LEVOFLOXACINA EN HELICOBACTER PYLORI by Eurostaga Eurostaga

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 Moja´car 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 Journal compilation ª 2006 Blackwell Publishing Ltd, doi:10.1111/j.1365-2036.2006.02737.x

36 J . P . G I S B E R T A N D F . D E L A M O R E N A

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 therapy1 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.

ª 2006 The Authors, Aliment Pharmacol Ther 23, 35–44 Journal compilation ª 2006 Blackwell Publishing Ltd

SYSTEMATIC REVIEW AND META-ANALYSIS: LEVOFLOXACIN-BASED RESCUE THERAPY 37

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 (v2) 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 v2 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

Subanalysis/sensitivity analysis

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).

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.

Assessment of study quality

RESULTS Description of studies

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 ª 2006 The Authors, Aliment Pharmacol Ther 23, 35–44 Journal compilation ª 2006 Blackwell Publishing Ltd

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

1 2

Perri et al.19 Gisbert et al.20

‡1

‡2

Nista et al.29

Wong et al.30

Coelho et al.31 –

–

PPI + A + C

PPI + A + C, PPI + C + M, PPI + B +T+M PPI + A + C PPI + A + C, PPI + B+T+M PPI + A + C PPI + A + C PPI + A + C PPI + A + C PPI + A + C, PPI + C + M, PPI + A + M, PPI + B + T + M, RBC + T + M, RBC + A + M – PPI + A + C mg mg mg mg mg

b.d. o.d. b.d. b.d. b.d.

500 mg o.d.

250 mg b.d. 500 mg o.d.

500 500 300 200 250

500 mg o.d. 500 mg b.d.

250 mg b.d.

1 1 1 1 1

g g g g g

b.d. b.d b.d. b.d. b.d.

A 1 g b.d. or M 500 mg b.d. A 1 g b.d. or Az 500 mg o.d. Rifabutin 300 mg o.d. Furazolidone 400 mg o.d.

A 1 g b.d. A 1 g b.d.

A A A A A

A 1 g b.d. A 1 g b.d.

A 1 g b.d.

Levofloxacin Second dose drug

7 12 7 7 10

7 10

R 20 mg o.d.

R 20 mg b.d.

E 40 mg o.d.

R 20 mg b.d

P 40 mg b.d. 10 R 20 mg b.d. 7 or 10

O 20 mg b.d. R 20 mg b.d. L 30 mg b.d. L 30 mg b.d. R 20 mg b.d.

P 40 mg b.d. O 20 mg b.d.

PPI standard dose b.d.

Third drug

0 – 3.3 0 5.5

(1/30) (0/33) (2/36)

(0/31)

1.6 (1/60) 1.8 (1/55)

0 (0/151)

% severe adverse effects (no. of patients)

67 86 70 70 83

(21/31) (43/50) (21/30) (23/33) (30/36)

63 (38/60) 67 (37/55)

76 (115/151)

% eradication (no. of patients)

50 (6/12)

16 (2/12)

83 (10/12)

28.2 (13/46) 70 (31/44) – LeAR10 91 (42/46) LeAR7 74 (37/50) LeAR 10 (7/70) 0 (0/140) LeAR 94 (66/70) LeMR 11 (8/70) LeTR 90 (63/70) LeAE 27 (8/30) 0 (0/60) LeAE 87 (26/30) LeAzE 23 (7/30) LeAzE 80 (24/30) 34 (19/56) 1.7 (1/56) 91 (51/56)

(12/31) (4/50) (3/30) (7/33) (7/36)

37 (17/46) –

40 8 10 21 19

5 (3/60) 9 (5/55)

3.3 (5/151)

% adverse effects (no. of Days of antibiotics patients)

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.

1–6 1

Nista et al.28

Bilardi et al.26 Nista et al.27

1 Gisbert et al.21 Orsi et al.22 1 Matsumoto et al.23 1 Watanabe et al.24 1 Zullo et al.25 2–3

Gatta et al.18

Author (references)

No. of Previous previous eradication eradication regimens failures

Table 1. Helicobacter pylori eradication efficacy with levofloxacin-based rescue regimens after one or more H. pylori treatment failures

38 J . P . G I S B E R T A N D F . D E L A M O R E N A

ª 2006 The Authors, Aliment Pharmacol Ther 23, 35–44 Journal compilation ª 2006 Blackwell Publishing Ltd

2005 Ab

2003 JA

2002 JA

2004 Ab

2005 Ab

2004 JA

2003 Ab

2003 JA

L 500 mg o.d. A 1 g b.d. P 40 mg b.d.

Levofloxacin regimen 63 (38/60)

5 (3/60)

1.6 (1/60)

% severe adverse effects (no. Quadruple of patients) regimen

63 (44/70) 7 days 68 (48/70) 14 days 68 (24/36)

91 (48/53)

71 (25/35)

68 (34/50)

37 (17/46)

88 (44/50)

83 (50/60)

% eradication (no. of Days of antibiotics patients)

