Review
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Sep 21, 2011; 17(35): 3971-3975
Published online Sep 21, 2011. doi: 10.3748/wjg.v17.i35.3971
A new look at anti-Helicobacter pylori therapy
Seng-Kee Chuah, Feng-Woei Tsay, Ping-I Hsu, Deng-Chyang Wu
Seng-Kee Chuah, Division of Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 833 Kaohsiung, Taiwan
Feng-Woei Tsay, Ping-I Hsu, Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, National Yang-Ming University, 813 Kaohsiung, Taiwan
Ping-I Hsu, Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, 110 Taipei, Taiwan
Deng-Chyang Wu, Department of Internal Medicine, Kaohsiung Medical University Hospital, 807 Kaohsiung, Taiwan
Author contributions: Chuah SK wrote the paper, Tsay FW and Wu DC revised the paper, Hsu PI drafted and approved the final version.
Correspondence to: Dr. Ping-I Hsu, Division of Gastroenterology, Department of Internal Medicine, Kaoshiung Veterans General Hospital, 386 Ta Chung 1st Road, 813 Kaohsiung, Taiwan. williamhsup@yahoo.com.tw
Telephone: +886-7-3462074 Fax: +886-7-3468237
Received: May 25, 2011
Revised: August 11, 2011
Accepted: August 15, 2011
Published online: September 21, 2011

Abstract

With the rising prevalence of antimicrobial resistance, the treatment success of standard triple therapy has recently declined to unacceptable levels (i.e., 80% or less) in most countries. Therefore, several treatment regimens have emerged to cure Helicobacter pylori (H. pylori) infection. Novel first-line anti-H. pylori therapies in 2011 include sequential therapy, concomitant quadruple therapy, hybrid (dual-concomitant) therapy and bismuth-containing quadruple therapy. After the failure of standard triple therapy, a bismuth-containing quadruple therapy comprising a proton pump inhibitor (PPI), bismuth, tetracycline and metronidazole can be employed as rescue treatment. Recently, triple therapy combining a PPI, levofloxacin and amoxicillin has been proposed as an alternative to the standard rescue therapy. This salvage regimen can achieve a higher eradication rate than bismuth-containing quadruple therapy in some regions and has less adverse effects. The best second-line therapy for patients who fail to eradicate H. pylori with first-line therapies containing clarithromycin, amoxicillin and metronidazole is unclear. However, a levofloxacin-based triple therapy is an accepted rescue treatment. Most guidelines suggest that patients requiring third-line therapy should be referred to a medical center and treated according to the antibiotic susceptibility test. Nonetheless, an empirical therapy (such as levofloxacin-based or furazolidone-based therapies) can be employed to terminate H. pylori infection if antimicrobial sensitivity data are unavailable.

Key Words: Bismuth-containing quadruple therapy, Concomitant quadruple therapy, Hybrid (dual-concomitant) therapy, Rescue anti- Helicobacter pylori treatment, Sequential therapy


Citation: Chuah SK, Tsay FW, Hsu PI, Wu DC. A new look at anti-Helicobacter pylori therapy. World J Gastroenterol 2011; 17(35): 3971-3975
INTRODUCTION

Helicobacter pylori (H. pylori) infection is the main cause of gastritis, gastroduodenal ulcer disease, gastric adenocarcinoma and mucosa-associated tissue lymphoma. The Maastricht III Consensus Report has recommended that proton pump inhibitor (PPI)-clarithromycin-amoxicillin or metronidazole treatment for 7 to 14 d is the first choice treatment for H. pylori infection[1]. As a general rule for the treatment of other infectious diseases, clinicians should prescribe therapeutic regimens that have a per-protocol eradication rate ≥ 90% for anti-H. pylori therapy[2]. However, several large clinical trials and meta-analyses have shown that the eradication rate of the standard triple therapy has generally declined to unacceptable levels (i.e., 80% or less) recently[3,4]. In some European countries, the success rates are disappointingly low with values of only 25%-60%[5,6]. The reasons for this fall in efficacy with time are uncertain but may be related to the increasing incidence of clarithromycin-resistant strains of H. pylori [3,4,7,8]. This article will review the most recent literature in an attempt to introduce novel first-line eradication regimens with a per-protocol eradication rate exceeding 90% and rescue regimens with an eradication rate exceeding 80%.

