert, 2008; Gisbert and Pajares, 2002, 2005].

Several 'rescue' therapies have been recommended, but they still fail to eradicate H. pylori in more than 20% of the cases [Gisbert and Pajares, 2002], and these patients constitute a therapeutic dilemma [Gisbert, 2008; Gisbert and Pajares, 2005]. Patients who are not cured with two consecutive treatments including clarithromycin and metronidazole will have at least single, and usually double, resistance [Romano et al. 2008; Megraud, 2004]. Furthermore, bismuth salts are not available worldwide anymore and, therefore, management of first-line eradication failures is becoming challenging. Currently, a standard third-line therapy is lacking, and European guidelines recommend culture in these patients to select a third-line treatment according to microbial sensitivity to antibiotics [Malfertheiner et al. 2007, 2002]. However, cultures are often carried out only in research centers, and the use of this procedure as 'routine practice' in patients who failed several treatments seems not to be feasible [Gisbert, 2008; Gisbert and Pajares, 2005; Zullo et al. 2003b; Gisbert and Pajares, 2002]. Therefore, the evaluation of drugs without cross-resistance to nitroimidazole or macrolides as components of retreatment combination therapies would be worthwhile [Graham, 2009].

Probiotics have been proposed as a useful adjunct. Some studies prescribing probiotics with H. pylori eradication therapy had no effect on the side-effect profile but did increase the rates of eradication [Kim et al. 2008]. However, other studies on concurrent probiotic administration suggested the inverse with better side-effect profiles but no increase in eradication or rates of compliance with therapy [Cremonini et al. 2002]. All these issues are important at the present time, but they will be even more relevant in a near future, as therapy for H. pylori infection is becoming more and more frequently prescribed. Therefore, the evaluation of second or third 'rescue' regimens for these problematic cases seems to be worthwhile. In designing a treatment strategy we should not focus on the results of primary therapy alone; an adequate strategy for treating this infection should use several therapies which, if consecutively prescribed, come as close to the 100% cure rate as possible [Calvet et al. 2001; De Boer and Tytgat, 2000; Gisbert, 2008; Gisbert et al. 2005a; Gisbert and Pajares, 2002].

The aim of the present manuscript will be to review the experience dealing with 'nonresponders' to H. pylori eradication therapy. As, at present, the current most prescribed first-line regimens include a combination of PPI plus two antibiotics, the present review will focus only in 'rescue' regimen when these triple combinations fail. Bibliographical searches were performed in the PubMed (Internet) database including studies available until July 2009, looking for the following words (all fields): pylori AND (retreatment OR re-treatment OR rescue OR failure OR salvage OR second-line OR third-line OR fourth-line). References of reviews on H. pylori eradication treatment, and from the articles selected for the study, were also examined in search of articles meeting inclusion criteria (i.e. dealing with H. pylori 'rescue' therapies).