Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure

Alimentary Pharmacology & Therapeutics Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure J. P. GISBERT & F. DE LA MORENA Department of Gastroenterology, University Hospital of La Princesa, Madrid, Spain Correspondence to: Dr J. P. Gisbert, Playa de Mojácar 29, Urb Bonanza, 28669 Boadilla del Monte, Madrid, Spain. E-mail: gisbert@meditex.es Publication data Submitted 26 September 2005 First decision 14 October 2005 Resubmitted 18 October 2005 Accepted 19 October 2005 SUMMARY Background A quadruple therapy has been generally recommended as rescue regimen for Helicobacter pylori eradication failures. Aims To systematically review the efficacy and tolerance of levofloxacin-based rescue regimens, and to conduct a meta-analysis of studies comparing these regimens with quadruple therapy for H. pylori eradication failures. Methods Selection of studies levofloxacin-based rescue regimens. For the meta-analysis, randomized-controlled trials comparing levofloxacinbased and quadruple regimens. Search strategy electronic and manual. Assessment of study quality independently by two reviewers. Data synthesis intention-to-treat eradication rate. Results Mean eradication rate with levofloxacin-based regimens was 80%. Tenday regimens were more effective than 7-day combinations (81% vs. 73%; P < 0.01). The meta-analysis showed better results with levofloxacin than with the quadruple combination (81% vs. 70%; OR ¼ 1.80; 95% CI ¼ 0.94 3.46). This difference reached statistical significance and heterogeneity markedly decreased when a single outlier study was excluded or when only high-quality studies were considered. Meta-analysis showed less adverse effects with levofloxacin than with quadruple regimen, both overall (19% vs. 44%; OR ¼ 0.27; 95% CI ¼ 0.16 0.46) and regarding severe adverse effects (0.8% vs. 8.4%; OR ¼ 0.20; 95% CI ¼0.06 0.67). Conclusions After H. pylori eradication failure, levofloxacin-based rescue regimen is more effective and better tolerated than the generally recommended quadruple therapy. A 10-day combination of levofloxacin amoxicillin proton pump inhibitor constitutes an encouraging second-line alternative. Aliment Pharmacol Ther 23, 35 44 ª 2006 The Authors 35, doi:10.1111/j.1365-2036.2006.02737.x

36 J. P. GISBERT AND F. DE LA MORENA INTRODUCTION Helicobacter pylori infection is the main cause of gastritis, gastroduodenal ulcer disease, and gastric cancer. After more than 20 years of experience in H. pylori treatment, however, the ideal regimen to treat this infection has still to be found. Thus, even with the current most effective treatment regimens, including proton pump inhibitors (PPIs) plus two antibiotics, approximately 20% of patients will fail to eradicate the infection and remain H. pylori positive. 1 After failure of a combination of a PPI-based triple regimen, the use of the so called quadruple therapy (that is, PPI, bismuth, tetracycline and metronidazole) has been generally used as the optimal second-line therapy 1 based on the relatively good results reported by several authors. 2 11 However, this regimen requires the administration of four drugs with a complex scheme (bismuth and tetracycline usually prescribed every 6 h, and metronidazole every 8 h) and is associated with a relatively high incidence of adverse effects. 1 Furthermore, this quadruple regimen still fails to eradicate H. pylori in approximately 20 30% of the patients, and these cases constitute a therapeutic dilemma, as patients who are not cured with two consecutive treatments including clarithromycin and metronidazole will have at least single, and usually double, resistance. 1 Levofloxacin is a fluoroquinolone antibacterial agent with a broad spectrum of activity against Grampositive and Gram-negative bacteria and atypical respiratory pathogens. 12 Several randomized-comparative trials have demonstrated the efficacy of levofloxacin in the treatment of infections of the respiratory tract, genitourinary tract, skin and skin structures. 12 Recently, some studies have evaluated the efficacy of new fluoroquinolones, such as levofloxacin, that could prove to be a valid alternative to standard antibiotics not only as first-line therapies but, more interesting, as rescue-regimens. 13 Therefore, the aim of the present study was to: (i) systematically review the H. pylori eradication efficacy and tolerance of levofloxacin-based rescue regimens after one or more treatment failures; and (ii) to conduct a meta-analysis of randomized-clinical trials comparing the efficacy and tolerance of the quadruple therapy (that is, PPI, bismuth, tetracycline and metronidazole) vs. levofloxacin-based triple regimens, for H. pylori eradication failures. PATIENTS AND METHODS Selection of studies Studies evaluating levofloxacin-based rescue regimens for the eradication of H. pylori after one or more treatment failures were considered. For the meta-analysis, the selected criteria were as follows: (i) Articles had to report comparative randomized-controlled trials. (ii) They had to include at least two branches of treatment consisting of (a) quadruple therapy (that is, PPI, bismuth, tetracycline and metronidazole; or ranitidine bismuth citrate plus these same antibiotics), and (b) levofloxacin-based regimen; (iii) Studies should evaluate these therapies as a rescue treatment for previous H. pylori eradication failures. Only studies with clear information about number of patients treated in each therapeutic group, drug dose and schedule, and rate of H. pylori eradication clearly stated (separately identified for each therapy) were included. Search strategy for identification of studies Trials were identified by searching the Cochrane Library (Issue 3 2005), MEDLINE (July 2005), EMBASE (July 2005), CINAHL (July 2005), and ISI Web of Knowledge (July 2005). A search strategy was constructed by using a combination of the following words: (Helicobacter pylori OR H. pylori) AND (levofloxacin OR fluoroquinolones OR quinolones). Articles published in any language were included. Reference lists from the trials selected by electronic searching were handsearched to identify further relevant trials. We also conducted a manual search of abstracts from 1995 to 2005 (July) from the following congresses: International Workshop of the European Helicobacter Study Group, American Digestive Disease Week (DDW), and United European Gastroenterology Week (UEGW). Abstracts of the articles selected in each of these multiple searches were reviewed and those meeting the inclusion criteria were recorded. References of reviews on H. pylori treatment with levofloxacin, and from the articles selected for the study, were also examined for articles meeting inclusion criteria. In case of duplicate reports, or studies obviously reporting results from the same study population, only the latest published results were used.