FIRST-LINE THERAPY

The main reasons for eradication failure of H. pylori infection include antibiotic resistance, poor compliance and rapid metabolism of PPI[3]. Clarithromycin resistance is the major cause of eradication failure for standard triple therapy[8]. Pooled data from 20 studies involving 1975 patients treated with standard triple therapy showed an eradication rate of 88% in clarithromycin-sensitive strains vs 18% in clarithromycin-resistant strains[8]. Therefore, the background rate of clarithromycin resistance is critically important as its presence negatively impacts the efficacy of standard triple therapy. A systemic review showed that the rate of clarithromycin-resistant strains ranged from 49% (Spain) to 1% (Netherland) worldwide[9]. In areas with clarithromycin resistance of < 10% [i.e., Netherland, Sweden, Ireland, Germany, Malaysia, Taiwan (South)], it is still possible to employ a standard triple therapy to achieve a per-protocol eradication rate > 90%. However, standard triple therapies should be abandoned in areas with clarithromycin resistance ≥ 20% [i.e., Spain, Turkey, Italy (Central), Alaska, China, Japan, Cameroon] because the per-protocol eradication rates of standard therapies are often less than 85% and the intention-to-treat eradication rates are usually less than 80%[2-8,10].

Recently, several studies showed that a novel 10-d sequential therapy can achieve a promising success rate of 90%-94%[11-13]. The regimen consists of a 5-d dual therapy with a PPI (standard dose, b.i.d.) and amoxicillin (1 g, b.i.d.) followed by a 5-d triple therapy with a PPI (standard dose, b.i.d.), clarithromycin (500 mg, b.i.d.) and metronidazole (500 mg, b.i.d.). Gatta et al[12] reported a rigorous systematic review that identified 13 trials evaluating 3271 patients. The data showed that sequential therapy achieved a 12% better absolute eradication rate than the standard triple therapy. A randomized, double-blind, placebo-controlled trial demonstrated that the per-protocol eradication rates of sequential therapy and standard triple therapy for clarithromycin-resistant strains were 89% and 29%, respectively[11]. However, it should be noted that most of the studies concerning sequential therapies were conducted in Italy. A recent trial in Korea showed that the per-protocol eradication rates of sequential therapy and standard triple therapy were 86% and 77%, respectively. The two therapies had comparable eradication rates[14]. There is, therefore, a clear need for well-designed randomized trials from countries other than Italy to determine the real advantages of this novel therapy.

Concomitant therapy is another novel regimen which was proved successful in the presence of clarithromycin resistance[15]. This is a 4-drug regimen containing a PPI (standard dose, b.i.d.), clarithromycin (500 mg, b.i.d.), amoxicillin (1 g, b.i.d.) and metronidazole (500 mg, b.i.d.) which are all given for the entire duration of therapy. This therapy is superior to standard triple therapy for H. pylori eradication[15]. It is also less complex than sequential therapy as this regimen does not involve changing drugs halfway through. A head-to-head non-inferiority trial of 10-d sequential and 10-d concomitant therapy showed that they were equivalent (93.1% vs 93.0% by per-protocol analysis)[16].

Recently, Hsu et al[17] reported a hybrid (dual-concomitant) therapy consisting of a dual therapy with a PPI (standard dose, b.i.d.) and amoxicillin (1 g, b.i.d.) for 7 d followed by a concomitant quadruple therapy with a PPI (standard dose, b.i.d.), amoxicillin (1 g, b.i.d.), clarithromcyin (500 mg, b.i.d.) and metronidazole (500 mg, b.i.d.) for 7 d. The new therapy extends the duration of amoxicillin treatment to 14 d and concomitantly employs three antibiotics in the last 7 d of the treatment course. In 117 H. pylori-infected subjects, the novel therapy provided excellent eradication rates of 99% and 97% according to per-protocol and intention-to-treat analysis, respectively. It is important to note that the new therapy has a high efficacy in the treatment of H. pylori strains harboring dual resistance to clarithromycin and metronidazole. Several studies have shown that sequential therapy is ineffective in clearing H. pylori with dual resistance[8]. The prolonged treatment duration of amoxicillin to 14 d in the hybrid therapy might account for the higher eradication rate in the face of H. pylori stains with dual resistance to clarithromycin and metronidazole. Further studies in populations with different levels of prevalence of clarithromycin and metronidazole resistance are needed to assess the efficacy of the new regimen.

