Peptic ulcer medical therapy: Difference between revisions

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{{Peptic ulcer}}
{{Peptic ulcer}}
{{CMG}}; Gerald Chi, M.D.
{{CMG}} ; {{AE}} {{MKK}}
 
==Overview==
==Overview==
Eradication of ''[[Helicobacter pylori]]'' with antimicrobial agents is indicated for patients with [[gastric ulcer|gastric]] or [[duodenal ulcer|duodenal peptic ulceration]] who are colonized with ''[[Helicobacter pylori]]'' and patients with [[MALT lymphoma]]. Eradication therapy should also be considered for patients with [[immune thrombocytopenic purpura]] who are ''[[H. pylori]]'' positive or patients who have undergone resection for early-stage [[gastric cancer]]. The use of antibiotics is discouraged in asymptomatic carriers.
The mainstay of treatment for peptic ulcer disease is pharmacotherapy. Treatment of ''[[Helicobacter pylori]]'' with antimicrobial agents is indicated for patients with [[gastric ulcer|gastric]] or [[duodenal]] [[ulceration]].  Pharmacologic therapies for peptic ulcer disease due to ''[[H. pylori]]'' is either triple or quadruple pharmacologic agents that include a [[Proton pump inhibitors]] plus a combination of antimicrobial agents. After the first line therapy, patient is tested for persistent H.pylori infection. If the patient has persistent infection, treatment is planned according to previous [[antibiotics]] therapy. Salvage treatment is used for failure of first line therapy. The use of antimicrobial therapy is discouraged among asymptomatic carriers.


