Helicobacter pylori Eradication by Sitafloxacin-Lansoprazole Combination and Sitafloxacin Pharmacokinetics in Mongolian Gerbils and ItsIn VitroActivity and Resistance Development

Abstract

A total of 293 strains of Helicobacter pylori, including strains resistant to levofloxacin, clarithromycin, metronidazole, or amoxicillin, were examined for in vitro susceptibility to 10 antimicrobial agents. Among these agents, sitafloxacin (a fluoroquinolone) showed the greatest activity (MIC 90 , 0.06 g/ml), with high bactericidal activity and synergy in sitafloxacin-lansoprazole (a proton pump inhibitor) combination. In a Mongolian gerbil model with a H. pylori ATCC 43504 challenge, marked eradication effects were observed at >1 mg/kg for sitafloxacin, >10 mg/kg for levofloxacin, and >10 mg/kg for lansoprazole, reflecting MIC levels for each agent (0.008, 0.25, and 2 g/ml, respectively). The therapeutic rates were 83.3% for the sitafloxacin (0.3 mg/kg)-lansoprazole (2.5 mg/kg) combination and 0% for either sitafloxacin or lansoprazole alone. The maximum serum concentration (C max ) of sitafloxacin was 0.080 ؎ 0.054 g/ml at 30 min, when orally administered at 1 mg/kg. The simultaneous administration of lansoprazole resulted in no difference. In the resistance development assay, MICs of levofloxacin increased 64-to 256-fold with gyrA mutations (Ala88Pro and Asn87Lys), while MICs of sitafloxacin only up to 16-fold with the Asn87Lys mutation. The data suggest that sitafloxacin exhibited superior anti-H. pylori activity with low rates of resistance development in vitro and that, reflecting high in vitro activities, sitafloxacin-lansoprazole combination exhibited strong therapeutic effects in Mongolian gerbils with a C max of sitafloxacin that was 10-fold higher than the MIC value at a 1-mg/kg administration.Helicobacter pylori is a spiral-shaped bacterium with one or two turns along its axis and has multiple polar flagella. Such strongly motile H. pylori colonizes the gastric mucosa of more than 50% of individuals worldwide. Children are a high-risk group for H. pylori infections, which may persist for years or be lifelong. H. pylori is closely associated with various diseases (2, 5, 13, 30), such as gastritis and peptic ulcers, mucosa-associated lymphoid tissue lymphoma, and idiopathic thrombocytopenic purpura or chronic urticaria, and is also a bacterial risk factor for gastric cancer.For the eradication of H. pylori, a combination therapy using an anti-acid agent (proton pump inhibitor [PPI] or H 2 blocker) and two anti-H. pylori agents (amoxicillin and either clarithromycin or metronidazole) has been recommended (3,11,19). Fluoroquinolones have also been selected as anti-H. pylori agents (3,11,19).Drug resistance has increasingly been reported (11,12,27). Metronidazole has a high primary rate of resistance: 60 to 100% in developing countries and 10 to 50% in developed countries. For clarithromycin, the primary rate of resistance to H. pylori in adults is relatively low, ca. 10%, with a recent increase in many countries. In addition, failure to eradicate the infection with clarithromycin treatment results in extremely high rates of resistance (36 to 85%) (27). Resistance to amoxicillin and fluoroquinolone is ...

Review article: the global emergence ofHelicobacter pyloriantibiotic resistance

“…Point mutations of gyrA , which codes for DNA gyrase, have been identified in the quinolone‐resistant determination region with the major mutations being found at position in the codons coding for amino acid 87, 88, 91 or 97, conferring resistance of levofloxacin and other quinolones . However, studies have shown that sitafloxacin may overcome the resistance conferred by these point mutations …”

“…185,186 However, studies have shown that sitafloxacin may overcome the resistance conferred by these point mutations. 187,188 Rifabutin Resistance to rifabutin is generally caused by point mutation in codons 524-545 or codon 585 of the rpoB gene. 189,190 Moreover, cross resistance between rifabutin and rifampin has been reported.…”

Efficacy and Pharmacological Mechanism of Pronase-Enhanced Low-Dose Antibiotics for Helicobacter pylori Eradication

“…pylori lives deep in the GML (5, 6), which is formed by two types of mucin layers that are derived from surface mucous cells and gland mucous cells (18). There is sufficient antibiotic concentration in the deep GML to effectively eradicate H. pylori (29)(30)(31). By detecting the antibiotic concentration in gastric tissue after oral treatment with pronase, the value of the amoxicillin concentration in the Am10-plus-Pr108 group was 3.8 times that of the Am10 group in 5 min.…”