Bismuth-containing quadruple therapy is an alternative first choice treatment for H. pylori infection recommended by the Maastricht III Consensus Report[1] and the Second Asia-Pacific Consensus Guidelines for H. pylori Infection[18]. Two studies each with more than 100 patients have shown eradication rates of > 90% with this combination given for 10 d[19,20]. Recently, Malfertheiner et al[21] compared the efficacy of a 10-d bismuth-containing quadruple therapy (omeprazole, bismuth, metronidazole and tetracycline) and a 7-d triple therapy (omeprazole, clarithromycin and amoxicillin). The data indicated that the former had a higher eradication rate than the latter (93% vs 70% by per-protocol analysis). Currently, the optimal treatment duration of bismuth-containing quadruple therapy remains unclear but a 10-14 d course is most commonly employed in clinical practice[22].

Based on a large body of published clinical trials, a quinolone-based triple therapy is effective in the first-line therapy of H. pylori infection. The eradication rates of levofloxacin-based triple therapy ranged from 72% to 96%[23]. The regimen might be considered in populations with clarithromycin resistance greater than 15%-20% and quinolone resistance less than 10%[23]. However, a quinolone-based triple therapy is not generally recommended as first-line therapy at the moment due to concerns about the rising prevalence of quinolone-resistant strains in the first-line and second-line anti-H. pylori therapies. Furthermore, greater use of quinolone would likely result in the development of more quinolone-resistant pathogens causing respiratory and urogenital tract infections.

SECOND-LINE THERAPY

The Maastricht III Consensus Report recommended a bismuth-containing quadruple therapy regimen comprising a PPI, bismuth, metronidazole and tetracycline as second-line therapy[1]. This rescue regimen fails in 5%-63% of patients with an average eradication rate of 76% on the basis of a pooled analysis[24-26]. The prevalence of metronidazole-resistant strains, dose and duration of rescue therapy seem to be important variables for the efficacy of this treatment. In bismuth-containing quadruple regimens, PPI should be prescribed in the usual dose and twice a day, colloidal bismuth subcitrate 120 mg four times a day, tetracycline 500 mg four times a day and metronidazole 500 mg three times a day. A report from Korea showed that the two-week bismuth-containing quadruple therapy was more effective than the 1-wk treatment (83% vs 64% by intention-to-treat analysis) [27].

Levofloxacin-based triple therapy consisting of levofloxacin (500 mg, q.d.), amoxicillin (1 g, b.i.d.) and a PPI (standard dose, b.i.d.) represents an encouraging strategy for second-line therapy. A meta-analysis by Saad et al[28] showed that a 10-d regimen of levofloxacin-based triple therapy was superior to a 7-d bismuth-based quadruple therapy. Another meta-analysis by Gisbert et al[29] demonstrated a borderline significance of higher H. pylori cure rates with levofloxacin-based triple regimens compared with quadruple therapies (81% vs 70%). Additionally, the study revealed fewer adverse effects with levofloxacin than with quadruple regimens (19% vs 44%). However, it is noteworthy that levofloxacin-based triple therapies seem less effective in Asia. Two randomized controlled trials from Taiwan and Hong Kong showed that levofloxacin-based triple therapy was comparable to quadruple therapy in the eradication efficacy of second-line therapy.[30,31]The second-line therapy for patients who fail to eradicate H. pylori new first-line therapies (such as sequential therapy, concomitant therapy or hybrid therapy) remains unclear. However, a recent study showed that a levofloxacin-based triple therapy with lansoprazole (30 mg, b.i.d.), levofloxacin (250 mg, b.i.d) and amoxicillin (1 g, b.i.d.) achieved a high eradication rate in patients who failed to clear H. pylori with sequential therapy[32].

