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Levofloxacin-based triple therapy for Helicobacter pylori re-treatment: Role of bacterial resistance
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Digestive and Liver Disease 39 (2007) 1001–1005
Alimentary Tract
Levofloxacin-based triple therapy for Helicobacter pylori re-treatment: Role of bacterial resistance F. Perna a , A. Zullo b,∗ , C. Ricci c , C. Hassan b , S. Morini b , D. Vaira a a
Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy b Gastroenterology Unit, “Nuovo Regina Margherita Hospital”, Rome, Italy c Gastroenterology Unit, University of Brescia, Brescia, Italy Received 25 March 2007; accepted 28 June 2007 Available online 21 September 2007
Abstract Background. First-line Helicobacter pylori therapy fails in more than 20% of patients. Quadruple therapy is the suggested second-line therapy, but bismuth salts are not anymore available worldwide. This study aimed to assess the efficacy of a levofloxacin–amoxycillin triple therapy as a second-line treatment, and the role of primary levofloxacin resistance. Methods. Forty patients, in whom first treatment with either standard 10-day triple or sequential therapy had failed, received 10-day triple therapy with rabeprazole (20 mg b.d.), levofloxacin (250 mg b.d.), and amoxycillin (1 g b.d.). Cure rates were evaluated by the 13 C-urea breath test. Primary levofloxacin resistance was detected by culture. Results. Bacterial culture was available in 33 (82.5%) out 40 patients, and primary levofloxacin resistance was detected in 10 (30.3%) patients. Overall, 33 of 40 patients accepted to participate in this study, and all returned for follow-up after therapy. Compliance to the therapy was safe except 1 patient only who stopped earlier the treatment due to side effects (oral candidiasis). H. pylori infection was eradicated in 24 patients, accounting for a 72.7% (95% CI: 57–88) eradication rate at both intention-to-treat and per protocol analyses. The eradication rate was higher in patients harbouring levofloxacin-susceptible than resistant strains (75% versus 33.3%; P = 0.074). Conclusions. The eradication rate achieved by a levofloxacin-based re-treatment seems to be decreasing, and its efficacy is reduced in presence of levofloxacin resistance. © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Bacterial resistance; H. pylori; Levofloxacin; Rescue therapy
1. Introduction Standard triple therapies fail to cure Helicobacter pylori infection in more than 20–30% of patients [1,2]. In the last five years, several studies have found an eradication rate lower than 75% [3–6], and values as low as 25–45% have been also recently reported [7,8]. A quadruple therapy with proton pump inhibitor, bismuth salt, tetracycline and metronidazole is currently advised as second-line therapy in ∗ Corresponding author at: Gastroenterology and Digestive Endoscopy, “Nuovo Regina Margherita” Hospital, Via E. Morosini, 30, 00153 Rome, Italy. Tel.: +39 06 58446608; fax: +39 06 58446533. E-mail address: [email protected] (A. Zullo).
eradication failure patients [9–11]. However, data regarding the eradication rate achieved following such a therapy regimen are controversial, with values widely ranging from 37 to 91% [12,13]. Moreover, bismuth salts (as well as ranitidine bismuth citrate) are not anymore available worldwide. Therefore, management of first-line eradication failure patients is become challenging. A levofloxacin–amoxycillin-based triple therapy has been proved to be acceptably effective as second- or even thirdline therapy [14–17], and two recent meta-analyses showed a higher eradication rate as compared to standard quadruple therapy as a re-treatment [18,19]. It has been found that a 10day levofloxacin-based regimen achieve higher cure rate than the 7-day regimen, whilst levofloxacin dose (250 mg b.d ver-
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sus 500 o.d.) seem to be equally effective [18,19]. Bacterial resistance to antibiotics is widely claimed as the most important factor reducing the efficacy of standard triple therapy [20]. However, only scanty data are currently available on the role of primary levofloxacin resistance on levofloxacin-based triple therapy efficacy [16,17,21]. The present study aimed to assess the efficacy of a levofloxacin–amoxycillin triple therapy as a second-line treatment, and the role of primary levofloxacin resistance.
