The increasing problem of failed eradication of H. pylori infection due to the development of resistance is of importance for all physicians treating dyspeptic patients. The results obtained in this study confirm the following: (i) the low estimated rate of resistance to tetracycline (5%) and (ii) the absence of resistance to amoxicillin after two failed treatments; (iii) the effectiveness of a third-line, culture-guided treatment strategy; and (iv) that a doxycycline- and amoxicillin-based quadruple regimen, including omeprazole and bismuth salts, may constitute an effective third-line option for treatment.
Quadruple regimens, including amoxicillin and tetracycline plus a proton pump inhibitor and bismuth salts, have already been demonstrated to be effective as second-line therapy, being capable of overcoming possible metronidazole resistance.28 Although already used in one of the two previous unsuccessful eradication regimens, our findings show that both amoxicillin and tetracycline may also be taken into consideration for a third-line ‘rescue’ treatment of H. pylori infection. In contrast, our data show that 100% and 95% of H. pylori isolates were resistant to metronidazole and clarithromycin, respectively. Therefore, these two drugs cannot be recommended for use in third-line treatment, and clinicians should expect a strong negative impact on the outcome of ‘rescue’ regimens including metronidazole and clarithromycin. Indeed, it has been demonstrated that resistance to these two drugs reduces the probability of eradication when using a drug combination including either of them.19, 29 Furthermore, our data showed high resistance rates to metronidazole and clarithromycin when the previously used regimens did not include either of these two drugs (for clarithromycin, in 86% of cases; for metronidazole, in 100% of cases). These latter findings suggest that a ‘primary resistance’ to clarithromycin and metronidazole may negatively affect a second-line treatment attempt.
Quadruple regimens represent the most widely used ‘rescue’ therapy. They include bismuth salts, which have a synergistic effect on antibiotics, possibly by decreasing the bacterial load, a proton pump inhibitor, which facilitates antibiotic activity by increasing the gastric pH, and tetracycline, an antibiotic for which resistance is not yet a great problem (as also confirmed by our data). Nevertheless, classical quadruple regimens also include metronidazole, an antibiotic for which we found, after two failure attempts, 100% resistance. Therefore, in the quadruple ‘package’, metronidazole has been successfully replaced in some trials by other effective drugs, such as furazolidone23, 30 or rifabutin. In particular, a 2-week rifabutin-based ‘rescue’ therapy (including omeprazole and amoxicillin) has been found to be an encouraging option for treatment after two eradication failures, with key antibiotics such as amoxicillin, clarithromycin, metronidazole and tetracycline (achieving an eradication rate of 79%).20 Other 2-week quadruple regimens have been successfully tested as salvage therapies without culture after multiple failures.31, 32 However, by performing culture after two treatment failures and therefore following the experts' recommendations,9 in the present study, we demonstrated that a culture-guided, third-line, 1-week therapeutic approach is safe and effective against H. pylori. Nevertheless, in the quadruple regimen, we included doxycycline, a tetracycline antibiotic widely used in out-patients, particularly for the treatment of pelvic inflammatory disease, acne and rickettsial infections. In some previous trials, doxycycline-containing therapies have been variously used, always in triple drug combinations. In particular, Perri et al. found that tetracycline (including doxycycline)–amoxicillin combinations were inadequate as therapy, when used with a proton pump inhibitor, for the eradication of H. pylori. In the study by Perri et al., however, doxycycline showed a slightly superior eradication capability with respect to tetracycline (36% vs. 35% by intention-to-treat analysis after 2 weeks of treatment).33 In contrast, Borody et al. showed that tetracycline was superior to doxycycline in triple therapy containing bismuth subcitrate and metronidazole (92% vs. 65%).34 Finally, Realdi et al. found that doxycycline was superior to amoxicillin and clarithromycin when included in a triple regimen containing metronidazole and omeprazole,35 while Heep et al., in a study to determine secondary resistance in H. pylori isolates from patients in whom one or more therapies for the eradication of H. pylori had failed, found 0% resistance to doxycycline.36 To our knowledge, our study is the first to use doxycycline in association with amoxicillin in a quadruple regimen as third-line treatment for H. pylori infection. Quadruple therapy is usually suggested in this situation, but there is some reluctance to use it in clinical practice due to the large number of tablets that need to be taken and concern about side-effects. Recently, a study by Chi et al. has demonstrated that tetracycline and amoxicillin may effectively co-exist in a quadruple, second-line regimen against H. pylori.28 An advantage of doxycycline with respect to tetracycline is that it requires the administration of only two tablets per day, therefore leading to better compliance of patients undergoing third-line ‘rescue’ treatment against H. pylori infection. Interestingly, in the present investigation, all patients completed the study, returning empty medicine boxes, and in no case did the number of tablets per day pose a problem. In addition to achieving a high eradication rate as third-line treatment (91% by intention-to-treat analysis), the quadruple regimen used in this study obtained excellent patient compliance: 99% of patients who received this regimen completed the study.
In contrast, our data indicate a resistance rate to levofloxacin of 31%, with a primary resistance to this drug after two failed treatments of 9%. Levofloxacin has been demonstrated to be effective when included in second-line regimens (in association with a proton pump inhibitor, rifabutin, amoxicillin and tinidazole),37–39 achieving in some studies a better rate of efficacy than standard quadruple regimens.38 In a single pilot study, it has been demonstrated that a 10-day levofloxacin- and amoxicillin-based triple therapy may constitute a promising third-line therapeutic approach for H. pylori eradication.21 Our results confirm that this drug may be taken into consideration for use in a third-line ‘rescue’ regimen, as three of four patients were successfully treated with a levofloxacin-based triple combination.
In conclusion, our data show that a culture-guided, third-line approach allows a high rate of eradication of multidrug-resistant H. pylori isolates to be achieved. Therefore, although some discrepancies between antibiotic susceptibility in vitro and H. pylori eradication in vivo may occur (due, for example, to the possibility of co-infection with different H. pylori strains),40 we emphasize the role of culture guidance to avoid the use of drugs which are likely to be ineffective in a ‘rescue’ therapeutic approach. Furthermore, a doxycycline- and amoxicillin-based quadruple regimen, including omeprazole and bismuth salts, may constitute an attractive option for third-line treatment.