THIRD-LINE THERAPY

Currently, a standard empirical third-line therapy is lacking. The Masstricht III Consensus Report recommended using bacterial culture with antimicrobial sensitivity tests to select antibiotics for third-line regimens[1]. Cammarota et al[33] analyzed H. pylori isolates from 94 consecutive patients in whom H. pylori infection had persisted after two eradication attempts. Ninety-four subjects (100%) were resistant to metronidazole, 89 (95%) to clarithromycin, 29 (31%) to levofloxacin and five (5%) to tetracycline. No resistance to amoxicillin was found in any of the patients. Patients were then treated with a culture-guided, third-line regimen: 89 patients with a 1-wk quadruple regimen including omeprazole, bismuth, doxycycline and amoxicillin, and five patients with a 1-wk triple regimen containing omeprazole, amoxicillin and levofloxacin or clarithromycin. Overall, H. pylori eradication was obtained in 90% of subjects treated by the culture-guided therapy.

However, it has been reported that the sensitivity of culture is less than 60%[34]. Additionally, in vitro antimicrobial sensitivity does not necessarily lead to eradication in vivo and vice versa. Recently, several empirical third-line therapies have been proposed to treat refractory H. pylori infection. A 10-d quadruple therapy comprising rabeprazole (20 mg b.i.d.), bismuth subcitrate (300 mg, q.i.d.), amoxicillin (500 mg, q.i.d.), and levofloxacin (500 mg, q.d.) achieved an eradication rate of 84% by both intention-to-treat analysis and per-protocol analysis in patients who failed to eradicate H. pylori with standard triple therapy and bismuth-based quadruple therapy[35].

Rifabutin is an antituberculous agent, which can be administered with PPI and amoxicillin for 10-14 d to eradicate H. pylori One study used rifabutin (150 mg, b.i.d.), amoxicillin (1 g, b.i.d.) and omeprazole (20 mg, b.i.d.) for 14 d as a third-line therapy[36]. Per-protocol and intention-to-treat eradication was achieved in 11/14 patients (79%). It is noteworthy that serious myelotoxicity and ocular adverse events have been reported with rifabutin therapy[37]. In addition, greater use of rifabutin would likely result in the development of more resistant strains to Myocbacterium tuberculosis and Mycobacterium avium.

Furazolidone-based therapy is another useful option to treat refractory H. pylori infection. A 7-d quadruple therapy consisting of lansoprazole (30 mg, b.i.d.), tripotassium dicitratobismuthate (240 mg, b.i.d.), furazolidone (200 mg, b.i.d.) and tetracycline (1 g, b.i.d.) has a high efficacy in third-line therapy with an eradication rate of 90% by both intention-to-treat and per-protocol analysis[38]. The recommended regimens for H. pylori therapies are summarized in Table 1.

Table 1 Recommended regimens for Helicobacter pylori therapy.
TreatmentRegimen
First-line therapy
Standard triple therapy1A PPI (standard dose, b.i.d.), clarithromycin (500 mg, b.i.d.) and amoxicillin (1 g, b.i.d.) for 7-14 d
Sequential therapyA 5-d dual therapy with a PPI (standard dose, b.i.d.) and amoxicillin (1 g, b.i.d.) followed by a 5-d triple therapy with a PPI (standard dose, b.i.d.), clarithromycin (500 mg, b.i.d.) and metronidazole (500 mg, b.i.d.)
Concomitant therapyA PPI (standard dose, b.i.d.), clarithromycin (500 mg, b.i.d.), amoxicillin (1 g, b.i.d.) and metronidazole (500 mg, b.i.d.) for 7-10 d
Hybrid therapyA 7-d dual therapy with a PPI (standard dose, b.i.d.) and amoxicillin (1 g, b.i.d.) followed by a 7-d quadruple therapy with a PPI (standard dose, b.i.d.), amoxicillin (1 g, b.i.d.), Clarithromycin (500 mg, b.i.d.) and metronidazole (500 mg, b.i.d.)
Bismuth-containing quadruple therapyA PPI (standard dose, b.i.d.), bismuth (standard dose, q.i.d.) tetracycline (500 mg, q.i.d.) and metronidazole (250 mg, q.i.d.) for 10-14 d
Second-line therapy
Bismuth–containing quadruple therapyA PPI (standard dose, b.i.d.), bismuth (standard dose, q.i.d.) tetracycline (500 mg, q.i.d.) and metronidazole (500 mg, t.i.d.) for 10-14 d
Levofloxacin-based triple therapy2A PPI (standard dose, b.i.d.), levofloxacin (500 mg, q.d.) and amoxicillin (1 g, b.i.d.) for 10 d
Third-line therapy
Culture-guided therapyA 10-d quadruple therapy comprising a PPI (standard dose, b.i.d.), bismuth (standard dose, q.i.d.) and two antibiotics selected by antimicrobial sensitivity tests
Levofloxacin-based quadruple therapyA PPI (standard dose, b.i.d.), bismuth (standard dose, q.i.d.), levofloxacin (500 mg, q.d.) and amoxicillin (500 mg, q.i.d.) for 10 d
Rifabutin-based triple therapyA PPI (standard dose, b.i.d.), rifabutin (150 mg b.i.d.) and amoxicillin (1 g b.i.d.) for 14 d
Furazolidone-based quadruple therapyA PPI (standard dose, b.i.d.), tripotassium dicitratobismuthate (240 mg, b.i.d.), furazolidone (200 mg, b.i.d.) and tetracycline (1 g, b.i.d.)