==Medical Therapy==
==Medical Therapy==
The mainstay of treatment for peptic ulcer disease is pharmacotherapy. Pharmacotherapy for peptic ulcer disease can be discussed under [[Helicobacter pylori]]-associated peptic ulcer and  Non- [[Helicobacter pylori]]-associated [[peptic ulcer]] disease.
===Eradication Therapy for ''Helicobacter pylori'' Infection===
The ACG’s 2017 treatment guideline on the management of [[H. pylori]] infection listed the following as established indications for diagnosis and treatment:<ref name="urlwww.nature.com">{{cite web |url=https://www.nature.com/ajg/journal/v112/n2/pdf/ajg2016563a.pdf |title=www.nature.com |format= |work= |accessdate=}}</ref>
====Indications====
*Active [[Peptic ulcer]] disease ([[gastric]] or [[duodenal]]).
*Confirmed history of PUD (not previously treated for [[H. pylori]])
*[[Gastric]] [[MALT lymphoma]] (low grade)
*After [[endoscopic]] resection of [[gastric cancer]]
'''Depending upon exposure of antibiotics and allergy to antibiotics, following treatments regimen are being used''':<ref name="pmid24574740">{{cite journal |vauthors=Federico A, Gravina AG, Miranda A, Loguercio C, Romano M |title=Eradication of Helicobacter pylori infection: which regimen first? |journal=World J. Gastroenterol. |volume=20 |issue=3 |pages=665–72 |year=2014 |pmid=24574740 |pmc=3921476 |doi=10.3748/wjg.v20.i3.665 |url=}}</ref><ref name="pmid10848654">{{cite journal |vauthors=Zullo A, Rinaldi V, Winn S, Meddi P, Lionetti R, Hassan C, Ripani C, Tomaselli G, Attili AF |title=A new highly effective short-term therapy schedule for Helicobacter pylori eradication |journal=Aliment. Pharmacol. Ther. |volume=14 |issue=6 |pages=715–8 |year=2000 |pmid=10848654 |doi= |url=}}</ref>
====Triple Therapy====
*Triple  therapy consisting of a [[Proton pump inhibitors]] and 2 [[antibiotics]]  for 14 days remains a recommended [[treatment]] in regions where [[H. pylori]] [[clarithromycin]] resistance is known to be <15% and in patients with no previous history of [[macrolide]] exposure.<ref name="pmid11232676">{{cite journal |vauthors=Maconi G, Parente F, Russo A, Vago L, Imbesi V, Bianchi Porro G |title=Do some patients with Helicobacter pylori infection benefit from an extension to 2 weeks of a proton pump inhibitor-based triple eradication therapy? |journal=Am. J. Gastroenterol. |volume=96 |issue=2 |pages=359–66 |year=2001 |pmid=11232676 |doi=10.1111/j.1572-0241.2001.03519.x |url=}}</ref><ref name="pmid17938394">{{cite journal |vauthors=Fuccio L, Minardi ME, Zagari RM, Grilli D, Magrini N, Bazzoli F |title=Meta-analysis: duration of first-line proton-pump inhibitor based triple therapy for Helicobacter pylori eradication |journal=Ann. Intern. Med. |volume=147 |issue=8 |pages=553–62 |year=2007 |pmid=17938394 |doi= |url=}}</ref><ref name="pmid15225176">{{cite journal |vauthors=Vakil N, Lanza F, Schwartz H, Barth J |title=Seven-day therapy for Helicobacter pylori in the United States |journal=Aliment. Pharmacol. Ther. |volume=20 |issue=1 |pages=99–107 |year=2004 |pmid=15225176 |doi=10.1111/j.1365-2036.2004.02029.x |url=}}</ref>
* '''<u>PCA regimen</u>'''
:* Preferred regimen (1):'''[[Proton pump inhibitor|P]]'''[[Proton pump inhibitor|roton pump inhibitor]] standard dose* PO q12h for 7–14 days {{and}}
:* Preferred regimen (2):[[Clarithromycin]] 500 mg PO q12h for 7–14 days {{and}}
:* Preferred regimen (3):[[Amoxicillin]] 1 g PO q12h for 7–14 days {{or}} [[Metronidazole]] 250 mg PO q6h for 7–14 days
* <u>'''PCM regimen'''</u>
:*Alternative regimen (1): [[Proton pump inhibitor]] standard dose* PO q12h  for 7–14 days {{and}}
:*Alternative regimen (2): [[Clarithromycin]] 500 mg PO  q12h for 7–14 days {{and}}
:*Alternative regimen (3): [[Metronidazole]] 250 mg PO q6h for 7–14 days
* '''<u>PLA regimen</u>'''
:*Alternative regimen (1): [[Proton pump inhibitor]] standard dose* PO q12h for 10 days {{and}}
:*Alternative regimen (2): [[Levofloxacin]] 500mg PO q12h for 10 days {{and}}
:*Alternative regimen (3): [[Amoxicillin]] 1g PO q12h for 10 days
* '''<u>PMA regimen</u>'''
:*Alternative regimen (1): [[Proton pump inhibitor]] standard dose* PO q12h for 7–14 days {{and}}
:*Alternative regimen (2): [[Metronidazole]] 250mg PO q6h for 7–14 days {{and}}
:*Alternative regimen (3): [[Amoxicillin]] 1g PO q12h for 7–14 days
* '''<u>PRA regimen</u>'''
:*Alternative regimen (1): [[Proton pump inhibitor]] standard dose* PO q12h for 10 days {{and}}
:*Alternative regimen (2): [[Rifabutin]] 150–300mg PO q 24h for 10 days {{and}}
:*Alternative regimen (3): [[Amoxicillin]] 1g PO q12h for 10 days
* '''Bismuth quadruple therapy'''
:*Preferred regimen (1): [[Proton pump inhibitor]] standard dose* PO q12h for 10–14 days {{and}}
:*Preferred regimen (2): [[Metronidazole]] 250mg PO q6h for 10–14 days {{and}}
:*Preferred regimen (3): [[Tetracycline]] 500 mg PO q6hfor 10–14 days {{and}}
:*Preferred regimen (4): [[Bismuth]] (dose depends on preparation) for 10–14 days
====Bismuth-containing quadruple therapy====
*Bismuth quadruple therapy particularly advised in patients with any previous macrolide exposure or clarithromycin resistance is known to be high or who are allergic to penicillin <ref name="pmid23880479">{{cite journal| author=Venerito M, Krieger T, Ecker T, Leandro G, Malfertheiner P| title=Meta-analysis of bismuth quadruple therapy versus clarithromycin triple therapy for empiric primary treatment of Helicobacter pylori infection. | journal=Digestion | year= 2013 | volume= 88 | issue= 1 | pages= 33-45 | pmid=23880479 | doi=10.1159/000350719 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?d.* Bismuthfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23880479  }} </ref>
:*Preferred regimen (1): [[Proton pump inhibitor]] standard dose* PO q12h for 10–14 days {{and}}
:*Preferred regimen (2): [[Metronidazole]] 250mg PO q6h  for 10–14 days {{and}}
:*Preferred regimen (3): [[Tetracycline]] 500 mg PO q6h for 10–14 days {{and}}
:*Preferred regimen (4): [[Bismuth]] (dose depends on preparation) for 10–14 days
====Non–Bismuth-containing quadruple therapy====
* '''Concomitant therapy:'''<ref name="pmid19804842">{{cite journal |vauthors=Wu DC, Hsu PI, Wu JY, Opekun AR, Kuo CH, Wu IC, Wang SS, Chen A, Hung WC, Graham DY |title=Sequential and concomitant therapy with four drugs is equally effective for eradication of H pylori infection |journal=Clin. Gastroenterol. Hepatol. |volume=8 |issue=1 |pages=36–41.e1 |year=2010 |pmid=19804842 |pmc=2838430 |doi=10.1016/j.cgh.2009.09.030 |url=}}</ref><ref name="pmid22046084">{{cite journal |vauthors=Chuah SK, Tsay FW, Hsu PI, Wu DC |title=A new look at anti-Helicobacter pylori therapy |journal=World J. Gastroenterol. |volume=17 |issue=35 |pages=3971–5 |year=2011 |pmid=22046084 |pmc=3199554 |doi=10.3748/wjg.v17.i35.3971 |url=}}</ref>
:*Preferred regimen (1): [[Proton pump inhibitor]] standard dose* PO q12h for 10–14 days {{and}}
:*Preferred regimen (2): [[Clarithromycin]] 500mg PO  q12h  for 10–14 days {{and}}
:*Preferred regimen (3): [[Amoxicillin]] 1g PO q12h  for 10-14 days {{and}}
:*Preferred regimen (4): [[Nitroimidazole ]] 250mg PO q6h  for 10–14 days
* '''Sequential therapy:'''<ref name="pmid19844205">{{cite journal |vauthors=Gatta L, Vakil N, Leandro G, Di Mario F, Vaira D |title=Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children |journal=Am. J. Gastroenterol. |volume=104 |issue=12 |pages=3069–79; quiz 1080 |year=2009 |pmid=19844205 |doi=10.1038/ajg.2009.555 |url=}}</ref><ref name="pmid17438314">{{cite journal |vauthors=Vaira D, Zullo A, Vakil N, Gatta L, Ricci C, Perna F, Hassan C, Bernabucci V, Tampieri A, Morini S |title=Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial |journal=Ann. Intern. Med. |volume=146 |issue=8 |pages=556–63 |year=2007 |pmid=17438314 |doi= |url=}}</ref><ref name="pmid20054285">{{cite journal |vauthors=Gisbert JP, Calvet X, O'Connor A, Mégraud F, O'Morain CA |title=Sequential therapy for Helicobacter pylori eradication: a critical review |journal=J. Clin. Gastroenterol. |volume=44 |issue=5 |pages=313–25 |year=2010 |pmid=20054285 |doi=10.1097/MCG.0b013e3181c8a1a3 |url=}}</ref>
:*Preferred regimen (1): [[Proton pump inhibitor|Proton pump inhibito'''r''']] standard dose* PO q12h  for 5-7 days {{and}}
:*Preferred regimen (2): [[Amoxicillin]] 1 g PO q12h for 5-7 days<BR><span style="text-indent: 50px;">'''<u>FOLLOWED BY</u>'''</span>
:*Preferred regimen (1): [[Proton pump inhibitor]] standard dose* PO  q12h for another 5-7days {{and}}
:*Preferred regimen (2): [[Clarithromycin]] 500 mg PO q12h for another 5-7 days {{and}}
:*Preferred regimen (3): [[Tinidazole]] 500 mg  PO q12h  for another 5-7 days
'''Hybrid therapy''':
:*Preferred regimen (1): [[Proton pump inhibitor]] standard dose* PO q12h for 7 days
:*Preferred regimen (2): [[Amoxicillin]] 1g PO q12h for 7 days '''<u>AND</u>'''  <u>'''FOLLOWED BY'''</u>
:*Preferred regimen (1): [[Proton pump inhibitor]] standard dose* PO  q12h for 5-7 days '''<u>AND</u>'''
:*Preferred regimen (2): [[Amoxicillin]] 1g PO q12h for 7 days '''<u>AND</u>'''
:*Preferred regimen (3): [[Clarithromycin]] 500mg PO  q12h for 7 days '''<u>AND</u>'''
:*Preferred regimen (4): [[Nitroimidazole |Nitroimidazol'''e ''']] 250mg PO q12h for 7 days
*'''Levofloxacin triple therapy'''<ref name="pmid20180787">{{cite journal |vauthors=Molina-Infante J, Perez-Gallardo B, Fernandez-Bermejo M, Hernandez-Alonso M, Vinagre G, Dueñas C, Mateos-Rodriguez JM, Gonzalez-Garcia G, Abadia EG, Gisbert JP |title=Clinical trial: clarithromycin vs. levofloxacin in first-line triple and sequential regimens for Helicobacter pylori eradication |journal=Aliment. Pharmacol. Ther. |volume=31 |issue=10 |pages=1077–84 |year=2010 |pmid=20180787 |doi=10.1111/j.1365-2036.2010.04274.x |url=}}</ref><ref name="pmid19844205">{{cite journal |vauthors=Gatta L, Vakil N, Leandro G, Di Mario F, Vaira D |title=Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children |journal=Am. J. Gastroenterol. |volume=104 |issue=12 |pages=3069–79; quiz 1080 |year=2009 |pmid=19844205 |doi=10.1038/ajg.2009.555 |url=}}</ref><ref name="pmid17606419">{{cite journal |vauthors=Caselli M, Zullo A, Maconi G, Parente F, Alvisi V, Casetti T, Sorrentino D, Gasbarrini G |title="Cervia II Working Group Report 2006": guidelines on diagnosis and treatment of Helicobacter pylori infection in Italy |journal=Dig Liver Dis |volume=39 |issue=8 |pages=782–9 |year=2007 |pmid=17606419 |doi=10.1016/j.dld.2007.05.016 |url=}}</ref><ref name="pmid20947881">{{cite journal |vauthors=Romano M, Cuomo A, Gravina AG, Miranda A, Iovene MR, Tiso A, Sica M, Rocco A, Salerno R, Marmo R, Federico A, Nardone G |title=Empirical levofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: a randomised trial |journal=Gut |volume=59 |issue=11 |pages=1465–70 |year=2010 |pmid=20947881 |doi=10.1136/gut.2010.215350 |url=}}</ref>:
:*Preferred regimen (1): [[Proton pump inhibitor]] standard dose* PO q12h  for 10-14 days '''<u>AND</u>'''
:*Preferred regimen (2): [[levofloxacin|'''l'''evofloxacin]] 500 mg  PO q12h  for 10–14 days '''<u>AND</u>'''
:*Preferred regimen (3): [[Amoxicillin]] 1g  PO q12h  for 10-14 days
*'''Fluoroquinolone sequential therapy'''
:*Preferred regimen (1): [[Proton pump inhibitor]] standard dose PO q12h for 5 -7 days '''<u>AND</u>'''
:*Preferred regimen (2): [[Amoxicillin]] 1g PO q12h '''<u>AND</u>'''    <u>'''FOLLOWED'''</u> '''<u>BY</u>'''
:*Preferred regimen (1): [[Proton pump inhibitor]] standard dose* PO q12h for 5–7 days '''<u>AND</u>'''
:*Preferred regimen (2): [[Fluoroquinolone]] 500mg PO q6h for 5–7 days '''<u>AND</u>'''
:*Preferred regimen (3): [[Nitroimidazole]] 250mg PO q6h for  5–7 days
<nowiki>*</nowiki>Standard dose of PPI: [[Lansoprazole]] 30 mg PO q12h, or [[Omeprazole]] 20 mg q12h, or [[Esomeprazole]] 40 mg PO q24h, or [[Rabeprazole]] 20 mg PO q12h
* After failure of second-line treatment, treatment should be guided by antimicrobial susceptibility testing whenever possible.The [[urea breath test]] or a laboratory based validated monoclonal stool test are both recommended as non-invasive tests for determining the success of eradication treatment.<ref>{{Cite journal| doi = 10.1136/gutjnl-2012-302084| issn = 1468-3288| volume = 61| issue = 5| pages = 646–664| last1 = Malfertheiner| first1 = Peter| last2 = Megraud| first2 = Francis| last3 = O'Morain| first3 = Colm A.| last4 = Atherton| first4 = John| last5 = Axon| first5 = Anthony T. R.| last6 = Bazzoli| first6 = Franco| last7 = Gensini| first7 = Gian Franco| last8 = Gisbert| first8 = Javier P.| last9 = Graham| first9 = David Y.| last10 = Rokkas| first10 = Theodore| last11 = El-Omar| first11 = Emad M.| last12 = Kuipers| first12 = Ernst J.| last13 = European Helicobacter Study Group| title = Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report| journal = Gut| date = 2012-05| pmid = 22491499}}</ref>
'''Selection of a first-line H. pylori treatment regimen.'''<br><br>
{{familytree/start}}
{{familytree |boxstyle=text-align: left; | | | | | | | | | A01 | | | |A01= Is there a penicillin (PCN) allergy?<br> •Previous [[macrolide]] (MCL) exposure for any reason ?<br>}}
{{familytree | | |,|-|-|-|-|v|-|^|-|v|-|-|-|.| ||}} 
{{familytree |boxstyle=text-align: left; | | B01 | | | B02 | | B03 | | B04||B01=•PCN allergy: '''No'''<br> •MCL exposure: '''No'''<br> |B02=•PCN allergy: '''No'''<br> •MCL exposure: '''Yes'''<br> |B03=•PCN allergy: '''Yes'''<br> •MCL exposure: '''No'''<br> |B04=•PCN allergy: '''Yes'''<br> •MCL exposure: '''Yes'''<br> }}
{{familytree | | |!| | | | |!| | | |!| | | |!| ||}} 
{{familytree |boxstyle=text-align: left; | | B01 | | | B02 | | B03 | | B04||B01='''Recomended treatment:'''<br> •[[Bismuth]] quadruple <br> •[[Clarithromycin]] triple with [[amoxicillin]]<br> '''Other options''':<br> •Sequential<br> •HYBRID<br> •[[Levofloxacin]] triple<br> •[[Levofloxacin]] sequential <br>•LOAD<br> |B02='''Recomended treatment:'''<br>•[[Bismuth]] quadruple <br>•[[Levofloxacin]] sequential<br>'''Other options''':<br>•Concomitant therapy<br>•Sequential therapy <br>• HYBRID<br> •LOAD<br>|B03='''Recommended treatment:'''<br> •[[Bismuth]] quadruple <br> •[[Clarithromycin]] triple <br> with [[metronidazole]]<br> •[[Bismuth]] quadruple<br>|B04= '''Recommended treatment:''' <br> •[[Bismuth]] quadruple <br> •[[Clarithromycin]] triple with [[metronidazole]]<br> •[[Bismuth]] quadruple<br>}}
{{Familytree/end}}
'''LOAD''' (Levofloxacin, Omeprazole, Alinia [nitazoxanide], and Doxycycline), 