SYSTEMATIC REVIEW AND META-ANALYSIS: LEVOFLOXACIN-BASED RESCUE THERAPY 37 Assessment of study quality The quality of the studies was assessed using the score proposed by Jadad et al. 14 based on three items: (i) randomization; (ii) double blinding; and (iii) description of withdrawals and dropouts. The items were presented as questions to elicit yes or no answers. Points awarded for items one and two depended on the quality of the description of the methods to generate the sequence of randomization and/or on the quality of the description of the method of double blinding. The third item, withdrawals and dropouts, was awarded as zero points for a negative answer and one point for a positive. For a positive answer, the number of withdrawals and dropouts and the reasons had to be stated in each of the comparison groups. Quality assessment of studies was performed independently by two reviewers. Discrepancies in the interpretation were resolved by consensus. mean (and corresponding 95% CI) to make due allowance for the number of patients included in each study. Categorical variables were compared with the chi-square (v 2 ) test, and a P-value <0.05 was considered statistically significant. For the meta-analysis, the homogeneity of effects throughout studies was appraised using a homogeneity test based on the v 2 test. Because of the low power of this test, a minimum cut-off P-value of 0.1 was established as a threshold of homogeneity: lower values indicated heterogeneity, and prevented us from relying on the combination of the study results. Meta-analysis was performed combining the Odds Ratios (OR) of the individual studies in a global OR, using a random effect model (DerSimonian and Laird). Significance and 95% CI were provided for the combined OR. All calculations were performed with the freeware program Review Manager 4.2.8., developed by the Cochrane Collaboration (Copenhagen, Denmark). Data extraction The following variables were extracted in a predefined data extraction form (see Table 1): author, number of previous eradication failures, type of previous eradication regimens, dose and scheme of levofloxacin and co-prescribed drugs (PPI and antibiotics), duration of treatment, number and percentage of adverse effects and severe adverse effects (which included all side effects defined as severe by the authors or explaining treatment discontinuation), and eradication rate (number of patients treated and eradicated). In addition, in studies included in the meta-analysis, the following variables were also extracted (see Table 2): year of publication, format (abstract or journal article), type of disease (peptic ulcer disease or non-ulcer disease), and quality score (see Jadad score in previous section, including items of randomization, double blinding, and description of withdrawal/dropouts). Data synthesis The outcome considered in this review was eradication of H. pylori. Eradication was analysed on an intention-to-treat if data were available. Articles that did not specify the type of analysis were assumed to report per-protocol data. The mean percentage of H. pylori eradication and adverse effects (both overall and severe) was calculated and expressed as weighted Subanalysis/sensitivity analysis In the meta-analysis, subanalyses of H. pylori eradication efficacy were planned a priori depending on: (i) the type of drugs co-prescribed with levofloxacin (as the combination with amoxicillin and a PPI is the most widely prescribed); (ii) the type of previous eradication treatment (including only studies evaluating second-line eradication regimens as rescue therapy after one eradication attempt with PPI, clarithromycin, and amoxicillin, the most widely used first-line eradication regimen); (iii) the dose of levofloxacin; and (iv) the quality of the studies (based on quality score proposed by Jadad, see appropriate section). In the meta-analysis of tolerance, subanalyses were planned considering adverse effects overall and severe adverse effects in particular. RESULTS Description of studies With the predefined search strategy, 149 articles were retrieved in MEDLINE, and 92 in EMBASE. The study by Cammarota et al. 15 was excluded because patients were treated with a culture-guided, third-line regimen (five patients received 1-week levofloxacin-based triple regimen). The study by Miehlke et al. 16 was excluded because it was not clear in text whether levofloxacin regimen was prescribed as first or second

