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World J Gastroenterol. Oct 28, 2018; 24(40): 4548-4553
Published online Oct 28, 2018. doi: 10.3748/wjg.v24.i40.4548
Second-line rescue treatment of Helicobacter pylori infection: Where are we now?
Te-Fu Lin, Ping-I Hsu
Te-Fu Lin, Ping-I Hsu, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
Author contributions: Hsu PI designed the study, reviewed the articles and drafted the manuscript; Lin TF reviewed the articles and drafted the manuscript.
Conflict-of-interest statement: Both authors have no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Ping-I Hsu, MD, Attending Doctor, Professor, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, No. 386, Ta-Chung 1st Rd, Kaohsiung 813, Taiwan.
Telephone: +886-7-3468233 Fax: +886-7-3468237
Received: August 7, 2018
Peer-review started: August 7, 2018
First decision: August 27, 2018
Revised: September 20, 2018
Accepted: October 5, 2018
Article in press: October 5, 2018
Published online: October 28, 2018
Core Tip

Core tip: The present article reviews current second-line anti-Helicobacter pylori (H. pylori) regimens. Bismuth quadruple therapy and levofloxacin-amoxicillin triple therapy have comparable eradication rates in the rescue treatment of H. pylori infection, while the former has more adverse effects than the latter. High-dose dual therapy has an eradication rate comparable with levofloxacin-amoxicillin triple therapy. Ten-day tetracycline-levofloxacin quadruple therapy achieves a markedly higher eradication rate compared with levofloxacin-amoxicillin triple therapy (98% vs 69%) in patients with failure of standard triple, bismuth quadruple or non-bismuth quadruple therapy. In conclusion, tetracycline-levofloxacin quadruple therapy has the potential to become a universal second-line treatment for H. pylori infection.


Helicobacter pylori (H. pylori) infects > 50% of humans globally. It is a major cause of chronic gastritis, peptic ulcer disease, gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue lymphoma[1,2]. With the rising prevalence of global antibiotic resistance, the eradication rate of H. pylori with standard triple therapy has decreased to < 80% worldwide[3]. Although there are other emerging 1st-line therapies, including bismuth quadruple therapy and non-bismuth quadruple (sequential, concomitant or hybrid) therapy, which can increase the eradication rate, H. pylori eradication still fails in 3%-24% of infected patients[4-7]. At present, the optimal choice for second-line anti-H. pylori therapy has not been well established. The present article aims to review and update the current options for second-line therapy against H. pylori infections.


Causes of treatment failure of anti-H. pylori therapies include antibiotic resistant bacteria, poor patient compliance, low gastric pH and a high bacterial load. Among these reasons, antibiotic resistance is the main factor which determines the efficacy of an eradication therapy[8]. Primary resistance to amoxicillin is either null or < 1% in most countries[9]. In contrast, the rate of primary clarithromycin-resistance ranges from 49% (Spain) to 1% (the Netherlands) worldwide[10]. High primary resistance to clarithromycin and low resistance to metronidazole have been observed in Japan; moderate resistance to clarithromycin and high resistance to metronidazole were reported in South Korea; and high primary resistance to both clarithromycin and metronidazole was observed in China[11]. High primary resistance to both clarithromycin and metronidazole has also been reported in some other countries, such as Italy, Spain, Mexico and Vietnam. Low clarithromycin resistance is generally observed in northern Europe, including the Netherlands, Sweden and Ireland[10,11].

In patients who experience eradication failure following standard triple therapy, the rates of drug resistance to clarithromycin, metronidazole, levofloxacin, amoxicillin and tetracycline are 65%-75%, 30%-56%, 26%-37%, 0%-6.1% and 0%-10%, respectively[12-16]. Whereas for patients who experience failure of non-bismuth quadruple therapy, the rates of drug resistance to clarithromycin, metronidazole, levofloxacin, amoxicillin and tetracycline are 75%, 75%, 25%, 0%, and 0%, respectively[17,18]. This data implies that amoxicillin, tetracycline and levofloxacin are good choices of antibiotics for rescue treatment of H. pylori infection.

Point mutations play a primary role in the antimicrobial resistance of H. pylori, and different mutations involving the rdxA gene have been identified in metronidazole resistant strains[19]. Resistance to clarithromycin in H. pylori is commonly caused by point mutations in the rrl gene encoding two 23S rRNA nucleotides, namely 2142 and 2143[20]. Another mechanism associated with the development of clarithromycin resistance is the efflux pump system[21,22]. Fluoroquinolone acts on the site of the type A DNA gyrase enzyme, which is encoded by the gyrA gene, to inhibit DNA cleavage and rejoining[23]. Gene mutations in gyrA are associated with fluoroquinolone resistance. In particular double mutations at both N87 and D91 in gyrA have been reported to increase fluoroquinolone resistance[24].


Current updated second-line therapies include bismuth quadruple therapy, fluoroquinolone-amoxicillin triple therapy, fluoroquinolone-amoxicillin quadruple therapy, tetracycline-levofloxacin (TL) quadruple therapy and high-dose dual therapy.