===Diagnostic testing===
'''Recommended first-line therapies for H pylori infection''':
{| style="float: right; width: 300px; margin: 5px 10px;"
<small>Adopted:American college of gasteroenterology<ref name="urlManagement of Patients with Ulcer Bleeding | American College of Gastroenterology" /> </small>
! style="font-size: 85%; background: #545454; color: #F8F8FF; padding: 5px 10px;" | Countries with a reported prevalence < 15% of ''H. pylori'' resistance to clarithromycin
{| class="wikitable"
!Regimen
!Drug dose
!Dosing frequency
!Duration(days)
!FDA approval
|-
|-
! style="font-size: 85%; background: #DCDCDC;" | Europe
|[[Clarithromycin]] triple
|[[PPI]] standard or double dose PO
[[Clarithromycin]] 500mg PO
 
[[Amoxicillin]] 1gm PO or [[Metronidazole]] 500mg PO TID
|BID
|14 days
|YES<sup>'''†'''</sup>
|-
|-
| style="font-size: 85%; background: #F5F5F5;" |
|[[Bismuth]] Quadruple
* Belgium (3%)
|[[PPI]]  standard dose PO
* Croatia (8.2%)
[[Bismuth]] subcitrate 120-300mg or Subsalicylate 300mg PO
* Denmark (11%)
 
* Finland (2%)
[[Tetracyclin]]  500mg PO
* Germany (2.2–4%)
 
* Italy (North) (1.8%)
[[Metronidazole]] 250-500mg
* Ireland (8.8%)
|BID
* Netherlands (1.7%)
QID
* Sweden (2.9%)
 
* UK (8.3–12.7%)
QID
 
TID to QID (500mg)  
|10-14 days
|NO<sup>'''‡'''</sup>
|-
|-
! style="font-size: 85%; background: #DCDCDC;" | North America
|Concomitant
|[[PPI]] standard dose PO
[[Clarithromycin]] 500mg PO
 
[[Amoxicillin]] 1gm PO
 
[[Nitroimidazole]] 500mg<sup>c</sup>
|BID
|10 -14 days
|NO
|-
|-
| style="font-size: 85%; background: #F5F5F5;" |
|Sequential
* Canada (12%)
|[[PPI]] standard dose +[[Amoxicillin]] 1gm PO
* USA (10.6–12.2%)
[[PPI]],[[Clarithromycin]] 500mg PO +[[Nitroimidazole]] 500mg <sup>c</sup>
|BID
 
BID
|5-7 days
 
5-7 days
|NO
|-
|-
! style="font-size: 85%; background: #DCDCDC;" | South America
|Hybrid
|[[PPI]] standard +[[Amoxicillin]] 1gm,[[PPI]],[[Amoxicillin]],[[Clarithromycin]] 500mg,[[Nitroimidazole]] 500mg<sup>c</sup>
|BID
BID
|7 days
7 days
|NO
|-
|-
| style="font-size: 85%; background: #F5F5F5;" |
|[[Levofloxacin]] triple
* Brazil (9.8%)
|[[PPI]] standard dose PO
[[Levofloxacin]] 500mg PO
 
[[Amoxicillin]] 1gm PO
|BID
QID
 
BID
 
|10-14 days
|NO
|-
|-
! style="font-size: 85%; background: #DCDCDC;" | Middle East
|[[Levofloxacin]] sequential
|[[PPI]] standard or double dose+[[Amoxicillin]] 1 gm PO
[[PPI]],[[Amoxicillin]],[[Levofloxacin]] 500mg  PO QD,[[Nitroimidazole]] 500mg<sup>c</sup>
|BID
BID
|5-7 days
|NO
|-
|-
| style="font-size: 85%; background: #F5F5F5;" |
|LOAD
* Israel (8.2%)
|[[Levofloxacin]] 250mg PO
* Saudi Arabia (4%)
[[PPI]] double dose PO
 
[[Nitazoxanide]] 500mg<sup>c</sup> 
 
[[Doxycycline]] 100mg PO
|QD
QD
 
BID
 
QD
|7-10 days
|NO
|-
|-
! style="font-size: 85%; background: #DCDCDC;" | Far East
|
| colspan="4" |'''†''': Several PPI, Clarithromycin, and Amoxicillin combinations have achieved FDA approval, PPI, Clarithromycin, Metronidazole are not an FDA approved treatment regimen.
'''‡:''' [[PPI]], [[Bismuth]], [[Tetracycline]], and [[metronidazole]] prescribed separately are not an FDA approved treatment regimen. However, Pylera, a combination product containing Bismuth subcitrate, Tetracycline, Metronidazole combination with PPI for 10 days is an FDA approved regimen.
*BID, twice daily; FDA, Food and Drug Administration; PPI, proton pump inhibitor; TID, three times daily; QD, once daily; QID, four times daily.
c: [[Metronidazole]] or [[Tinidazole]]<ref name="urlwww.nature.com">{{cite web |url=https://www.nature.com/ajg/journal/v112/n2/pdf/ajg2016563a.pdf |title=www.nature.com |format= |work= |accessdate=}}</ref>
<small>*Adopted:American college of gasteroenterology<ref name="urlManagement of Patients with Ulcer Bleeding | American College of Gastroenterology">{{cite web |url=https://gi.org/guideline/management-of-patients-with-ulcer-bleeding/ |title=Management of Patients with Ulcer Bleeding &#124; American College of Gastroenterology |format= |work= |accessdate=}}</ref> </small>
 
|}
 
===Persistent Helicobacter Pylori infection ===
With declining success rates for [[H. pylori]] eradication therapy, many patients will be persistently infected after treatment and will therefore remain at risk for the complications of [[H. pylori]]-related disease, such as [[peptic]] [[ulceration]] and [[gastric]] [[malignancy]], testing to prove eradication should be performed using a [[urea breath test]], fecal antigen test or biopsy-based testing at least 4 weeks after the completion of [[antibiotic]] therapy and after [[PPI]] therapy has been withheld for 1–2 weeks.In patients with persistent [[H. pylori]] infection, every effort should be made to avoid [[antibiotics]] that have been previously taken by the patient.<ref name="urlwww.nature.com">{{cite web |url=https://www.nature.com/ajg/journal/v112/n2/pdf/ajg2016563a.pdf |title=www.nature.com |format= |work= |accessdate=}}</ref><ref name="pmid17608775">{{cite journal |vauthors=Chey WD, Wong BC |title=American College of Gastroenterology guideline on the management of Helicobacter pylori infection |journal=Am. J. Gastroenterol. |volume=102 |issue=8 |pages=1808–25 |year=2007 |pmid=17608775 |doi=10.1111/j.1572-0241.2007.01393.x |url=}}</ref>
 
