from december 2007 to may 2013 , 59 h.  pylori - infected patients with two previous eradication failures were enrolled for this study prospectively .
the study design was based on a single - centered , randomized , open - label , and controlled clinical trial .
the study protocol was approved by the institutional review board at yongin severance hospital and confirmed to the ethical guidelines of the declaration of helsinki , 1964 , as revised in 2004 . the requirement for informed consent
was waived , and all subjects signed written informed consent . the intended sample of 55 recruited subjects ( 32 patients for group a and 27 patients for group b ) provided a power of approximately 90% , assuming a significance level < .01 .
the dropout rate was expected to be < 10% , based on the documented good tolerability of drugs .
all patients received first - line eradication therapies ( lansoprazole 30  mg bid , clarithromycin 500  mg bid , amoxicillin 1  g bid ) for 7  days and received second - line eradication therapy ( lansoprazole 30  mg bid , tripotassium - dicitrato - bismuthate 600  mg bid , metronidazole 500  mg tid , tetracycline 500  mg qid ) for 7  days .
the eligible patients were randomly assigned to either group a who received lansoprazole 30  mg bid , amoxicillin 1.0  g tid , and rifabutin 150  mg bid for 1  week or group b who received lansoprazole 60  mg bid , amoxicillin 1.0  g tid , and rifabutin 150  mg bid for 7  days .
h.  pylori infection was defined a positivity according to at least one of the following two tests : a positive rapid urease test ( clo test delta west , bently , australia ) using a specimen from antrum or histologic evidence of h.  pylori in any of two specimen taken from corpus by hematoxylin and eosin stain .
the eradication of h.  pylori was assessed with c - urea breath test 4  weeks after the therapy .
exclusion criteria included the patients with the coexistence of serious concomitant illness 8 ( e.g. , liver cirrhosis with decompensation , and uremia ) , pregnant women , allergic history to the medications used and patients with previous gastric surgery antibiotics , bismuth and ppi within the previous 2 weeks and nonsteroidal anti - inflammatory drugs within the previous 4 weeks .
compliance with therapy was defined as intake of 80% more of the prescribed study medication .
in addition , the patients were instructed to contact the study site immediately in case of any severe adverse event .
from december 2007 to may 2013 , 59 h.  pylori - infected patients with two previous eradication failures were enrolled for this study prospectively .
the study design was based on a single - centered , randomized , open - label , and controlled clinical trial .
the study protocol was approved by the institutional review board at yongin severance hospital and confirmed to the ethical guidelines of the declaration of helsinki , 1964 , as revised in 2004 . the requirement for informed consent
was waived , and all subjects signed written informed consent . the intended sample of 55 recruited subjects ( 32 patients for group a and 27 patients for group b ) provided a power of approximately 90% , assuming a significance level < .01 .
the dropout rate was expected to be < 10% , based on the documented good tolerability of drugs .
all patients received first - line eradication therapies ( lansoprazole 30  mg bid , clarithromycin 500  mg bid , amoxicillin 1  g bid ) for 7  days and received second - line eradication therapy ( lansoprazole 30  mg bid , tripotassium - dicitrato - bismuthate 600  mg bid , metronidazole 500  mg tid , tetracycline 500  mg qid ) for 7  days .
the eligible patients were randomly assigned to either group a who received lansoprazole 30  mg bid , amoxicillin 1.0  g tid , and rifabutin 150  mg bid for 1  week or group b who received lansoprazole 60  mg bid , amoxicillin 1.0  g tid , and rifabutin 150  mg bid for 7  days .
h.  pylori infection was defined a positivity according to at least one of the following two tests : a positive rapid urease test ( clo test delta west , bently , australia ) using a specimen from antrum or histologic evidence of h.  pylori in any of two specimen taken from corpus by hematoxylin and eosin stain .
the eradication of h.  pylori was assessed with c - urea breath test 4  weeks after the therapy .
exclusion criteria included the patients with the coexistence of serious concomitant illness 8 ( e.g. , liver cirrhosis with decompensation , and uremia ) , pregnant women , allergic history to the medications used and patients with previous gastric surgery antibiotics , bismuth and ppi within the previous 2 weeks and nonsteroidal anti - inflammatory drugs within the previous 4 weeks .