38 J. P. GISBERT AND F. DE LA MORENA Table 1. Helicobacter pylori eradication efficacy with levofloxacin-based rescue regimens after one or more H. pylori treatment failures Author (references) No. of previous eradication failures Previous eradication regimens Levofloxacin dose Second drug Third drug Days of antibiotics % adverse effects % severe adverse effects (no. of % eradication Gatta et al. 18 2 PPI + A + C, PPI + C + M, PPI + B +T+M 250 mg b.d. A 1 g b.d. PPI standard dose b.d. 10 3.3 (5/151) 0 (0/151) 76 (115/151) Perri et al. 19 1 PPI + A + C 500 mg o.d. A 1 g b.d. P 40 mg b.d. 7 5 (3/60) 1.6 (1/60) 63 (38/60) Gisbert et al. 20 2 PPI + A + C, PPI + 500 mg b.d. A 1 g b.d. O 20 mg b.d. 10 9 (5/55) 1.8 (1/55) 67 (37/55) B+T+M Gisbert et al. 21 1 PPI + A + C 500 mg b.d. A 1 g b.d. O 20 mg b.d. 7 40 (12/31) 0 (0/31) 67 (21/31) Orsi et al. 22 1 PPI + A + C 500 mg o.d. A 1 g b.d R 20 mg b.d. 12 8 (4/50) 86 (43/50) Matsumoto et al. 23 1 PPI + A + C 300 mg b.d. A 1 g b.d. L 30 mg b.d. 7 10 (3/30) 3.3 (1/30) 70 (21/30) Watanabe et al. 24 1 PPI + A + C 200 mg b.d. A 1 g b.d. L 30 mg b.d. 7 21 (7/33) 0 (0/33) 70 (23/33) Zullo et al. 25 2 3 PPI + A + C, PPI + C + M, PPI +A+M,PPI+B+ T + M, RBC + T + M, RBC+A+M 250 mg b.d. A 1 g b.d. R 20 mg b.d. 10 19 (7/36) 5.5 (2/36) 83 (30/36) Bilardi et al. 26 1 6 250 mg b.d. A 1 g b.d. P 40 mg b.d. 10 37 (17/46) 28.2 (13/46) 70 (31/44) Nista et al. 27 1 PPI + A + C 500 mg o.d. A 1 g b.d. R 20 mg b.d. 7 or 10 LeAR10 91 (42/46) LeAR7 74 (37/50) Nista et al. 28 1 PPI + A + C 500 mg o.d. A 1 g b.d. or M 500 mg b.d. Nista et al. 29 1 PPI + A + C 500 mg o.d. A 1 g b.d. or Az 500 mg o.d. Wong et al. 30 1 500 mg o.d. Rifabutin 300 mg o.d. Coelho et al. 31 2 500 mg o.d. Furazolidone 400 mg o.d. R 20 mg b.d 10 LeAR 10 (7/70) LeMR 11 (8/70) 0 (0/140) LeAR 94 (66/70) LeTR 90 (63/70) E 40 mg o.d. 10 LeAE 27 (8/30) 0 (0/60) LeAE 87 (26/30) LeAzE 23 (7/30) LeAzE 80 (24/30) R 20 mg b.d. 7 34 (19/56) 1.7 (1/56) 91 (51/56) R 20 mg o.d. 10 50 (6/12) 16 (2/12) 83 (10/12) PPI, proton pump inhibitor; C, clarithromycin; A, amoxicillin; M, metronidazole or tinidazole; B, bismuth; T, tetracycline; Az, azithromycin; O, omeprazole; L, lansoprazole; LE, levofloxacin; P, pantopraxole; R, rabeprazole; E, esomeprazole; RBC, ranitidine bismuth citrate; o.d., once daily; b.d., twice daily.

SYSTEMATIC REVIEW AND META-ANALYSIS: LEVOFLOXACIN-BASED RESCUE THERAPY 39 Table 2. Characteristics of included studies comparing Helicobacter pylori eradication efficacy with levofloxacin-based triple regimens vs. quadruple therapy Authors (references) Year Format Disease Levofloxacin regimen % eradication % adverse effects % severe adverse effects (no. of Quadruple regimen Days of antibiotics % eradication % adverse effects % severe adverse effects Q Perri et al. 19 2003 JA PUD (74/180) NUD (106/180) L 500 mg o.d. A 1 g b.d. P 40 mg b.d. Orsi et al. 22 2003 Ab L 500 mg o.d. A 1 g b.d. R 20 mg b.d. Bilardi et al. 26 2004 JA PUD (5/100) NUD (95/100) L 250 mg b.d. A 1 g b.d. P 40 mg b.d. Nista et al. 27 2005 Ab L 500 mg o.d. A 1 g b.d. R 20 mg b.d. Nista et al. 29 2004 Ab L 500 mg o.d. A 1 g b.d./ Az 500 mg o.d. E 40 mg o.d. Wong et al. 30 2002 JA PUD (29/105) NUD (76/105) Nista et al. 28 2003 JA NUD (280/280) Gisbert et al. 21 2005 Ab PUD (15/67) NUD (52/67) L 500 mg o.d. Rif 300 mg o.d. R 20 mg b.d. L 500 mg o.d. A 1 g/ti 500 mg b.d. R 20 mg b.d. L 500 mg b.d. A 1 g b.d. O 20 mg b.d. 63 (38/60) 5 (3/60) 1.6 (1/60) P 40 mg b.d. B 240 mg b.d. M 500 mg b.d. 86 (43/50) 8 (4/50) R 20 mg b.d. B 240 mg b.d. T 500 mg t.d.s. Ti 500 mg b.d. 70 (31/44) 25 (11/44) 2.2 (1/44) O 20 mg b.d. B 240 mg b.d. T 250 mg q.d.s. M 500 mg b.d. LAR10 91(42/46) LAR7 74 (37/50) LAE 87 (26/30) LAzE 80 (24/30) R 20 mg b.d. B 120 mg q.i.d M 400 mg t.d.s. LAE 27 (8/30) LAzE 23 (7/30) 0 (0/60) R 20 mg b.d. B 120 mg q.i.d M 500 mg t.d.s. 91 (51/56) 34 (19/56) 1.7 (1/56) R 20 mg b.d. B 120 mg q.i.d M 400 mg t.d.s. LAR 94 (66/70) LTR 90 (63/70) LAR 10 (7/70) LTR 11 (8/70) 0 (0/140) R 20 mg b.d. B 120 mg q.i.d M 400 mg t.d.s. 67 (21/31) 40 (12/31) 0 (0/31) RBC 400 mg b.d. M 250 mg q.d.s. 7 83 (50/60) 28 (17/60) 5 (3/60) 2 12 88 (44/50) 22 (11/50) 1 7 37 (17/46) 28 (13/46) 2.1 (1/46) 3 7 68 (34/50) 8 (4/50) 2 7 71 (25/35) 60 (21/30) 11 (4/35) 2 7 91 (48/53) 58 (31/53) 0 (0/53) 5 7/14 63 (44/70) 7 days 68 (48/70) 14 days 28 (20/70) 7 days 43 (30/70) 14 days 16 (11/70) 7 days 26 (15/70) 14 days 7 68 (24/36) 38.8 (14/36) 0 (0/36) 2 3 Ab, abstract; JA, journal article; PUD, peptic ulcer disease; NUD, non-ulcer disease; Q, quality score (Jadad scale, from 0 to 5 points, see Patients and Methods); o.d., once a day; b.d., twice a day; t.d.s., three times a day; q.d.s., four times a day; L, levofloxacin; A, amoxicillin; Az, azithromycin; Ti, tinidazole; Rif, rifabutin; O, omeprazole; P, pantoprazole; R, rabeprazole; B, bismuth; RBC, ranitidine bismuth citrate; T, tetracycline; M, metronidazole. Severe adverse effects included all side effects defined as severe by the authors or explaining treatment discontinuation.

