Published online Oct 28, 2018. doi: 10.3748/wjg.v24.i40.4548
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
At present, the best rescue therapy for Helicobacter pylori (H. pylori) infection following failure of first-line eradication remains unclear. The Maastricht V/Florence Consensus Report recommends bismuth quadruple therapy, or fluoroquinolone-amoxicillin triple/quadruple therapy as the second-line therapy for H. pylori infection. Meta-analyses have shown that bismuth quadruple therapy and levofloxacin-amoxicillin triple therapy have comparable eradication rates, while the former has more adverse effects than the latter. There are no significant differences between the eradication rates of levofloxacin-amoxicillin triple and quadruple therapies. However, the eradication rates of both levofloxacin-containing treatments are suboptimal. An important caveat of levofloxacin-amoxicillin triple or quadruple therapy is poor eradication efficacy in the presence of fluoroquinolone resistance. High-dose dual therapy is an emerging second-line therapy and has an eradication efficacy comparable with levofloxacin-amoxicillin triple therapy. Recently, a 10-d tetracycline-levofloxacin (TL) quadruple therapy comprised of a proton pump inhibitor, bismuth, tetracycline and levofloxacin has been developed, which 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. The present article reviews current second-line anti-H. pylori regimens and treatment algorisms. In conclusion, bismuth quadruple therapy, levofloxacin-amoxicillin triple/quadruple therapy, high-dose dual therapy and TL quadruple therapy can be used as second-line treatment for H. pylori infection. Current evidence suggests that 10-d TL quadruple therapy is a simple and effective regimen, and has the potential to become a universal rescue treatment following eradication failure by all first-line eradication regimens for H. pylori infection.
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. 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.
ANTIBIOTIC RESISTANCE IN ANTI-H. PYLORI THERAPY
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. Primary resistance to amoxicillin is either null or < 1% in most countries. In contrast, the rate of primary clarithromycin-resistance ranges from 49% (Spain) to 1% (the Netherlands) worldwide. 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. 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. 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. 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. 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.
UPDATED SECOND-LINE THERAPIES
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.