the first - line regimen for the treatment of helicobacter pylori ( h. pylori ) infection in japan is triple therapy with a proton pump inhibitor ( ppi ) , amoxicillin and clarithromycin [ 1 , 2 ] .
failure of eradication of h. pylori infection with this first - line therapy has been reported in approximately 20% of infected patients [ 3 , 4 ] . with
the increase in the frequency of clarithromycin - resistant h. pylori , there is rising concern about the potential decline in the eradication rate of this infection .
although 7-days therapy with ppi - amoxicillin - metronidazole has been found to be effective as a second - line regimen in patients showing failure of the first - line regimen , approximately 10% of patients fail to respond to even the second - line treatment [ 6 , 7 ] .
we recently developed a useful predictor of the response to metronidazole - containing second - line regimens based on the minimal inhibitory concentrations ( mics ) of both amoxicillin and metronidazole , and the results of the urea breath test .
since a high eradication resistance index signals a poor response to second - line eradication therapy , patients with a high eradication resistance index may benefit from a change to other treatment regimens selected based on the results of drug susceptibility testing .
currently , a standard third - line therapy still remains to be established , and european guidelines recommend culture before the selection of a third - line treatment based on the microbial sensitivity to the antibiotics .
h. pylori isolates after two eradication failures are often resistant to both metronidazole and clarithromycin .
therefore , these two drugs are not recommended for inclusion in third - line regimens .
the alternative candidates for third - line therapy are quinolones , tetracycline , rifabutin , furazolidone ; high - dose ppi / amoxicillin therapy is also promising [ 10 , 11 ] .
quinolones show good oral absorption , no major side effects and marked activity against h. pylori .
a recent in vitro study showed synergistic effects of a quinolone and ppi against h. pylori strains .
some studies have evaluated the efficacy of quinolones for use in a third - line regimen .
herein , we discuss the usefulness of quinolone - based therapy as a third - line regimen .
primary resistance of h. pylori to quinolones has been reported to range between 2%22% in different countries or regions [ 1421 ] .
the prevalence of quinolone resistance is higher in japan , korea and italy ( 1522% ) , and the prevalence is very low in china and egypt ( about 2% , fig .  1 ) .
we reported ahigh resistance rate ( 47.9% ) togatifloxacin ( 8-methoxy quinolone ) after eradication failure in japan .
resistance to quinolones is easily acquired , and the resistance rate is relatively high in countries with a high consumption rate of these drugs .
this enzyme , in addition to relaxing supercoiled dna , introduces negative supercoils into the dna causing the bacterial chromosome to be maintained in a negatively supercoiled state .
the bacterial enzyme gyrase is a tetramer consisting of two a and two b subunits encoded by the gyra and gyrb genes , respectively .
quinolones exert their antimicrobial activity at the level of the a subunit of the dna gyrase .
this subunit , responsible for dna cleavage and rejoining , is also the site of action of quinolones .
several studies have shown that the  quinolone resistance - determining region  ( qrdr ) of the gyra gene plays a critical role in the resistance of h. pylori to quinolones .
h. pylori does not possess a gene encoding topoisomerase iv , an important quinolone target in other bacteria .
we recently demonstrated a significant association between the mics of gatifloxacin equal to or greater than 1  g / ml against h. pylori and mutations of the qpdr of the gyra .
furthermore , we recently designed a rapid test based on an allele - specific polymerase chain reaction ( pcr ) to detect gyra mutations . because the traditional culture test for bacterial susceptibility to antibiotics is expensive and requires 1014 days , this test is not feasible in routine clinical practice .
however , the genotyping by allele - specific pcr takes less than 34  h and the allele - specific - pcr method is useful for easy identification of quinolone - resistant strains of h. pylori .
a few years ago , we showed the in vitro development of gatifloxacin resistance of h. pylori strains in gatifloxacin - containing agar culture . in these studies
, four gatifloxacin and clarithromycin - susceptible strains were serially plated onto gatifloxacin - containing agar or clarithromycin - containing agar , respectively , of increasing agar density .
none of the strains plated on the clarithromycin - containing agar developed resistance to clarithromycin , until the 10th generation of repeated culture .
