Journal of Antimicrobial Chemotherapy (2002) 49, 1039-1040
© 2002 The British Society for Antimicrobial Chemotherapy
Correspondence |
Synergic effect of quinolone antibacterial agents and proton pump inhibitors on Helicobacter pylori
1New Product Research Laboratories I, Daiichi Pharmaceutical Co. Ltd, 16-13 Kitakasai 1-Chome, Edogawa-ku, Tokyo 134-8630; 2Department of Preventive Dentistry, Health Sciences University of Hokkaido, 5Hokkaido Institute of Technology and 6Third Department of Internal Medicine, Hokkaido University School of Medicine, Hokkaido; 3Division of Animal Experimentation, Sapporo Medical University; 4Department of Microbiology, Jichi Medical University, Japan
Sir,
Helicobacter pylori is known to be a principal cause of chronic gastritis and is associated with peptic ulcers and gastric cancer.1 Eradication of H. pylori prevents relapse of duodenal ulcers, and treatment of this infection has now become standard for patients with peptic ulcers.2 Antibacterial treatment of H. pylori commonly includes a proton pump inhibitor and two antibacterial agents such as clarithromycin, amoxicillin or metronidazole; however, the use of clarithromycin and metronidazole has resulted in the development of resistance.3,4 In addition, the fluoroquinolones have been reported to have antibacterial activity against H. pylori.5 In this study, we investigated the interaction between proton pump inhibitors and fluoroquinolones, and compared the effects with those of proton pump inhibitors combined with clarithromycin or amoxicillin.
Sitafloxacin (formerly DU-6859a), levofloxacin, amoxicillin, clarithromycin, pantoprazole, omeprazole and lansoprazole were used in this study. Sitafloxacin, levofloxacin and pantoprazole were obtained from Daiichi Pharmaceutical Co. Ltd, Tokyo, Japan. The other compounds were purchased from their manufacturers or from Sigma Aldrich Japan (Tokyo, Japan). A total of 17 clinical isolates was used, each from a separate patient; nine were isolated from patients with gastric ulcers, four were from chronic gastritis patients and four were from gastric cancer patients. The MICs were determined by the two-fold serial agar dilution method with Brain Heart Infusion agar (Merck, Tokyo, Japan) supplemented with 9% horse blood. Drug-containing agar plates were inoculated with one loopful (10 µL) of inoculum, corresponding to c. 106 cfu per spot, and were incubated at 37°C for 4 days under 10% CO2. The MIC was defined as the lowest drug concentration that prevented visible growth of bacteria. Synergy testing was carried out by the standard checquerboard titration method with two-fold serial agar dilutions of an antibacterial agent and a proton pump inhibitor. For quantification of synergy, the fractional inhibitory concentration (FIC) index was obtaind by adding the FIC values, which were calculated as the MIC of drug A or B in combination/MIC of drug A or B alone. The FIC index was interpreted as follows: 
0.5, synergy; >0.5–1.0, additive effect; >1.0–4.0, indifference; and >4.0, antagonism.
Clarithromycin showed the highest antibacterial activity with MICs 0.025–0.10 mg/L, and the MIC ranges of sitafloxacin, levofloxacin and amoxicillin were 0.05–0.10, 1–2 and 0.1 mg/L, respectively. Among the proton pump inhibitors, lansoprazole showed the highest antibacterial activity with MICs 1.56–12.5 mg/L; however, the activity was lower than those of the antibacterial agents tested. The MIC ranges of omeprazole and pantoprazole were 12.5–25 and 200 mg/L, respectively. The MIC range of these compounds was similar to those reported previously.5
The results of synergy testing are summarized in Table 1. A synergic effect was observed for all 17 strains for the combinations of pantoprazole and sitafloxacin, pantoprazole and levofloxacin, omeprazole and levofloxacin, and lansoprazole and sitafloxacin. The mean FIC index for all combination patterns of one proton pump inhibitor and sitafloxacin or levofloxacin gave a value <0.292, which indicates that these combinations were synergic. When clarithromycin was combined with amoxicillin, pantoprazole, omeprazole and lansoprazole, a synergic effect was observed for one (5.9%), one (5.9%), two (11.8%) and seven (41.2%) strains, and an additive effect was observed for 14 (82.4%), 15 (88.2%), 15 (88.2%) and 10 (58.8%) strains, respectively. The mean FIC indices for clarithromycin in combination with these compounds ranged from 0.544 to 0.899, which are defined as additive effects. With amoxicillin combined with proton pump inhibitors, the mean FIC index values were 
1.467; thus, there were no synergic or additive effects.
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Sitafloxacin or levofloxacin in combination with proton pump inhibitors showed synergic effects, which indicates that there may be a clinical benefit in using these compounds as combination therapy. However, these in vitro synergic effects should be considered together with the pharmacokinetic profiles for applications to treatment. A recent clinical study demonstrated that rabeprazole, a newer proton pump inhibitor, and levofloxacin-based triple therapy achieved good eradication rates and proved to be safe.6 We suggest that further studies are needed to determine whether these compounds can be used to eradicate H. pylori in vivo.
Footnotes
* Corresponding author. Tel: +81-3-5696-8236;Fax: +81-3-5696-4264; E-mail: tanakpmj{at}daiichipharm.co.jp 
References
1 . Konturek, P. C., Bielaski, W., Konturek, S. J. & Hahn, E. G. (1999). Helicobacter pylori associated gastric pathology. Journal of Physiology and Pharmacology 50, 695–710.[Web of Science][Medline]
2 . Adamsson, I., Edlund, C. & Nord C. E. (2000). Microbial ecology and treatment of Helicobacter pylori infections: review. Journal of Chemotherapy 12, 5–16.[Web of Science][Medline]
3 . Ellenrieder, V., Boeck, W., Richter, C., Marre, R., Adler, G. & Glasbrenner, B. (1999). Prevalence of resistance to clarithromycin and its clinical impact on the efficacy of Helicobacter pylori eradication. Scandinavian Journal of Gastroenterology 34, 750–6.[Medline]
4 . Ling, T. K., Cheng, A. F., Sung, J. J., Yiu, P. Y. & Chung, S. S. (1996). An increase in Helicobacter pylori strains resistant to metronidazole: a five-year study. Helicobacter 1, 57–61.[Medline]
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Sanchez, J. E., Saenz, N. G., Rincon, M. R., Martin, I. T., Sanchez, E. G. & Martinez, M. J. (2000). Susceptibility of Helicobacter pylori to mupirocin, oxazolidinones, quinupristin/dalfopristin and new quinolones. Journal of Antimicrobial Chemotherapy 46, 283–5.
6 . Cammarota, G., Cianci, R., Cannizzaro, O., Cuoco, L., Pirozzi, G., Gasbarrini, A. et al. (2000). Efficacy of two one-week rabeprazole/levofloxacin-based triple therapies for Helicobacter pylori infection. Alimentary Pharmacology and Therapeutics 14, 1339–43.[Medline]
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