Eradication of H. pylori Infection in Patients Allergic to Penicillin Using Triple Therapy with a PPI, Metronidazole and Sitafloxacin

CASE REPORT Eradication of H. pylori Infection in Patients Allergic to Penicillin Using Triple Therapy with a PPI, Metronidazole and Sitafloxacin Takahisa Furuta 1, Mitsushige Sugimoto 2, Mihoko Yamade 2, Takahiro Uotani 2, Shu Sahara 2, Hitomi Ichikawa 2, Takuma Kagami 2, Takanori Yamada 2, Satoshi Osawa 3, Ken Sugimoto 2, Hiroshi Watanabe 4 and Kazuo Umemura 5 Abstract Eradication of H. pylori in patients allergic to penicillin should be performed using regimens without penicillin derivatives. We treated a total of 28 patients allergic to penicillin with a proton pump inhibitor (PPI), metronidazole (250 mg bid) and sitafloxacin (100 mg bid) for one to two weeks. At four to eight weeks after the treatment, the patients underwent the [ 13 C]-urea breath test. The overall eradication rate was 100.0%. Mild adverse events were observed. Triple therapy with a PPI, metronidazole and sitafloxacin is well tolerated and effective for the eradication of H. pylori in patients allergic to penicillin. Key words: penicillin allergy, H. pylori, metronidazole, sitafloxacin () () Introduction Eradication of H. pylori is now performed to treat a variety of disorders, including peptic ulcers, gastritis and gastric MALT lymphoma, and to prevent conditions such as gastric cancer and idiopathic thrombocytopenic purpura (1). Most standard eradication regimens contain amoxicillin, including triple therapy with a PPI, clarithromycin and amoxicillin or a PPI, metronidazole and amoxicillin. However, such amoxicillin-based regimens cannot be used in patients allergic to penicillin. The incidence of penicillin allergies has been reported to be 3-7% in Japan (2, 3). Alternative regimens should be used in such patients. As a regimen without amoxicillin, triple therapy with a proton pump inhibitor (PPI), clarithromycin and metronidazole (4) has been reported. However, the eradication rate associated with this triple therapy is low in patients infected with clarithromycinresistant strains of H. pylori (5). The incidence of clarithromycin-resistant strains has increased in Japan (6). Triple therapy with a PPI, minocycline and metronidazole (7) is also candidate treatment in such cases; however, the eradication rates obtained with this regimen are not always sufficient (6). Recently, sitafloxacin, a fluoroquinolone, has become clinically available in Japan and is reported to have a lower minimum inhibitory concentration (MIC) for H. pylori (8). Researchers have used sitafloxacin in patients allergic to penicillin with metronidazole and a PPI since 2008 and reported excellent eradication rates. In this report, we discuss the efficacy of triple therapy with a PPI, metronidazole and sitafloxacin in patients allergic to penicillin. Center for Clinical Research, Hamamatsu University School of Medicine, Japan, First Department of Medicine, Hamamatsu University School of Medicine, Japan, Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Japan, Department of Clinical Pharmacology & Therapeutics, Hamamatsu University School of Medicine, Japan and Department of Pharmacology, Hamamatsu University School of Medicine, Japan Received for publication September 1, 2013; Accepted for publication October 6, 2013 Correspondence to Dr. Takahisa Furuta, furuta@hama-med.ac.jp 571

Methods Case Report A total of 28 patients allergic to penicillin who were treated with triple therapy containing a PPI (e.g., rabeprazole (10 mg bid or qid), lansoprazole (30 mg bid) or esomeprazole (20 mg bid)), metronidazole (250 mg bid) and sitafloxacin (100 mg bid) for one or two weeks from November 2008 to May 2013 were retrospectively studied. The clinical characteristics of the patients are presented in Table. The male to female ratio was 12:16. The mean ± S.D. age was 56.8±11.3 years. The subjects consisted of patients with gastric ulcers (n=4), duodenal ulcers (n=5), idiopathic thrombocytopenic purpura (n=1) and gastritis only (n=18). Of the 28 patients, 11 were diagnosed as being allergic to penicillin derivatives based on an allergic reaction, such as a skin rash, observed during the previous use of penicillin derivatives. The remaining 17 patients experienced an allergic reaction either during or just after the end of first- or second-line therapy with a PPI, amoxicillin and clarithromycin or metronidazole and thus exhibited a failure of eradication therapy. All patients underwent