compliance with therapy was defined as intake of 80% more of the prescribed study medication .
in addition , the patients were instructed to contact the study site immediately in case of any severe adverse event .
patients who had not taken antibiotics or antisecretary drugs were fasted for 6  hours before performing the ub t - test ( heliprobetm ; noster system ab , stockholm , sweden ) .
the gelatin capsule containing c - urea was swallowed with water by the patient to avoid contamination with oral bacteria .
patients were instructed to exhale into the breathcard , which was inserted into the heliprobe ( noster system ab , stockholm , sweden ) instrument .
the result was considered   >  50 positive is based on clinical trials using the 1 curie 14c - ubt .
the eradication rates and their 95% confidence intervals ( ci ) at both intention - to - treat ( itt ) and per - protocol ( pp ) analyses were calculated for each treatment regimen . for all other variables , fisher 's exact
test and t - test were used as appropriate , and p values < .05 were considered significant .
this study was approved by ethics committee of our institution ( yongin severance hospital , yonsei university , republic of korea ) .
chicago , il , u.s.a ) . the eradication rates and their 95% confidence intervals ( ci ) at both intention - to - treat ( itt ) and per - protocol ( pp ) analyses were calculated for each treatment regimen . for all other variables , fisher 's exact
test and t - test were used as appropriate , and p values < .05 were considered significant . the difference between the proportions eradicated was estimated . before pooling these estimates ,
this study was approved by ethics committee of our institution ( yongin severance hospital , yonsei university , republic of korea ) .
from december 2007 to may 2013 , a total of 59 patients were enrolled in the study ( mean age , 55.3  years , range , 3474  years ) .
they took as first - line therapy with ppi , clarithromycin , and amoxicillin and as second - line therapy with quadruple therapy consisting of a ppi , a bismuth salt , metronidazole , and tetracycline .
group a had 32 patients with lansoprazole 30 mg bid including rifabutin 150 mg bid daily and amoxicillin 1 g tid for 7 days .
group b had 27 patients with lansoprazole 60 mg bid including rifabutin 150 mg bid ( daily ) and amoxicillin 1 g tid for 7 days ( fig.1 ) .
there were 25 males ( mean age 58.8  years ) and 34 females ( mean age 52.9  years ) .
indications for eradication therapy mainly included peptic ulcer disease ( 32/58 ) and nonulcer disease ( 27/58 ) .
a history of smoking and alcohol use was present in 9 ( 15.5% ) and 12 ( 20.7% ) patients , respectively .
there were no statistically significant differences between the two groups in terms of demographic characteristics , history of smoking and alcohol , and indication for eradication therapy .
one patient in group a was not enrolled for pp analysis due to adverse events such as abdominal pain and red - colored urine and one patient in group b due to loss of follow - up ; 56 patients were fully compliant with the treatment taking more than 80% of the prescribed tablets . in group
a , h.  pylori eradication was achieved in 25 ( 78.1% ) of the 32 patients in the itt analysis and in 25 ( 80.6% ) of the 31 patients in the pp analysis . in group b ,
h.  pylori eradication was achieved in 26 ( 96.3% ) of the 27 patients in the itt analysis and in 27 ( 100% ) of the 27 patients in the pp analysis .
there was statistically significant difference between the two groups in terms of the eradication rates in pp analysis ( p  =  .047 ) , whereas a marginally statistical significance was found in terms of the eradication rates in itt analysis ( p  =  .051 ; table2 ) .
clinical characteristics of patients eradication rates of helicobacter pylori the most common adverse events were epigastric pain in the three patients ( 9.3% ) versus one patient ( 3.7% ) , epigastric discomfort in two patients ( 6.2% ) versus , one patient ( 3.7% ) , and nausea in one patient ( 3.1% ) versus one patient ( 3.7% ) , in the groups a and b. there was no statistically significant difference between the two groups in terms of adverse events ( table3 ) . reported side effects were mild , and treatment was well tolerated .
no major changes in physical examination or in standard laboratory parameters were observed after treatment . as drug compliance and tolerability were optimal in all patients , we searched for other factors possibly associated with treatment failure ( table4 ) .