40 J. P. GISBERT AND F. DE LA MORENA line therapy. The study by Oksanen et al. 17 was also excluded because all patients included in the protocol were known to be resistant to both metronidazole and clarithromycin (previously to the treatment with levofloxacin). The characteristics of the 14 studies included assessing levofloxacin-based regimens for the eradication of H. pylori, with 977 patients in total, are summarized in Table 1. 18 31 All but four studies prescribed levofloxacin at doses of 250 mg twice daily or 500 mg once daily. In two studies, higher doses 20, 21 of levofloxacin (500 mg b.d.) were administered. Most of the studies combined a PPI and amoxicillin together with levofloxacin, and only three studies used azithromycin, 29 rifabutin 30 or furazolidone 31 instead of amoxicillin. All studies administering amoxicillin prescribed 1 g of this drug twice daily, while the PPI was used at the standard dose twice daily. The antibiotic regimen was prescribed for 7 or 10 days in all but one study. 22 Characteristics of the eight studies comparing efficacy with the quadruple therapy and the levofloxacin-based triple regimens for H. pylori 19, 21, eradication failures are summarized in Table 2. 22, 26 30 In the quadruple therapy, the PPI was always prescribed at the standard doses twice daily, while tetracycline was generally used at doses of 500 mg four times per day. In the levofloxacin regimen, this antibiotic was prescribed at doses of 250 mg twice daily or 500 mg once daily, except in one study, where higher doses of levofloxacin (500 mg b.d.) were administered. 21 The co-prescribed antibiotic in this regimen was amoxicillin (at doses of 1 g b.d.), excepting in three studies, which used azithromycin, 29 rifabutin 30 or tinidazole. 28 The PPI in the levofloxacin-based regimens was administered at the standard doses twice daily in all but one study (where esomeprazole 40 mg o.d. was used. 29 Efficacy on Helicobacter pylori eradication Helicobacter pylori eradication rate (weighted mean) with levofloxacin-based regimens was, overall, 80% (95% CI, 77 82%). When only combinations administered for 7 days were included, cure rate was 73% (95% CI, 68 79%), while this figure was higher (P < 0.01) when 10-day regimens were considered (81%; 95% CI, 78 84%). In particular, levofloxacin amoxicillin PPI combination administered for 7 and 10 days achieved a mean eradication rate, respectively, of 68% (95% CI, 62 75%) and 80% (95% CI, 77 83%) (P < 0.001). The results of the meta-analysis comparing the levofloxacin-based triple regimens vs. the quadruple regimens for H. pylori eradication failures are summarized in Figure 1. Mean H. pylori eradication rate (pooled data) with levofloxacin was 81% (95% CI, 78 85%), and 70% (95% CI, 66 74%) with the quadruple regimen. The OR for this comparison was 1.80 (95% CI, 0.9 3.5), results being statistically heterogeneous (test for heterogeneity v 2, P < 0.001). However, this difference reached statistical significance and heterogeneity markedly decreased when a single outlier study was excluded. 19 Thus, after excluding this discordant study, the OR increased up to 2.2 (95% CI, 1.3 3.9). The advantage (although statistically non-significant) of the levofloxacine-regimen was also observed when the meta-analysis included the levofloxacin amoxicillin PPI combination in particular (OR, 1.7; 95% CI, 0.71 4.0; heterogeneous results, P < 0.001), or when only studies evaluating second-line eradication regimens as rescue therapy after one eradication attempt with PPI, clarithromycin, and amoxicillin were included (OR, 1.7, 95% CI, 0.79 3.7; heterogeneous results, P < 0.001). Our initial intention was to perform subanalysis depending on the dose of levofloxacin. However, all but one study included in the meta-analysis prescribed levofloxacin at doses of 500 mg per day, precluding adequate comparison of the study results. Finally, subanalysis depending on the quality of the study was performed including only studies with a score 3 (which has been reported to indicate high quality). 