 
{{familytree/start}}
{{familytree| | | | | | | | | | | | | | | | | | A01 | | | | | |A01=Persistent [[Helicobacter Pylori]] infection }}
{{familytree| | | | | | | | | |,|-|-|-|-|-|-|-|-|^|-|-|-|-|-|-|-|-|.| |}}
{{familytree| | | | | | | | | B01 | | | | | | | | | | | | | | | | B02 ||B01=Patient recieved [[clarithromycin]] triple therapy|B02=Patient received [[Bismuth]] quadriple therapy }}
{{familytree| | |,|-|-|-|v|-|-|^|-|-|v|-|-|-|.| | | |,|-|-|-|v|-|-|^|-|-|v|-|-|-|.|}}
{{familytree|boxstyle=text-align: left; | C01 | | C02 | | | | C03 | | C04 | | C05 | | C06 | | | | C07 | | C08 | |C01= •No previous Quinolone exposure<br>•No PCN allergy<br>'''Recomended treatment:'''<br> •[[Bismuth]] quadruple<br> •[[Levofloxacin]]<br> •[[Rifabutin]] triple<br> •High dose dual|C02= •Previous Quinolone exposure<br> •No PCN Allergy<br>'''Recomended treatment:'''<br> •[[Bismuth]] quadruple therapy<br> •Rifabutin triple<br> •High dose dual<br>|C03= •No previous Quinolone exposure<br> •PCN Allergy<br> '''Recomended treatment:'''<br>•[[Bismuth]] quadruple| C04=•Previous Quinolone exposure<br> •PCN Allergy<br>'''Recomended treatment:'''<br> •[[Bismuth]] quadruple<br>|C05=•No previous Quinolone exposure<br>•No PCN allergy<br>'''Recomended treatment:'''<br>•[[Levofloxacin]] triple concomitant<br>•Rifabutin triple<br>•High dose triple<br>|C06=•Previous Quinolone exposure<br> •No PCN Allergy<br>'''Recomended treatment:'''<br>•Concomitant Rifabutin triple <br>•High dose dual<br>|C07=•No previous Quinolone<br> exposure<br> •PCN Allergy<br> '''Recomended treatment:'''<br>•[[PPI]],[[Clarithromycin]]<br>,[[Metronidazole]]<br>•[[PPI]],[[Levofloxacin]],<br>[[Metronidazole]]|C08=•Previous Quinolone exposure<br> •No PCN Allergy<br>'''Recomended treatment:'''<br> •[[PPI]],[[Clarithromycin]],<br>[[Metronidazole]]<br>•[[Bismuth]] quadruple }}
{{familytree/end}} Adopted:American college of gasteroenterology[17]
 
====Salvage treatment====
After the failure of first-line therapy, such patients should be considered for referral for salvage treatment.
{| class="wikitable"
! colspan="5" |Salvage therapies for Helicobacter pylori infection
|-
|-
| style="font-size: 85%; background: #F5F5F5;" |
|Regimen
* Bangladesh (10%)
|Drugs(doses)
* Hong Kong (4.5%)
|Dosing frequency
* Korea (14%)
|Duration(days)
* Malaysia (2.1%)
|FDA approval
* New Zealand (11%)
|-
|-
! style="font-size: 85%; background: #545454; color: #F8F8FF; padding: 5px 10px;" | Countries with a reported prevalence ≥ 15% of ''H. pylori'' resistance to clarithromycin
|[[Bismuth]] quadruple
|
* [[PPI]] standard dose PO
* [[Bismuth]] subcitrate 120-300mg or sub salicylate 300mg
* [[Tetracycline]] 500mg
|BID
 
QID
 
QID
 
TID or QID
|14
|NO<sup>(a)</sup>
|-
|-
! style="font-size: 85%; background: #DCDCDC;" | Europe
|[[Levofloxacin]] triple
|-
|
| style="font-size: 85%; background: #F5F5F5;" |
* [[PPI]] standard dose
* Bulgaria (18.4%)
* [[Levofloxacin]] 500mg
* France (20%)
* [[Amoxicillin]] 1gm
* Italy (central) (23.4%)
|BID
* Portugal (22%)
 
* Spain (49.2%)
QD
* Turkey (48.2%)
 
|-
BID
! style="font-size: 85%; background: #DCDCDC;" | South America
|14
|-
|NO
| style="font-size: 85%; background: #F5F5F5;" |
* Mexico (25%)
|-
|-
! style="font-size: 85%; background: #DCDCDC;" | Middle East
|Concomitant
|-
|
| style="font-size: 85%; background: #F5F5F5;" |
* [[PPI]] standard dose
* Iran (17%)
* [[Clarithromycin]] 500mg
|-
* [[Amoxicillin]] 1gm
! style="font-size: 85%; background: #DCDCDC;" | Far East
* [[Nitroimidazole]] 500mg
|-
|BID
| style="font-size: 85%; background: #F5F5F5;" |
* China (18%)
* India (33%)
* Japan (27.7%)
|}


The American Journal of Gastroenterology guidelines recommend that '''[[endoscopy]]''' should be performed to rule out [[peptic ulcer disease]], esophagogastric [[malignancy]], and other rare upper gastrointestinal tract disease in the following settings:
BID
* [[Dyspeptic]] patients <u>more than 55 years old</u> {{or2}}
* [[Dyspeptic]] patients with <u>alarm features</u>
:* [[Bleeding]]
:* [[Anemia]]
:* [[Early satiety]]
:* Unexplained [[weight loss]] (> 10% body weight)
:* Progressive [[dysphagia]]
:* [[Odynophagia]]
:* Persistent [[vomiting]]
:* A family history of gastrointestinal cancer
:* Previous esophagogastric [[malignancy]]
:* Previous documented [[peptic ulcer]], [[lymphadenopathy]], or an abdominal mass


In patients aged 55 years or younger with no alarm features, two management options may be considered:
BID
* '''Test-and-treat strategy''' using a validated noninvasive test (urea breathing test or stool antigen test) for ''[[H. pylori]]'' and a trial of acid suppression if eradication is successful but symptoms do not resolve – preferable in populations with a moderate to high prevalence of ''[[H. pylori]]'' infection (≥ 10%)
* '''Empiric trial of acid suppression''' with a [[proton pump inhibitor]] for 4–8 weeks – preferable in low prevalence situations


Repeat [[endoscopy]] is not recommended once a firm diagnosis of functional [[dyspepsia]] has been established, unless new symptoms or alarm features develop.<ref>{{Cite journal| doi = 10.1111/j.1572-0241.2005.00225.x| issn = 0002-9270| volume = 100| issue = 10| pages = 2324–2337| last1 = Talley| first1 = Nicholas J.| last2 = Vakil| first2 = Nimish| last3 = Practice Parameters Committee of the American College of Gastroenterology| title = Guidelines for the management of dyspepsia| journal = The American Journal of Gastroenterology| date = 2005-10| pmid = 16181387}}</ref>  Testing to prove ''[[H. pylori]]'' eradication is most accurate if performed 4 weeks after the completion of therapy.<ref>{{cite journal| author=Malfertheiner P, Megraud F, O'Morain CA, Atherton J, Axon AT, Bazzoli F et al.| title=Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report. | journal=Gut | year= 2012 | volume= 61 | issue= 5 | pages= 646-64 | pmid=22491499 | doi=10.1136/gutjnl-2012-302084 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22491499}}</ref>
BID or TID
|10-14
|NO
|-
|[[Rifabutin]] triple
|
* [[PPI]] standard dose
* [[Rifabutin]] 300mg
* [[Amoxicillin]] 1gm
|BID


===Treatment strategies===
QD
* The use of high-dose (twice a day) '''[[PPI|proton pump inhibitor (PPI)]]''' increases the efficacy of triple therapy.
* In areas of low clarithromycin resistance, '''[[clarithromycin]]-containing treatments (PCA or PCM)''' are recommended for first-line empirical treatment.  '''[[Bismuth]]-containing quadruple treatment''' is also an alternative.
* In areas of high clarithromycin resistance, '''[[bismuth]]-containing quadruple treatment''' is recommended for first-line empirical treatment.  If this regimen is not available, '''sequential treatment''' is recommended.
* Extending the duration of triple treatment from 7 to 10–14 days improves the eradication success rate and may be considered.
* After failure of a PPI-clarithromycin containing therapy, either a '''[[bismuth]]-containing quadruple treatment''' or '''[[levofloxacin]]-containing triple therapy (PLA)''' is recommended.
* After failure of second-line treatment, treatment should be guided by antimicrobial susceptibility testing whenever possible.
* The urea breath test or a laboratory based validated monoclonal stool test are both recommended as non-invasive tests for determining the success of eradication treatment.<ref>{{cite journal| author=Malfertheiner P, Megraud F, O'Morain CA, Atherton J, Axon AT, Bazzoli F et al.| title=Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report. | journal=Gut | year= 2012 | volume= 61 | issue= 5 | pages= 646-64 | pmid=22491499 | doi=10.1136/gutjnl-2012-302084 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22491499}}</ref>


==Eradication Therapy for ''Helicobacter pylori'' Infection==
BID
|10
|NO
|-
|High-dose dual
|
* [[PPI]] standard to double dose
* [[Amoxicillin]] 1gm TID or 750mg QID
|TID or QID