endoscopy before receiving eradication therapy. During endoscopy, gastric tissue samples were obtained for the rapid urease test (HelicoCheck, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan) and a culture test. Measurement of the MICs of the H. pylori strains to the antimicrobial agents was performed at a laboratory company, SRL, Inc. (Tokyo, Japan). The cut-off concentration used to define resistance was more than 0.5 μg/ml for amoxicillin, more than 1.0 μg/ml for clarithromycin, more than 8.0 μg/ml for metronidazole and 1.0 μg/ml for levofloxacin, in accordance with previous reports (9, 10). Susceptibility to clarithromycin and the CYP2C19 genotype was also measured using the GeneCube (11) in all patients. Written informed consent was obtained in advance from each patient for the CYP2C19 genetic testing. The use of the study regimen was not supported by the health insurance system of Japan. Results The overall eradication rate was 100.0% (28/28, 95% CI: 89.8-100.0%). Of the 28 patients, 19 were treated for one week and the remaining nine were treated for two weeks. Both the 1-week and 2-week regimens attained excellent eradication rates (100.0% [19/19, CI: 85.4-100.0%] and 100.0% [9/9, CI: 71.7-100.0%], p>0.999 [Fisher s exact test]). The MICs of the strains to the antimicrobial agents were measured in 15 cases. The incidence of strains resistant to amoxicillin, clarithromycin, metronidazole and levofloxacin based on culture tests was 0.0% (0/15), 46.7% (7/15), 13.3% (2/15) and 60.0% (9/15), respectively. The incidence of strains resistant to clarithromycin based on genetic tests was 71.4% (20/28). The incidence of clarithromycinresistant strains in the group without a history of eradication was 90.9% (10/11), which was higher than that observed in the group with a history of failed eradication (58.8%, 10/ 17). The incidence of strains resistant to metronidazole and levofloxacin was 14.3% (1/7) and 57.1% (4/7), respectively, in the group without a history of eradication and 12.5% (1/ 8) and 62.5% (5/8), respectively, in the patients with a history of failed eradication. There were no statistically significant differences in the incidences of strains resistant to metronidazole and levofloxacin between the groups with or without a history of eradication. Adverse events were observed in 16 patients. Major adverse events included diarrhea (21.4%, 6/28) and loose stools (35.7%, 10/28). However, no severe adverse events were observed, and no patients discontinued the medications due to adverse events. Discussion We experienced that triple therapy containing a PPI, metronidazole and sitafloxacin attains excellent eradication rates in patients allergic to penicillin derivatives. In this study, the adverse events attributed to this regimen were not severe. Therefore, this triple therapy is recommended as a candidate therapy for patients allergic to penicillin derivatives. Amoxicillin is one of the most effective antimicrobial agents against H. pylori. Most regimens for H. pylori infection include amoxicillin. However, patients allergic to penicillin cannot be treated with penicillin derivatives or agents having beta-lactam rings. Therefore, the number of regimens available for patients allergic to penicillin is limited, and physicians must make several attempts to prevent such patients from failing to achieve eradication within the limited regimens. One major reason for eradication failure is bacterial resistance to antimicrobial agents. Therefore, physicians must choose antimicrobial agents with a lower MIC for H. pylori. Levofloxacin is known to have a low MIC for H. pylori and is often used in rescue regimens. However, the eradication rate of levofloxacin-based regimens in patients infected with levofloxacin-resistant strains of H. pylori is low (12). The incidence of levofloxacin-resistant strains of H. pylori is high in Japan (13). In this study, 60.0% of the patients were infected with levofloxacin-resistant strains of H. pylori. However, sitafloxacin is reported to have a lower MIC than levofloxacin and to be effective in patients infected with strains with mutations in gyra, a genetic marker for resistance to levofloxacin (8, 14). Therefore, in the present study, we used sitafloxacin in patients allergic to penicillin derivatives. Moreover, the combination of sitafloxacin and metronidazole is reported to be effective as third-line rescue therapy (15). Hence, we treated the patients allergic to penicillin with a sitafloxacin-based regimen. The combination of clarithromycin and metronidazole is also a candidate regimen for treating patients allergic to 572