in contrast , all four strains plated on the gatifloxacin - containing agar developed gatifloxacin resistance , and three of these four strains had mutations of gyra .
these data suggest that resistance to quinolones is easily acquired and widespread prescription of quinolones may lead to the spread of resistance of h. pylori to quinolones .
zullo et al .   evaluated the efficacy of a combination of levofloxacin - amoxicillin in 36 patients with a history of failure of two or more therapeutic attempts . a 10-day regimen of rabeprazole ( 20  mg b.i.d . ) , levofloxacin ( 250  mg b.i.d . ) , and amoxicillin ( 1  g b.i.d . )
h. pylori was successfully eradicated in 30 patients , representing an eradication rate of 83.3% ( 95% confidence interval , 71.295.5 ) and 88.2% ( 95% confidence interval , 77.499 ) by intention - to - treat ( itt ) and per protocol ( pp ) analysis , respectively .
this study demonstrated that levofloxacin - amoxicillin triple therapy administered for 10 days is a successful third - line therapeutic approach for h. pylori eradication ( table  1 ) .
in a prospective multicenter study , managed 100 patients with a history of two consecutive h. pylori eradication failures with a third - line levofloxacin - based regimen .
patients with failure of a first trial of omeprazole - clarithromycin - amoxicillin and a second trial of omeprazole - bismuth - tetracycline - metronidazole ( or ranitidine bismuth citrate with these antibiotics ) were enrolled . a 10-day regimen consisting of omeprazole ( 20  mg b.i.d . ) , levofloxacin ( 500  mg b.i.d . ) , and amoxicillin ( 1  g b.i.d . ) was administered .
the eradication rates determined by pp and itt analyses were 66% ( 95% confidence interval , 5675% ) and 60% ( 95% confidence interval , 5070% ) , respectively , suggesting that levofloxacin - based rescue therapy may represent an encouraging empirical third - line strategy after multiple previous h. pylori eradication failures .
furthermore , gisbert et al .   compared rifabutin and levofloxacin rescue regimens in patients with two consecutive h. pylori eradication failures .
patients who failed two eradication attempts received 10 days treatment with either rifabutin ( 150  mg b.i.d . ) or levofloxacin ( 500  mg b.i.d . ) , plus amoxicillin ( 1  g b.i.d . ) and omeprazole ( 20  mg b.i.d . ) .
the cure rate obtained by per - protocol analysis was 45% ( 95% confidence interval , 2666% ) in the rifabutin group and 81% ( 5793% ) in the levofloxacin group ( p<0.05 ) .
the eradication rates obtained by itt analysis were 45% ( 2666% ) and 85% ( 6495% ) , respectively ( p<0.01 ) .
this study demonstrated that a triple levofloxacin - based rescue regimen administered for 10 days is more effective than a rifabutin - based triple regimen after two previous h. pylori eradication failures .
hsu et al .   designed the prospective study to assess the efficacy of levofloxacin , amoxicillin , bismuth and rabeprazole quadruple therapy as a third - line treatment for h. pylori infection .
the patients were 37 consecutive h. pylori - infected patients with a history of failure of standard first - line and second - line treatments and received a 10-day quadruple therapy comprising rabeprazole ( 20  mg b.i.d . ) , bismuth subcitrate ( 300  mg q.d.s . ) , amoxicillin ( 500  mg q.d.s . ) and levofloxacin ( 500  mg o.d . ) .
h. pylori was successfully eradicated in 84% of the patients , as determined by both itt analysis and pp analysis .
this study suggested that a 10-day regimen of levofloxacin and amoxicillin - based quadruple therapy is well tolerated and yields a high eradication rate as a third - line empirical treatment regimen for h. pylori infection .
recently novel quinolones were developed , and superior in vitro activity of gatifloxacin over that of levofloxacin against h. pylori was reported .
furthermore , garenoxacin ( des - fluoro(6 ) quinolone ) and sitafloxacin show activities four - fold or greater than those of gatifloxacin [ 2931 ] .