===First-line therapies===
TID or QID
{{rx|Triple therapy (PCA or PCM regimen)}}
|14
* '''[[Proton pump inhibitor]]''' (standard dose twice daily) for 7–14 days {{and}}
|NO
* '''[[Clarithromycin]]''' (500 mg twice daily) for 7–14 days {{and}}
|}
* '''[[Amoxicillin]]''' (1 g twice daily) for 7–14 days {{or}} '''[[Metronidazole]]''' (250 mg four times daily) for 7–14 days
(a)[[PPI]],[[Bismuth]],[[Tetracycline|tetracyclin]] and [[metronidazole]] prescribed separately is not an FDA-approved treatment regimen.However,Pylera,a combination product containing [[bismuth]] subcitrate,[[tetracycline]] and [[metronidazole]] combined with a [[PPI]] for 10 days is an [[FDA-]]<nowiki/>approved treatment regimen
</li>
*BID, twice daily; FDA, Food and Drug Administration; [[PPI]]-[[proton pump inhibitor]]; TID-three times daily; QD-once daily; QID-four times daily<ref name="urlwww.nature.com">{{cite web |url=https://www.nature.com/ajg/journal/v112/n2/pdf/ajg2016563a.pdf |title=www.nature.com |format= |work= |accessdate=}}</ref>
{{rx|Quadruple therapy}}
Adopted:American college of gasteroenterology[17]
* '''[[Proton pump inhibitor]]''' (standard dose twice daily) for 10–14 days {{and}}
* '''[[Metronidazole]]''' (250 mg four times daily) for 10–14 days {{and}}
* '''[[Tetracycline]]''' (500 mg four times daily) for 10–14 days {{and}}
* '''[[Bismuth]]''' (dose depends on preparation) for 10–14 days
</li>
{{rx|Sequential therapy}}
* '''[[Proton pump inhibitor]]''' (standard dose twice daily) for 5 days {{and}}
* '''[[Amoxicillin]]''' (1 g twice times daily) for 5 days<BR><span style="text-indent: 50px;">'''<u>FOLLOWED BY</u>'''</span>
* '''[[Proton pump inhibitor]]''' (standard dose twice daily) for another 5 days {{and}}
* '''[[Clarithromycin]]''' (500 mg twice daily) for another 5 days {{and}}
* '''[[Tinidazole]]''' (500 mg twice daily) for another 5 days
</li>


===Second-line therapies===
====Medical therapy for Non Helicobacter pylori-associated Peptic ulcer disease:====
{{rx|Triple therapy (PLA regimen)}}
* [[NSAIDs]] is most common cause of non-[[helicobacter pylori]] associated [[peptic ulcer]] disease
* '''[[Proton pump inhibitor]]''' (standard dose twice daily) for 10 days {{and}}
* First step in management is to stop taking NSAIDs
* '''[[Levofloxacin]]''' (500 mg twice daily) for 10 days {{and}}
* Medical treatment for [[NSAIDs]] associated [[peptic ulcer]] :
* '''[[Amoxicillin]]''' (1 g twice daily) for 10 days
H2- receptor Antagonist
</li>
* [[Cimetidine]] 800 mg
{{rx|Triple therapy (PMA regimen)}}
* [[Ranitidine]]/[[Niizatidine]] 300 mg
* '''[[Proton pump inhibitor]]''' (standard dose twice daily) for 7–14 days {{and}}
* [[Famotidine]] 40 mg
* '''[[Metronidazole]]''' (250 mg four times daily) for 7–14 days {{and}}
[[Proton pump inhibitor|Proton pump inhibitors]]
* '''[[Amoxicillin]]''' (1 g twice daily) for 7–14 days
* [[Omeprazole]] 20 mg
</li>
* [[Lansoprazole]] 30 mg
{{rx|Triple therapy (PRA regimen)}}
* [[Rabeprazole]] 20 mg
* '''[[Proton pump inhibitor]]''' (standard dose twice daily) for 10 days {{and}}
* [[Pantoprazole]] 40 mg
* '''[[Rifabutin]]''' (150–300 mg/day) for 10 days {{and}}
{| class="wikitable"
* '''[[Amoxicillin]]''' (1 g twice daily) for 10 days
! colspan="2" |Prevention of NSAID-induced ulcers
</li>
|-
|Drug
|Dose
|-
|[[Misoprostol]]
|200 μg q8h
|-


==Algorithm for the Approach to Dyspepsia==
|Drug
<div style="font-size: 90%;">
|Dose
{{Familytree/start}}
|-
{{Familytree|boxstyle=border: 0;| | | | | | A01 | | | | | | | | | | |A01={{F1|Age ≥ 55 or ⊕ alarm features?}}}}
|[[Misoprostol]]
{{Familytree|boxstyle=border: 0;| |,|-|-|-|-|^|-|-|-|-|.| | | | | | |}}
|200 μg  q8h
{{Familytree|boxstyle=border: 0;| B01 | | | | | | | | B02 | | | | | |B01={{F1|YES}}|B02={{F1|NO}}}}
|-
{{Familytree|boxstyle=border: 0;| |!| | | | | | | | | |!| | | | | | |}}
|Proton pump inhibitors
{{Familytree|boxstyle=border: 0;| C01 | | | | | | | | C02 | | | | | |C01={{F2|Endoscopy}}|C02={{F1|''H. pylori'' prevalence?}}}}
* [[Omeprazole]] 20 mg
{{Familytree|boxstyle=border: 0;| |!| | | | |,|-|-|-|-|^|-|-|-|-|.| |}}
* [[Lansoprazole]] 30 mg
{{Familytree|boxstyle=border: 0;| |!| | | | D01 | | | | | | | | D02 |D01={{F1|High}}|D02={{F1|Low}}}}
* [[Rabeprazole]] 20 mg
{{Familytree|boxstyle=border: 0;| |!| | | | |!| | | | | | | | | |!| |}}
* [[Pantoprazole]] 40 mg
{{Familytree|boxstyle=border: 0;| |!| | | | E01 | | | | | | | | E02 |E01={{F2|Test-and-treat strategy}}|E02={{F2|Acid suppression trial}}}}
|q 24 hourly
{{Familytree|boxstyle=border: 0;| |`|-|-|-|-|+|-|-|-|-|-|-|-|-|-|'| |}}
|}
{{Familytree|boxstyle=border: 0;| | | | | | F01 | | | | | | | | | | |F01={{F1|If treatment is indicated}}}}
'''Treatment of ulcer according to stage of ulcer :'''
{{Familytree|boxstyle=border: 0;| |,|-|-|-|-|^|-|-|-|-|.| | | | | | |}}
{| class="wikitable"
{{Familytree|boxstyle=border: 0;| G01 | | | | | | | | G02 | | | | | |G01={{F1|Clarithromycin resistance ≥ 15%}}|G02={{F1|Clarithromycin resistance < 15%}}}}
! colspan="2" |Active Ulcer
{{Familytree|boxstyle=border: 0;| |!| | | | | | | | | |!| | | | | | |}}
|-
{{Familytree|boxstyle=border: 0;| H01 | | | | | | | | H02 | | | | | |H01={{F2|Quadruple or sequential therapy}}|H02={{F2|PCA or PCM regimen}}}}
!Drug
{{Familytree|boxstyle=border: 0;| |!| | | | | | | | | |!| | | | | | |}}
!Dose
{{Familytree|boxstyle=border: 0;| I01 | | | | | | | | I02 | | | | | |I01={{F2|PLA regimen}}|I02={{F2|Quadruple therapy or PLA regimen}}}}
|-
{{Familytree|boxstyle=border: 0;| |`|-|-|-|-|v|-|-|-|-|'| | | | | | |}}
|H2- receptor Antagonist
{{Familytree|boxstyle=border: 0;| | | | | | F01 | | | | | | | | | | |F01={{F1|Adjust Rx per susceptibility test}}}}
* [[Cimetidine]] 800 mg
{{Familytree/end}}
* [[Ranitidine]]/nizatidine 300 mg
</div>
* [[Famotidine]] 40 mg
|q 24 hourly(night)
|-
|Proton pump inhibitors
* [[Omeprazole]] 20 mg
* [[Lansoprazole]] 30 mg
* [[Rabeprazole]] 20 mg
* [[Pantoprazole]] 40 mg
|q 24 hourly(empty stomach)
|-
| colspan="2" |'''Maintenance therapy'''
|-
|H2-receptor antagonists
* [[Cimetidine]] 400 mg
* [[Ranitidine]]/nizatidine 150 mg
* [[Famotidine]] 20 mg
|q 24 hourly(at night)
|-
|Proton pump inhibitors
* [[Omeprazole]] 20 mg
* [[Lansoprazole]] 30 mg
* [[Rabeprazole]] 20 mg
* [[Pantoprazole]] 40 mg
|q 24 hourly (empty stomach)
|}


==Contraindicated Medications==
==Contraindicated Medications==
{{MedCondContrAbs|MedCond = Bleeding peptic ulcer|Ketorolac tromethamine|Mefenamic acid|Ticlopidine|Prasugrel|Reserpine|Streptokinase|Vorapaxar}}
{{MedCondContrAbs|MedCond = Bleeding peptic ulcer|Ketorolac tromethamine|Mefenamic acid|Ticlopidine|Prasugrel|Reserpine|Streptokinase|Vorapaxar}}