In conclusion, with the rising prevalence of antimicrobial resistance, the treatment success of standard triple therapy has recently declined to unacceptable levels. Novel first-line anti-H. pylori therapies in 2011 include sequential therapy, concomitant quadruple therapy, hybrid (dual-concomitant) therapy and bismuth-containing quadruple therapy. After the failure of standard triple therapy, a bismuth-containing quadruple therapy or a levofloxacin-based triple therapy can be employed as rescue treatment. The best second-line therapy for patients who fail to eradicate H. pylori with first-line therapies containing clarithromycin, amoxicillin and metronidazole is unclear. However, a levofloxacin-based triple therapy is an accepted salvage treatment. With regard to third-line therapy of H. pylori infection, a culture-guided therapy has been recommended. If antimicrobial sensitivity data are unavailable, an empirical therapy (such as levofloxacin-based, rifabutin-based, or furazolidone-based therapies) can be employed to terminate H. pylori infection. In spite of many emerging therapies, none have been included into current major consensuses so far. Hopefully, the upcoming Maastricht IV meeting will bring a wind of change.

Footnotes

Peer reviewers: György M Buzás, MD, Department of Gastroenterology, Ferencváros Health Center, IX. District Policlinic, Mester u 45, 1095 Budapest, Hungary; David J McGee, PhD, Associate Professor, Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Highway, Shreveport, LA 71130, United States; Nawfal Hussein, PhD, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom

S- Editor Tian L L- Editor Webster JR E- Editor Xiong L

References
1.  Malfertheiner P, Megraud F, O'Morain C, Bazzoli F, El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N, Kuipers EJ. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut. 2007;56:772-781.  [PubMed]  [DOI]
2.  Rimbara E, Fischbach LA, Graham DY. Optimal therapy for Helicobacter pylori infections. Nat Rev Gastroenterol Hepatol. 2011;8:79-88.  [PubMed]  [DOI]
3.  Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut. 2010;59:1143-1153.  [PubMed]  [DOI]
4.  Gisbert JP, Pajares R, Pajares JM. Evolution of Helicobacter pylori therapy from a meta-analytical perspective. Helicobacter. 2007;12 Suppl 2:50-58.  [PubMed]  [DOI]
5.  Gumurdulu Y, Serin E, Ozer B, Kayaselcuk F, Ozsahin K, Cosar AM, Gursoy M, Gur G, Yilmaz U, Boyacioglu S. Low eradication rate of Helicobacter pylori with triple 7-14 days and quadriple therapy in Turkey. World J Gastroenterol. 2004;10:668-671.  [PubMed]  [DOI]
6.  Bigard MA, Delchier JC, Riachi G, Thibault P, Barthelemy P. One-week triple therapy using omeprazole, amoxycillin and clarithromycin for the eradication of Helicobacter pylori in patients with non-ulcer dyspepsia: influence of dosage of omeprazole and clarithromycin. Aliment Pharmacol Ther. 1998;12:383-388.  [PubMed]  [DOI]
7.  Cianci R, Montalto M, Pandolfi F, Gasbarrini GB, Cammarota G. Third-line rescue therapy for Helicobacter pylori infection. World J Gastroenterol. 2006;12:2313-2319.  [PubMed]  [DOI]
8.  Mégraud F. H pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut. 2004;53:1374-1384.  [PubMed]  [DOI]
9.  De Francesco V, Giorgio F, Hassan C, Manes G, Vannella L, Panella C, Ierardi E, Zullo A. Worldwide H. pylori antibiotic resistance: a systematic review. J Gastrointestin Liver Dis. 2010;19:409-414.  [PubMed]  [DOI]
10.  Graham DY, Lu H, Yamaoka Y. Therapy for Helicobacter pylori infection can be improved: sequential therapy and beyond. Drugs. 2008;68:725-736.  [PubMed]  [DOI]
11.  Vaira D, Zullo A, Vakil N, Gatta L, Ricci C, Perna F, Hassan C, Bernabucci V, Tampieri A, Morini S. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial. Ann Intern Med. 2007;146:556-563.  [PubMed]  [DOI]
12.  Gatta L, Vakil N, Leandro G, Di Mario F, Vaira D. Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am J Gastroenterol. 2009;104:3069-3079; quiz 1080.  [PubMed]  [DOI]
13.  Hsu PI, Wu DC, Wu JY, Graham DY. Is there a benefit to extending the duration of Helicobacter pylori sequential therapy to 14 days? Helicobacter. 2011;16:146-152.  [PubMed]  [DOI]
14.  Choi WH, Park DI, Oh SJ, Baek YH, Hong CH, Hong EJ, Song MJ, Park SK, Park JH, Kim HJ. [Effectiveness of 10 day-sequential therapy for Helicobacter pylori eradication in Korea]. Korean J Gastroenterol. 2008;51:280-284.  [PubMed]  [DOI]
15.  Essa AS, Kramer JR, Graham DY, Treiber G. Meta-analysis: four-drug, three-antibiotic, non-bismuth-containing "concomitant therapy" versus triple therapy for Helicobacter pylori eradication. Helicobacter. 2009;14:109-118.  [PubMed]  [DOI]
16.  Wu DC, Hsu PI, Wu JY, Opekun AR, Kuo CH, Wu IC, Wang SS, Chen A, Hung WC, Graham DY. Sequential and concomitant therapy with four drugs is equally effective for eradication of H pylori infection. Clin Gastroenterol Hepatol. 2010;8:36-41.e1.  [PubMed]  [DOI]
17.  Hsu PI, Wu DC, Wu JY, Graham DY. Modified sequential Helicobacter pylori therapy: proton pump inhibitor and amoxicillin for 14 days with clarithromycin and metronidazole added as a quadruple (hybrid) therapy for the final 7 days. Helicobacter. 2011;16:139-145.  [PubMed]  [DOI]
18.  Fock KM, Katelaris P, Sugano K, Ang TL, Hunt R, Talley NJ, Lam SK, Xiao SD, Tan HJ, Wu CY. Second Asia-Pacific Consensus Guidelines for Helicobacter pylori infection. J Gastroenterol Hepatol. 2009;24:1587-1600.  [PubMed]  [DOI]
19.  O'Morain C, Borody T, Farley A, De Boer WA, Dallaire C, Schuman R, Piotrowski J, Fallone CA, Tytgat G, Mégraud F. Efficacy and safety of single-triple capsules of bismuth biskalcitrate, metronidazole and tetracycline, given with omeprazole, for the eradication of Helicobacter pylori: an international multicentre study. Aliment Pharmacol Ther. 2003;17:415-420.  [PubMed]  [DOI]