evaluated the efficacy of a 7-day regimen of gatifloxacin ( 400  mg o.d . ) , amoxicillin ( 1  g b.i.d . ) and rabeprazole ( 20  mg b.i.d . ) in 45 patients as a second - line treatment .
h. pylori was successfully eradicated in 84.4% of the patients , as determined by both itt analysis and pp analysis ( 95% confidence interval , 7495% ) .
although the meta - analysis of gisbert et al . showed that 10-day regimens were more effective than 7-day regimens in the case levofloxacin - based triple therapy , ( 81% vs 73% ; p<0.01 ) , gatifloxacin - based triple therapy was sufficiently effective even when administered for only 7 days .
we recently investigated the efficacy of gatifloxacin - based triple therapy as a third - line treatment for h. pylori eradication , administered after assessment of the susceptibility of the organisms to gatifloxacin and the presence of gyra mutations .
a 7-day regimen of gatifloxacin ( 400  mg o.d . ) , amoxicillin ( 500  mg q.d.s . ) and rabeprazole ( 10  mg q.d.s . ) was administered in 11 patients .
successful eradication of h. pylori was achieved in 63.6% of the patients , as assessed by both itt analysis and pp analysis .
the eradication rate was 100% in the patients infected with gatifloxacin - susceptible bacteria and/or bacteria without gyra mutations , but only 33.3% in those infected with gatifloxacin - resistant bacteria or bacteria with gyra mutations .
this difference in the eradication rate between patients infected with gatifloxacin - susceptible and gatifloxacin - resistant bacteria was statistically significant ( p<0.05 ) .
our data suggest that the selection of gatifloxacin for third - line therapy should be based on the results of drug susceptibility testing or gyra analysis .
gisbert et al .   reported that adverse effects occurred in 25% of the patients ( 23/91 ) administered the 10-day regimen of levofloxacin , rabeprazole and amoxicillin , consisting mainly of metallic taste ( 8% ) , nausea ( 8% ) , myalgia / arthralgia ( 5% ) , and diarrhea ( 4% ) .
reported that adverse effects occurred in 8.9% of the patients ( 4/45 ) treated with a 7-day regimen of gatifloxacin , rabeprazole and amoxicillin mainly consisting of nausea , headache and mild diarrhea , none of which necessitated discontinuation of therapy .
however , they mention that clinicians should be aware of possible alterations in the blood glucose levels , which finally leads to the withdrawal of gatifloxacin , qtc interval prolongation , seizures and phototoxicity with the use of fluoroquinolones , especially in patients with other risk factors for these conditions .
quinolone - based rescue therapy serves as an encouraging third - line strategy after multiple previous h. pylori eradication failures .
novel quinolones , including sitafloxacin or garenoxacin , are more potent against h. pylori than levofloxacin and gatifloxacin , and switching to these quinolones may improve third - line eradication efficacy .
european guidelines recommend culture before the selection of a third - line treatment based on microbial sensitivity to the antibiotics .
the selection of quinolones for third - line therapy should be based on the results of drug susceptibility testing or gyra analysis .
as other alternatives for third - line rescue therapy , rifabutin - based triple therapy [ 36 , 37 ] , high - dose ppi / amoxicillin therapy and furazolidone - based therapy , if available , have been suggested .
 currently , a standard third - line therapy for helicobacter pylori ( h. pylori ) eradication remains to be established . 
 quinolones show good oral absorption , no major side effects , and marked activity against h. pylori . 
 several authors have studied quinolone - based third - line therapy and reported encouraging results , with the reported h. pylori cure rates ranging from 60% to 84% . 
 resistance to quinolones is easily acquired , and the resistance rate is relatively high in countries with a high consumption rate of these drugs . 
 we recently reported a significant difference in the eradication rate obtained between patients infected with gatifloxacin - susceptible and gatifloxacin - resistant h. pylori , suggesting that the selection of quinolones for third - line therapy should be based on the results of drug susceptibility testing . 
 as other alternatives of third - line rescue therapies , rifabutin - based triple therapy , high - dose proton pump inhibitor / amoxicillin therapy and furazolidone - based therapy have been suggested . 
Introduction
Quinolone Resistance and 
Quinolone-Based Triple Therapy
Adverse Effects
Conclusion