2. Methods 2.1. Patients This was a prospective, open-label study performed in two centres (Bologna and Rome). All patients enrolled in previous trial [22] and with persistent H. pylori infection following a first-line therapy were invited to participate in this study. There were 40 patients who failed either a 10day triple therapy (pantoprazole 40 mg b.d., clarithromycin 500 mg b.d., and amoxycillin 1 g b.d.) (N = 30) or a 10-day sequential regimen (pantoprazole 40 mg b.d. plus amoxycillin 1 g for the first 5 days, followed by pantoprazole 40 mg b.d., clarithromycin 500 mg b.d., and tinidazole 500 mg b.d. for the remaining 5 days) (N = 10). Patients underwent endoscopy with biopsies for histology (two samples from the antrum and two samples from the corpus), rapid urease test (one sample from the antrum) and culture (one sample from the antrum). Patients were considered infected if two of three tests were positive or culture was positive alone. All patients gave informed consent to participate into the study. 2.2. Bacterial culture and susceptibility testing Biopsies, collected for bacterial culture, were sent within 24 h to a single microbiological laboratory (Bologna) streaked onto Columbia agar enriched with 5% horse blood and containing vancomycin, trimethoprim, polymixin B and nalidixic acid to inhibit the growth of microbes other then H. pylori. The plates were incubated in a microaerobic environment at 37 ◦ C for 7 days, and inspected daily from the third day. The isolates were identified by Gram stain and by oxidase, catalase and urease tests. Suspensions from primary plates were prepared in sterile saline solution to have approximately 108 cells/ml to perform Etest. A blood agar plate was streaked in three directions with a swab dipped into each bacterial suspension to produce a lawn of growth, an E-test strip (E-test; AB Biodisk, Solna, Sweden) were placed each onto a separate plate, which was immediately incubated in a microaerobic atmosphere at 37 ◦ C for 72 h. Isolated strains were tested for primary levofloxacin resistance, using as break point the minimal inhibitory concentration (MIC) ≥1 mg/L, as suggested [23].
2.3. Treatment and follow-up All patients received a 10-day triple therapy including rabeprazole 20 mg b.d., levofloxacin 250 mg b.d., and amoxycillin 1 g b.d. The proton pump inhibitor was given 30 min before breakfast and dinner, whilst both antibiotics were administered following these meals. Patients were asked to return at end of eradication therapy to assess side effect and compliance to the therapy. After 4–6 week, patients underwent a 13 C urea breath test. Urea breath tests were carried out after an overnight fast. A baseline breath sample was obtained and then 75 mg of 13 C-urea with citric acid (1.5 g) was administered as an aqueous solution. Another breath sample was collected 30 min after administration of the test solution and the test was considered positive if there was a difference between the baseline sample and the 30 min sample that exceeded 4.5 parts per 1000 of 13 CO2 . All the breath samples were analysed using a single gas isotope ratio mass spectrometer (Finnigan, Bremen, Germany) located in Bologna. The accuracy of this urea breath was previously validated in our laboratory, reporting sensitivity and specificity values of 94.7 and 95.7%, respectively [24]. 2.4. Statistical analysis The eradication rates and their 95% confidence intervals at both intention-to-treat (ITT) and per protocol (PP) analyses were calculated. At ITT analysis were included all patients who took at least one dose of medication, whilst they were not incorporated at PP analysis when consumption of the prescribed drugs was <50% or if they did not complete the follow-up. The Fisher’s exact test was used for comparison between groups, and P-values less than 0.05 were considered significant. The difference between the proportions eradicated in the two participating centres was estimated. Before pooling that estimates, a Fisher’s exact test was applied to investigate heterogeneity between the differences.
