the greatest association of helicobacter pylori ( h. pylori ) infection is with peptic ulcer disease .
recently , the association between h. pylori and the development of gastric cancer is more clearly established than before , and by the announcement of the japanese society for helicobacter research , h. pylori eradication should be undertaken in all subjects who are infected [ 1 , 2 ] .
the treatment to eradicate h. pylori by a triple therapy using a proton pump inhibitor ( ppi ) , amoxicillin ( ampc ) and clarithromycin ( cam ) was approved and covered by insurance in japan in november , 2000 . in february 2003
, the eradication therapy went into broad use as a result of the eradication guidelines of the japanese society for helicobacter research .
the initial eradication rate was good at about 90% , but a decline in eradication rate attributable to an increase in cam resistance was pointed out . consequently , the japanese society for helicobacter research conducted sensitivity surveillance from 2002 through 2006 in order to determine the prevalence of h. pylori drug resistance in japan .
the results revealed that the cam resistance rate from 2002 to 2003 was 18.9% , followed by 21.1% in 20032004 , 27.7% in 20042005 .
the reports also demonstrated that the cam resistance rate in japan since 2003 exceeded 20% , the condition the maastricht iii consensus report recommends the triple therapy using ppi , ampc and cam .
in such a situation ( cam resistance rate > 20% ) , it is recommended that drug sensitivity tests be carried out prior to eradication , but in japan sensitivity testing is not common because eradication therapies other than the ppi , ampc , and cam triple therapy are not approved for the first - line eradication therapy . in this study , we conducted a retrospective analysis of the status of eradication rate by ppi , ampc , and cam in our hospital in japan , where the rate of cam resistance is high .
we retrospectively investigated the h. pylori eradication rate over time in 750 patients , who had been diagnosed as h. pylori - infected by at least one positive result from culture test , microscopy or c - urea breath test ( ubt ) .
the 750 patients had received the triple therapy based on a ppi ( omeprazole ( opz ) 20  mg or lansoprazole ( lpz ) 30  mg or rabeprazole ( rpz ) 10  mg twice as day ) , ampc ( 750  mg twice as day ) , and cam ( 200  mg or 400  mg twice a day ) at nagoya city university hospital from january , 1997 until december , 2008 .
successful eradication was determined by performing a ubt following the first month after eradication , and <2.5 was defined as successful eradication .
we also investigated the relationship between the eradication rate and the h. pylori cam primary resistance ( from the flat dilution method , mic > 8  g / ml ) in four terms detected at nagoya city university hospital from january 1997 until december 2008 .
terms were divided as follows ; term 1 : 19972000 , before eradication therapy was approved and covered by insurance in japan ; term 2 : 20012003 , the first half of period when only omeprazole and lansoprazole were approved , term 3 : 20042006 , the latter half of period when only omeprazole and lansoprazole were approved ; term 4 : 20072008 , after rabeprazole was approved .
the eradication rate by type of ppi was evaluated as well . the kruskal - wallis test and
491 men and 259 women with the average age of 56.1    14.2 years were enrolled in the study .
the classification of disorders were gastric ulcers ( 258/750 , 34.4% ) , duodenal ulcers ( 188/750 25.1% ) , gastroduodenal ulcers ( 57/750 , 7.6% ) , other gastrointestinal disorders ( 247/750 , 32.9% ) .
the patients with gastrointestinal disorders mainly comprised patients with atrophic gastritis or patients having undergone endoscopic treatment for a gastric tumor .
709 patients were tested by ubt to determine whether the h. pylori was eradicated , and successful eradication was assessed in 559 of these patients .
we divided the study into the four terms of 1997 to 2000 ( term 1 ) , before h. pylori eradication therapy was indicated and covered by insurance in japan ; the first half of the period from 2001 to 2006 , when eradication therapy was based on opz and lpz ( term 2 , from 2001 to 2003 ) ; and the second half of that ( 20042006 , term 3 ) ; and 2007 and later years ( term 4 ) , when treatment with rpz was approved for insurance coverage .
there were no differences based on gender or type of disorder from term 1 to term 4 , but the ages were significantly higher in terms 3 and 4 compared it in term 1 .
eradication rates significantly declined over time from 90.6% to 80.2% , 76.0% and 74.8% between term 1 and term 4 ( fig .  1 ) .
on the other hand , primary cam resistance rose significantly over time between 1997 and 2008 from 8.7% in term 1 , prior to 2000 ; 23.5% in term 2 ; 26.7% in term 3 ; and 34.5% in term 4 ( fig .  2 ) .
in 159 patients who were tested for cam susceptibility , the eradication rate in those with cam susceptibility was 86.7% while the eradication rate in those with cam - resistant bacteria was 25.0% , which resulted in a significant difference .
therefore , the rise in primary cam resistance is considered to be a major factor leading the decline in the first - line eradication rate based on triple therapy with the ppi , ampc , and cam .
we also investigated the differences over time in the eradication rate for the different types of ppis .
rpz was not used for eradication treatment from 2000 , when eradication therapy was approved in japan , until 2007 , when rpz was approved for insurance coverage .
therefore , we compared the eradication rates by rpz for term 1 with term 4 .
for opz and lpz , eradication rates were compared in all four terms . a significant decline over time in eradication rates by opz
/ lpz from terms 1 to term 4 was observed ; 91.2% , 80.2% , 76.0% and 69.0% . on the other hand ,
no significant difference was found in the rpz eradication rates ; 89.2% in term 1 and 79.4% in term 4 ( fig . 