Table. Clinical Characteristics of Patients No Age Sex History of Disease for CYP2C19 CYP2C19 Clarithromycin Susceptibility to antimicrobial agents by culture test Details of the regimen Success or eradication eradication phenotype genotype susceptibility Susceptibility Susceptibility Susceptibility Susceptibility PPI Metronidazole Sitafloxacin Dosing failure of based on to to to to period eradication genetic test amoxicillin clarithromycin metronidazole levofloxacin 1 37 M Twice failed Gastritis IM *1/*2 S ND ND ND ND RPZ 10 mg bid 250 mg bid 100 mg bid 1 week Success 2 64 F Twice failed DU IM *1/*2 S S S S S RPZ 10 mg bid 250 mg bid 100 mg bid 1 week Success 3 60 M Non polyp RM *1/*1 R ND ND ND ND RPZ 10 mg bid 250 mg bid 100 mg bid 2 weeks Success 4 55 F Non Gastritis IM *1/*2 R S S S S RPZ 10 mg bid 250 mg bid 100 mg bid 1 week Success 5 79 M Non Gastritis RM *1/*1 S ND ND ND ND PPZ 20 mg bid 250 mg bid 100 mg bid 1 week Success 6 37 F Once failed Gastritis RM *1/*1 R S S S S RPZ 10 mg qid 250 mg bid 100 mg bid 1 week Success 7 62 M Once failed GU IM *1/*3 R S S S S RPZ 10 mg bid 250 mg bid 100 mg bid 1 week Success 8 54 M Twice failed GU RM *1/*1 R ND ND ND ND RPZ 10 mg bid 250 mg bid 100 mg bid 1 week Success 9 42 F Once failed DU IM *1/*3 S ND ND ND ND RPZ 10 mg bid 250 mg bid 100 mg bid 1 week Success 10 63 F Non DU RM *1/*1 R S S R R RPZ 10 mg bid 250 mg bid 100 mg bid 1 week Success 11 70 F Once failed GU RM *1/*1 S ND ND ND ND RPZ 10 mg qid 250 mg bid 100 mg bid 1 week Success 12 56 F Non Gastritis IM *1/*2 R ND ND ND ND RPZ 10 mg bid 250 mg bid 100 mg bid 1 week Success 13 56 M Twice failed GU RM *1/*1 R ND ND ND ND RPZ 10 mg qid 250 mg bid 100 mg bid 2 weeks Success 14 66 F Once failed Gastritis/ RM *1/*1 R ND ND ND ND RPZ 10 mg qid 250 mg bid 100 mg bid 2 weeks Success 15 51 F Twice failed Gastritis IM *1/*3 S S S S S RPZ 10 mg qid 250 mg bid 100 mg bid 2 weeks Success 16 42 M Non Gastritis IM *1/*3 R ND ND ND ND RPZ 10 mg bid 250 mg bid 100 mg bid 1 week Success 17 41 F Once failed Gastritis RM *1/*1 S ND ND ND ND RPZ 10 mg qid 250 mg bid 100 mg bid 2 weeks Success 18 40 F Once failed Gastritis RM *1/*1 R S R S S EPZ 20 mg bid 250 mg bid 100 mg bid 1 week Success 19 60 M Once failed DU IM *1/*2 R S R R R EPZ 20 mg bid 250 mg bid 100 mg bid 1 week Success 20 70 F Non DU RM *1/*1 R S R S S EPZ 20 mg bid 250 mg bid 100 mg bid 1 week Success 21 62 M Once failed ITP RM *1/*1 R ND ND ND ND EPZ 20 mg bid 250 mg bid 100 mg bid 1 week Success 22 68 M Once failed Gastritis PM *2/*3 S ND ND ND ND RPZ 10 mg bid 250 mg bid 100 mg bid 1 week Success 23 61 F Once failed Gastritis RM *1/*1 R S R S S RPZ 10 mg qid 250 mg bid 100 mg bid 1 week Success 24 66 M Non Gastritis PM *3/*3 R S S S S RPZ 10 mg bid 250 mg bid 100 mg bid 2 weeks Success 25 44 F Non Gastritis RM *1/*1 R S R S S RPZ 10 mg qid 250 mg bid 100 mg bid 2 weeks Success 26 65 F Non Gastritis IM *1/*3 R S R S S EPZ 20 mg bid 250 mg bid 100 mg bid 2 weeks Success 27 67 F Non Gastritis IM *1/*3 R S S S S LPZ 30 mg bid 250 mg bid 100 mg bid 1 week Success 28 53 M Once failed Gastritis IM *1/*3 R S R S S RPZ 10 mg bid 250 mg bid 100 mg bid 2 weeks Success Judgment of eradication Adverse events M: male, F: female, DU: duodenal ulcer, GU: gastric ulcer, RM: rapid metabolizer of CYP2C19, IM: intermediate metabolizer of CYP2C19, PM: poor metabolizer of CYP2C19, R: resistant, S: sensitive, RPZ: rabeprazole, LPZ : lansoprazole, EPZ: esomeprazole, 13 C-UBT: 13 C-urea breath test, RUT: rapid urease test 13 C-UBT 573

penicillin. Gsibert et al. (16, 17) reported that the eradication rate of triple therapy with omeprazole (20 mg bid), clarithromycin (500 mg bid) and metronidazole (500 mg bid) for seven days ranges from 55% to 64% (PP analyses). Although the incidence of clarithromycin-resistant strains of H. pylori in this study was unclear, the combination of clarithromycin and metronidazole does not appear to achieve a sufficient eradication rate. The authors also reported that the combination of omeprazole, clarithromycin and levofloxacin attains a relatively high eradication rate (73% [11/15] 16 and 100.0% [2/2] 17). However, this combination of medications increases the risk of prolonging the QT interval (18). Therefore, we cannot draw a definitive conclusion that the combination of clarithromycin and levofloxacin is recommended for patients allergic to penicillin. Interestingly, in