3. Results Forty patients (Bologna: 25 patients; Rome: 15 patients) with persistent H. pylori infection after a first-line therapy were identified. Overall, bacterial culture was successful achieved in 33 (82.5%) cases, and 10 (30.3%) of these patients were infected with a levofloxacin resistant strain. The prevalence of primary levofloxacin resistance did not differ between the two participating centres (7/22, 31.8% versus 3/11, 27.3%, P = 0.3), nor between patients who previously failed standard or sequential therapy (6/23, 26.1% versus 4/10, 40%, P = 0.2). Overall, 33 (Males/females: 13/20; Mean age: 49.8 ± 12 years) accepted to participate in the present study, whilst the remaining seven refused. Bacterial culture was available in 26 (78.8%) of these patients, and primary levofloxacin resis-
F. Perna et al. / Digestive and Liver Disease 39 (2007) 1001–1005
tance was detected in 6 (23.1%) cases. All patients completed both therapy and follow-up. H. pylori infection was successfully cured in 24 patients, accounting for a 72.7% (95% CI: 57–88) eradication rate at both ITT and PP analyses. No difference was detected in the eradication rate between the two centres (12/18, 66.7% versus 12/15, 80%; P = 0.2). Overall, the cure rate was distinctly higher in patients harbouring levofloxacin-susceptible (15/20, 75%; 95% CI: 56–94) than resistant strains (2/6, 33.3%; 95% CI: 0–71), although the difference failed to reach a statistical significance (P = 0.074). Compliance to the therapy was excellent in all but one patient, who stopped the treatment at 8 days for oral candidiasis. Overall, 5 (15.5%) patients complained of side effects, including diarrhoea (2 patients), glossitis (2) and oral candidiasis (1).
4. Discussion Recent data suggest that the success rate of standard 7–14 days triple therapies is decreasing worldwide [1–8]. Moreover, it is known that bacterial eradication following a failed initial therapy is notoriously difficult to achieve. Current US, Canadian, and European guidelines suggest the use of a quadruple therapy as a second-line therapy [9–11], but bismuth salts are not any more available worldwide. Therefore, H. pylori management in the clinical practice remains a challenge for the physicians. In the last few years, a triple therapy including a levofloxacin–amoxycillin combination has been proposed for either first-line or rescue therapy regimen to cure H. pylori infection [12–17]. Moreover, two large meta-analysis showed that this therapy achieve a success rate significantly higher as compared to the quadruple regimen, with lower incidence of side-effects and adverse effects prompting discontinuation of therapy [18,19]. Such a therapy regimen has been also proved to be superior to a rifabutin–amoxycillin combination [25]. In the present study, the levofloxacin-based re-treatment achieved an overall eradication rate (72.7%), which tended to be lower as compared to 76–85.7% we previously reported [14–16], and in agreement with the results of other recent Italian, European and Asian studies [13,17,26–28]. This finding could depend on the higher prevalence of primary levofloxacin resistance observed in this study (30.3%) which is twice compared to that found in our previous trial (16.9%) [16]. Indeed, we showed that the presence of bacterial resistance towards this antibiotic halves the success rate of a triple therapy including levofloxacin. Such a finding is in agreement with our previous observation [16], and with the result of another Italian study in which the presence of levofloxacin resistance significantly reduced the eradication rate following a similar second-line therapy [21]. Unfortunately, the prevalence of primary levofloxacin resistance rate is increasing, with values ranging from 8.8% in Alaska [29], 5.5–14.3% in Japan [17,28,30] to 16.8% in Belgium [23], 17% in Brazil
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[31], 18% in Hong Kong [25], 21.5% in Korea [32], 22.1% in Germany [33], and 9–32.3% in Italy [16,21,34]. Such an increase in the bacterial resistance against levofloxacin presumably comes from treatment of pulmonary or urinary infections with quinolones. Indeed, we recently found that levofloxacin resistance was significantly higher in old than younger patients [35]. Based on these observations, it could be useful to test the efficacy of other rescue regimens including a higher levofloxacin dose. Indeed, 500 mg levofloxacin twice daily has been administered in some studies, although data seems to be not promising [18,19,27].
Practice points • A levofloxacin–amoxycillin-based triple therapy has been proved to be an acceptably effective second-line therapy for H. pylori infection, but the role of levofloxacin resistance on its efficacy is unclear. • We evaluated the efficacy of a 10-day levofloxacin–amoxycillin triple therapy on consecutive patients who failed a 10-day, standard triple or sequential therapy, according to levofloxacin resistance. • Overall, H. pylori infection was cured 72.7% eradication rate at both ITT and PP analyses. The eradication rate was higher in patients harbouring levofloxacin-susceptible than resistant strains (75% versus 33.3%; P = 0.074). • The eradication rate achieved by a levofloxacin-based re-treatment seems to be decreasing, and its efficacy is reduced in presence of levofloxacin resistance.
