The success rates of Helicobacter pylori eradication treatment may be decreasing in clinical practice, mainly because of the widespread use of antibiotics. Fortunately, the resistance to amoxicillin, tetracycline, and rifabutin has remained low. After the failure of second-line treatment, subsequent treatment should be guided by antimicrobial susceptibility testing whenever possible. With the addition of newer rapid molecular tests to detect H. pylori and the determination of the presence of point mutations, resistance-guided therapy may play a more important role in the future. During empirical third-line therapy, antibiotics used previously should be avoided. Third-line treatment options include fluoroquinolone, rifabutin, tetracycline, furazolidone, and high-dose proton pump inhibitor/amoxicillin therapy. Sitafloxacin shows activities 8–16-fold or greater than those of levofloxacin and could overcome the resistance of H. pylori with gyrA mutations. However, sitafloxacin is not widely available in many countries and has predominantly been employed in Japan. The use of rifabutin should be reserved for the treatment of multiresistant Mycobacterium tuberculosis strains, so that rifabutin is preferably used only as a last resort after amoxicillin, clarithromycin, metronidazole, tetracycline, and fluoroquinolone have failed to eradicate H. pylori.
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