this study, the rate of clarithromycin resistance based on genetic testing was higher in the patients without a history of eradication therapy than in those with a history of eradication failure. We are unable to offer an appropriate explanation for the high rate of resistant observed in the former patients. We assume that the previous abuse of antimicrobial agents is associated with the acquisition of sensitization to penicillin as well as resistance to clarithromycin. Regardless, the high rate of strains resistant to clarithromycin causes us to refrain from the use of clarithromycin in patients allergic to penicillin. Rodriguez-Torres et al. (19) reported that a 10-day regimen consisting of esomeprazole (40 mg qid), tetracycline (500 mg qid) and metronidazole (500 mg qid) attained an eradication rate of 17% in patients allergic to penicillin. Therefore, this regimen is an alternative regimen in such patients. Acid suppression during eradication therapy also influences the outcome of the eradication therapy (20). In order to prevent insufficient acid inhibition, we evaluated the CYP2C19 genotype in advance and used higher doses of the PPI in rapid metabolizers of CYP2C19. However, some patients were treated with a twice daily dose of the PPI at a standard dose and also achieved eradication of H. pylori. How much gastric acid secretion suppression is needed for therapy using a combination including sitafloxacin should be verified in the future. Nineteen patients were treated for one week, while the remaining patients were treated for two weeks. The incidence of adverse events was similar between these two groups. Therefore, a 1-week regimen appears to be adequate. Our results must be interpreted within the study limitations, as follows. First, 17 of the subjects exhibited an allergic reaction during their previous eradication therapy. From the viewpoint of frequency, amoxicillin was most often regarded to be the causative drug in such cases. However, there is a possibility that some of the patients were allergic to other agents, such as clarithromycin, metronidazole and specific PPIs. In such patients, clarithromycin and metronidazole should not be used, and the type of PPI should be changed in the next regimen. Fortunately, no patients experienced an allergic reaction during the triple PPI/metronidazole/sitafloxacin therapy used in this study, suggesting that no patients were allergic to metronidazole. However, there is a possibility that we will encounter patients allergic to metronidazole in the future. Therefore, we must pay attention not only to amoxicillin, but also all other drugs used in the previous regimens. Second, we were able to measure the MICs for levofloxacin, but not sitafloxacin. Therefore, the prevalence of strains resistant to sitafloxacin is unclear, and it is also unclear whether the regimen used in this study is effective in patients infected with sitafloxacin-resistant strains of H. pylori. In conclusion, we are tempted to conclude that triple therapy containing a PPI, sitafloxacin and metronidazole is useful, as it can attain a sufficient rate of eradication of H. pylori in patients allergic to penicillin. The clinical usefulness of this regimen should be verified in a larger study under the appropriate protocol. Author s disclosure of potential Conflicts of Interest (COI). Takahisa Furuta: Advisory role, Eisai; Honoraria, Eisai, Daiichi Sankyo and AstraZeneca. Mitsushige Sugimoto: Honoraria, Eisai, Daiichi Sankyo and AstraZeneca. Takahisa Furuta, Mitsushige Sugimoto, Mihoko Yamade, Takahiro Uotani, Shu Sahara, Hitomi Ichikawa, Takuma Kagami, Takanori Yamada, Satoshi Osawa and Ken Sugimoto: Research funding, Takeda Pharmaceutical, AstraZeneca, Eisai and Daiichi-Sankyo. Acknowledgement The assistance of the endoscopy staff and laboratory staff is greatly appreciated. References 1. Malfertheiner P. Guidelines for the diagnosis and treatment of H. pylori infection. MMW Fortschr Med 145: 42-45, 2003. 2. Muranaka M, Kabe J, Umezono K, et al. Incidence of drug hypersensitivity. Jpn J Allergol 13: 431-434, 1964 (in Japanese, Abstract in English). 3. Muranaka M, Okumura H, Takeda K, et al. Population studies on drug hypersensitivities. Acta Allergol 28: 50-61, 1973. 4. Harris AW, Pryce DI, Gabe SM, et al. Lansoprazole, clarithromycin and metronidazole for seven days in Helicobacter pylori infection. Aliment Pharmacol Ther 10: 1005-1008, 1996. 5. Dore MP, Leandro G, Realdi G, et al. 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