==Guidelines and Resources==
==Guidelines and Resources==
Line 183: Line 381:
* American Society for Gastrointestinal Endoscopy (ASGE) – The role of endoscopy in gastroduodenal obstruction and gastroparesis.<ref>{{Cite journal| doi = 10.1016/j.gie.2010.12.003| issn = 1097-6779| volume = 74| issue = 1| pages = 13–21| last1 = ASGE Standards of Practice Committee| last2 = Fukami| first2 = Norio| last3 = Anderson| first3 = Michelle A.| last4 = Khan| first4 = Khalid| last5 = Harrison| first5 = M. Edwyn| last6 = Appalaneni| first6 = Vasudhara| last7 = Ben-Menachem| first7 = Tamir| last8 = Decker| first8 = G. Anton| last9 = Fanelli| first9 = Robert D.| last10 = Fisher| first10 = Laurel| last11 = Ikenberry| first11 = Steven O.| last12 = Jain| first12 = Rajeev| last13 = Jue| first13 = Terry L.| last14 = Krinsky| first14 = Mary Lee| last15 = Maple| first15 = John T.| last16 = Sharaf| first16 = Ravi N.| last17 = Dominitz| first17 = Jason A.| title = The role of endoscopy in gastroduodenal obstruction and gastroparesis| journal = Gastrointestinal Endoscopy| date = 2011-07| pmid = 21704805}}</ref>
* American Society for Gastrointestinal Endoscopy (ASGE) – The role of endoscopy in gastroduodenal obstruction and gastroparesis.<ref>{{Cite journal| doi = 10.1016/j.gie.2010.12.003| issn = 1097-6779| volume = 74| issue = 1| pages = 13–21| last1 = ASGE Standards of Practice Committee| last2 = Fukami| first2 = Norio| last3 = Anderson| first3 = Michelle A.| last4 = Khan| first4 = Khalid| last5 = Harrison| first5 = M. Edwyn| last6 = Appalaneni| first6 = Vasudhara| last7 = Ben-Menachem| first7 = Tamir| last8 = Decker| first8 = G. Anton| last9 = Fanelli| first9 = Robert D.| last10 = Fisher| first10 = Laurel| last11 = Ikenberry| first11 = Steven O.| last12 = Jain| first12 = Rajeev| last13 = Jue| first13 = Terry L.| last14 = Krinsky| first14 = Mary Lee| last15 = Maple| first15 = John T.| last16 = Sharaf| first16 = Ravi N.| last17 = Dominitz| first17 = Jason A.| title = The role of endoscopy in gastroduodenal obstruction and gastroparesis| journal = Gastrointestinal Endoscopy| date = 2011-07| pmid = 21704805}}</ref>
* American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) – Reducing the gastrointestinal risks of antiplatelet therapy and NSAID use.<ref>{{Cite journal| doi = 10.1161/CIRCULATIONAHA.108.191087| issn = 1524-4539| volume = 118| issue = 18| pages = 1894–1909| last1 = Bhatt| first1 = Deepak L.| last2 = Scheiman| first2 = James| last3 = Abraham| first3 = Neena S.| last4 = Antman| first4 = Elliott M.| last5 = Chan| first5 = Francis K. L.| last6 = Furberg| first6 = Curt D.| last7 = Johnson| first7 = David A.| last8 = Mahaffey| first8 = Kenneth W.| last9 = Quigley| first9 = Eamonn M.| last10 = American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents| title = ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents| journal = Circulation| date = 2008-10-28| pmid = 18836135}}</ref>
* American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) – Reducing the gastrointestinal risks of antiplatelet therapy and NSAID use.<ref>{{Cite journal| doi = 10.1161/CIRCULATIONAHA.108.191087| issn = 1524-4539| volume = 118| issue = 18| pages = 1894–1909| last1 = Bhatt| first1 = Deepak L.| last2 = Scheiman| first2 = James| last3 = Abraham| first3 = Neena S.| last4 = Antman| first4 = Elliott M.| last5 = Chan| first5 = Francis K. L.| last6 = Furberg| first6 = Curt D.| last7 = Johnson| first7 = David A.| last8 = Mahaffey| first8 = Kenneth W.| last9 = Quigley| first9 = Eamonn M.| last10 = American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents| title = ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents| journal = Circulation| date = 2008-10-28| pmid = 18836135}}</ref>
* The European Helicobacter Study Group (EHSG) – Management of ''Helicobacter pylori'' infection.<ref>{{cite journal| author=Malfertheiner P, Megraud F, O'Morain CA, Atherton J, Axon AT, Bazzoli F et al.| title=Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report. | journal=Gut | year= 2012 | volume= 61 | issue= 5 | pages= 646-64 | pmid=22491499 | doi=10.1136/gutjnl-2012-302084 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22491499}}</ref>
* The European Helicobacter Study Group (EHSG) – Management of ''Helicobacter pylori'' infection.<ref>{{Cite journal| doi = 10.1136/gutjnl-2012-302084| issn = 1468-3288| volume = 61| issue = 5| pages = 646–664| last1 = Malfertheiner| first1 = Peter| last2 = Megraud| first2 = Francis| last3 = O'Morain| first3 = Colm A.| last4 = Atherton| first4 = John| last5 = Axon| first5 = Anthony T. R.| last6 = Bazzoli| first6 = Franco| last7 = Gensini| first7 = Gian Franco| last8 = Gisbert| first8 = Javier P.| last9 = Graham| first9 = David Y.| last10 = Rokkas| first10 = Theodore| last11 = El-Omar| first11 = Emad M.| last12 = Kuipers| first12 = Ernst J.| last13 = European Helicobacter Study Group| title = Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report| journal = Gut| date = 2012-05| pmid = 22491499}}</ref>


==References==
==References==
{{reflist|2}}
{{reflist|2}}
<references />


[[Category:Abdominal pain]]
[[Category:Abdominal pain]]
[[Category:Disease]]
[[Category:Disease]]
[[Category:Gastroenterology]]
[[Category:Gastroenterology]]
[[Category:Primary care]]

Latest revision as of 23:37, 29 July 2020

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Case #1

2017 ACG Guidelines for Peptic Ulcer Disease

Guidelines for the Indications to Test for, and to Treat, H. pylori Infection

Guidelines for First line Treatment Strategies of Peptic Ulcer Disease for Providers in North America

Guidlines for factors that predict the successful eradication when treating H. pylori infection

Guidelines to document H. pylori antimicrobial resistance in the North America

Guidelines for evaluation and testing of H. pylori antibiotic resistance

Guidelines for when to test for treatment success after H. pylori eradication therapy

Guidelines for penicillin allergy in patients with H. pylori infection

Guidelines for the salvage therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Overview

The mainstay of treatment for peptic ulcer disease is pharmacotherapy. Treatment of Helicobacter pylori with antimicrobial agents is indicated for patients with gastric or duodenal ulceration. Pharmacologic therapies for peptic ulcer disease due to H. pylori is either triple or quadruple pharmacologic agents that include a Proton pump inhibitors plus a combination of antimicrobial agents. After the first line therapy, patient is tested for persistent H.pylori infection. If the patient has persistent infection, treatment is planned according to previous antibiotics therapy. Salvage treatment is used for failure of first line therapy. The use of antimicrobial therapy is discouraged among asymptomatic carriers.

Medical Therapy

The mainstay of treatment for peptic ulcer disease is pharmacotherapy. Pharmacotherapy for peptic ulcer disease can be discussed under Helicobacter pylori-associated peptic ulcer and Non- Helicobacter pylori-associated peptic ulcer disease.

Eradication Therapy for Helicobacter pylori Infection

The ACG’s 2017 treatment guideline on the management of H. pylori infection listed the following as established indications for diagnosis and treatment:[1]

Indications

Depending upon exposure of antibiotics and allergy to antibiotics, following treatments regimen are being used:[2][3]

Triple Therapy

  • PCM regimen
  • PLA regimen
  • PMA regimen
  • Alternative regimen (1): Proton pump inhibitor standard dose* PO q12h for 7–14 days AND
  • Alternative regimen (2): Metronidazole 250mg PO q6h for 7–14 days AND
  • Alternative regimen (3): Amoxicillin 1g PO q12h for 7–14 days
  • PRA regimen
  • Alternative regimen (1): Proton pump inhibitor standard dose* PO q12h for 10 days AND
  • Alternative regimen (2): Rifabutin 150–300mg PO q 24h for 10 days AND
  • Alternative regimen (3): Amoxicillin 1g PO q12h for 10 days
  • Bismuth quadruple therapy
  • Preferred regimen (1): Proton pump inhibitor standard dose* PO q12h for 10–14 days AND
  • Preferred regimen (2): Metronidazole 250mg PO q6h for 10–14 days AND
  • Preferred regimen (3): Tetracycline 500 mg PO q6hfor 10–14 days AND
  • Preferred regimen (4): Bismuth (dose depends on preparation) for 10–14 days