Research agenda • The efficacy of a triple therapy regimen including higher levofloxacin dose (500 mg twice daily) could be tested as a second-line therapy. • The combination of levofloxacin with other antibiotics, instead of amoxicillin, deserves further investigation. • Since primary levofloxacin resistance reduces the efficacy of therapy, to monitor levofloxacin resistance in different geographical areas is crucial in order to tailor therapy in different setting.
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Recent studies have proposed a triple therapy with levofloxacin and either azithromycin, furazolidone or rifabutin instead of amoxycillin. The former combination give disappointing results as a first-line treatment [36], whilst a high eradication rate was achieved following the therapy with furazolidone (83%) or with rifabutin (91%) as re-treatment [12,31]. Unfortunately, the onset of myelotoxicity has been observed following rifabutin, suggesting that more caution should be used in such therapeutic approach [37]. In addition, rifabutin is an expensive antimycobacterial drug particularly useful for tuberculosis treatment in AIDS patients, and it deserve a careful use. A possible limitation of the present study is the small sample size. It is therefore possible that some differences – i.e. the eradication rate between levofloxacin-susceptible and resistant strains – failed to reach the statistical significance. However, it has the relevant value of susceptibility testing towards levofloxacin, which is scantily performed in the clinical trials. In conclusion, the eradication rate following a levofloxacin–amoxycillin triple therapy seems to be decreasing in Italy, and its efficacy is reduced in presence of primary levofloxacin resistance. Conflict of interest statement None declared.
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F. Perna et al. / Digestive and Liver Disease 39 (2007) 1001–1005 [27] Gisbert JP, Gisbert JL, Marcos S, Moreno-Otero R, Pajares JM. Levofloxacin- versus ranitidine bismuth citrate-containing therapy after H. pylori treatment failure. Helicobacter 2007;12:68– 73. [28] Matsumoto Y, Miki I, Aoyama N, Shirasaka D, Watanabe Y, Morita Y, et al. Levofloxacin- versus metronidazole-based rescue therapy for H. pylori infection in Japan. Dig Liver Dis 2005;37:821–5. [29] Carothers JJ, Bruce MG, Hennessy TW, Bensler M, Morris JM, Reasonover AL, et al. The relationship between previous fluoroquinolone use and levofloxacin resistance in Helicobacter pylori infection. Clin Infect Dis 2007;44:5–8. [30] Fujimura S, Kato S, Iinuma K, Watanabe A. In vitro activity of fluoroquinolone and the gyrA gene mutation in Helicobacter pylori strains isolated from children. J Med Microbiol 2004;53:1019–22. [31] Coelho LG, Moretzsohn LD, Vieira WL, Gallo MA, Passos MC, Cindr JM, et al. New once-daily, highly effective rescue triple therapy after multiple Helicobacter pylori treatment failures: a pilot study. Aliment Pharmacol Ther 2005;21:783–7. [32] Kim JM, Kim JS, Kim N, Kim SG, Jung HC, Song IS. Comparison of primary and secondary antimicrobial minimum inhibitory concen-
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Digestive and Liver Disease 39 (2007) 1001–1005
Alimentary Tract
Levofloxacin-based triple therapy for Helicobacter pylori re-treatment: Role of bacterial resistance F. Perna a , A. Zullo b,∗ , C. Ricci c , C. Hassan b , S. Morini b , D. Vaira a a
Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy b Gastroenterology Unit, “Nuovo Regina Margherita Hospital”, Rome, Italy c Gastroenterology Unit, University of Brescia, Brescia, Italy Received 25 March 2007; accepted 28 June 2007 Available online 21 September 2007
Abstract Background. First-line Helicobacter pylori therapy fails in more than 20% of patients. Quadruple therapy is the suggested second-line therapy, but bismuth salts are not anymore available worldwide. This study aimed to assess the efficacy of a levofloxacin–amoxycillin triple therapy as a second-line treatment, and the role of primary levofloxacin resistance. Methods. Forty patients, in whom first treatment with either standard 10-day triple or sequential therapy had failed, received 10-day triple therapy with rabeprazole (20 mg b.d.), levofloxacin (250 mg b.d.), and amoxycillin (1 g b.d.). Cure rates were evaluated by the 13 C-urea breath test. Primary levofloxacin resistance was detected by culture. Results. Bacterial culture was available in 33 (82.5%) out 40 patients, and primary levofloxacin resistance was detected in 10 (30.3%) patients. Overall, 33 of 40 patients accepted to participate in this study, and all returned for follow-up after therapy. Compliance to the therapy was safe except 1 patient only who stopped earlier the treatment due to side effects (oral candidiasis). H. pylori infection was eradicated in 24 patients, accounting for a 72.7% (95% CI: 57–88) eradication rate at both intention-to-treat and per protocol analyses. The eradication rate was higher in patients harbouring levofloxacin-susceptible than resistant strains (75% versus 33.3%; P = 0.074). Conclusions. The eradication rate achieved by a levofloxacin-based re-treatment seems to be decreasing, and its efficacy is reduced in presence of levofloxacin resistance. © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Bacterial resistance; H. pylori; Levofloxacin; Rescue therapy