from december 2007 to may 2013 , a total of 59 patients were enrolled in the study ( mean age , 55.3  years , range , 3474  years ) .
they took as first - line therapy with ppi , clarithromycin , and amoxicillin and as second - line therapy with quadruple therapy consisting of a ppi , a bismuth salt , metronidazole , and tetracycline .
group a had 32 patients with lansoprazole 30 mg bid including rifabutin 150 mg bid daily and amoxicillin 1 g tid for 7 days .
group b had 27 patients with lansoprazole 60 mg bid including rifabutin 150 mg bid ( daily ) and amoxicillin 1 g tid for 7 days ( fig.1 ) .
there were 25 males ( mean age 58.8  years ) and 34 females ( mean age 52.9  years ) .
indications for eradication therapy mainly included peptic ulcer disease ( 32/58 ) and nonulcer disease ( 27/58 ) .
a history of smoking and alcohol use was present in 9 ( 15.5% ) and 12 ( 20.7% ) patients , respectively .
there were no statistically significant differences between the two groups in terms of demographic characteristics , history of smoking and alcohol , and indication for eradication therapy .
one patient in group a was not enrolled for pp analysis due to adverse events such as abdominal pain and red - colored urine and one patient in group b due to loss of follow - up ; 56 patients were fully compliant with the treatment taking more than 80% of the prescribed tablets . in group
a , h.  pylori eradication was achieved in 25 ( 78.1% ) of the 32 patients in the itt analysis and in 25 ( 80.6% ) of the 31 patients in the pp analysis . in group b ,
h.  pylori eradication was achieved in 26 ( 96.3% ) of the 27 patients in the itt analysis and in 27 ( 100% ) of the 27 patients in the pp analysis .
there was statistically significant difference between the two groups in terms of the eradication rates in pp analysis ( p  =  .047 ) , whereas a marginally statistical significance was found in terms of the eradication rates in itt analysis ( p  =  .051 ; table2 ) .
clinical characteristics of patients eradication rates of helicobacter pylori the most common adverse events were epigastric pain in the three patients ( 9.3% ) versus one patient ( 3.7% ) , epigastric discomfort in two patients ( 6.2% ) versus , one patient ( 3.7% ) , and nausea in one patient ( 3.1% ) versus one patient ( 3.7% ) , in the groups a and b. there was no statistically significant difference between the two groups in terms of adverse events ( table3 ) . reported side effects were mild , and treatment was well tolerated .
no major changes in physical examination or in standard laboratory parameters were observed after treatment . as drug compliance and tolerability were optimal in all patients , we searched for other factors possibly associated with treatment failure ( table4 ) .
our study shows that as empirical third - line therapy , rifabutin - based high - dose ppi and amoxicillin combined therapy is more effective in patients with refractory h.  pylori infection after two eradication failures with key antibiotics such as clarithromycin , metronidazole , and tetracycline previously prescribed .
high - dose ppi and amoxicillin are recommended as one of several options for empirical rescue therapy for h.  pylori infection in the absence of antimicrobial susceptibility testing .
antibiotics with the beta - lactam ring , such as amoxicillin , have little postantibiotic effects on the gram - negative rods 22 .
the frequent dosing of amoxicillin is required to sustain the levels of amoxicillin higher than the mic level for a long time , which makes the bioavailability of amoxicillin enhanced in comparison with the twice - daily dosing from the point of view of pharmacology of antibiotics 23 .
24 reported in pp analysis , eradication rate of high - dose rabeprazole ( 40  mg trice ) and amoxicillin 1.0  g trice for 14  days was 75% .
four studies from japan reported the efficacy of a second - line treatment with a ppi plus amoxicillin after the failure of the standard triple therapy 2325 .
surprisingly , three of these studies ( 106 patients ) reported optimal results ( eradication rates of 87 , 91 and 100% ) , dosing 10  mg of rabeprazole and 500  mg of amoxicillin four times daily , for 14  days . the fourth study ( 63 patients ) , with a 58% eradication , administered 20  mg of rabeprazole plus 1  g of amoxicillin twice a day , for 14  days .
the differences between these studies may be explained by the different dosage scheme , especially on the pharmacokinetics of these drugs .