the h. pylori eradication rate by triple therapy based on a ppi , ampc and cam is thought to be affected by age , smoking habits , drug compliance , polymorphisms of the cyp2c19 gene , and drug susceptibility , and cam resistance , in particular , is viewed to have a large effect on the eradication rate [ 610 ] . that arises from the big deterioration in eradication rate from about 80.6%98.3% for cam - susceptible bacteria to 0%33.3% for cam - resistant bacteria
iii consensus report , triple therapy based on a ppi , ampc , and cam were recommended as the primary eradication drugs in areas where cam resistance is < 20% . in a report on the eradication rate in the united kingdom over the 11 years from 1991 to 2001 ,
a good eradication rate of 89.9% was reported for triple therapy using a ppi , ampc , and cam when the cam resistance ranged 3.810.3% . in the present study period ,
the cam resistance had been low at 8.7% with a good eradication rate at 90.6% for the triple therapy before 2000 , when eradication therapy was approved in japan .
however , after that , the cam resistance rate rose over 20% , the surveillance by the japanese society for helicobacter research revealed . in our facility , as well , cam resistance had exceeded 20% in 2000 and reached > 30% over the past two years , which resulted in the remarkable decline in eradication rate along , falling to the 70% level .
triple therapy with a ppi , ampc and cam needs to be re - examined in japan .
triple therapy using a ppi , ampc , and metronidazole ( mnz ) is used in second - line eradication , and a high eradication rate over 90% has been reported in japan [ 1416 ] .
in addition , new approaches to improve the eradication rate by concomitant with a mucoprotective drug or lactobacillus are attempted [ 17 , 18 ] .
triple therapy using mnz as first line eradication and new regimen using quinolone like levofloxacin , gatifloxacin , sitafloxacin or garenoxacin need to be developed [ 19 , 20 ] .
mean age of patients taking significantly rose in term 3 and 4 compared to term 1 in the present study as seen in table 1
. however , broutet et al .   reported higher failure rate among young patients , therefore , the significant higher age in term 3 and 4 was considered not to have influenced the lowering eradication rate in the present study . on the other hand , the eradication rate for triple therapies is reported to depend on the degree of acid secretion suppression , in addition to cam resistance , and the importance of acid secretion suppression has also drawn attention .
the effect of suppressing acid secretion by a ppi was reported to rely on a polymorphism of the cyp2c19 gene .
that the eradication rates for triple therapy based on a ppi , ampc and cam differ due to polymorphisms of the cyp2c19 gene is also reported in a meta - analysis . in patients with cam - resistant bacteria , in particular ,
the eradication rate is reported to be greatly affected by polymorphisms of the cyp2c19 gene .
it was shown that the eradication rate for a double eradication therapy of ppi and ampc is affected by the extent to which acid secretion can be suppressed , and that is thought to be because the ppi 's ability to suppress acid secretion affects the eradication rate more for cam - resistant bacteria . in japan ,
opz , lpz and rpz are used in the eradication treatment , but rpz is reported to be less likely affected by cyp2c19 than the other two ppis [ 27 , 28 ] .
in fact , a meta - analysis reported the less influence of cyp2c19 polymorphism on triple therapy using rpz unlike the case of opz or lpz . in japan
, there is a great deal of variety in polymorphisms of the cyp2c19 gene , and that is why we investigated eradication rates in triple therapy groups and in the group using rpz and the other groups using the opz or lpz . while the eradication rates in opz and lpz groups decreased significantly over time , no apparent decline in eradication rate was seen for the rpz group .
also , rpz itself is indicated to possess antibiotic effects of against h. pylori , and it might have helped as well . however , we did not conduct detailed investigations because it was a retrospective study , nor did we measure cyp2c19 polymorphisms , and h. pylori drug susceptibility tests were carried out only for some cases . in the current situation
where prevalence of primary resistance to cam increased , it was difficult to ascertain the reasons why differences arose in the effectiveness of h. pylori eradication by acid secretion - suppressing agents and triple therapy based on a ppi , ampc , and cam .
however , the eradication rate for large - scale triple therapy using rpz is reported to be good and to be 90% , in spite of increase in the cam resistance rate in recent years .
in addition , a prospective study reported a higher eradication rate of 91% with rpz than it of 81% with lpz prior to our report .
the selection of a ppi should also be important in first line eradication today , and we need to make it clearer hereafter .
the present study demonstrated the evident decline in eradication rates for the triple therapy using a ppi , ampc and cam in japan , and the increase in cam resistance rate is considered to be associated with the lower eradication rate .
the first line eradication with new regimens must be developed and used . at the same time , ppi from which a higher eradication rate can be obtained should be selected from current regimen as well .
 a triple therapy based on a proton pump inhibitor ( ppi ) , amoxicillin ( ampc ) , and clarithromycin ( cam ) is recommended as a first - line therapy for helicobacter pylori ( h. pylori ) eradication and is widely used in japan . 
 however , a decline in eradication rate associated with an increase in prevalence of cam resistance is viewed as a problem . 
 we investigated cam resistance and eradication rates over time retrospectively in 750 patients who had undergone the triple therapy as first - line eradication therapy at nagoya city university hospital from 1995 to 2008 , divided into four terms ( term 1 : 19972000 , term 2 : 20012003 , term 3 : 20042006 , term 4 : 20072008 ) . 
 primary resistance to cam rose significantly over time from 8.7% to 23.5% , 26.7% and 34.5% while the eradication rate decreased significantly from 90.6% to 80.2% , 76.0% and 74.8% . 
 based on the ppi type , significant declines in eradication rates were observed with omeprazole or lansoprazole , but not with rabeprazole . a decrease in the h. pylori eradication rate after triple therapy using a ppi  +  ampc  +  cam has been acknowledged , and an increase in cam resistance is considered to be a factor . from now on , a first - line eradication regimen that results in a higher eradication rate ought to be investigated . 
Introduction
Materials and Methods
Results
Discussion