20.  Laine L, Hunt R, El-Zimaity H, Nguyen B, Osato M, Spénard J. Bismuth-based quadruple therapy using a single capsule of bismuth biskalcitrate, metronidazole, and tetracycline given with omeprazole versus omeprazole, amoxicillin, and clarithromycin for eradication of Helicobacter pylori in duodenal ulcer patients: a prospective, randomized, multicenter, North American trial. Am J Gastroenterol. 2003;98:562-567.  [PubMed]  [DOI]
21.  Malfertheiner P, Bazzoli F, Delchier JC, Celiñski K, Giguère M, Rivière M, Mégraud F. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial. Lancet. 2011;377:905-913.  [PubMed]  [DOI]
22.  Chey WD, Wong BC. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808-1825.  [PubMed]  [DOI]
23.  Berning M, Krasz S, Miehlke S. Should quinolones come first in Helicobacter pylori therapy? Therap Adv Gastroenterol. 2011;4:103-114.  [PubMed]  [DOI]
24.  Wu DC, Hsu PI, Tseng HH, Tsay FW, Lai KH, Kuo CH, Wang SW, Chen A. Helicobacter pylori infection: a randomized, controlled study comparing 2 rescue therapies after failure of standard triple therapies. Medicine (Baltimore). 2011;90:180-185.  [PubMed]  [DOI]
25.  Gisbert JP. "Rescue" regimens after Helicobacter pylori treatment failure. World J Gastroenterol. 2008;14:5385-5402.  [PubMed]  [DOI]
26.  Hojo M, Miwa H, Nagahara A, Sato N. Pooled analysis on the efficacy of the second-line treatment regimens for Helicobacter pylori infection. Scand J Gastroenterol. 2001;36:690-700.  [PubMed]  [DOI]
27.  Lee BH, Kim N, Hwang TJ, Lee SH, Park YS, Hwang JH, Kim JW, Jeong SH, Lee DH, Jung HC. Bismuth-containing quadruple therapy as second-line treatment for Helicobacter pylori infection: effect of treatment duration and antibiotic resistance on the eradication rate in Korea. Helicobacter. 2010;15:38-45.  [PubMed]  [DOI]
28.  Saad RJ, Schoenfeld P, Kim HM, Chey WD. Levofloxacin-based triple therapy versus bismuth-based quadruple therapy for persistent Helicobacter pylori infection: a meta-analysis. Am J Gastroenterol. 2006;101:488-496.  [PubMed]  [DOI]
29.  Gisbert JP, Morena F. Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure. Aliment Pharmacol Ther. 2006;23:35-44.  [PubMed]  [DOI]
30.  Kuo CH, Hu HM, Kuo FC, Hsu PI, Chen A, Yu FJ, Tsai PY, Wu IC, Wang SW, Li CJ. Efficacy of levofloxacin-based rescue therapy for Helicobacter pylori infection after standard triple therapy: a randomized controlled trial. J Antimicrob Chemother. 2009;63:1017-1024.  [PubMed]  [DOI]
31.  Wong WM, Gu Q, Chu KM, Yee YK, Fung FM, Tong TS, Chan AO, Lai KC, Chan CK, Wong BC. Lansoprazole, levofloxacin and amoxicillin triple therapy vs. quadruple therapy as second-line treatment of resistant Helicobacter pylori infection. Aliment Pharmacol Ther. 2006;23:421-427.  [PubMed]  [DOI]
32.  Pontone S, Standoli M, Angelini R, Pontone P. Efficacy of H. pylori eradication with a sequential regimen followed by rescue therapy in clinical practice. Dig Liver Dis. 2010;42:541-543.  [PubMed]  [DOI]
33.  Cammarota G, Martino A, Pirozzi G, Cianci R, Branca G, Nista EC, Cazzato A, Cannizzaro O, Miele L, Grieco A. 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;19:789-795.  [PubMed]  [DOI]
34.  Savarino V, Zentilin P, Pivari M, Bisso G, Raffaella Mele M, Bilardi C, Borro P, Dulbecco P, Tessieri L, Mansi C. The impact of antibiotic resistance on the efficacy of three 7-day regimens against Helicobacter pylori. Aliment Pharmacol Ther. 2000;14:893-900.  [PubMed]  [DOI]
35.  Hsu PI, Wu DC, Chen A, Peng NJ, Tseng HH, Tsay FW, Lo GH, Lu CY, Yu FJ, Lai KH. Quadruple rescue therapy for Helicobacter pylori infection after two treatment failures. Eur J Clin Invest. 2008;38:404-409.  [PubMed]  [DOI]
36.  Gisbert JP, Calvet X, Bujanda L, Marcos S, Gisbert JL, Pajares JM. 'Rescue' therapy with rifabutin after multiple Helicobacter pylori treatment failures. Helicobacter. 2003;8:90-94.  [PubMed]  [DOI]
37.  Apseloff G. Severe neutropenia among healthy volunteers given rifabutin in clinical trials. Clin Pharmacol Ther. 2003;74:591-592; discussion 592-593.  [PubMed]  [DOI]
38.  Treiber G, Ammon S, Malfertheiner P, Klotz U. Impact of furazolidone-based quadruple therapy for eradication of Helicobacter pylori after previous treatment failures. Helicobacter. 2002;7:225-231.  [PubMed]  [DOI]