an oral dose of 500  mg of amoxicillin is rapidly absorbed , with a peak in plasma concentrations between 1 and 2  hours , and approximately a 75% is excreted between 6 and 8  hours after its administration .
a dosage of 500  mg every 6  hours can probably maintain higher plasma dosages of amoxicillin than a dosage of 1000  mg twice daily 26 .
the large multicenter surveillance studies have confirmed that resistance of h.  pylori to amoxicillin is in the order of 1% 27,28 . in korea ,
primary amoxicillin resistance was seen in 2.2 - 5.6% ( mean 2.3% , 8/350 ) 29,30 .
other clinical trials did not detect any pre- or post - treatment resistance to amoxicillin 31,32 .
also , it is known that the genotype of cyp2c19 is associated with the metabolism of the ppis .
not knowing whether the patients are extensive or poor metabolizers , or their cyp2c19 polymorphisms , higher ppi doses or newer ppi types might be more effective 3335 .
furthermore , acid inhibition allows h.  pylori to reach its growth phase , rendering the bacteria more sensitive to antibiotics .
the distribution frequencies of people with the homem genotype are 3040% in asian countries 36 .
the usual doses ppis used in the standard regimen are insufficient for patients with the homem genotype , as well as that a higher dose of a ppi causes few adverse effects and is considered to be sufficiently safe 36
. the rifabutin - based high - dose ppi and amoxicillin combined therapy can resolve the problems of clarithromycin and metronidazole resistance and homozygous extensive metabolizers of cyp2c19 gene polymorphisms , the main reasons for eradication failure 37 .
rifabutin - based triple therapy was found to be highly effective and reliable as an alternative rescue therapy for the treatment of h.  pylori infection after two failed eradication treatments .
showed a 12  days of half the dose of rifabutin ( 150  mg daily ) combined with a high dose of pantoprazole ( 80  mg thrice daily ) and amoxicillin ( 1  g or 1.5  g thrice daily ) produced higher eradication rates of 91 and 97% , respectively , as a rescue therapy , suggesting that the treatment regimen is considered highly effective as a rescue therapy .
in the presence of low - dose rifabutin ( 150  mg ) , combined frequent high dosing of ppi and amoxicillin for 12  days is effective for rescue therapy 38 .
our present open single - center study showed that high dose of ppi ( lansoprazole 60  mg twice daily ) and amoxicillin ( 1  g trice daily ) combined rifabutin therapy achieved significant better eradication rate ( 100% ) than standard dose of ppi ( lansoprazole 30  mg twice daily ) 80.6% in pp analysis ( p  =  .047 ) after failures in two courses of previous h.  pylori eradication therapy .
primary rifabutin resistance in h.  pylori isolates is low , ranging from 1.3% to 2.4% . unlike other antibiotics , rifabutin is chemically stable at a wide ph range and is not likely affected by inadequate acid suppression 39 .
the combination of rifabutin with either metronidazole or amoxicillin shows additive effects 40 . for treating h.  pylori infection , the length of treatment for the rifabutin regimen has controversies , as does the influence this has on the treatment outcome
. a mean h.  pylori eradication rate of 75% ( 95% ci from 68 to 83% ) for the 7-day regimen was calculated , while the 10- to 14-day regimen was similar or even slightly lower ( 71% ; 95% ci , 6379% ) 21 .
however , as previously reviewed , when a subanalysis was performed depending on the duration of the second - line rifabutin therapy , better results were observed with 1012  days ( 92% ) than with 7  days ( 69% ) . finally , therapies between 12 and 14  days have yielded results similar to the 10-day course and are likely to increase the incidence of adverse event 21 .
our data suggest that in the presence of 7  days relatively short duration , frequent dosing of amoxicillin and a high - dose ppi can improve eradication rate and reducing side effects .
it has been suggested that rifabutin efficacy decreases with increasing number of failed previous therapies , perhaps due to patients who had failed at least two courses of eradication therapy and may have harbored h.  pylori strains that were more difficult to eradicate 41 .
overall , mean h.  pylori eradication rate ( intention - to - treat analysis ) with rifabutin - containing regimens ( 1008 patients ) was 73% ( 6779% ) .