14 When only high-quality studies were considered (see Table 2), the advantage of the levofloxacin regimen over the quadruple regimen increased (88%, 95% CI, 84 92%; vs. 64%, 95% CI, 58 70%), resulting in an OR of 4.11 (95% CI, 1.89 8.95), and heterogeneity almost disappeared (P ¼ 0.08). Adverse effects Adverse effects were reported, overall, by 18% (95% CI, 15 21%) of the patients treated with levofloxacin-based therapies. These adverse effects were severe in 3% of the cases (95% CI, 1.9 4.5%). Respective incidence of adverse effect and severe adverse effects with the levofloxacin amoxicillin PPI regimen in particular was 16% (95% CI, 13 19%) and 3.3% (95% CI, 2.1 5.2%). The incidence of

SYSTEMATIC REVIEW AND META-ANALYSIS: LEVOFLOXACIN-BASED RESCUE THERAPY 41 Comparison: Outcome: 01 Levofloxacin regimen vs. quadruple regimen (eradication) 01 Levofloxacin vs. quadruple (overall) Study Levofloxacin Quadruple OR (random) Weight OR (random) or sub-category n/n n/n 95% CI % 95% CI Bilardi et al. 2004 Gisbert et al. 2005 Nista et al. 2003a Nista et al. 2003b Nista et al. 2004a Nista et al. 2004b Nista et al. 2005 Orsi et al. 2003 Perri et al. 2003 Wong et al. 2002 Total (95% CI) Total events: 400 (Levofloxacin), 355 (Quadruple) Test for heterogeneity: c 2 = 35.78, df = 9 (P < 0.0001), I 2 = 74.8% Test for overall effect: Z = 1.77 (P = 0.08) 0.1 0.2 0.5 1 2 5 10 Favours quadruple Favours levofloxacin Figure 1. Meta-analysis comparing Helicobacter pylori eradication efficacy with levofloxacin-based triple regimens vs. quadruple therapy. adverse effects was not different when this combination (levofloxacin amoxicillin PPI) was administered for one week (18%; 95% CI, 11 23%) and for 10 days (17%; 95% CI, 13 20%). The results of the meta-analysis comparing the incidence of adverse effects with levofloxacin-based triple regimens and quadruple regimens are summarized in Figure 2. Mean incidence of adverse effects (pooled data) with levofloxacin was 19% (95% CI, 15 22%), and 44% (95% CI, 40 49%) with the quadruple regimen. The OR for this comparison was 0.27 (95% CI, 0.16 0.46), results being statistically heterogeneous (test for heterogeneity v 2, P < 0.01). A higher incidence was also demonstrated in the group receiving the quadruple treatment when the meta-analysis included only the severe adverse effects: 0.8% (95% CI, 0.3 2.2%) with levofloxacin and 8.4% (95% CI, 5.7 11%) with the quadruple regimen (OR, 0.20; 95% CI, 0.06 0.67), but in this case results were homogeneous (P ¼ 0.28). DISCUSSION Quadruple therapy (that is, PPI, bismuth, tetracycline and metronidazole) has been generally used as the optimal second-line therapy after failure of the first H. pylori eradication trial, and has been the recommended rescue regimen in several guidelines. 32 34 Nevertheless, this rescue regimen still fails to eradicate H. pylori infection in approximately 20 30% of the cases, and these patients constitute a therapeutic dilemma. 13 Levofloxacin-based rescue therapies represent an encouraging strategy for eradication failures, as some studies have demonstrated that levofloxacin has, in vitro, remarkable activity against H. pylori, 35 and that primary resistances to such antibiotic are infrequent. 18, 36, 37 A recent in vitro study also showed a synergistic effect of quinolone antimicrobial agents and PPIs on strains of H. pylori. 38 Furthermore, it has been shown that levofloxacin retains its activity in vitro when H. pylori strains are resistant to clarithromycin and metronidazole. 24 These favourable results have been confirmed in vivo, indicating that most of the patients with both metronidazole and clarithromycin resistance 18, 26 are cured with the levofloxacin-based regimen. Some authors have reported encouraging experiences with levofloxacin. A combination of a PPI, amoxicillin and levofloxacin, as first-line regimen, has been associated with favourable results, with mean eradication rates of about 90%. 39 Later, other authors studied this same regimen in patients with at least one previous eradication failure, also reporting exciting results. Furthermore, our systematic review showed a mean eradication rate with levofloxacin-based rescue regimens (combined with amoxicillin and a PPI in most studies) of 80%, which represents a relatively high figure when considering that this regimen was evaluated as a rescue therapy. We found higher H. pylori cure rates with 10-day that with 7-day regimens, both in

