Efficacy of tailored Helicobacter pylori eradication therapy based on antibiotic susceptibility and CYP2C19 genotype

Abstract

The cure rates of Helicobacter pylori (H. pylori) eradication therapy using a proton pump inhibitor (PPI) and antimicrobial agents such as amoxicillin, clarithromycin, and metronidazole are mainly influenced by bacterial susceptibility to antimicrobial agents and the magnitude of the inhibition of acid secretion. Annual cure rates have gradually decreased because of the increased prevalence of H. pylori strains resistant to antimicrobial agents, especially to clarithromycin. Alternative regimens have therefore been developed incorporating different antimicrobial agents. Further, standard PPI therapy (twice-daily dosing) often fails to induce a long-term increase in intragastric pH > 4.0. Increasing the eradication rate requires more frequent and higher doses of PPIs. Therapeutic efficacy related to acid secretion is influenced by genetic factors such as variants of the genes encoding drug-metabolizing enzymes (e.g., cytochrome P450 2C19, CYP2C19), drug transporters (e.g., multidrug resistance protein-1; ABCB1), and inflammatory cytokines (e.g., interleukin-1β). For example, quadruple daily administration of PPI therapy potently inhibits acid secretion within 24 h, irrespective of CYP2C19 genotype. Therefore, tailored H. pylori eradication regimens that address acid secretion and employ optimal antimicrobial agents based on results of antimicrobial agent-susceptibility testing may prove effective in attaining higher eradication rates.

Keywords: Clarithromycin; Cytochrome P450 2C19; Helicobacter pylori; Proton pomp inhibitor; Tailored eradication therapy.

Figures

Figure 1

Success of Helicobacter pylori eradication treatment as a function of pH. A, B: Median 24-h pH values (A) and the percentage of the times when pH < 4.0 during eradication therapy according to successful and failed treatment (B); C: Variation of pH and the percentage of time at pH < 4.0[51]. The median pH of successfully treated patients was significantly higher than compared with patients that failed treatment (A). The median percentage of the time when pH < 4.0 in successfully treated patients was significantly shorter compared with unsuccessfully treated patients (B). The majority of patients were cured using triple therapy when the percentage of time at pH < 4.0 during the 24-h post-dose period was < 10% and the 24-h pH was > 6.0 (shaded area) (C). CAM: Clarithromycin.

Figure 2

Metabolism of omeprazole, lansoprazole, rabeprazole, and esomeprazole by cytochrome P450 isoenzymes. Reproduced from Chang et al[61].

Figure 3

Median 24-h intragastric pH profiles (A) and median 24-h pH values after administering a standard dose of a proton pump inhibitor to patients with the three CYP2C19 genotypes (B). Proton pump inhibitor (PPI) treatment of poor metabolizers (PMs) inhibited gastric acid secretion more effectively than that of rapid metabolizers (RMs) and intermediate metabolizers (IMs).

Figure 4

Genetic polymorphisms of CYP2C19. More than 20 variants have been discovered.

Figure 5

Median 24-h pH values as a function of dosing frequency using 40 mg of rabeprazole (A), and the pH attained using three different dosing regimens as a function of CYP2C19 genotype (B). Reproduced from Sugimoto et al[25]. PMs: Poor metabolizers; RMs: Rapid metabolizers; IMs: Intermediate metabolizers.

Figure 6

Study design and outcomes. A: Patients were classified into two treatment regimens: standard treatment group (first- or second-line standard Japanese regimen) and tailored treatment group (based on clarithromycin-susceptibility); B: Eradication rates for the standard and tailored regimens for eradication of Helicobacter pylori; C: Eradication rates for the standard and tailored regimens among different CYP2C19 genotypes. CAM: Clarithromycin; PPI: Proton pump inhibitor; AMPC: Amoxicillin; MNZ: Metronidazole; RPZ: Rabeprazole.