1. Introduction Standard triple therapies fail to cure Helicobacter pylori infection in more than 20–30% of patients [1,2]. In the last five years, several studies have found an eradication rate lower than 75% [3–6], and values as low as 25–45% have been also recently reported [7,8]. A quadruple therapy with proton pump inhibitor, bismuth salt, tetracycline and metronidazole is currently advised as second-line therapy in ∗ Corresponding author at: Gastroenterology and Digestive Endoscopy, “Nuovo Regina Margherita” Hospital, Via E. Morosini, 30, 00153 Rome, Italy. Tel.: +39 06 58446608; fax: +39 06 58446533. E-mail address: [email protected] (A. Zullo).
eradication failure patients [9–11]. However, data regarding the eradication rate achieved following such a therapy regimen are controversial, with values widely ranging from 37 to 91% [12,13]. Moreover, bismuth salts (as well as ranitidine bismuth citrate) are not anymore available worldwide. Therefore, management of first-line eradication failure patients is become challenging. A levofloxacin–amoxycillin-based triple therapy has been proved to be acceptably effective as second- or even thirdline therapy [14–17], and two recent meta-analyses showed a higher eradication rate as compared to standard quadruple therapy as a re-treatment [18,19]. It has been found that a 10day levofloxacin-based regimen achieve higher cure rate than the 7-day regimen, whilst levofloxacin dose (250 mg b.d ver-
1590-8658/$30 © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2007.06.016
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F. Perna et al. / Digestive and Liver Disease 39 (2007) 1001–1005
sus 500 o.d.) seem to be equally effective [18,19]. Bacterial resistance to antibiotics is widely claimed as the most important factor reducing the efficacy of standard triple therapy [20]. However, only scanty data are currently available on the role of primary levofloxacin resistance on levofloxacin-based triple therapy efficacy [16,17,21]. The present study aimed to assess the efficacy of a levofloxacin–amoxycillin triple therapy as a second-line treatment, and the role of primary levofloxacin resistance.
2. Methods 2.1. Patients This was a prospective, open-label study performed in two centres (Bologna and Rome). All patients enrolled in previous trial [22] and with persistent H. pylori infection following a first-line therapy were invited to participate in this study. There were 40 patients who failed either a 10day triple therapy (pantoprazole 40 mg b.d., clarithromycin 500 mg b.d., and amoxycillin 1 g b.d.) (N = 30) or a 10-day sequential regimen (pantoprazole 40 mg b.d. plus amoxycillin 1 g for the first 5 days, followed by pantoprazole 40 mg b.d., clarithromycin 500 mg b.d., and tinidazole 500 mg b.d. for the remaining 5 days) (N = 10). Patients underwent endoscopy with biopsies for histology (two samples from the antrum and two samples from the corpus), rapid urease test (one sample from the antrum) and culture (one sample from the antrum). Patients were considered infected if two of three tests were positive or culture was positive alone. All patients gave informed consent to participate into the study. 2.2. Bacterial culture and susceptibility testing Biopsies, collected for bacterial culture, were sent within 24 h to a single microbiological laboratory (Bologna) streaked onto Columbia agar enriched with 5% horse blood and containing vancomycin, trimethoprim, polymixin B and nalidixic acid to inhibit the growth of microbes other then H. pylori. The plates were incubated in a microaerobic environment at 37 ◦ C for 7 days, and inspected daily from the third day. The isolates were identified by Gram stain and by oxidase, catalase and urease tests. Suspensions from primary plates were prepared in sterile saline solution to have approximately 108 cells/ml to perform Etest. A blood agar plate was streaked in three directions with a swab dipped into each bacterial suspension to produce a lawn of growth, an E-test strip (E-test; AB Biodisk, Solna, Sweden) were placed each onto a separate plate, which was immediately incubated in a microaerobic atmosphere at 37 ◦ C for 72 h. Isolated strains were tested for primary levofloxacin resistance, using as break point the minimal inhibitory concentration (MIC) ≥1 mg/L, as suggested [23].