42 J. P. GISBERT AND F. DE LA MORENA Comparison: Outcome: 02 Levofloxacin regimen vs. quadruple regimen (adverse effects) 01 Levofloxacin vs. quadruple (overall) Study Levofloxacin Quadruple OR (random) Weight OR (random) or sub-category n/n n/n 95% CI % 95% CI Bilardi et al. 2004 Gisbert et al. 2005 Nista et al. 2003a Nista et al. 2003b Nista et al. 2004a Nista et al. 2004b Orsi et al. 2003 Perri et al. 2003 Wong et al. 2002 Total (95% CI) Total events: 82 (Levofloxacin), 202 (Quadruple) Test for heterogeneity: c 2 = 21.43, df = 8 (P = 0.006), I 2 = 62.7% Test for overall effect: Z = 4.77 (P < 0.00001) 0.01 0.1 1 10 100 >AE quadruple >AE levofloxacin Comparison: Outcome: 02 Levofloxacin regimen vs. quadruple regimen (adverse effects) 02 Levofloxacin vs. quadruple (severe) Study Levofloxacin Quadruple OR (random) Weight OR (random) or sub-category n/n n/n 95% CI % 95% CI Bilardi et al. 2004 Gisbert et al. 2005 Nista et al. 2003a Nista et al. 2003b Nista et al. 2004a Nista et al. 2004b Perri et al. 2003 Wong et al. 2002 Total (95% CI) Total events: 3 (Levofloxacin), 34 (Quadruple) Test for heterogeneity: c 2 = 7.50, df = 6 (P = 0.28), I 2 = 20.0% Test for overall effect: Z = 2.62 (P = 0.009) 0.001 0.01 0.1 1 10 100 1000 >SAE quadruple >SAE levofloxacin Figure 2. Meta-analysis comparing the incidence of adverse effects (AE, top) and severe adverse effects (SAE, bottom) with levofloxacin-based triple regimens vs. quadruple therapy. general (81% vs. 73%) and also with the levofloxacin amoxicillin PPI combination in particular (80% vs. 68%), suggesting that the 10-day therapeutic scheme should be chosen. The results of our meta-analysis demonstrated higher H. pylori cure rates with the levofloxacin-based triple regimens than with the quadruple combinations (81% vs. 70%, borderline statistical significance). Nevertheless, results were heterogeneous, mainly because of the discordant results of the study by Perri et al., 19 who reported a cure rate of only 63% with the levofloxacin-regimen, the lowest reported in the literature, a figure that contrasts with the mean eradication rate of 80% calculated in our systematic review. Although primary resistances to levofloxacin are infrequent, 18, 36, 37 it has been shown that resistance to quinolones is easily acquired, and in areas with a high consumption of these drugs, the resistance rate is relatively high. 40 Nevertheless, when that single outlier study 19 was excluded from the meta-analysis, the difference between cure rates with both regimens reached statistical significance and heterogeneity markedly decreased. Furthermore, when only high-quality studies were considered, the advantage of the levofloxacin regimen over the quadruple regimen increased (88% vs. 64%), also achieving statistical significance, and heterogeneity among studies almost disappeared. Moreover, it has been suggested that levofloxacinbased therapies may also represent an alternative when two (or even more) consecutive eradication treatments 18, 20, 25, 26, 30, 31 have failed to eradicate the infection. In this respect, we have recently confirmed that levofl-

SYSTEMATIC REVIEW AND META-ANALYSIS: LEVOFLOXACIN-BASED RESCUE THERAPY 43 oxacin-based regimen can also be used as a fourth-line regimen after three previous eradication failures with antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline, and even rifabutin. 41 The quadruple regimen requires the administration of four drugs with a complex scheme (bismuth and tetracycline usually prescribed every 6 h, and metronidazole every 8 h). 1 On the contrary, levofloxacinbased regimens (with amoxicillin and PPIs administered twice daily, and levofloxacin every 12 or 24 h) represents an encouraging alternative to quadruple therapy, with the advantage of simplicity. The quadruple regimen is associated with a relatively high incidence of adverse effects. 1 In contrast, levofloxacin is generally well tolerated, and most adverse events associated with its use are mild to moderate in severity and transient. 12 The most frequent adverse effects affect the gastrointestinal tract. 