The possible causes for eradication therapy failure include antibiotic resistance, smoking, bacterial load before treatment, bacterial genotype, poor patient compliance, and polymorphisms of metabolism of PPIs. With the increasing prevalence of antimicrobial resistance, the eradication rate of H. pylori have been declined. The Maastricht IV/Florence consensus report recommends that culture and antimicrobial sensitivity testing should be performed after one or two treatment failures with different antibiotics [3]. Meanwhile, according to the Maastricht V/Florence consensus report, after the first failure, if endoscopy is carried out, culture and standard antimicrobial susceptibility testing are recommended to tailor the treatment [11].
The prevalence of H. pylori strains resistant to more than one antibiotic was 15% in the United States and 8.9% in Europe [12]. According to the study of Liou et al. [13], the secondary resistance rates of clarithromycin, levofloxacin, and metronidazole were as high as 92.5%, 70.1%, and 87.7%, respectively, in patients who had received these antibiotics in their prior therapies in Taiwan.
When selecting salvage therapy, previously used antibiotics should be avoided. The use of a salvage regimen for patients with persistent H. pylori infection is an increasingly common scenario but remains a challenge for clinicians because only a few antibiotics are available. Currently, a standard salvage regimen is still lacking. Our data showed 10 days rifabutin-based triple therapy was well tolerated and yielded an acceptable H. pylori eradication rate for patients infected with dual drug-resistant strains to clarithromycin and levofloxacin.
Rifabutin inhibits the beta-subunit of DNA-dependent RNA polymerase of H. pylori, which is encoded by the rpoB gene. Rifabutin-based triple therapy has been applied as a rescue treatment. A low rate of resistance (0.24%) to rifabutin was noted in H. pylori strains isolated from 414 Japanese patients. The only rifabutin-resistant strain detected showed a point mutation in the rpoB gene and was isolated from a patient with a history of rifampin treatment for pulmonary tuberculosis. The mean H. pylori rifabutin resistance rate (calculated from 11 studies, including 2982 patients) was 1.3% (95% confidence interval [CI], 0.9–1.7%) [14]. The respective cure rates for second-line (223 patients), third-line (342 patients), and fourth-/fifth-line (95 patients) rifabutin therapies were 79% (95% CI, 67–92%), 66% (95% CI, 55–77%), and 70% (95% CI, 60–79%), respectively [14].
The American College of Gastroenterology clinical guideline suggests a rifabutin triple regimen consisting of a PPI, amoxicillin, and rifabutin for 10 days as a suggested salvage regimen, but it has a very low quality of evidence for duration [15]. The ideal length of treatment for the rifabutin regimen remains unclear. In some reports, a 7-day course has been equally effective as the 10- to 14-day regimens, whereas others have found that this shorter duration dramatically reduced the efficacy in terms of eradication rates. High-dose proton pump inhibitor seems to play some role. One Korea study demonstrated that higher eradication rate was achieved when double doses (lansoprazole 60 mg bid) were administered instead of standard doses (lansoprazole 30 mg bid) with the same rifabutin-amoxicillin combination (intention-to-treat, 96.3% vs 78.1%. p = 0.51) [19]
A recent study by Fiorini et al. [16] reported that the efficacy of the 12-day rifabutin-based triple therapy (with esomeprazole 40 mg bid, amoxicillin 1 g bid, and rifabutin 150 mg od) for patients infected with multidrug-resistant strains (clarithromycin, metronidazole, and levofloxacin) was 82.9% (95% CI, 78.3–87.5) by intention-to-treat analysis and 88.7% (95% CI, 84.7–92.7) at per-protocol analysis. The mean rate of adverse effects was 22% (19–25%). A long-term prospective study in a large cohort with 302 difficult-to-treat patients revealed that rifabutin 150 mg, amoxicillin 1 g and a standard dose of proton pump inhibitor, twice daily for 14 days achieved eradication rate in 72.7% (per-protocol ) and 71.5% (intention-to-treat) respectively. A univariate analysis showed that gender, ethnic background, smoking habits and familial history of gastric diseases were not predictive factors of response [17]. The efficacy of rifabutin treatment is summarized in Table 4.
Table 4
Summary of outcomes of rifabutin based triple therapy in Helicobacter pylori infection
Author(s) and year | Country | Drugs and doses | Duration of treatment (days) | No. of patients | No. of previously failed treatment | Eradication rate (%) |
Fiorini G 2018 [16] | Italy. | esomeprazole 40 mg bid, amoxicillin 1 g bid, and rifabutin 150 mg od | 12 | 254 | 2 | 82.9% intention-to-treat |
Ribaldone DG 2019 [17] | Italy. | Rifabutin 150 mg bid Amoxicillin 1 g bid PPI bid | 14 | 302 | 2 | 71.5% intention-to-treat |
Van Zanten et al. 2010 [18] | Canada | Rifabutin 300 mg od Amoxicillin 1 g bid PPI bid | 7 | 16 | 3 | 63% |
Lim et al. 2014 [19] | Korea | Rifabutin 150 mg bid Amoxicillin 1 g tid Lansoprazole 60 mg bid | 7 | 27 | 2 | 96.3 intention-to-treat |
Lim et al. 2014 [19] | Korea | Rifabutin 150 mg bid Amoxicillin 1 g tid Lansoprazole 30 mg bid | 7 | 32 | 2 | 78.1 intention-to-treat |
Ierardi et al. 2014 [20] | Italy | Rifabutin 150 mg bid Minocycline 100 mg bid Bismuth 120 mg qid Rabeprazole 20 mg bid | 10 | 21 | 2 | 77.7% |
One significant concerning in rifabutin treating was adverse effects of myelotoxicity. Lower doses and/or a shorter duration would lower the possibility of myelotoxicity. In the present study, we used rifabutin 150 mg bid, amoxicillin 1 g bid and esomeprazole 40 mg bid for 10 days and no case of neutropenia was observe.