P 40 mg b.d. 7 B 240 mg b.d. T 500 mg q.d.s. M 500 mg b.d. L 500 mg o.d. 86 (43/50) 8 (4/50) – R 20 mg b.d. 12 A 1 g b.d. B 240 mg b.d. R 20 mg b.d. T 500 mg t.d.s. Ti 500 mg b.d. PUD L 250 mg b.d. 70 (31/44) 25 (11/44) 2.2 (1/44) O 20 mg b.d. 7 A 1 g b.d. B 240 mg b.d. (5/100) NUD P 40 mg b.d. T 250 mg q.d.s. M 500 mg b.d. (95/100) – L 500 mg o.d. LAR10 91(42/46) – – R 20 mg b.d. 7 A 1 g b.d. LAR7 74 (37/50) B 120 mg q.i.d R 20 mg b.d. T 500 mg q.d.s. M 400 mg t.d.s. – L 500 mg o.d. LAE 87 (26/30) LAE 27 (8/30) 0 (0/60) R 20 mg b.d. 7 A 1 g b.d./ LAzE 80 (24/30) LAzE 23 (7/30) B 120 mg q.i.d Az 500 mg o.d. T 500 mg q.d.s. E 40 mg o.d. M 500 mg t.d.s. PUD L 500 mg o.d. 91 (51/56) 34 (19/56) 1.7 (1/56) R 20 mg b.d. 7 (29/105) Rif 300 mg o.d. B 120 mg q.i.d NUD R 20 mg b.d. T 500 mg q.d.s. (76/105) M 400 mg t.d.s. NUD L 500 mg o.d. LAR 94 (66/70) LAR 10 (7/70) 0 (0/140) R 20 mg b.d. 7/14 (280/280) A 1 g/Ti 500 mg b.d. LTR 90 (63/70) LTR 11 (8/70) B 120 mg q.i.d R 20 mg b.d. T 500 mg q.d.s. M 400 mg t.d.s. PUD L 500 mg b.d. 67 (21/31) 40 (12/31) 0 (0/31) RBC 400 mg b.d. 7 (15/67) A 1 g b.d. T 500 mg q.d.s. O 20 mg b.d. M 250 mg q.d.s. NUD (52/67)

PUD (74/180) NUD (106/180) –

Year Format Disease

% adverse effects (no. of patients)

–

5 (3/60)

% severe adverse effects (no. of patients)

8 (4/50)

0 (0/53)

28 (20/70) 16 (11/70) 3 7 days 7 days 43 (30/70) 26 (15/70) 14 days 14 days 38.8 (14/36) 0 (0/36) 2

58 (31/53)

60 (21/30) 11 (4/35)

–

28 (13/46) 2.1 (1/46)

22 (11/50)

28 (17/60)

% adverse effects (no. of patients)

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.

Gisbert et al.

Nista et al.

Wong et al.

Nista et al.

Bilardi et al.

Orsi et al.

Perri et al.

Authors (references)

% eradication (no. of patients)

Table 2. Characteristics of included studies comparing Helicobacter pylori eradication efficacy with levofloxacin-based triple regimens vs. quadruple therapy

SYSTEMATIC REVIEW AND META-ANALYSIS: LEVOFLOXACIN-BASED RESCUE THERAPY 39

40 J . P . G I S B E R T A N D F . D E L A M O R E N A

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 of levofloxacin (500 mg b.d.) were administered.20, 21 Most of the studies combined a PPI and amoxicillin together with levofloxacin, and only three studies used azithromycin,29 rifabutin30 or furazolidone31 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 eradication failures are summarized in Table 2.19, 21, 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 rifabutin30 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

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 v2, 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).

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,

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 ª 2006 The Authors, Aliment Pharmacol Ther 23, 35–44 Journal compilation ª 2006 Blackwell Publishing Ltd

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 or sub-category

Levofloxacin n/N

Quadruple n/N

OR (random) 95% CI

Weight %

OR (random) 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) 2 2 Test for heterogeneity: c = 35.78, df = 9 (P < 0.0001), I = 74.8% Test for overall effect: Z = 1.77 (P = 0.08) 0.1

0.2

0.5

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 v2, 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 ª 2006 The Authors, Aliment Pharmacol Ther 23, 35–44 Journal compilation ª 2006 Blackwell Publishing Ltd

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 are cured with the levofloxacin-based regimen.18, 26 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 . G I S B E R T A N D F . D E L A M O R E N A Comparison: Outcome:

02 Levofloxacin regimen vs. quadruple regimen (adverse effects) 01 Levofloxacin vs. quadruple (overall)

Study or sub-category

Levofloxacin n/N

Quadruple n/N

OR (random) 95% CI

Weight %

OR (random) 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) 2 2 Test for heterogeneity: c = 21.43, df = 8 (P = 0.006), I = 62.7% Test for overall effect: Z = 4.77 (P < 0.00001) 0.01

0.1

>AE quadruple

Comparison: Outcome:

100

>AE levofloxacin

02 Levofloxacin regimen vs. quadruple regimen (adverse effects) 02 Levofloxacin vs. quadruple (severe)

Study or sub-category

Levofloxacin n/N

Quadruple n/N

OR (random) 95% CI

Weight %

OR (random) 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) 2 2 Test for heterogeneity: c = 7.50, df = 6 (P = 0.28), I = 20.0% Test for overall effect: Z = 2.62 (P = 0.009) 0.001 0.01

0.1

>SAE quadruple

100

1000

>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 eas-

ily acquired, and in areas with a high consumption of these drugs, the resistance rate is relatively high.40 Nevertheless, when that single outlier study19 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 have failed to eradicate the infection.18, 20, 25, 26, 30, 31 In this respect, we have recently confirmed that levoflª 2006 The Authors, Aliment Pharmacol Ther 23, 35–44 Journal compilation ª 2006 Blackwell Publishing Ltd

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 afore-

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, Martıńez A, Rodrı´guez C, Jimeńez J. Eficacia de dos tratamientos consecutivos en la erradicacioń de Helicobacter 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.

mentioned 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.

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ª 2006 The Authors, Aliment Pharmacol Ther 23, 35–44 Journal compilation ª 2006 Blackwell Publishing Ltd