12 In our systematic review, adverse effects were reported, overall, by 18% of the patients treated with levofloxacin-based therapies, and these adverse effects were severe (defined so by the authors or explaining treatment discontinuation) in only 3% of the cases. Furthermore, the incidence of adverse effects was not different when levofloxacin amoxicillin PPI was administered for 7 or 10 days, supporting the aforementioned recommendation of prescribing the more effective 10-day regimen. Moreover, our meta-analysis demonstrated a lower incidence of adverse effects with levofloxacin-based treatments than with the quadruple combinations, with respective rates of 19% and 44%. Finally, severe adverse effects were also less frequent with the levofloxacin-based regimen (0.8% vs. 8.4%). In summary, the conclusion of this systematic review and meta-analysis is that, after H. pylori eradication failure, levofloxacin-based rescue regimen is more effective and better tolerated that the generally recommended quadruple therapy. A 10-day combination of levofloxacin, amoxicillin and a PPI, constitutes an encouraging empirical second-line strategy and may be recommended after previous H. pylori eradication failures. POTENTIAL CONFLICT OF INTEREST None known. ACKNOWLEDGEMENT Supported in part by a Grant from the Instituto de Salud Carlos III (C03/02). This study was not funded by any Pharmaceutical Company. REFERENCES 1 Gisbert JP, Pajares JM. Review article: Helicobacter pylori rescue regimen when proton pump inhibitor-based triple therapies fail. Aliment Pharmacol Ther 2002; 16: 1047 57. 2 Gisbert JP, Boixeda D, Bermejo F, et al. Re-treatment after Helicobacter pylori eradication failure. Eur J Gastroenterol Hepatol 1999; 11: 1049 54. 3 Elizalde IR, Borda F, Jara C, Martínez A, Rodríguez C, Jiménez J. Eficacia de dos tratamientos consecutivos en la erradicación dehelicobacter pylori. Anales Sis San Navarra 1998; 21(Suppl. 2): 83 88. 4 Gomollon F, Ducons JA, Ferrero M, et al. Quadruple therapy is effective for eradicating Helicobacter pylori after failure of triple proton-pump inhibitorbased therapy: a detailed, prospective analysis of 21 consecutive cases. Helicobacter 1999; 4: 222 5. 5 Gasbarrini A, Ojetti V, Pitocco D, et al. Efficacy of different Helicobacter pylori eradication regimens in patients affected by insulin-dependent diabetes mellitus. Scand J Gastroenterol 2000; 35: 260 3. 6 Lee JM, Breslin NP, Hyde DK, Buckley MJ, O Morain CA. Treatment options for Helicobacter pylori infection when proton pump inhibitor-based triple therapy fails in clinical practice. Aliment Pharmacol Ther 1999; 13: 489 96. 7 Gisbert JP, Gisbert JL, Marcos S, Gravalos RG, Carpio D, Pajares JM. Seven-day rescue therapy after Helicobacter pylori treatment failure: omeprazole, bismuth, tetracycline and metronidazole vs. ranitidine bismuth citrate, tetracycline and metronidazole. Aliment Pharmacol Ther 1999; 13: 1311 6. 8 Perri F, Festa V, Clemente R, et al. Randomized study of two rescue therapies for Helicobacter pylori- infected patients after failure of standard triple therapies. Am J Gastroenterol 2001; 96: 58 62. 9 Sicilia B, Sierra E, Lago A, Villar M, Garcia S, Gomollon F. High eradication rates in Helicobacter pylori infection in patients with duodenal ulcer who failed previous eradication therapy. Med Clin (Barc) 2000; 115: 641 3. 10 Baena Diez JM, Lopez Mompo C, Rams Rams F, Garcia Lareo M, Rosario Hernandez Ibanez M, Teruel Gila J. Efficacy of a multistep strategy for Helicobacter pylori eradication: quadruple therapy with omeprazole, metronidazole, tetracycline and bismuth after failure of a combination of omeprazole, clarithromycin and amoxycillin. Med Clin (Barc) 2000; 115: 617 9. 11 Michopoulos S, Tsibouris P, Bouzakis H, et al. Randomized study comparing omeprazole with ranitidine as antisecretory agents combined in quadruple second-line Helicobacter pylori eradica-

44 J. P. GISBERT AND F. DE LA MORENA tion regimens. Aliment Pharmacol Ther 2000; 14: 737 44. 12 Croom KF, Goa KL. Levofloxacin: a review of its use in the treatment of bacterial infections in the United States. Drugs 2003; 63: 2769 802. 13 Gisbert JP, Pajares JM. Helicobacter pylori rescue therapy after failure of two eradication treatments. Helicobacter 2005; 10: 363 72. 14 Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 1 12. 15 Cammarota G, Martino A, Pirozzi G, et al. High efficacy of 1-week doxycycline- and amoxicillin-based quadruple regimen in a culture-guided, third-line treatment approach for Helicobacter pylori infection. Aliment Pharmacol Ther 2004; 19: 789 95. 16 Miehlke S, Madisch A, Bästlein E, et al. One-week triple theraphy with esomeprazole, levofloxacin and amoxicillin is effective for eradication of Helicobacter pylori sensitive or resistant to metronidazole and/or clarithromycin. Helicobacter 2003; 8: 464. 