Bismuth-containing quadruple therapy

  • Bismuth quadruple therapy particularly advised in patients with any previous macrolide exposure or clarithromycin resistance is known to be high or who are allergic to penicillin [7]
  • Preferred regimen (1): Proton pump inhibitor standard dose* PO q12h for 10–14 days AND
  • Preferred regimen (2): Metronidazole 250mg PO q6h for 10–14 days AND
  • Preferred regimen (3): Tetracycline 500 mg PO q6h for 10–14 days AND
  • Preferred regimen (4): Bismuth (dose depends on preparation) for 10–14 days

Non–Bismuth-containing quadruple therapy

  • Preferred regimen (1): Proton pump inhibitor standard dose* PO q12h for 5-7 days AND
  • Preferred regimen (2): Amoxicillin 1 g PO q12h for 5-7 days
    FOLLOWED BY
  • Preferred regimen (1): Proton pump inhibitor standard dose* PO q12h for another 5-7days AND
  • Preferred regimen (2): Clarithromycin 500 mg PO q12h for another 5-7 days AND
  • Preferred regimen (3): Tinidazole 500 mg PO q12h for another 5-7 days

Hybrid therapy:

  • Fluoroquinolone sequential therapy

*Standard dose of PPI: Lansoprazole 30 mg PO q12h, or Omeprazole 20 mg q12h, or Esomeprazole 40 mg PO q24h, or Rabeprazole 20 mg PO q12h

  • After failure of second-line treatment, treatment should be guided by antimicrobial susceptibility testing whenever possible.The urea breath test or a laboratory based validated monoclonal stool test are both recommended as non-invasive tests for determining the success of eradication treatment.[16]

Selection of a first-line H. pylori treatment regimen.

 
 
 
 
 
 
 
 
Is there a penicillin (PCN) allergy?
•Previous macrolide (MCL) exposure for any reason ?
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•PCN allergy: No
•MCL exposure: No
 
 
•PCN allergy: No
•MCL exposure: Yes
 
•PCN allergy: Yes
•MCL exposure: No
 
•PCN allergy: Yes
•MCL exposure: Yes
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recomended treatment:
Bismuth quadruple
Clarithromycin triple with amoxicillin
Other options:
•Sequential
•HYBRID
Levofloxacin triple
Levofloxacin sequential
•LOAD
 
 
Recomended treatment:
Bismuth quadruple
Levofloxacin sequential
Other options:
•Concomitant therapy
•Sequential therapy
• HYBRID
•LOAD
 
Recommended treatment:
Bismuth quadruple
Clarithromycin triple
with metronidazole
Bismuth quadruple
 
Recommended treatment:
Bismuth quadruple
Clarithromycin triple with metronidazole
Bismuth quadruple

LOAD (Levofloxacin, Omeprazole, Alinia [nitazoxanide], and Doxycycline), 


Recommended first-line therapies for H pylori infection: Adopted:American college of gasteroenterology[17]

Regimen Drug dose Dosing frequency Duration(days) FDA approval
Clarithromycin triple PPI standard or double dose PO

Clarithromycin 500mg PO

Amoxicillin 1gm PO or Metronidazole 500mg PO TID

BID 14 days YES
Bismuth Quadruple PPI standard dose PO

Bismuth subcitrate 120-300mg or Subsalicylate 300mg PO

Tetracyclin 500mg PO

Metronidazole 250-500mg

BID

QID

QID

TID to QID (500mg)

10-14 days NO
Concomitant PPI standard dose PO

Clarithromycin 500mg PO

Amoxicillin 1gm PO

Nitroimidazole 500mgc

BID 10 -14 days NO
Sequential PPI standard dose +Amoxicillin 1gm PO

PPI,Clarithromycin 500mg PO +Nitroimidazole 500mg c

BID

BID

5-7 days

5-7 days

NO
Hybrid PPI standard +Amoxicillin 1gm,PPI,Amoxicillin,Clarithromycin 500mg,Nitroimidazole 500mgc BID

BID

7 days

7 days

NO
Levofloxacin triple PPI standard dose PO

Levofloxacin 500mg PO

Amoxicillin 1gm PO

BID

QID

BID

10-14 days NO
Levofloxacin sequential PPI standard or double dose+Amoxicillin 1 gm PO

PPI,Amoxicillin,Levofloxacin 500mg PO QD,Nitroimidazole 500mgc

BID

BID

5-7 days NO
LOAD Levofloxacin 250mg PO

PPI double dose PO

Nitazoxanide 500mgc

Doxycycline 100mg PO

QD

QD

BID

QD

7-10 days NO
: Several PPI, Clarithromycin, and Amoxicillin combinations have achieved FDA approval, PPI, Clarithromycin, Metronidazole are not an FDA approved treatment regimen.

‡: PPI, Bismuth, Tetracycline, and metronidazole prescribed separately are not an FDA approved treatment regimen. However, Pylera, a combination product containing Bismuth subcitrate, Tetracycline, Metronidazole combination with PPI for 10 days is an FDA approved regimen.

  • BID, twice daily; FDA, Food and Drug Administration; PPI, proton pump inhibitor; TID, three times daily; QD, once daily; QID, four times daily.

c: Metronidazole or Tinidazole[1] *Adopted:American college of gasteroenterology[17]

Persistent Helicobacter Pylori infection

With declining success rates for H. pylori eradication therapy, many patients will be persistently infected after treatment and will therefore remain at risk for the complications of H. pylori-related disease, such as peptic ulceration and gastric malignancy, testing to prove eradication should be performed using a urea breath test, fecal antigen test or biopsy-based testing at least 4 weeks after the completion of antibiotic therapy and after PPI therapy has been withheld for 1–2 weeks.In patients with persistent H. pylori infection, every effort should be made to avoid antibiotics that have been previously taken by the patient.[1][18]


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Persistent Helicobacter Pylori infection
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient recieved clarithromycin triple therapy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient received Bismuth quadriple therapy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•No previous Quinolone exposure
•No PCN allergy
Recomended treatment:
Bismuth quadruple
Levofloxacin
Rifabutin triple
•High dose dual
 
•Previous Quinolone exposure
•No PCN Allergy
Recomended treatment:
Bismuth quadruple therapy
•Rifabutin triple
•High dose dual
 
 
 
•No previous Quinolone exposure
•PCN Allergy
Recomended treatment:
Bismuth quadruple
 
•Previous Quinolone exposure
•PCN Allergy
Recomended treatment:
Bismuth quadruple
 
•No previous Quinolone exposure
•No PCN allergy
Recomended treatment:
Levofloxacin triple concomitant
•Rifabutin triple
•High dose triple
 
•Previous Quinolone exposure
•No PCN Allergy
Recomended treatment:
•Concomitant Rifabutin triple
•High dose dual
 
 
 
•No previous Quinolone
exposure
•PCN Allergy
Recomended treatment:
PPI,Clarithromycin
,Metronidazole
PPI,Levofloxacin,
Metronidazole
 
•Previous Quinolone exposure
•No PCN Allergy
Recomended treatment:
PPI,Clarithromycin,
Metronidazole
Bismuth quadruple
 

Adopted:American college of gasteroenterology[17]

Salvage treatment

After the failure of first-line therapy, such patients should be considered for referral for salvage treatment.

Salvage therapies for Helicobacter pylori infection
Regimen Drugs(doses) Dosing frequency Duration(days) FDA approval
Bismuth quadruple BID

QID

QID

TID or QID

14 NO(a)
Levofloxacin triple BID

QD

BID

14 NO
Concomitant BID

BID

BID

BID or TID

10-14 NO
Rifabutin triple BID

QD

BID

10 NO
High-dose dual TID or QID

TID or QID

14 NO

(a)PPI,Bismuth,tetracyclin and metronidazole prescribed separately is not an FDA-approved treatment regimen.However,Pylera,a combination product containing bismuth subcitrate,tetracycline and metronidazole combined with a PPI for 10 days is an FDA-approved treatment regimen

  • BID, twice daily; FDA, Food and Drug Administration; PPI-proton pump inhibitor; TID-three times daily; QD-once daily; QID-four times daily[1]

Adopted:American college of gasteroenterology[17]

Medical therapy for Non Helicobacter pylori-associated Peptic ulcer disease:

H2- receptor Antagonist

Proton pump inhibitors

Prevention of NSAID-induced ulcers
Drug Dose
Misoprostol 200 μg q8h
Drug Dose
Misoprostol 200 μg q8h
Proton pump inhibitors q 24 hourly

Treatment of ulcer according to stage of ulcer :

Active Ulcer
Drug Dose
H2- receptor Antagonist q 24 hourly(night)
Proton pump inhibitors q 24 hourly(empty stomach)
Maintenance therapy
H2-receptor antagonists q 24 hourly(at night)
Proton pump inhibitors q 24 hourly (empty stomach)

Contraindicated Medications

Bleeding peptic ulcer is considered an absolute contraindication to the use of the following medications:


Guidelines and Resources

  • American College of Gastroenterology (ACG) – Guidelines for the management of dyspepsia.[19]
  • American Society for Gastrointestinal Endoscopy (ASGE) – The role of endoscopy in dyspepsia.[20]
  • American Society for Gastrointestinal Endoscopy (ASGE) – The role of endoscopy in gastroduodenal obstruction and gastroparesis.[21]
  • American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) – Reducing the gastrointestinal risks of antiplatelet therapy and NSAID use.[22]
  • The European Helicobacter Study Group (EHSG) – Management of Helicobacter pylori infection.[23]

References

  1. 1.0 1.1 1.2 1.3 "www.nature.com" (PDF).
  2. Federico A, Gravina AG, Miranda A, Loguercio C, Romano M (2014). "Eradication of Helicobacter pylori infection: which regimen first?". World J. Gastroenterol. 20 (3): 665–72. doi:10.3748/wjg.v20.i3.665. PMC 3921476. PMID 24574740.
  3. Zullo A, Rinaldi V, Winn S, Meddi P, Lionetti R, Hassan C, Ripani C, Tomaselli G, Attili AF (2000). "A new highly effective short-term therapy schedule for Helicobacter pylori eradication". Aliment. Pharmacol. Ther. 14 (6): 715–8. PMID 10848654.
  4. Maconi G, Parente F, Russo A, Vago L, Imbesi V, Bianchi Porro G (2001). "Do some patients with Helicobacter pylori infection benefit from an extension to 2 weeks of a proton pump inhibitor-based triple eradication therapy?". Am. J. Gastroenterol. 96 (2): 359–66. doi:10.1111/j.1572-0241.2001.03519.x. PMID 11232676.
  5. Fuccio L, Minardi ME, Zagari RM, Grilli D, Magrini N, Bazzoli F (2007). "Meta-analysis: duration of first-line proton-pump inhibitor based triple therapy for Helicobacter pylori eradication". Ann. Intern. Med. 147 (8): 553–62. PMID 17938394.
  6. Vakil N, Lanza F, Schwartz H, Barth J (2004). "Seven-day therapy for Helicobacter pylori in the United States". Aliment. Pharmacol. Ther. 20 (1): 99–107. doi:10.1111/j.1365-2036.2004.02029.x. PMID 15225176.
  7. Venerito M, Krieger T, Ecker T, Leandro G, Malfertheiner P (2013). Bismuthfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23880479 "Meta-analysis of bismuth quadruple therapy versus clarithromycin triple therapy for empiric primary treatment of Helicobacter pylori infection" Check |url= value (help). Digestion. 88 (1): 33–45. doi:10.1159/000350719. PMID 23880479.
  8. Wu DC, Hsu PI, Wu JY, Opekun AR, Kuo CH, Wu IC, Wang SS, Chen A, Hung WC, Graham DY (2010). "Sequential and concomitant therapy with four drugs is equally effective for eradication of H pylori infection". Clin. Gastroenterol. Hepatol. 8 (1): 36–41.e1. doi:10.1016/j.cgh.2009.09.030. PMC 2838430. PMID 19804842.
  9. Chuah SK, Tsay FW, Hsu PI, Wu DC (2011). "A new look at anti-Helicobacter pylori therapy". World J. Gastroenterol. 17 (35): 3971–5. doi:10.3748/wjg.v17.i35.3971. PMC 3199554. PMID 22046084.
  10. 10.0 10.1 Gatta L, Vakil N, Leandro G, Di Mario F, Vaira D (2009). "Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children". Am. J. Gastroenterol. 104 (12): 3069–79, quiz 1080. doi:10.1038/ajg.2009.555. PMID 19844205.
  11. Vaira D, Zullo A, Vakil N, Gatta L, Ricci C, Perna F, Hassan C, Bernabucci V, Tampieri A, Morini S (2007). "Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial". Ann. Intern. Med. 146 (8): 556–63. PMID 17438314.
  12. Gisbert JP, Calvet X, O'Connor A, Mégraud F, O'Morain CA (2010). "Sequential therapy for Helicobacter pylori eradication: a critical review". J. Clin. Gastroenterol. 44 (5): 313–25. doi:10.1097/MCG.0b013e3181c8a1a3. PMID 20054285.
  13. Molina-Infante J, Perez-Gallardo B, Fernandez-Bermejo M, Hernandez-Alonso M, Vinagre G, Dueñas C, Mateos-Rodriguez JM, Gonzalez-Garcia G, Abadia EG, Gisbert JP (2010). "Clinical trial: clarithromycin vs. levofloxacin in first-line triple and sequential regimens for Helicobacter pylori eradication". Aliment. Pharmacol. Ther. 31 (10): 1077–84. doi:10.1111/j.1365-2036.2010.04274.x. PMID 20180787.
  14. Caselli M, Zullo A, Maconi G, Parente F, Alvisi V, Casetti T, Sorrentino D, Gasbarrini G (2007). ""Cervia II Working Group Report 2006": guidelines on diagnosis and treatment of Helicobacter pylori infection in Italy". Dig Liver Dis. 39 (8): 782–9. doi:10.1016/j.dld.2007.05.016. PMID 17606419.
  15. Romano M, Cuomo A, Gravina AG, Miranda A, Iovene MR, Tiso A, Sica M, Rocco A, Salerno R, Marmo R, Federico A, Nardone G (2010). "Empirical levofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: a randomised trial". Gut. 59 (11): 1465–70. doi:10.1136/gut.2010.215350. PMID 20947881.
  16. Malfertheiner, Peter; Megraud, Francis; O'Morain, Colm A.; Atherton, John; Axon, Anthony T. R.; Bazzoli, Franco; Gensini, Gian Franco; Gisbert, Javier P.; Graham, David Y.; Rokkas, Theodore; El-Omar, Emad M.; Kuipers, Ernst J.; European Helicobacter Study Group (2012-05). "Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report". Gut. 61 (5): 646–664. doi:10.1136/gutjnl-2012-302084. ISSN 1468-3288. PMID 22491499. Check date values in: |date= (help)
  17. 17.0 17.1 "Management of Patients with Ulcer Bleeding | American College of Gastroenterology".
  18. Chey WD, Wong BC (2007). "American College of Gastroenterology guideline on the management of Helicobacter pylori infection". Am. J. Gastroenterol. 102 (8): 1808–25. doi:10.1111/j.1572-0241.2007.01393.x. PMID 17608775.
  19. Talley, Nicholas J.; Vakil, Nimish; Practice Parameters Committee of the American College of Gastroenterology (2005-10). "Guidelines for the management of dyspepsia". The American Journal of Gastroenterology. 100 (10): 2324–2337. doi:10.1111/j.1572-0241.2005.00225.x. ISSN 0002-9270. PMID 16181387. Check date values in: |date= (help)
  20. Ikenberry, Steven O.; Harrison, M. Edwyn; Lichtenstein, David; Dominitz, Jason A.; Anderson, Michelle A.; Jagannath, Sanjay B.; Banerjee, Subhas; Cash, Brooks D.; Fanelli, Robert D.; Gan, Seng-Ian; Shen, Bo; Van Guilder, Trina; Lee, Kenneth K.; Baron, Todd H.; ASGE STANDARDS OF PRACTICE COMMITTEE (2007-12). "The role of endoscopy in dyspepsia". Gastrointestinal Endoscopy. 66 (6): 1071–1075. doi:10.1016/j.gie.2007.07.007. ISSN 0016-5107. PMID 18028927. Check date values in: |date= (help)
  21. ASGE Standards of Practice Committee; Fukami, Norio; Anderson, Michelle A.; Khan, Khalid; Harrison, M. Edwyn; Appalaneni, Vasudhara; Ben-Menachem, Tamir; Decker, G. Anton; Fanelli, Robert D.; Fisher, Laurel; Ikenberry, Steven O.; Jain, Rajeev; Jue, Terry L.; Krinsky, Mary Lee; Maple, John T.; Sharaf, Ravi N.; Dominitz, Jason A. (2011-07). "The role of endoscopy in gastroduodenal obstruction and gastroparesis". Gastrointestinal Endoscopy. 74 (1): 13–21. doi:10.1016/j.gie.2010.12.003. ISSN 1097-6779. PMID 21704805. Check date values in: |date= (help)
  22. Bhatt, Deepak L.; Scheiman, James; Abraham, Neena S.; Antman, Elliott M.; Chan, Francis K. L.; Furberg, Curt D.; Johnson, David A.; Mahaffey, Kenneth W.; Quigley, Eamonn M.; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (2008-10-28). "ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents". Circulation. 118 (18): 1894–1909. doi:10.1161/CIRCULATIONAHA.108.191087. ISSN 1524-4539. PMID 18836135.
  23. Malfertheiner, Peter; Megraud, Francis; O'Morain, Colm A.; Atherton, John; Axon, Anthony T. R.; Bazzoli, Franco; Gensini, Gian Franco; Gisbert, Javier P.; Graham, David Y.; Rokkas, Theodore; El-Omar, Emad M.; Kuipers, Ernst J.; European Helicobacter Study Group (2012-05). "Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report". Gut. 61 (5): 646–664. doi:10.1136/gutjnl-2012-302084. ISSN 1468-3288. PMID 22491499. Check date values in: |date= (help)