2.3. Treatment and follow-up All patients received a 10-day triple therapy including rabeprazole 20 mg b.d., levofloxacin 250 mg b.d., and amoxycillin 1 g b.d. The proton pump inhibitor was given 30 min before breakfast and dinner, whilst both antibiotics were administered following these meals. Patients were asked to return at end of eradication therapy to assess side effect and compliance to the therapy. After 4–6 week, patients underwent a 13 C urea breath test. Urea breath tests were carried out after an overnight fast. A baseline breath sample was obtained and then 75 mg of 13 C-urea with citric acid (1.5 g) was administered as an aqueous solution. Another breath sample was collected 30 min after administration of the test solution and the test was considered positive if there was a difference between the baseline sample and the 30 min sample that exceeded 4.5 parts per 1000 of 13 CO2 . All the breath samples were analysed using a single gas isotope ratio mass spectrometer (Finnigan, Bremen, Germany) located in Bologna. The accuracy of this urea breath was previously validated in our laboratory, reporting sensitivity and specificity values of 94.7 and 95.7%, respectively [24]. 2.4. Statistical analysis The eradication rates and their 95% confidence intervals at both intention-to-treat (ITT) and per protocol (PP) analyses were calculated. At ITT analysis were included all patients who took at least one dose of medication, whilst they were not incorporated at PP analysis when consumption of the prescribed drugs was <50% or if they did not complete the follow-up. The Fisher’s exact test was used for comparison between groups, and P-values less than 0.05 were considered significant. The difference between the proportions eradicated in the two participating centres was estimated. Before pooling that estimates, a Fisher’s exact test was applied to investigate heterogeneity between the differences.
3. Results Forty patients (Bologna: 25 patients; Rome: 15 patients) with persistent H. pylori infection after a first-line therapy were identified. Overall, bacterial culture was successful achieved in 33 (82.5%) cases, and 10 (30.3%) of these patients were infected with a levofloxacin resistant strain. The prevalence of primary levofloxacin resistance did not differ between the two participating centres (7/22, 31.8% versus 3/11, 27.3%, P = 0.3), nor between patients who previously failed standard or sequential therapy (6/23, 26.1% versus 4/10, 40%, P = 0.2). Overall, 33 (Males/females: 13/20; Mean age: 49.8 ± 12 years) accepted to participate in the present study, whilst the remaining seven refused. Bacterial culture was available in 26 (78.8%) of these patients, and primary levofloxacin resis-
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tance was detected in 6 (23.1%) cases. All patients completed both therapy and follow-up. H. pylori infection was successfully cured in 24 patients, accounting for a 72.7% (95% CI: 57–88) eradication rate at both ITT and PP analyses. No difference was detected in the eradication rate between the two centres (12/18, 66.7% versus 12/15, 80%; P = 0.2). Overall, the cure rate was distinctly higher in patients harbouring levofloxacin-susceptible (15/20, 75%; 95% CI: 56–94) than resistant strains (2/6, 33.3%; 95% CI: 0–71), although the difference failed to reach a statistical significance (P = 0.074). Compliance to the therapy was excellent in all but one patient, who stopped the treatment at 8 days for oral candidiasis. Overall, 5 (15.5%) patients complained of side effects, including diarrhoea (2 patients), glossitis (2) and oral candidiasis (1).