respective cure rates for second - line ( 223 patients ) , third - line ( 342 patients ) , and fourth-/fifth - line ( 95 patients ) rifabutin therapies were 79% ( 6792% ) , 66% ( 5577% ) , and 70% ( 6079% ) , respectively 41 .
antimicrobial susceptibility testing of h.  pyloriis was desirable before initiation of third - line therapy , although the culture - based antibiotic susceptibility testing for h.  pylori is expensive , time - consuming , and not always available on a routine basis 42 .
the sensitivity of a bacterial culture is not 100% , and therefore , the antimicrobial susceptibility can not be obtained in all cases .
therefore , rifabutin ( together with a ppi and amoxicillin ) can be administered as a rescue treatment without the need for a prior antibiogram 13 .
the mean rate of adverse effects to rifabutin treatment in h.  pylori studies has been approximately 22% 21 . in our study , this incidence was reported to be somewhat lower ( 15.5% ) , but in most cases , symptoms were well tolerated and no side effects were considered serious . in our study , most frequent side effects were epigatric pain ( 7.0% ) , epigastric discomfort ( 5.2% ) , and nausea ( 3.5% ) .
overall , this complication is rare and is far more likely when high dose ( 600  mg / day ) and prolonged duration therapy is used .
however , myelotoxicity was not reported in most of the studies evaluating rifabutin for h.  pylori infection .
first , this drug is extremely expansive ; second , severe leucopenia and thrombocytopenia can occur to a patient under treatment with rifabutin .
finally , there is some concern about widespread use of rifabutin , a member of class of established antimycobacterial drugs in patients with h.  pylori infection 45 .
because multiresistant strains of mycobacterium tuberculosis have increased in number , indications for these drugs should be chosen very carefully to avoid further acceleration of development of resistance .
rifabutin should be used only as rescue therapy after amoxicillin , clarithromycin , metronidazole , tetracycline , and levofloxacin have failed to eradicate to patients who have experienced failure of h.  pylori 
 42 .
the main limitation of our study is that it was a single - centered study and that no antibiotic testing has been performed . in conclusion ,
rifabutin - based high - dose ppi - combined therapy as empirical rescue treatment is more effective than standard dose ppi - combined rifabutin - based therapy , safe and best tolerable in third - line therapy in the korean population .
the key to successful rescue therapy with rifabutin  amoxicillin  ppi regimen may be to increase doses of ppi and amoxicillin .
 backgroundrifabutin has been known to be effective in multidrug - resistant helicobacter pylori - harboring patients undergoing treatment failure for h.  pylori infection.aimto evaluate the efficacy of 7-day treatment regimen consisting rifabutin daily but increasing the dose of amoxicillin and lansoprazole in patients who have failed first and second eradication and to assess the side effect profiles in south korea.methodsfrom december 2007 to may 2013 , 59 h.  pylori - infected patients with two previous eradication failures were enrolled for this study prospectively . 
 the eligible patients were randomly assigned to either group a or b. group a received lansoprazole 30 mg bid , amoxicillin 1.0 g tid and rifabutin 150 mg bid during 7 days , whereas group b received lansoprazole 60 mg bid , amoxicillin 1.0 g tid and rifabutin 150 mg bid during 7 days.resultsin group a , h.  pylori eradication was achieved in 25 ( 78.1% ) of the 32 patients in the itt analysis and in 25 ( 80.6% ) of the 31 patients in the pp analysis . in group b , 
 h.  pylori eradication was achieved in 26 ( 96.3% ) of the 27 patients in the itt analysis and in 27 ( 100% ) of the 26 patients in the pp analysis . 
 there was statistically significant difference between the two groups in terms of the eradication rates in pp analysis ( p  =  .047 ) , whereas a marginally statistical significance was found in terms of the eradication rates in itt analysis ( p  =  .051 ) . 
 reported side effects were mild , and treatment was well tolerated . 
 no major changes in physical examination or in standard laboratory parameters were observed after treatment.conclusionsrifabutin-based high - dose proton - pump inhibitor ( ppi)-combined therapy as empirical rescue treatment is more effective than standard dose ppi - combined rifabutin - based therapy , safe and best tolerable in third - line therapy in the korean population . 
 the key to successful rescue therapy with rifabutin  amoxicillin  ppi regimen may be to increase doses of ppi . 