17 Oksanen AM, Rautelin H. Levofloxacin combination therapy for clamithromycin and metronidazole resistant Helicobacter pylori strains. Helicobacter 2003; 8: 476. 18 Gatta L, Zullo A, Perna F, et al. A 10- day levofloxacin-based triple therapy in patients who have failed two eradication courses. Aliment Pharmacol Ther 2005; 22: 45 9. 19 Perri F, Festa V, Merla A, Barberani F, Pilotto A, Andriulli A. Randomized study of different second-line therapies for Helicobacter pylori infection after failure of the standard Maastricht triple therapy. Aliment Pharmacol Ther 2003; 18: 815 20. 20 Gisbert JP, Perez-Aisa A, Castro-Fernandez M, et al. Rescue therapy with levofloxacin after multiple H. pylori treatment failures. Helicobacter 2005; 10: 531. 21 Gisbert JP, Gisbert JL, Marcos S, Olivares D, Pajares JM. 7-day ranitidine bismuth citrate- vs. levofloxacin-based triple theraphy after H. pylori treatment failure. Helicobacter 2005; 10: 533. 22 Orsi P, Pinazzi O, Aragona G, Di Mario F. Rabeprazole/levofloxacin based triple therapy as a salvatage treatment after failure of H. pylori eradication with standard regimens. Helicobacter 2003; 8: 339 493. 23 Matsumoto Y, Nobuo A, Iyuka M, et al. A High Dosage of Levofloxacin- vs. Metronidazole-based triple therapy as a second-line treatment after failure of Helicobacter pylori eradication with standard triple therapy in Japan. Gastroentorology 2005; 128: T963. 24 Watanabe Y, Aoyama N, Shirasaka D, et al. Levofloxacin based triple therapy as a second-line treatment after failure of Helicobacter pylori eradication with standard triple therapy. Dig Liver Dis 2003; 35: 711 5. 25 Zullo A, Hassan C, De Francesco V, et al. A third-line levofloxacin-based rescue therapy for Helicobacter pylori eradication. Dig Liver Dis 2003; 35: 232 6. 26 Bilardi C, Dulbecco P, Zentilin P, et al. A 10-day levofloxacin-based therapy in patients with resistant Helicobacter pylori infection: a controlled trial. Clin Gastroenterol Hepatol 2004; 2: 997 1002. 27 Nista EC, Candelli MMS, et al. Levofloxacin-based triple theraphy in secondline treatment for H. pylori eradication: update. Gastroenterology 2005; 128: 427. 28 Nista EC, Candelli M, Cremonini F, et al. Levofloxacin-based triple therapy vs. quadruple therapy in second-line Helicobacter pylori treatment: a randomized trial. Aliment Pharmacol Ther 2003; 18: 627 33. 29 Nista EC, Candelli M, Fini L, et al. 10 days levofloxacin-based triple therapy in second-line treatment for Helicobacter pylori eradication. Gastroenterology 2004; 126: 576. 30 Wong WM, Gu Q, Lam SK, et al. Randomized controlled study of rabeprazole, levofloxacin and rifabutin triple therapy vs. quadruple therapy as second-line treatment for Helicobacter pylori infection. Aliment Pharmacol Ther 2003; 17: 553 60. 31 Coelho LG, Moretzsohn LD, Vieira WL, 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 Malfertheiner P, Megraud F, O Morain C, et al. Current concepts in the management of Helicobacter pylori infection the Maastricht 2 2000 Consensus Report. Aliment Pharmacol Ther 2002; 16: 167 80. 33 Lam SK, Talley NJ. Report of the 1997 Asia Pacific Consensus Conference on the management of Helicobacter pylori infection. J Gastroenterol Hepatol 1998; 13: 1 12. 34 Gisbert JP, Calvet X, Gomollon F, Mones J. Eradication treatment of Helicobacter pylori. Recommendations of the II Spanish Consensus Conference. Med Clin (Barc) 2005; 125: 301 16. 35 Sanchez JE, Saenz NG, Rincon MR, Martin IT, Sanchez EG, Martinez MJ. Susceptibility of Helicobacter pylori to mupirocin, oxazolidinones, quinupristin/ dalfopristin and new quinolones. J Antimicrob Chemother 2000; 46: 283 5. 36 Xia HH, Yu Wong BC, Talley NJ, Lam SK. Alternative and rescue treatment regimens for Helicobacter pylori eradication. Expert Opin Pharmacother 2002; 3: 1301 11. 37 Zou J, Yang ZX, Qin ZM. Laboratory and clinical study of levofloxacin against Helicobacter pylori. Zhonghua Yi Xue Za Zhi 2003; 83: 1778 81. 38 Tanaka M, Isogai E, Isogai H, et al. Synergic effect of quinolone antibacterial agents and proton pump inhibitors on Helicobacter pylori. J Antimicrob Chemother 2002; 49: 1039 40. 39 Gisbert JP, Pajares JM. Helicobacter pylori therapy: first-line options and rescue regimen. Dig Dis 2001; 19: 134 43. 40 Cabrita J, Oleastro M, Matos R, et al. Features and trends in Helicobacter pylori antibiotic resistance in Lisbon area, Portugal (1990 1999). J Antimicrob Chemother 2000; 46: 1029 31. 41 Gisbert JP. Rescue therapy with levofloxacin after multiple H. pylori treatment failures. Aliment Pharmacol Ther 2005; 22: 653 4.