4. Discussion Recent data suggest that the success rate of standard 7–14 days triple therapies is decreasing worldwide [1–8]. Moreover, it is known that bacterial eradication following a failed initial therapy is notoriously difficult to achieve. Current US, Canadian, and European guidelines suggest the use of a quadruple therapy as a second-line therapy [9–11], but bismuth salts are not any more available worldwide. Therefore, H. pylori management in the clinical practice remains a challenge for the physicians. In the last few years, a triple therapy including a levofloxacin–amoxycillin combination has been proposed for either first-line or rescue therapy regimen to cure H. pylori infection [12–17]. Moreover, two large meta-analysis showed that this therapy achieve a success rate significantly higher as compared to the quadruple regimen, with lower incidence of side-effects and adverse effects prompting discontinuation of therapy [18,19]. Such a therapy regimen has been also proved to be superior to a rifabutin–amoxycillin combination [25]. In the present study, the levofloxacin-based re-treatment achieved an overall eradication rate (72.7%), which tended to be lower as compared to 76–85.7% we previously reported [14–16], and in agreement with the results of other recent Italian, European and Asian studies [13,17,26–28]. This finding could depend on the higher prevalence of primary levofloxacin resistance observed in this study (30.3%) which is twice compared to that found in our previous trial (16.9%) [16]. Indeed, we showed that the presence of bacterial resistance towards this antibiotic halves the success rate of a triple therapy including levofloxacin. Such a finding is in agreement with our previous observation [16], and with the result of another Italian study in which the presence of levofloxacin resistance significantly reduced the eradication rate following a similar second-line therapy [21]. Unfortunately, the prevalence of primary levofloxacin resistance rate is increasing, with values ranging from 8.8% in Alaska [29], 5.5–14.3% in Japan [17,28,30] to 16.8% in Belgium [23], 17% in Brazil
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[31], 18% in Hong Kong [25], 21.5% in Korea [32], 22.1% in Germany [33], and 9–32.3% in Italy [16,21,34]. Such an increase in the bacterial resistance against levofloxacin presumably comes from treatment of pulmonary or urinary infections with quinolones. Indeed, we recently found that levofloxacin resistance was significantly higher in old than younger patients [35]. Based on these observations, it could be useful to test the efficacy of other rescue regimens including a higher levofloxacin dose. Indeed, 500 mg levofloxacin twice daily has been administered in some studies, although data seems to be not promising [18,19,27].
Practice points • A levofloxacin–amoxycillin-based triple therapy has been proved to be an acceptably effective second-line therapy for H. pylori infection, but the role of levofloxacin resistance on its efficacy is unclear. • We evaluated the efficacy of a 10-day levofloxacin–amoxycillin triple therapy on consecutive patients who failed a 10-day, standard triple or sequential therapy, according to levofloxacin resistance. • Overall, H. pylori infection was cured 72.7% eradication rate at both ITT and PP analyses. The eradication rate was higher in patients harbouring levofloxacin-susceptible than resistant strains (75% versus 33.3%; P = 0.074). • The eradication rate achieved by a levofloxacin-based re-treatment seems to be decreasing, and its efficacy is reduced in presence of levofloxacin resistance.
Research agenda • The efficacy of a triple therapy regimen including higher levofloxacin dose (500 mg twice daily) could be tested as a second-line therapy. • The combination of levofloxacin with other antibiotics, instead of amoxicillin, deserves further investigation. • Since primary levofloxacin resistance reduces the efficacy of therapy, to monitor levofloxacin resistance in different geographical areas is crucial in order to tailor therapy in different setting.
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Recent studies have proposed a triple therapy with levofloxacin and either azithromycin, furazolidone or rifabutin instead of amoxycillin. The former combination give disappointing results as a first-line treatment [36], whilst a high eradication rate was achieved following the therapy with furazolidone (83%) or with rifabutin (91%) as re-treatment [12,31]. Unfortunately, the onset of myelotoxicity has been observed following rifabutin, suggesting that more caution should be used in such therapeutic approach [37]. In addition, rifabutin is an expensive antimycobacterial drug particularly useful for tuberculosis treatment in AIDS patients, and it deserve a careful use. A possible limitation of the present study is the small sample size. It is therefore possible that some differences – i.e. the eradication rate between levofloxacin-susceptible and resistant strains – failed to reach the statistical significance. However, it has the relevant value of susceptibility testing towards levofloxacin, which is scantily performed in the clinical trials. In conclusion, the eradication rate following a levofloxacin–amoxycillin triple therapy seems to be decreasing in Italy, and its efficacy is reduced in presence of primary levofloxacin resistance. Conflict of interest statement None declared.
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